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Statins are microorganism derived drugs that greatly impair the cell synthesis of cholesterol by competitively inhibiting the activity of the enzyme HMG-CoA reductase. Statins, however lower the blood level of cholesterol chiefly by increasing the number of high affinity receptors that recognize plasma LDL and by diminishing the VLDL synthesis rate in the liver. The latter explains the mild triglyceride reducing effect of these drugs. Statins efficiency in lowering the plasma cholesterol concentration is comparable to that of the bile acid binding polymers, but is better than that of the fibrates and nicotinic acid. Statins are better tolerated than the latter two drugs but are less efficient in lowering plasma triglycerides and in increasing the HDL-cholesterol concentrations. Tissue selectivity varies for the different statins but this is a secondary issue when the rarity of side effects is taken into account. Statins should be prescribed considering solely their pharmacologic efficiency and cost. Coronary angiography studies in coronary heart disease patients treated with placebo as compared to statins alone, or combined to other lipid lowering drugs, indicate that coronary artery disease regression can be achieved by pharmacological means." | Hydroxymethylglutaryl CoA Reductases |
Immunological tests are valuable aids for diagnosis of mycotic infections and, in some cases, as objective guides for clinical management and prognosis. The usefulness of these procedures is limited to the extents that crude antigen preparations are employed, that these are difficult to standardize uniformly, and that they contain antigens common to several species of pathogenic fungi. Analysis by two-dimensional immunoelectrophoresis methods of the two crude preparations used for coccidioidomycosis demonstrated that coccidioidin contained at least 26 antigens, with 10 of these found also in spherulin. In addition, spherulin contained two antigens not demonstrated in coccidioidin. No single test detected all antigens present, and multiple procedures were required to display the complete array of antigens. A reference system was established for coccidioidin and precipitated immunoglobulins from a burro hyperimmunized with coccidioidin. Evaluation of the reference system demonstrated that it was highly reproducible with respect to the reagents used, to repeated tests by the same person, and to comparative tests by two individuals using the same reagents. Applications of this reference system for standardization of reagents, for detecting common antigens, for monitoring successive steps during fractionation of crude preparations, and for fingerprinting strains for ecological and epidemiological studies are presented. | Coccidioidin |
The following six novel methyl ether derivatives of brassinolide were prepared and their brassinosteroid activity was measured by means of the rice leaf lamina inclination bioassay: 2-O-methylbrassinolide, 3-O-methylbrassinolide, 2,22,23-tri-O-methylbrassinolide, 3,22,23-tri-O-methylbrassinolide, 2-O-methyl-25-methoxybrassinolide and 3-O-methyl-25-methoxybrassinolide. Brassinolide was used as a standard for comparison. All six compounds were also tested in the presence of 1000 ng of indole-3-acetic acid (IAA), an auxin that synergizes the effects of brassinosteroids. The 2-O-methyl- and 3-O-methylbrassinolide derivatives showed weak activity at high doses, which was enhanced by IAA, especially in the case of the 3-O-methyl derivative. Similarly, the 2,22,23-tri-O-methyl- and 3,22,23-tri-O-methyl derivatives displayed weak bioactivity on their own, but significantly stronger activity when applied with IAA. The 3-O-methyl and 3,22,23-tri-O-methyl analogues plus IAA were comparable in bioacivity to brassinolide alone, but were less active than brassinolide plus IAA. In each case, O-methylation at C-2 resulted in a greater loss of activity than O-methylation at C-3 under the same conditions. The relatively strong activity of 3,22,23-tri-O-methylbrassinolide in the presence of IAA is especially noteworthy as it indicates that free hydroxyl groups at C-3, C-22, and C-23 are not essential for bioactivity. Finally, 2-O-methyl- and 3-O-methyl-25-methoxybrassinolide were essentially inactive alone, and showed only a modest increase in bioactivity when coapplied with IAA. | Methyl Ethers |
A multilaboratory study was performed to establish broth microdilution MIC quality control (QC) guidelines for 10 investigational drugs which previously demonstrated significant activity against Haemophilus influenzae. MIC QC ranges for H. influenzae ATCC 49247 with Haemophilus test medium were determined by using multiple contemporary lots of Haemophilus test medium and the National Committee for Clinical Laboratory Standards' recommended numbers of replicate tests. On the basis of these results, QC ranges (generally modal MIC +/- one log2 dilution) are proposed for cefdinir, cefepime, cefetamet, cefpirome, ceftibuten, fleroxacin, temafloxacin, clarithromycin, RP59500, and trospectomycin. The proposed QC guidelines for clarithromycin and temafloxacin were recently accepted by the National Committee for Clinical Laboratory Standards. | Spectinomycin |
Oxidative modification to the side chain of histidine can noticeably change the collision-induced dissociation (CID) pathways of peptides containing this oxidized residue. In cases where an oxidized peptide consists two or more isomers differing only in the site of modification, oxidation to histidine usually causes the other oxidized sites to be mis-assigned in CID spectra. These spectral misassignments can sometimes be avoided by using multiple stages of MS/MS (MS(n)) or via specially optimized liquid chromatographic separation conditions. In this manuscript, we demonstrate that these misassignments can be more readily and easily avoided by using electron-transfer dissociation (ETD) to dissociate the oxidized peptides. Furthermore, we find that the relative insensitivity of ETD to side-chain chemistry allows the extent of oxidative modification to be determined readily for peptide isomers having more than one site of oxidation. The current results along with previous studies of oxidized peptides suggest that ETD is probably a better technique than CID for obtaining correct sequence and modification information for oxidized peptides. | Histidine |
The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete alpha-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-gamma coactivator (PGC)-1alpha and PGC-1beta are critical components of this melanogenic system in melanocytes. alpha-MSH signaling strongly induces PGC-1alpha expression and stabilizes both PGC-1alpha and PGC-1beta proteins. The PGC-1s in turn activate the MITF promoter, and their expression correlates strongly with that of MITF in human melanoma cell lines and biopsy specimens. Inhibition of PGC-1alpha and PGC-1beta blocks the alpha-MSH-mediated induction of MITF and melanogenic genes. Conversely, overexpression of PGC-1alpha induces pigment formation in cell culture and transgenic animals. Finally, polymorphism studies reveal expression quantitative trait loci in the PGC-1beta gene that correlate with tanning ability and protection from melanoma in humans. These data identify PGC-1 coactivators as regulators of human tanning. | Suntan |
A pilot study was undertaken in patients with human immunodeficiency virus type 1 (HIV-1) infection to examine the effects of infusing autologous lymph node lymphocytes that had been cultured ex vivo in conditions designed to maximize the specific secretion of HIV-1-suppressive factors, including beta chemokines. Ten patients with CD4 cell counts between 119 and 436/microliter on antiretroviral drugs received a single infusion of CD4 and CD8 lymph node lymphocytes. There were no serious acute or chronic adverse clinical effects. Increases in serum levels of macrophage inflammatory protein 1beta (MIP-1beta) and increases in the production of MIP-1beta by peripheral blood lymphocytes in response to HIV-1 env were observed. Increases in CD4 and CD8 cell counts and skin test reactivity to recall antigens and decreases in HIV-1 virus load were also observed. This cellular immunotherapy can modulate beta chemokine production in patients with advanced HIV-1 infection and may contribute immunorestorative and antiviral activities. | Lymphocyte Transfusion |
RATIONALE: Electrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic frequency stimuli. We postulated that nicotine enhances related auditory processing in humans. OBJECTIVES: The main hypothesis was that nicotine improves auditory performance. A secondary hypothesis was that the degree of nicotine-induced improvement depends on the individual's baseline performance. METHODS: Young (18-27 years old), normal-hearing nonsmokers received nicotine (Nicorette gum, 6mg) or placebo gum in a single-blind, randomized, crossover design. Subjects performed four experiments involving tone-in-noise detection, temporal gap detection, spectral ripple discrimination, and selective auditory attention before and after treatment. The perceptual differences between posttreatment nicotine and placebo conditions were measured and analyzed as a function of the pre-treatment baseline performance. RESULTS: Nicotine significantly improved performance in the more difficult tasks of tone-in-noise detection and selective attention (effect size = - 0.3) but had no effect on relatively easier tasks of temporal gap detection and spectral ripple discrimination. The two tasks showing significant nicotine effects further showed no baseline-dependent improvement. CONCLUSIONS: Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation. | Nicotine Chewing Gum |
In recent years, essential oils have received a growing interest because of the positive health effects of their novel characteristics such as antibacterial, antifungal, and antioxidant activities. For the extraction of plant-derived essential oils, there is the need of advanced analytical techniques and innovative methodologies. An exhaustive study of hydrodistillation, supercritical fluid extraction, ultrasound- and microwave-assisted extraction, solid-phase microextraction, pressurized liquid extraction, pressurized hot water extraction, liquid-liquid extraction, liquid-phase microextraction, matrix solid-phase dispersion, and gas chromatography (one- and two-dimensional) hyphenated with mass spectrometry for the extraction through various plant species and analysis of essential oils has been provided in this review. Essential oils are composed of mainly terpenes and terpenoids with low-molecular-weight aromatic and aliphatic constituents that are particularly important for public health. | Plant Oils |
Three new tetrahydrobenzocyclooctabenzofuranone lignan glucosides, longipedunculatins A-C (1-3), a new dibenzocyclooctadiene lignan glucoside, longipedunculatin D (4), a new dibenzocyclooctadiene lignan (5), five new tetrahydrobenzocyclooctabenzofuranone lignans (6-10), and two new simple lignans (11, 12) were isolated from the roots of Kadsura longipedunculata. Their structures and absolute configurations were established using a combination of MS, NMR, and experimental and calculated electronic circular dichroism data. Compound 7 showed moderate hepatoprotective activity against N-acetyl-p-aminophenol-induced toxicity in HepG2 cells with a cell survival rate at 10 muM of 50.8%. Compounds 2, 7, and 12 showed significant in vitro inhibitory effects with an inhibition rate of 55.1%, 74.9%, and 89.8% on nitric oxide production assays at 10 muM. | Cyclooctanes |
Levodopa (L-DOPA) is an essential drug for the treatment of Parkinson's disease. Currently, L-DOPA can be produced by chemical synthesis and can also be found naturally in many herbs, especially Mucuna Pruriens (MP). According to clinical research, the MP extract containing L-DOPA for the treatment of Parkinson's disease could reduce side effects more than the synthetic one. Unfortunately, MP extracts can be easily degraded. Changes in physical and chemical properties such as the appearance (color, melt, solid lump) and the reduction of L-DOPA content in the extract were commonly observed. Therefore, it is necessary to develop an extraction procedure to stabilize the extract of L-DOPA. This study attempted to enhance the extraction process by modifying the traditional acidification approach using hydrochloric acid, citric acid, or ascorbic acid. According to the stability test results, using Phyllanthus emblica water (PEW) as a solvent improved the preservative properties more than other solvents. The color of the PEW-MP powder changed slightly after 12 months of accelerated storage, but the amount of L-DOPA remained the highest (73.55%). Moreover, L-DOPA was only detected in MP and PEW-MP, but not PEW alone (the HPTLC chromatogram at Rf 0.48 and the HPLC chromatogram at Rt 6.0 min). The chemical profiles of PEW and L-DOPA observed in the chromatograms indicated that they are independently separated. As a result, they can be applied to a quality control process. Therefore, PEW was proven to be a powerful solvent for L-DOPA herbal extract that could be readily used as a raw material for herbal products. | Mucuna |
BACKGROUND AND STUDY AIMS: Sphincter of Oddi manometry (SOM), performed at endoscopic retrograde cholangiopancreatography (ERCP), is the gold standard for diagnosing sphincter of Oddi dysfunction (SOD). The question remains as to whether the short-term manometric recordings reflect the 24-hour pathophysiology of the sphincter. The aim of this study was to determine the frequency of SOD in persistently symptomatic patients with previously normal SOM studies. PATIENTS AND METHODS: All patients who underwent ERCP for suspected SOD over a 13-year period (1994 - 2007) were considered for inclusion in the study. Patients with an intact papilla and a previously normal SOM who had a repeat ERCP for persistent symptoms formed the study group. SOM was performed in conventional retrograde fashion. RESULTS: In all, 5352 patients without prior papillary intervention underwent SOM during the study period. A total of 1037 patients had normal SOM, and of these, 30 patients (27 female, mean age 40.1 years) underwent repeat ERCP for persistent symptoms. The median duration between the two ERCPs was 493.5 days (range 52-3538 days). In these 30 patients, SOD classification prior to the initial ERCP was: type I in one patient (not treated in 1994), type II in 17 patients, and type III in 12 patients. Of the 30 patients, 12 (40%) had normal SOM at repeat ERCP; SOD was diagnosed in 18/30 (60%) patients. CONCLUSIONS: A single SOM study may not represent the day-to-day physiology of the sphincter of Oddi; sphincter pathology may progress over time. One normal exam may not rule out SOD. A repeat ERCP with manometry may be warranted in a subset of patients with persistent debilitating symptoms and a high index of suspicion for SOD. Outcome data are needed to determine whether this approach justifies the potential risks of ERCP. | Sphincter of Oddi Dysfunction |
BACKGROUND: Macular pigment optical density (MPOD) remains an indispensable biomarker to measure fruit and vegetable intake, with a biologically plausible correlation to vision and cognition. However, evidence in the sub-Saharan regions, including Ghana, is lacking. OBJECTIVE: This study explored dietary carotenoid intake on MPOD and its influence on cognitive and visual function in a healthy Ghanaian sample. METHODS: The MPOD of 301 healthy subjects (aged 21.1+/-1.9 years) was evaluated using the customized Macular DensitometerTM. A battery of cognitive tests and standard vision assessments were employed to assess cognition and visual function, respectively. Dietary lutein and zeaxanthin (L and Z) were estimated based on a twenty-four-hour repeated dietary recall. RESULTS: The mean MPOD at 0.5 degrees and 1.0 degrees eccentricities were 0.37+/-0.16 and 0.34+/-0.15 optical density units, respectively. Dietary intake of L (4.06+/-10.54 mg/day) was considerably higher than Z (0.33+/-2.25 mg/day), with cumulative L+Z estimated at 4.39+/-11.58 mg/day. MPOD was not significantly influenced by demographic, dietary, and visual measures (p>/=0.05). However, after statistical adjustment, we found a small but statistically significant positive relationship between F-A-S phonemic verbal fluency (Unstandardized co-efficient (beta) = 0.002, p = 0.016) and the never consumed alcohol category (beta= 0.062, p = 0.02) with MPOD. CONCLUSION: The findings in this population showed significant positive relationships between measures of cognition and no alcohol intake, with MPOD. These findings necessitate dietary education to augment carotenoid intake and limit alcohol intake for better cognitive functioning. | Macular Pigment |
In a climate of increased funding for vaccines, chemotherapy, and prevention of vector-borne diseases, fewer resources have been directed toward improving disease and vector surveillance. Recently developed light-emitting diode (LED) technology was applied to standard insect-vector traps to produce a more effective lighting system. This approach improved phlebotomine sand fly capture rates by 50%, and simultaneously reduced the energy consumption by 50-60%. The LEDs were incorporated into 2 lighting designs, 1) a LED combination bulb for current light traps and 2) a chip-based LED design for a modified Centers for Disease Control and Prevention light trap. Detailed descriptions of the 2 designs are presented. | Insect Control |
The antinociceptive effects of the stable adenosine analogues N6-phenylisopropyladenosine (L-PIA), N6-cyclohexyladenosine (CHA) and 5'-N-ethylcarboxamidoadenosine (NECA) were investigated in conscious rats using cutaneous thermal tests (hot plate and tail flick). Subcutaneous administration of the adenosine analogues induced a dose-dependent antinociceptive response for all agents. However, NECA was approximately 15 times more potent than PIA and CHA. Approximately the same potency order and response was seen when the adenosine analogues were administered intrathecally at the lumbar level. By this route of administration, the adenosine analogues were approximately 10-20 times more potent than after S.C. administration. Intracerebroventricular administration (lateral ventricles), however, induced a variable response, in most cases a slight hyperalgesia. The nonspecific adenosine antagonist theophylline (S.C.) rapidly reduced the antinociceptive effect induced by PIA (S.C.) but enprofylline, a bronchodilating xanthine with low ability to antagonize adenosine did not influence PIA-induced antinociception. It is concluded that stable adenosine analogues and presumably adenosine itself have potent antinociceptive effects via specific adenosine receptors in the rat. The effects seem to be mediated mainly by a spinal mechanism of action." | Adenosine-5'-(N-ethylcarboxamide) |
Pentapeptide infused intravenously in graded doses provoked at a dose of 1.5 microg per kg per hour a peak HCl output, which was significantly higher than the HCl secretion induced by intravenous histamine in a dose of 40 microg per kg per hour in five healthy subjects. Pentapeptide infusion test at a dose of 1.5 microg per kg per hour appears to be a very reproducible and safe mode of gastric stimulation, giving a sustained and high level of gastric secretion in 20 subjects, including 10 healthy men and 10 duodenal ulcer patients. Infusion test with pentapeptide has some advantage over histamine stimulation in so far as it is safe, and almost completely free of side-effects. No difference in the response curves to pentapeptide and histamine was found between the normal subjects and duodenal ulcer patients. | Pentagastrin |
The aim of our study was to assess the effects of aviation noise on reproduction and cub mortality in farmed blue foxes. Eighty artificially inseminated blue fox vixens (45 primiparous and 35 multiparous) were exposed to aviation noise on 5 days when they were pregnant or had cubs. The noise during the exposures varied from 85 to 121 dB (L(AFmax)). Vixens (45 primiparous and 34 multiparous) on a farm without flight action acted as controls. Cubs were counted 1, 3, 7, 14 and 49 days postpartum and at the beginning of July. Litter size (cubs per whelped vixen), reproductive performance (cubs per mated vixen) and cub losses (lost cubs per whelped vixen) were analyzed from both experimental farms (A and C). The flight action had no effect on reproductive success. Reproductive performance in primiparous vixens was 4.2+/-3.8 and 4.3+/-3.6 cubs (ns, Mann-Whitney U-test) in the control and aviation group, respectively, while in multiparous vixens the corresponding figures were 7.1+/-4.4 and 7.3+/-3.8 cubs (ns). In general, litter size declined from birth to weaning (in primiparous vixens from 8.1+/-3.8 to 5.4+/-3.2 cubs, and in multiparous from 9.7+/-3.8 to 7.2+/-3.8 cubs, P<0.001, GLM for repeated measures). The decline was greater in primiparous than in multiparous vixens (P<0.01). There were no differences in total cub losses between the experimental groups (ns). Accordingly, the present results show that exposure to severe and repeated aviation noise does not impair the reproductive success of farmed blue foxes. | Pregnancy, Animal |
Knowledge of intrinsic neuronal firing dynamics is a critical first step to establishing an accurate biophysical model of any neuron. In this study we examined cerebellar Purkinje cells to determine the bifurcations likely to underlie firing dynamics within a biophysically realistic and experimentally supported model. We show that Purkinje cell dynamics are consistent with a system undergoing a saddle-node bifurcation of fixed points in the transition from rest to firing and a saddle homoclinic bifurcation from firing to rest. Our analyses account for numerous observed Purkinje cell firing properties that include bistability, plateau potentials, specific aspects of the frequency-current (F-I) relationship, first spike latency, and the ability for climbing fiber input to induce state transitions in the bistable regime. We also experimentally confirm new properties predicted from our model and analysis that include the presence of a depolarizing afterpotential (DAP), the ability to fire at low frequencies (<50 Hz) and with a high gain in the F-I relationship, and a bistable region limited to low-frequency firing. Purkinje cell dynamics, including bistability, prove to arise from numerous biophysical factors that include the DAP, fast refractory dynamics, and a long membrane time constant. A hyperpolarizing activated cation current (I(H)) is shown not to be directly involved in establishing bistable dynamics but rather reduces the range for bistability. A combined electrophysiological and modeling approach thus accounts for several properties of Purkinje cells, providing a firm basis from which to assess Purkinje cell output patterns. | Purkinje Cells |
Campylobacter jejuni is recognized as an important causative agent of bacterial gastroenteritis in the developed world. Despite the identification of several factors contributing to infection, characterization of the virulence strategies employed by C. jejuni remains a significant challenge. Bacterial autotransporter proteins are a major class of secretory proteins in Gram-negative bacteria, and notably, many autotransporter proteins contribute to bacterial virulence. The aim of this study was to characterize the C. jejuni 81116 C8J_1278 gene (capC), predicted to encode an autotransporter protein, and examine the contribution of this factor to virulence of C. jejuni The predicted CapC protein has a number of features that are consistent with autotransporters, including the N-terminal signal sequence and the C-terminal beta-barrel domain and was determined to localize to the outer membrane. Inactivation of the capC gene in C. jejuni 81116 and C. jejuni M1 resulted in reduced insecticidal activity in Galleria mellonella larvae. Furthermore, C. jejuni capC mutants displayed significantly reduced adherence to and invasion of nonpolarized, partially differentiated Caco-2 and T84 intestinal epithelial cells. Gentamicin treatment showed that the reduced invasion of the capC mutant is primarily caused by reduced adherence to intestinal epithelial cells, not by reduced invasion capability. C. jejuni capC mutants caused reduced interleukin 8 (IL-8) secretion from intestinal epithelial cells and elicited a significantly diminished immune reaction in Galleria larvae, indicating that CapC functions as an immunogen. In conclusion, CapC is a new virulence determinant of C. jejuni that contributes to the integral infection process of adhesion to human intestinal epithelial cells.IMPORTANCECampylobacter jejuni is a major causative agent of human gastroenteritis, making this zoonotic pathogen of significant importance to human and veterinary public health worldwide. The mechanisms by which C. jejuni interacts with intestinal epithelial cells and causes disease are still poorly understood due, in part, to the heterogeneity of C. jejuni infection biology. Given the importance of C. jejuni to public health, the need to characterize novel and existing virulence mechanisms is apparent. The significance of our research is in demonstrating the role of CapC, a novel virulence factor in C. jejuni that contributes to adhesion and invasion of the intestinal epithelium, thereby in part, addressing the dearth of knowledge concerning the factors involved in Campylobacter pathogenesis and the variation observed in the severity of human infection. | Type V Secretion Systems |
UVA exposure induces DNA damage that could result in skin carcinogenesis. Antioxidants are usually employed as protective agents to avoid this problem: in particular, both beta-carotene and alpha-tocopherol can protect the skin against UVA-induced damage. It is well known that the photochemical instability of these compounds has been a limiting factor for their applications to protect skin. In this study, stearyl ferulate-based solid lipid nanoparticles (SF-SLNs), as vehicles for beta-carotene and alpha-tocopherol, were formulated to improve the stability of these compounds. The SF-SLNs were characterized for entrapment efficiency, size and shape together with their cytotoxicity and capability to inhibit lipid peroxidation. After treatment with a pro-oxidant and/or exposition to sunlight the antioxidants entrapped in SF-SLNs were extremely stable. The results highlighted how SF-SLNs represent a suitable vehicle for beta-carotene and alpha-tocopherol stabilizing and protecting them from degradation. A dermatological formulation in order to prevent skin damages is, therefore, suggested. | Stearates |
Extracorporeal circulatory devices such as hemodialysis and extracorporeal membrane oxygenation can be lifesaving; however, they are also prone to pathologic events including device failure, venous and arterial thrombosis, hemorrhage, and an accelerated risk for atherosclerotic disease due to interactions between blood components and device surfaces of varying biocompatibility. While extracorporeal devices may be used acutely for limited periods of time (eg, extracorporeal membrane oxygenation, continuous venovenous hemofiltration, therapeutic apheresis), some patients require chronic use of these technologies (eg, intermittent hemodialysis and left ventricular assist devices). Given the substantial thrombotic risks associated with extracorporeal devices, multiple antiplatelet and anticoagulation strategies-including unfractionated heparin, low-molecular-weight heparin, citrate, direct thrombin inhibitors, and direct oral anticoagulants, have been used to mitigate the thrombotic milieu within the patient and device. In the following manuscript, we outline the current data on anticoagulation strategies for commonly used extracorporeal circulatory devices, highlighting the potential benefits and complications involved with each. | Extracorporeal Circulation |
Based on the results of previous microarray analyses of murine NIH3T3/PG13Luc cells irradiated with continuous low-dose-rate (LDR) gamma-ray or end-high-dose-rate-irradiations (end-HDR) at the end of the LDR-irradiation period, the inverse dose-rate-effects on gene expression levels were observed. To compare differences of the effects between LDR-irradiation and HDR-irradiation, HDR-irradiations at 2 different times, one (ini-HDR) at the same time at the start of LDR-irradiation and the other (end-HDR), were performed. The up-regulated genes were classified into two types, in which one was up-regulated in LDR-, ini-HDR-, and end-HDR irradiation such as Cdkn1a and Ccng1, which were reported as p53-dependent genes, and the other was up-regulated in LDR- and ini-HDR irradiations such as pro-collagen TypeIa2/Col1a2, TenascinC/Tnc, and Fibulin5/Fbln5, which were reported as extra-cellular matrix-related (ECM) genes. The time dependent gene expression patterns in LDR-irradiation were also classified into two types, in which one was an early response such as in Cdkn1a and Ccng1 and the other was a delayed response such as the ECM genes which have no linearity to total dose. The protein expression pattern of Cdkn1a increased dose dependently in LDR- and end-HDR-irradiations, but those of p53Ser15/18 and MDM2 in LDR-irradiations were different from end-HDR-irradiations. Furthermore, the gene expression levels of the ECM genes in embryonic fibroblasts from p53-deficient mice were not increased by LDR- and end-HDR-irradiation, so the delayed expressions of the ECM genes seem to be regulated by p53. Consequently, the inverse dose-rate-effects on the expression levels of the ECM genes in LDR- and end-HDR-irradiations may be explained from different time responses by p53 status. | Genes, p53 |
OBJECTIVE: Insulin resistance associates with chronic inflammation, and participatory elements of the immune system are emerging. We hypothesized that bacterial elements acting on distinct intracellular pattern recognition receptors of the innate immune system, such as bacterial peptidoglycan (PGN) acting on nucleotide oligomerization domain (NOD) proteins, contribute to insulin resistance. RESEARCH DESIGN AND METHODS: Metabolic and inflammatory properties were assessed in wild-type (WT) and NOD1/2(-/-) double knockout mice fed a high-fat diet (HFD) for 16 weeks. Insulin resistance was measured by hyperinsulinemic euglycemic clamps in mice injected with mimetics of meso-diaminopimelic acid-containing PGN or the minimal bioactive PGN motif, which activate NOD1 and NOD2, respectively. Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand-injected mice. Cytokine secretion, glucose uptake, and insulin signaling were assessed in adipocytes and primary hepatocytes exposed to NOD ligands in vitro. RESULTS: NOD1/2(-/-) mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance. Conversely, direct activation of NOD1 protein caused insulin resistance. NOD1 ligands induced peripheral and hepatic insulin resistance within 6 h in WT, but not NOD1(-/-), mice. NOD2 ligands only modestly reduced peripheral glucose disposal. NOD1 ligand elicited minor changes in circulating proinflammatory mediators, yet caused adipose tissue inflammation and insulin resistance of muscle AS160 and liver FOXO1. Ex vivo, NOD1 ligand caused proinflammatory cytokine secretion and impaired insulin-stimulated glucose uptake directly in adipocytes. NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1(-/-), mice. CONCLUSIONS: We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. Hence, NOD1 is a plausible, new link between innate immunity and metabolism." | Nod Signaling Adaptor Proteins |
CONTEXT/OBJECTIVES: Aquatic therapy (AT) has been reported to be beneficial for individuals with spinal cord injury or disorder (SCI/D); however, AT has also been reported to be underutilized in SCI/D rehabilitation. We aimed to understand the knowledge and current practice of AT for clients with SCI/D by physiotherapists, physiotherapy assistants and kinesiologists across Canada. DESIGN/METHOD: A survey with closed- and open-ended questions was distributed (July-October 2019) to professionals through letters sent by professional associations. Non-parametric analyses were used to compare AT knowledge and practice between AT and non-AT users; content analysis was used to identify the themes from open-ended questions. RESULTS: Seventy-eight respondents from 10 provinces were included in the analysis: 33 physiotherapists, 5 physiotherapy assistants and 40 kinesiologists. Respondents using AT (73%) reported greater knowledge of AT benefits and confidence to apply AT than respondents not using AT (p<0.01). Four themes were identified: 1-Variety of physical and psychosocial benefits of AT for people with SCI/D; 2-Attainment of movement and independence not possible on land; 3-Issues around pool accessibility; and 4-Constraints on AT implementation. CONCLUSIONS: Respondents implemented AT to improve health outcomes for patients with SCI/D, despite facing challenges with pool accessibility and numerous constraints. Respondents who provided AT reported having better knowledge of AT and a supported AT practice in the work environment than respondents not providing AT. This study will inform AT stakeholders and institutions when considering strategies to increase the access to AT after SCI/D. | Aquatic Therapy |
Batrachotoxins, including many congeners not previously described, were detected, and relative amounts were measured by using HPLC-mass spectrometry, in five species of New Guinean birds of the genus Pitohui as well as a species of a second toxic bird genus, Ifrita kowaldi. The alkaloids, identified in feathers and skin, were batrachotoxinin-A cis-crotonate (1), an allylically rearranged 16-acetate (2), which can form from 1 by sigmatropic rearrangement under basic conditions, batrachotoxinin-A and an isomer (3 and 3a, respectively), batrachotoxin (4), batrachotoxinin-A 3'-hydroxypentanoate (5), homobatrachotoxin (6), and mono- and dihydroxylated derivatives of homobatrachotoxin. The highest levels of batrachotoxins were generally present in the contour feathers of belly, breast, or legs in Pitohui dichrous, Pitohui kirhocephalus, and Ifrita kowaldi. Lesser amounts are found in head, back, tail, and wing feathers. Batrachotoxin (4) and homobatrachotoxin (6) were found only in feathers and not in skin. The levels of batrachotoxins varied widely for different populations of Pitohui and Ifrita, a result compatible with the hypothesis that these birds are sequestering toxins from a dietary source. | Batrachotoxins |
BACKGROUND: Animal models are frequently used to generate and test hypotheses about amnesia resulting from electroconvulsive therapy (ECT). Although many predictors of ECT-induced amnesia are known, their relative effects have been inadequately researched in the context of the animal models. OBJECTIVE: We sought to determine the relative retrograde amnestic effects of electroconvulsive shock (ECS) stimulus intensity (dose) and number on strong memories in rats. We also sought to identify dose-dependent ceiling amnestic effects, if any. METHODS: Adult rats (n = 144) were overtrained in a passive avoidance task using a step down apparatus. The rats were then randomized in a factorial design to receive one, two, or three once-daily bilateral ECS at 0-mC (sham ECS), 30-mC, 60-mC, 120-mC, or 180-mC doses. Recall of the pre-ECS training was assessed 1 day after the last ECS. RESULTS: Retrograde amnesia was observed only in rats that received 3 ECS; dose-dependent amnestic effects did not emerge. Higher stimulus intensity was associated with a small (13%) but significant increase in motor seizure duration, but only at the first ECS; stimulus intensity did not influence the attenuation of seizure duration across repeated occasions of ECS. CONCLUSION: With bilateral ECS, the number of ECSs administered is a more important variable than the ECS dose in weakening a strong, recently acquired, noxious memory; this finding may have important clinical implications. Higher stimulus intensity marginally increases motor seizure duration at the first ECS but does not influence the decrease in seizure duration across repeated ECSs. | Overlearning |
Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines. | Dendritic Spines |
Health care depends on the organizational and financial decisions which constituted each national system. Since those decisions were made at various times over the preceding years under different macroeconomic conditions, current expenditures are a distributed lag function of GDP growth and inflation rates. The accuracy of forecasts from such causal econometric models are compared to exponential smoothing, moving average, and ARIMA methods. Data fro 19 OECD countries 1965-79 are used for calibration, and then ex ante forecasts are generated for 1980-87 so that actual forecast accuracy can be tested. The greatest reduction in mean absolute error was obtained with the econometric model estimated in aggregate across all 19 countries, although single-country models, exponential smoothing and international averaging were also effective. A combination of all four forecasts was more accurate than any one alone, reducing MAE by 25% relative to a constant growth projection. | Health Expenditures |
This study investigated whether dominant negative summating potential (DNSP) is absent at all stages of induced hydrops development, including the early stages of hydrops formations. Electrocochleography (ECoG) was done 3 days to 20 weeks after obliteration of the endolymphatic sac in guinea pigs, by electrodes attached to the cochlear bony wall on the scala vestibuli of the basal turn. DNSP was noticed only during the early stages of endolymphatic hydrops formation, before hydrops was fully developed. There was no DNSP when the distension of Reissner's membrane was marked. Increased endolymphatic pressure and/or changes in biochemical composition were thought to be the causes of DNSP. | Cochlear Duct |
Asclepiad pollinaria (including pollen masses) attach to diverse body parts of flower visitors in many ways. In this paper, we observed nocturnal moths (Lepidoptera: Pyralidae and Noctuidae) transporting the pollinaria of the Japanese species Metaplexis japonica (Thunb.) Makino (Apocynaceae: Asclepiadoideae) on the tip of the proboscis. Flowers of this species may induce nectar-feeding moths to pull out the proboscis along a guide rail (anther slit), thus clipping the pollinaria onto the tip of the proboscis and transferring the pollinaria to the next flower. The transfer of pollinaria on the unique vector of a moth proboscis tip is an interesting pollination mechanism among previously reported entomophiles. | Gentianales |
The harvesting of protein crystals is almost always a necessary step in the determination of a protein structure using X-ray crystallographic techniques. However, protein crystals are usually fragile and susceptible to damage during the harvesting process. For this reason, protein crystal harvesting is the single step that remains entirely dependent on skilled human intervention. Automation has been implemented in the majority of other stages of the structure-determination pipeline, including cloning, expression, purification, crystallization and data collection. The gap in automation between crystallization and data collection results in a bottleneck in throughput and presents unfortunate opportunities for crystal damage. Several automated protein crystal harvesting systems have been developed, including systems utilizing microcapillaries, microtools, microgrippers, acoustic droplet ejection and optical traps. However, these systems have yet to be commonly deployed in the majority of crystallography laboratories owing to a variety of technical and cost-related issues. Automation of protein crystal harvesting remains essential for harnessing the full benefits of fourth-generation synchrotrons, free-electron lasers and microfocus beamlines. Furthermore, automation of protein crystal harvesting offers several benefits when compared with traditional manual approaches, including the ability to harvest microcrystals, improved flash-cooling procedures and increased throughput. | Crystallography, X-Ray |
Interleukin-7 (IL-7) supports the growth and chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL), particularly the early T-cell precursor subtype (ETP-ALL), which frequently has activating mutations of IL-7 signaling. Signal transducer and activator of transcription (STAT5) is an attractive therapeutic target because it is almost universally activated in ETP-ALL, even in the absence of mutations of upstream activators such as the IL-7 receptor (IL-7R), Janus kinase, and Fms-like tyrosine kinase 3 (FLT3). To examine the role of activated STAT5 in ETP-ALL, we have used a Lmo2-transgenic (Lmo2Tg) mouse model in which we can monitor chemoresistant preleukemia stem cells (pre-LSCs) and leukemia stem cells (LSCs) that drive T-ALL development and relapse following chemotherapy. Using IL-7R-deficient Lmo2Tg mice, we show that IL-7 signaling was not required for the formation of pre-LSCs but essential for their expansion and clonal evolution into LSCs to generate T-ALL. Activated STAT5B was sufficient for the development of T-ALL in IL-7R-deficient Lmo2Tg mice, indicating that inhibition of STAT5 is required to block the supportive signals provided by IL-7. To further understand the role of activated STAT5 in LSCs of ETP-ALL, we developed a new transgenic mouse that enables T-cell specific and doxycycline-inducible expression of the constitutively activated STAT5B1 *6 mutant. Expression of STAT5B1 *6 in T cells had no effect alone but promoted expansion and chemoresistance of LSCs in Lmo2Tg mice. Pharmacologic inhibition of STAT5 with pimozide-induced differentiation and loss of LSCs, while enhancing response to chemotherapy. Furthermore, pimozide significantly reduced leukemia burden in vivo and overcame chemoresistance of patient-derived ETP-ALL xenografts. Overall, our results demonstrate that STAT5 is an attractive therapeutic target for eradicating LSCs in ETP-ALL. | Interleukin-7 |
Congenital hypoplasia of the posterior arch of the atlas (C1), a developmental failure of chondrogenesis, is a rare anomaly and may range from partial clefts to total agenesis of the posterior arch. Ossification of the posterior arch usually occurs between the 3rd and 5th years of life. The incidence of posterior arch anomalies of the atlas is between 0.69% and 2.95%. For the evaluation of the patient, cervical lateral plain radiography, 2D or 3D reconstructed CT and MRI are very useful and important tools in initial diagnosis. Surgery is the treatment of choice in symptomatic compression. Excision of the posterior arch is performed. during surgery. After the surgery, patients may be followed up for instability and treated as necessary. A patient, admitted to the emergency department with head and neck trauma after a traffic accident is presented in this article. C1 hypoplasia was determined after detailed imagining studies and the radiology department consulted. When upper cervical anomalies are found in a young patient, the patient should be evaluated in detail with advanced radiological studies to avoid misinterpretation as fractures, luxation, osteolysis or instability. Consulting a radiologist could help making an accurate diagnosis and deciding on current therapeutic interventions. | Cervical Atlas |
The hypothesis was tested that the variation of in vivo glycolytic flux with contraction frequency in skeletal muscle can be qualitatively and quantitatively explained by calcium-calmodulin activation of phosphofructokinase (PFK-1). Ischemic rat tibialis anterior muscle was electrically stimulated at frequencies between 0 and 80 Hz to covary the ATP turnover rate and calcium concentration in the tissue. Estimates of in vivo glycolytic rates and cellular free energetic states were derived from dynamic changes in intramuscular pH and phosphocreatine content, respectively, determined by phosphorus magnetic resonance spectroscopy ((31)P-MRS). Computational modeling was applied to relate these empirical observations to understanding of the biochemistry of muscle glycolysis. Hereto, the kinetic model of PFK activity in a previously reported mathematical model of the glycolytic pathway (Vinnakota KC, Rusk J, Palmer L, Shankland E, Kushmerick MJ. J Physiol 588: 1961-1983, 2010) was adapted to contain a calcium-calmodulin binding sensitivity. The two main results were introduction of regulation of PFK-1 activity by binding of a calcium-calmodulin complex in combination with activation by increased concentrations of AMP and ADP was essential to qualitatively and quantitatively explain the experimental observations. Secondly, the model predicted that shutdown of glycolytic ATP production flux in muscle postexercise may lag behind deactivation of PFK-1 (timescales: 5-10 s vs. 100-200 ms, respectively) as a result of accumulation of glycolytic intermediates downstream of PFK during contractions." | Phosphofructokinase-1, Muscle Type |
BACKGROUND: Extension of the intervals at which maintenance venom immunotherapy (MVIT) is administered has been attempted for many years. However, published evidence on its effect, especially in intervals of longer than 3 months, is sparse. OBJECTIVE: To examine whether the administration of a bee venom (BV) maintenance dose at 6-month intervals is safe and efficacious. METHODS: The 3-month intervals at which venom-allergic patients were receiving their MVIT were gradually extended to 6 months. Systemic reactions (SRs) to immunotherapy injections or to field stings were regularly recorded. Patients who were allergic to BV alone or also to other venoms were deliberately sting challenged by a honeybee after reaching the 6-month interval. RESULTS: The 3-month intervals were extended in 47 patients. A single patient (2%) developed an SR after receiving the injection at an interval of 4 months. Two field stings in 2 patients resulted in a mild SR in 1 patient. Of 14 sting-challenged patients, 3 (21%) developed an SR after the challenge. The 3 SRs occurred only among the 8 patients (38%) who were allergic to BV alone. The 3 patients with the SR to the challenge continued to receive the regular maintenance dose at monthly intervals 3 to 5 more times. Repeated sting challenges were then well tolerated in all 3 patients. CONCLUSION: The administration of MVIT at 6-month intervals does not provide suitable protection in BV-allergic patients, and they should continue MVIT at the accepted 1- to 3-month intervals. | Bee Venoms |
A small heat shock protein, AgsA, possesses chaperone activity that can reduce the amount of heat-aggregated protein in vivo, and suppress the aggregation of chemical- and heat-denatured proteins in vitro. Therefore, we examined the ability of AgsA to stabilize the activity of several enzymes by using this chaperone activity. We observed that AgsA can stabilize the enzymatic activities of Renilla (Renilla reniformis) luciferase, firefly (Photinus pyralis) luciferase, and beta-galactosidase, and showed comparable or greater stabilization of these enzymes than bovine serum albumin (BSA), a well-known stabilizer of enzyme activities. In particular, AgsA revealed better stabilization of Renilla luciferase and beta-galactosidase than BSA under disulfide bond-reducing conditions with dithiothreitol. In addition, AgsA also increased the enzymatic performance of beta-galactosidase and various restriction enzymes to a comparable or greater extent than BSA. These data indicate that AgsA may be useful as a general stabilizer of enzyme activities. | Heat-Shock Proteins, Small |
INTRODUCTION: Idiopathic granulomatous mastitis (IGM) is a rare benign inflammatory breast disease that presents with variable local manifestations. We describe here the different management protocols based on the clinical presentation of these patients. METHODS: A retrospective review of 20 histopathologic confirmed cases of IGM seen over a period of 10 years was performed. RESULTS: The median age was 34 years (age range: 21-45 years). All were married, parous with history of breast feeding. Ill-defined mass mimicking carcinoma was the commonest presentation (70%); however, with the presence of signs of inflammation like pain (55%), redness (40%), and peau d'orange (40%), an inflammatory process appeared more likely. Axillary lymph node enlargement was infrequently seen (40%). Radiologic findings (mammography and ultrasound) were nonspecific. Histopathology showed the characteristic lobular distribution of granulomatous inflammation in all cases. Surgically, 7 patients had abscess drainage with open biopsy, and 7 patients had lumpectomy. Six patients with diffuse breast involvement were diagnosed by core needle biopsy only. Microbial cultures showed no growth. Antibiotics were given empirically when signs of inflammation where present. Two patients needed further abscess drainage followed by persistent sinus excision 3-6 weeks later. The median follow-up was 24 months (range: 15-42 months). Seventeen patients (85%) were recurrence-free, and 3 patients (15%) were lost to follow-up. CONCLUSIONS: Management of IGM cases needs to be tailored according to the clinical presentation. Precise radiologic and pathologic data interpretation by a multidisciplinary breast team will facilitate diagnosis and minimize unnecessary intervention. | Mastitis |
IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. OBJECTIVE: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18â¯526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346â¯546 participants) and the MyCode Study (42â¯782 participants). EXPOSURES: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. MAIN OUTCOMES AND MEASURES: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 x 10-3. RESULTS: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 x 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 x 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41â¯200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). CONCLUSIONS AND RELEVANCE: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship. | Loss of Function Mutation |
This study, for the first time in Turkey, investigated the existence of Chlamydophila psittaci and determined the prevalence of its disease, chlamydiosis, in pet birds. Polymerase chain reaction (PCR) was compared with other testing methods that have been typically used in the diagnosis of C. psittaci. Fecal specimens (n =96) of avian origin were tested by PCR and two identification methods, modified Gimenez staining (mGS) and direct fluorescein-conjugated monoclonal antibody staining (FA). The identification methods were implemented by staining the yolk sacs of embryonated chicken eggs inoculated at 6 days of age and harvested between 3 and 10 days after inoculation. Fecal specimens from pet birds were randomly collected from pet shops and homes. These specimens were then used to isolate C. psittaci and to detect its specific DNA. The inocula that were prepared from fecal specimens were then inoculated into yolks of 6-day-old embryonated chicken eggs. The preparations from egg yolk sacs were examined with mGS and direct FA after three blind passages. The PCR method was used to detect specific DNA in feces. In 96 fecal specimens, 33 (34.4%) were positive with PCR, 21 (21.9%) were positive with mGS, and 29 (30.2%) were positive with FA. Among 33 positive specimens with PCR, 28 specimens were positive with FA, and 20 specimens were positive with mGS. The sensitivity and specificity were 59% and 94% between FA and mGS, and 97% and 93% between FA and PCR, respectively. | Chlamydophila psittaci |
Convalescent plasma (CP) therapy has been suggested as a treatment for emerging viral diseases. Moreover, many studies have been conducted to evaluate the efficacy of COVID-19 CP therapy, with some of them indicating that CP may be a promising treatment for the disease. However, the evidence for CP therapy's effectiveness in severe COVID-19 cases is limited. So, this study aimed to assess the probable effects of CP therapy in patients diagnosed with severe COVID-19. The study was designed as a single-arm, retrospective cohort of patients with severe COVID. Demographic data, laboratory test reports, and convalescent plasma transfusion doses were collected from medical records for patients before and after convalescent plasma transfusion. The clinical outcomes were hospital discharge and death. Also, laboratory parameters considered secondary outcomes. After CP therapy, some symptoms improved, especially in patients under 55 years old, as follows. Respiratory function was significantly enhanced after convalescent plasma transfusion, and the inflammatory biomarkers' values decreased significantly (p < 0.05). Moreover, the estimated median of partial thromboplastin time (PTT) and Prothrombin time (PT) in patients did not change after CP therapy (p > 0.05). Regarding COVID-19 mortality, a strong association was found between older ages and death (p < 0.001). Also, CP transfusion in the early days of admission was effective in treatment outcomes (p = 0.023). Other characteristics, including sex, blood group, number of CP transfusions, and preexisting conditions, did not significantly correlate with mortality. In conclusion, this study demonstrates the effectiveness of CP therapy in patients under the age of 55. Despite some improvement, we could not say that they were entirely due to the CP treatment. More extensive randomized clinical trials that cover different stages of the disease are needed. | COVID-19 Serotherapy |
BioBreeding Worcester diabetes-prone (BBdp) rats develop insulin-dependent autoimmune-driven diabetes mellitus spontaneously and intravenous administration of 1 x 10(7) p.f.u. of lymphocytic choriomeningitis virus (LCMV) to young adult mice prevents disease. The virus is lymphotropic, binding to and replicating in such cells. BBdp rats fail to generate virus-specific major histocompatibility complex-restricted cytotoxic T lymphocyte (CTL) responses when challenged with this dose or other doses of LCMV, Pichinde virus or vaccinia virus. Yet such rats clear virus effectively and show no evidence of persistent infection. Associated with this clearance of virus and establishment of immunity is the production of neutralizing antibodies. In contrast, diabetes-resistant (BBdr) rats generate virus-specific CTL responses. Furthermore LCMV binds to fewer lymphoid cells of BBdr rats (in comparison to those of BBdp rats) and replicates in fewer lymphocytes (by one order of magnitude) from these rats. Thus, unlike mice in which CTLs play a dominant role in the control of LCMV infection, BBdp rats do not overcome this infection via CTLs. In addition, both the BBdp rats and their BBdr counterpart may provide useful models for determining whether or how individual lymphocyte subsets function in the induction of CTL responses, for the analysis of virus-induced immunosuppression and for the use of viruses or their products as therapeutic modalities." | Lymphocytic choriomeningitis virus |
Endothelin-1 (ET-1) elicited a concentration-dependent positive inotropic effect on the rabbit isolated papillary muscle (electrically driven at 1 Hz at 37 degrees C). The duration of isometric contractions was prolonged by ET-1 in a concentration-dependent manner mainly by prolongation of relaxation time. A tumor-promoting phorbol ester, i.e., phorbol-12,13-dibutyrate (PDBu), inhibited selectively the positive inotropic effect of ET-1 at the concentration that it did not (10 nmol/L) or only slightly (10-20% at 100 nmol/L) reduced the basal force of contraction and the positive inotropic effect of Bay K 8644. The positive inotropic effect of 10 mumol/L of phenylephrine mediated via myocardial alpha 1-adrenoceptors (in the presence of 0.3 mumol/L of bupranolol) was likewise inhibited by PDBu in the same concentration range as it suppressed the ET-1-induced positive inotropic effect. PDBu at concentrations higher than 100 nmol/L inhibited the positive inotropic effects of Bay K 8644 and isoproterenol, and decreased the basal force of contraction in a concentration-dependent manner to a similar extent. Thus, PDBu exhibited selective and potent inhibitory action on the ET-1-induced and alpha 1-adrenoceptor-mediated positive inotropic effect (compared with that on the effect of the Ca2+ channel agonist Bay K 8644 and a beta-adrenoceptor agonist). The present findings indicate that ET-1 elicits a positive inotropic effect on the rabbit ventricular myocardium, the characteristics of which are similar to those of myocardial alpha-adrenoceptor activation, which may involve the phosphoinositide hydrolysis." | 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester |
STAT1/STAT3 transcription factors are important regulators for development of normal, infected or inflammed cells. They are also critically involved in the progression of various malignant tumours, including epithelial-derived carcinomas. Here, we focus on colorectal cancer (CRC) insights for STAT1/3, where controversial functions for STAT3 were reported. For a long time STAT3 has been regarded as a driver of tumour malignancy and its activation was associated with negative clinical outcome. In contrast, STAT1 was generally viewed as an independent tumour suppressor and positive prognostic marker. Here we discuss the experimental evidence for the tight association and regulation of oncogenic STAT3 transcription kept at bay by nuclear STAT1. We summarise current research and describe cellular models of different STAT1/STAT3 expression ratios. STAT1/3 expression levels are influenced by the mutational status of carcinoma cells associated with nuclear unphosphorylated STAT1. Animal tumour models and results from in vitro experiments allow for the conclusion that both proteins interact as antagonistic transcription factors in CRC cells. These STATs steer also important processes during infection and inflammation that influence development and progression of CRC. The STAT1/3 interplay is important to understand gene regulation and we describe it here similar like the YIN/YANG dualism. Thus, we propose to evaluate both STAT1 and STAT3 expression patterns in cancers in a dual manner instead of regarding them as independent transcription factors. This conceptual dualistic view could advance diagnostic predictions in the future. | STAT Transcription Factors |
The prognosis and life expectancy of chronic myeloid leukemia (CML) patients have improved significantly with the launch of first tyrosine kinase inhibitor (TKI), imatinib. Maintaining at least one major molecular response in CML patients without the use of TKI is known as treatment-free remission (TFR). The safety of the first TFR (TFR1) effort has been reported by numerous studies. However, some patients relapse during TFR1. A second TFR (TFR2) can be tried again in those patients. This systematic review aims to evaluate individual patient characteristics for a TFR2, factors predicting successful TFR2, monitoring, consequences of the cessation of TKI, and studies about TFR2. We identified 5 studies related TFR2. The results showed that the first failed TKI discontinuation attempt is not an indicator of a second TKI discontinuation failure. TKIs could safely and successfully be discontinued for a second time in chronic phase CML patients despite a TFR1 failure. The most important factors for estimating TFR2 success are the speed of molecular relapse and the TKI-free duration after the first TKI discontinuation attempt. New trends in the management of CML patients are reducing the side effects of treatment, lessening the financial burden, and improving the quality of life of patients as CML has developed into a manageable chronic disease rather than an aggressive cancer. Although there are many studies and guidelines on TFR1, there are few studies on TFR2 and predictive factors. More data is still needed regarding TFR2 attempt in patients with CML. | Imatinib Mesylate |
BACKGROUND: Ferroptosis is involved in the drug resistance mechanisms of some tumors. The present study aimed to explore the role of tissue inhibitor of matrix metalloprotease 1 (TIMP1) in sorafenib-triggered ferroptosis in colorectal cancer (CRC). METHODS: HCT-8 CRC cell lines were generated that were sorafenib-resistant or that under- or overexpressed TIMP1. The levels of reactive oxygen species (ROS), iron, and malondialdehyde (MDA) were compared across the different cell lines. The half-maximal inhibitory concentration of sorafenib against the different lines was determined based on cell viability. Expression of ferroptosis-related genes and the corresponding proteins was determined by quantitative RT-PCR or western blotting. RESULTS: TIMP1 overexpression induced sorafenib resistance in HCT-8 cells. TIMP1 knockdown repressed the activation of the PI3K/Akt pathway and reduced levels of glutathione peroxidase 4 (GPX4), enhancing sorafenib-induced ferroptosis. This led to accumulation of ROS, iron, and MDA. Giving sorafenib and the GPX4 inhibitor RSL3 to sorafenib-resistant HCT-8 cells induced ferroptosis, leading to elevated levels of iron and lipid peroxides, ultimately reducing cell viability. TIMP1 depletion in CRC cells enhances sorafenib-triggered ferroptosis by reducing PI3K/Akt axis signal transduction. CONCLUSION: The combination of sorafenib and GPX4 inhibitors such as RSL3 may be a promising therapy against CRC. | Sorafenib |
The rarity of symbiotic nitrogen-fixing trees in higher-latitude compared to lower-latitude forests is paradoxical because higher-latitude soils are relatively N poor. Using national-scale forest inventories from the United States and Mexico, we show that the latitudinal abundance distribution of N-fixing trees (more than 10 times less abundant poleward of 35 degrees N) coincides with a latitudinal transition in symbiotic N-fixation type: rhizobial N-fixing trees (which are typically facultative, regulating fixation to meet nutritional demand) dominate equatorward of 35 degrees N, whereas actinorhizal N-fixing trees (typically obligate, maintaining fixation regardless of soil nutrition) dominate to the north. We then use theoretical and statistical models to show that a latitudinal shift in N-fixation strategy (facultative vs. obligate) near 35 degrees N can explain the observed change in N-fixing tree abundance, even if N availability is lower at higher latitudes, because facultative fixation leads to much higher landscape-scale N-fixing tree abundance than obligate fixation. | Nitrogen Fixation |
Poisoning by blue-green algae occurs after an algal bloom" caused by warm weather and algal concentration. On death or disintegration, the algae release liver toxins and neurotoxins (fast death factor). Although deaths are common in animal exposures, human exposures have been limited to various allergic reactions, mild liver enzyme elevation, and gastroenteritis. A case of animal deaths and its relationship to human exposures is discussed." | Cyanobacteria Toxins |
OBJECTIVE: The aim of the present study was to investigate the therapeutic equivalence between the follitropin alpha biosimilar and the reference medication in women undergoing assisted reproductive technologies (ART). STUDY DESIGN: This multicenter, randomized (1:1), embryologist-blinded, parallel-group, comparative phase III study involved 110 women aged 20-35 years old with tubal and/or male factors of infertility. All of the subjects underwent controlled ovarian hyperstimulation (COH) using a gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. Over the 5-day fixed-dose regimen, the women received 150 IU/day of follitropin alpha biosimilar (n = 55) or original follitropin alpha (n = 55), followed by dose adaptation. The primary endpoint for assessing the therapeutic equivalence was the number of retrieved oocytes using a pre-determined clinical equivalence margin of +/- 3.4 oocytes. RESULTS: Similar numbers of oocytes were retrieved in both groups: 12.16 +/- 7.28 in the follitropin alpha biosimilar group and 11.62 +/- 6.29 in the original follitropin alpha group, with mean difference of 0.546 +/- 1.297 oocytes (95% confidence interval [CI]: -2.026, 3.116), p = 0.002 (intention-to-treat [ITT] population). Additionally, no statistically significant differences were found for secondary endpoints: the onset of biochemical (34.7% and 36.7%, p = 0.883), clinical pregnancy (26.5% and 32.7%, p = 0.507), delivery (26.5% and 24.5%, p = 0.817) and take-home baby rate (28.6% and 26.5%, p = 0.816) for the follitropin biosimilar and original follitropin groups (per-protocol [PP] population). Ovarian hyperstimulation syndrome was observed in subjects with a positive pregnancy test in 0% and 3.64% of cases and after triggering ovulation in 7.27% and 3.64% for the follitropin biosimilar and original follitropin groups, respectively. CONCLUSIONS: This study demonstrated similar therapeutic equivalence and safety profiles between the follitropin alpha biosimilar and the reference follitropin in women who underwent COH in GnRH-ant cycles. TRIAL REGISTRATION NUMBER: 1. Name of the registry: ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT03088137. Date of registration: 02.03.2017, retrospectively registered. Trial conducted between 08.02.2017 and 17.08.2018, the date of enrollment of the first participant - 08.02.2017. 2. Name of the registry: Russian Ministry of Health, grls.rosminzdrav.ru. TRIAL REGISTRATION NUMBER: RCT 754. Date of registration: 26.10.2016, prospectively registered. | Ovulation Induction |
Several critical aspects of cross-linked polyanhydrides made using thiol-ene polymerization are reported, in particular the erosion, release, and solution properties, along with their cytotoxicity toward fibroblast cells. The monomers used to synthesize these polyanhydrides were 4-pentenoic anhydride and pentaerythritol tetrakis(3-mercaptopropionate). Techniques used to evaluate the erosion mechanism indicate a complex situation in which several phenomena, such as hydrolysis rates, local pH, water diffusion, and solubility, may be influencing the erosion process. The mass loss profile, the release rate of a hydrophilic dye, the rate of hydrolysis of the polyanhydride, the hydrolysis product solubility as a function of pH, average pK(a) and its cytotoxicity toward fibroblast cells were all determined. The solubility of the degradation product is low at pH values less than 6-7, and the average pKa was determined to be ~5.3. The cytotoxicity of the polymer and the degradation product was found to be low, with cell viabilities of >97% for the various samples studied at concentrations of ~1000-1500 ppm. These important parameters help determine the potential of the thiol-ene polyanhydrides in various biomedical applications. These polyanhydrides can be used as a delivery vehicle, and although the release profile qualitatively followed the mass loss profile for a hydrophilic dye, the release rate appears to be by both diffusion and mass loss mechanisms. | Polyanhydrides |
ACSL4 is generally considered to be universally required for ferroptosis, a form of cell death induced by phospholipid peroxidation. In this issue of Cell Chemical Biology, Magtanong et al. (2022) report the surprising finding that ACSL4 is only required for ferroptosis in certain circumstances, raising interesting questions about the regulation of this cell death pathway. | Carbon-Sulfur Ligases |
Although recognized as highly crucial to supervision practice (e.g., Tummala-Narra, 2004), culture has been addressed minimally in the psychoanalytic supervision literature. Calls to remedy that limitation have been made and making culture matter has been identified as a most pressing need for psychoanalytic supervision. But how then do we as supervisors go about doing that? How might we better position culture in, and make culture central to, our psychoanalytic supervisory conceptualization and conduct? We subsequently take up those questions, expanding upon our earlier proposals about cultural humility and the Cultural Third (Watkins and Hook, 2016) by (a) proposing a tripartite multicultural perspective (i.e., cultural humility-cultural comfort-cultural opportunities) as supervision sine qua non; (b) using recognition theory as a way to better understand that very process of Third creation and elaboration; and (c) providing a rupture/repair case example that shows efforts to create and build the Cultural Third in supervision. The Cultural Third is conceptualized as a product of doers-doing with so as to culturally learn together through not knowing"." | Psychoanalytic Therapy |
Harmonia axyridis has been introduced as a biological control agent in Europe and the USA. Since its introduction, it has established and spread, and it is now regarded as an invasive alien species. It has been suggested that intraguild predation is especially important for the invasion success of H. axyridis. The aim of this study was to compare the intraguild predation behaviour of three ladybird species (Coccinella septempunctata, Adalia bipunctata, and H. axyridis). Predation behaviour was investigated in semi-field experiments on small lime trees (Tilia platyphyllos). Two fourth-instar larvae placed on a tree rarely made contact during 3-hour observations. When placed together on a single leaf in 23%-43% of the observations at least one contact was made. Of those contacts 0%-27% resulted in an attack. Harmonia axyridis attacked mostly heterospecifics, while A. bipunctata and C. septempunctata attacked heterospecifics as often as conspecifics. In comparison with A. bipunctata and C. septempunctata, H. axyridis was the most successful intraguild predator as it won 86% and 44% of heterospecific battles against A. bipunctata and C. septempunctata respectively, whilst A. bipunctata won none of the heterospecific battles and C. septempunctata won only the heterospecific battles against A. bipunctata. Coccinella septempunctata dropped from a leaf earlier and more often than the other two species but was in some cases able to return to the tree, especially under cloudy conditions. The frequency with which a species dropped did not depend on the species the larva was paired with. The results of these semi-field experiments confirm that H. axyridis is a strong intraguild predator as a consequence of its aggressiveness and good defence against predation from heterospecific species. The fact that H. axyridis is such a strong intraguild predator helps to explain its successful establishment as invasive alien species in Europe and the USA. | Citrus aurantiifolia |
Canavan disease (CD) is a rare autosomal recessive disorder characterized by macrocephaly and progressive leukodystrophy. Up to now biopsy or necropsy were required to define the diagnosis. Recently the disease has been related to N-acetylaspartic aciduria and deficiency of aspartoacylase, an enzyme possibly involved in the myelin synthesis. These biochemical findings have provided a diagnostic marker for the disease. We report a new case of infantile CD in which the demonstration of N-acetylaspartic aciduria and a marked deficiency of aspartoacylase activity confirmed the diagnosis." | Diffuse Cerebral Sclerosis of Schilder |
OBJECTIVES: Manual cardiopulmonary resuscitation (CPR) during vertical transport in small elevators using standard stretcher for out-of-hospital cardiac arrest can raise concerns with diminishing quality. Mechanical CPR on a reducible stretcher (RS-CPR) that can be shortened in the length was tested to compare the CPR quality with manual CPR on a standard stretcher (SS-CPR). METHODS: A randomized crossover manikin simulation was designed. Three teams of emergency medical technicians were recruited to perform serial CPR simulations using two different protocols (RS-CPR and SS-CPR) according to a randomization; the first 6 minutes of manual CPR at the scene was identical for both scenarios and two different protocols during vertical transport in a small elevator followed on a basis of cross-over assignment. The LUCAS-2 Chest Compression System (Zolife AB, Lund, Sweden) was used for RS-CPR. CPR quality was measured using a resuscitation manikin (Resusci Anne QCPR, Laerdal Medical, Stavanger, Norway) in terms of no flow fraction, compression depth, and rate (median and IQR). RESULTS: A total of 42 simulations were analyzed. CPR quality did not differ significantly at the scene. No flow fraction (%) was significantly lower when the stretcher was moving in RS-CPR then SS-CPR (36.0 (33.8-38.7) vs 44.0 (36.8-54.4), P< .01). RS-CPR showed significantly better quality than SS-CPR; 93.2 (50.6-95.6) vs 14.8 (0-20.8) for adequate depth (P< 0.01), and 97.5 (96.6-98.2) vs 68.9(43.4-78.5) for adequate rate (P< .01). CONCLUSION: Mechanical CPR on a reducible stretcher during vertical transport showed significant improvement in CPR quality in terms of no-flow fraction, compression depth, and rate compared with manual CPR on a standard stretcher. | Stretchers |
OBJECTIVE: The apparent effect of superior semicircular canal dehiscence (SSCD) on middle ear- and cochlear impedance has led researchers to investigate the use of wideband acoustic immittance as a screening tool when SSCD is suspected. The purpose of the study was to describe the absorbance characteristics and tympanometric values of ears with confirmed SSCD measured at tympanometric peak pressure (TPP) and at ambient pressure. METHODS: Wideband Acoustic Immittance was performed at ambient pressure and at TPP on ten participants (12 ears) with confirmed SSCD, as well as on an age- and gender matched control group (12 ears). Inferential statistics were used to determine whether statistical differences existed for the absorbance values at each of the averaged frequencies, the resonance frequency (RF) and tympanometric data between the SSCD and control groups. RESULTS: The mean absorbance of the SSCD group reached a maximum at 890.9 Hz and a minimum at 6349.6 Hz. When testing absorbance at TPP, a statistically significant increase/peak in the absorbance values of the SSCD group (compared to those of the control group) was found from 630 to 890.9 Hz and a decrease from 4489.8 to 6349.6 Hz. Similar patterns were observed for absorbance at ambient pressure. A lower mean RF for ears with SSCD as well as an increased mean admittance magnitude (AM) value at RF was found compared to those of the control group. CONCLUSION: The use of SSCD as a screening tool when SSCD is suspected was strengthened by results similar to those of previous studies. As a result of the significant difference in RF of SSCD ears compared to the RF of the control group, the potential value of measuring the RF of the middle ear to differentiate between mass-and stiffness dominated pathologies, was also illustrated. | Semicircular Canal Dehiscence |
The purpose of this study was to investigate the effects of Panax notoginseng extracts on inferior sperm motility in vitro. Semen samples were collected from 23 patients with sperm motility between 20% and 40%. The sperm count was over 20 x 10(6)/ml in accordance with the World Health Organization standard. 1.0 mg/ml and 2.0 mg/ml of Panax notoginseng extracts including aqueous extract, n-butanol extract, and polysaccharide fraction on sperm motility and progression were evaluated by computer assisted semen analysis. The results demonstrated that sperm motility as well as progression on inferior sperm motility were enhanced at 1 hour and 2 hours after incubation with all three types of extracts. | Sperm Motility |
Prostaglandin D2 (PGD2) released from immune cells or other cell types activates its receptors, D prostanoid receptor (DP)1 and 2 (DP1 and DP2), to promote inflammatory responses in allergic and lung diseases. Prostaglandin-mediated inflammation may also contribute to vascular diseases such as abdominal aortic aneurysm (AAA). However, the role of DP receptors in the pathogenesis of AAA has not been systematically investigated. In the present study, DP1-deficient mice and pharmacological inhibitors of either DP1 or DP2 were tested in two distinct mouse models of AAA formation: angiotensin II (AngII) infusion and calcium chloride (CaCl2) application. DP1-deficient mice [both heterozygous (DP1+/-) and homozygous (DP1-/-)] were protected against CaCl2-induced AAA formation, in conjunction with decreased matrix metallopeptidase (MMP) activity and adventitial inflammatory cell infiltration. In the AngII infusion model, DP1+/- mice, but not DP1-/- mice, exhibited reduced AAA formation. Interestingly, compensatory up-regulation of the DP2 receptor was detected in DP1-/- mice in response to AngII infusion, suggesting a potential role for DP2 receptors in AAA. Treatment with selective antagonists of DP1 (laropiprant) or DP2 (fevipiprant) protected against AAA formation, in conjunction with reduced elastin degradation and aortic inflammatory responses. In conclusion, PGD2 signaling contributes to AAA formation in mice, suggesting that antagonists of DP receptors, which have been extensively tested in allergic and lung diseases, may be promising candidates to ameliorate AAA. | Receptors, Prostaglandin |
Nausea and vomiting are common experiences in pregnancy, affecting 70% to 80% of all pregnant women. Various metabolic and neuromuscular factors have been implicated in the pathogenesis of nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum (HG), an entity distinct from NVP. However, their exact cause is unknown. Consequently, treatment of NVP and HG can be difficult, as neither the optimal targets for treatment nor the full effects of potential treatments on the developing fetus are known. This article reviews the epidemiology, pathology, diagnosis, outcomes, and treatment of NVP and HG. | Signs and Symptoms, Digestive |
Endocytosis is the major regulator of signaling from receptor tyrosine kinases (RTKs). The canonical model of RTK endocytosis involves rapid internalization of an RTK activated by ligand binding at the cell surface and subsequent sorting of internalized ligand-RTK complexes to lysosomes for degradation. Activation of the intrinsic tyrosine kinase activity of RTKs results in autophosphorylation, which is mechanistically coupled to the recruitment of adaptor proteins and conjugation of ubiquitin to RTKs. Ubiquitination serves to mediate interactions of RTKs with sorting machineries both at the cell surface and on endosomes. The pathways and kinetics of RTK endocytic trafficking, molecular mechanisms underlying sorting processes, and examples of deviations from the standard trafficking itinerary in the RTK family are discussed in this work. | Endosomes |
A gingival localization of fibrosarcoma of soft oral tissues was described in a 58-year-old female. Primary fibrosarcoma of the head and neck region is rare. The histological appearance of the tumour is related to its grade of differentiation. The amount of collagen is variable. The accepted treatment is radical surgery; but metastases occur frequently in the lungs. | Gingival Neoplasms |
Binding of elongation factor Spt6 to Iws1 provides an effective means for coupling eukaryotic mRNA synthesis, chromatin remodelling and mRNA export. We show that an N-terminal region of Spt6 (Spt6N) is responsible for interaction with Iws1. The crystallographic structures of Encephalitozoon cuniculi Iws1 and the Iws1/Spt6N complex reveal two conserved binding subdomains in Iws1. The first subdomain (one HEAT repeat; HEAT subdomain) is a putative phosphoprotein-binding site most likely involved in an Spt6-independent function of Iws1. The second subdomain (two ARM repeats; ARM subdomain) specifically recognizes a bipartite N-terminal region of Spt6. Mutations that alter this region of Spt6 cause severe phenotypes in vivo. Importantly, the ARM subdomain of Iws1 is conserved in several transcription factors, including TFIIS, Elongin A and Med26. We show that the homologous region in yeast TFIIS enables this factor to interact with SAGA and the Mediator subunits Spt8 and Med13, suggesting the molecular basis for TFIIS recruitment at promoters. Taken together, our results provide new structural information about the Iws1/Spt6 complex and reveal a novel interaction domain used for the formation of transcription networks. | Elongin |
The tetraspanin web refers to a network of molecular interactions involving tetraspanins and other molecules. Inside the tetraspanin web, small primary complexes containing only one tetraspanin and one specific partner molecule such as CD151/alpha3beta1 integrin and CD9/CD9P-1 (FPRP) can be observed under particular conditions. Here we demonstrate that when cells are lysed with Brij97, the tetraspanins CD151 and CD9 allow and/or stabilize the interaction of their partner molecules with other tetraspanins and that their two partners associate under conditions maintaining tetraspanin/tetraspanin interactions. The tetraspanins were also found to partition into a detergent-resistant membrane environment to which the integrin alpha3beta1 was relocalized upon expression of CD151. | Tetraspanin 29 |
The intracranial pressure was measured by an intraventricular catheter in 53 patients, in the course of 156 infusions of 40% Sorbitol and 72 infusions of 20% Mannitol. The amounts given and the rate of infusion were varied. The results show that the rate of the infusion is decisive in determining the fall in intracranial pressure, while the duration of the fall is dependent on the amount injected. After Sorbitol the influence on lowering the pressure was more marked and longer lasting than after injections of Mannitol. As a possible treatment for raised intracranial pressure one may conclude that small amounts given over a shorter time (50-80 ml/5 min) produce the most favourable effect. | Intracranial Pressure |
Several lines of evidence favour the hypothesis that intracellular biosynthetic protein transport in eukaryotes is mediated by non-clathrin-coated vesicles (for a review see Rothman and Orci, 1992). The vesicles have been isolated and a set of their surface proteins has been characterized as coat proteins (COPs). These COPs exist in the cytosol as a preformed complex, the coatomer, which was prior to this study known to contain six subunits: four (alpha-, beta-, gamma- and delta-COP) with molecular weights between 160 and 58 kDa, and two additional proteins of approximately 36 and 20 kDa, epsilon- and xi-COP. Here we describe a novel subunit of the coatomer complex, beta'-COP. This subunit occurs in amounts stoichiometric to the established COPs both in the coatomer and in nonclathrin-coated vesicles and shows homology to the beta-subunits of trimeric G proteins. | Coatomer Protein |
: Pregnancy carries a high risk of thromboembolic complications, especially in the postpartum period. This risk is particularly high in women with inherited thrombophilias, among these antithrombin deficiency seems to carry the highest risk. In this case, the use of low molecular weight heparin (LMWH) is recommended, while the use of antithrombin concentrate is controversial. We report our experience of seven pregnancies occurred in five women: two, with a personal and familiar history negative for venous thromboembolism, were treated with LMWH during pregnancy and antithrombin concentrate immediately before and after the delivery. The other three women had a personal and familiar history positive for venous thromboembolism and were treated with LMWH and antithrombin concentrate during all the pregnancy and the postpartum period. No thromboembolic or hemorrhagic complications were observed in both groups, demonstrating that our strategy could be safe and effective. | Antithrombin III Deficiency |
Cellulose cotton linter was oxidized with sodium hypochlorite with catalytic amounts of sodium bromide and 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) under various conditions. After this TEMPO-mediated oxidation, water-insoluble fractions were collected and characterized in terms of carboxylate and aldehyde contents, crystallinities and crystal sizes, degrees of polymerization, morphology, and water retention values. Carboxylate and aldehyde groups were introduced into the water-insoluble fractions up to about 0.7 and 0.3 mmol/g, respectively, by the oxidation, where recovery of the water-insoluble fractions were generally higher than 80%. Crystallinities and crystal sizes of cellulose I were nearly unchanged during the oxidation, and thus, carboxylate and aldehyde groups were introduced selectively on crystal surfaces and in disordered regions of the water-insoluble fractions. Water retention values of cotton linter can be increased from 60% to about 280% through the introduction of hydrophilic carboxylate groups and morphological changes from fibrous forms to short fragments by the TEMPO-mediated oxidation. | Heterocyclic Oxides |
Gonococci producing a distinct opacity protein (OpaA in strain MS11) adhere to and are efficiently internalized by cultured epithelial cells such as the Chang conjunctiva cell line. Both adherence and uptake require interactions between OpaA and heparan sulfate proteoglycans on the mammalian cell surface. Chinese hamster ovary (CHO) cells also support adherence of gonococci through interactions of OpaA with cell surface heparan sulfate proteoglycans. However, despite this similarity in the requirements for adherence, CHO cells are not capable of internalizing gonococci. In this report, we characterized this apparent deficiency and identified a factor in fetal calf serum (FCS) which is capable of mediating uptake of gonococci by CHO cells. In the absence of FCS, OpaA+ gonococci adhered to but were not internalized by CHO cells, whereas in the presence of up to 15% FCS, the bacteria were efficiently internalized by the cells. Preincubation of bacteria, but not cells, with FCS also stimulated internalization, suggesting that a factor present in FCS was binding to the surface of gonococci and subsequently stimulating entry. Using a combination of chromatographic purification procedures, we identified the adhesive glycoprotein vitronectin as the serum factor which mediates the internalization of gonococci by CHO cells. Vitronectin-depleted serum did not support gonococcal entry, and this deficiency was restored by the addition of purified vitronectin. Further experiments using a set of gonococcal recombinants, each expressing a single member of the family of Opa outer membrane proteins, demonstrated that vitronectin bound to the surface of OpaA-producing gonococci only and that the vitronectin-mediated uptake by the CHO cells was limited to this bacterial phenotype. To our knowledge, our data are the first example that vitronectin can serve as a molecule that drives bacterial entry into epithelial cells. | Vitronectin |
There is a clear unmet medical need for a vaccine that would prevent infections from Staphylococcus aureus (S. aureus). To validate antigens as potential vaccine targets it has to be demonstrated that the antigens are expressed in vivo. Using murine bacteremia and wound infection models, we demonstrate that the expression of clumping factor A (ClfA) and capsular polysaccharide antigens are heterogeneous and dependent on the challenge strains examined and the in vivo microenvironment. We also demonstrate opsonophagocitic activity mediated by either antigen is not impeded by the presence of the other antigen. The data presented in this report support a multiantigen approach for the development of a prophylactic S. aureus vaccine to ensure broad coverage against this versatile pathogen. | Coagulase |
The identification of causal genomic loci and their interactions underlying various traits in plants has been greatly aided by progress in understanding the organization of the nuclear genome. This provides clues to the responses of plants to environmental stimuli at the molecular level. Apart from other uses, these insights are needed to fully explore the potential of new breeding techniques that rely on genome editing. However, genome analysis and sequencing is not straightforward in the many agricultural crops and their wild relatives that possess large and complex genomes. Chromosome genomics streamlines this task by dissecting the genome to single chromosomes whose DNA is then used instead of nuclear DNA. This results in a massive and lossless reduction in DNA sample complexity, reduces the time and cost of the experiment, and simplifies data interpretation. Flow cytometric sorting of condensed mitotic chromosomes makes it possible to purify single chromosomes in large quantities, and as the DNA remains intact this process can be coupled successfully with many techniques in molecular biology and genomics. Since the first experiments with flow cytometric sorting in the late 1980s, numerous applications have been developed, and chromosome genomics has been having a significant impact in many areas of research, including the sequencing of complex genomes of important crops and gene cloning. This review discusses these applications, describes their contribution to advancements in plant genome analysis and gene cloning, and outlines future directions. | Genome, Plant |
Objectives:This study aims to examine whether subjective memory complaints (SMC) contribute to social participation among older adults.Method:The study sample was 4,713 community-dwelling older adults aged 65 years and older from four waves (2010, 2012, 2014, 2016) of the Health and Retirement Study. Hierarchical linear modeling analysis was used to examine the association of SMC with social participation after controlling for factors influencing social participation. Demographic factors (i.e. age, gender, and perceived socioeconomic status) were entered in block 1, health-related factors (i.e. health conditions, perceived health, instrumental activities of daily living, memory-immediate and delayed, and depressive symptoms) were entered in block 2, environmental factors (i.e. perceived social support and strain from spouse, child, family, and friend) were entered in block 3, and SMC was entered in block 4.Results:The result showed that factors significantly contributing to social participation are age (standardized beta = -0.08, p < 0.01), perceived socioeconomic status (beta = 0.16, p < 0.001), perceived health (beta = 0.15, p < 0.001), instrumental activities of daily living (beta = 0.12, p < 0.001), memory-immediate and delayed (beta = 0.09, p < 0.001; beta = 0.08, p < 0.001, respectively), social support from spouse and friend (beta = 0.04, p < 0.05; beta = 0.13, p < 0.001, respectively), social strain from friend (beta = 0.07, p < 0.001), and SMC (beta = -0.05, p < 0.001). The demographic factors explained 9.5%, health-related factors explained 8.5%, environmental factors explained 2.4%, and SMC explained 0.1% of the variance in social participation.Conclusion: This finding suggests that SMC may contribute to social participation in older adults.Supplemental data for this article can be accessed online at https://doi.org/10.1080/13607863.2021.1961123 . | Activities of Daily Living |
INTRODUCTION: Subjective well-being (SWB) is attributable to both individual and environmental attributes. However, extant studies have paid little attention to the contribution of environmental attributes at the urban level to SWB or their nonlinear associations with SWB. METHODS: This study applies a machine learning approach called gradient boosting decision trees (GBDTs) to the 2013 China Household Income Survey data to investigate the relative importance of urban and individual attributes to and their nonlinear associations with SWB. RESULTS: The urban and individual attributes make similar relative contributions to SWB. Income and age are the most important predictors. Urban facilities make a larger contribution than urban development factors. Moreover, urban attributes exert nonlinear and threshold effects on SWB. Cultural facilities and green space have inverted U-shaped correlations with SWB. Educational facilities, medical facilities, and population size are monotonically associated with SWB and have specific thresholds. DISCUSSION: Improving urban attributes is important to enhancing residents' SWB. | Decision Trees |
Insulin-like growth factors (IGFs) are indispensable peptide hormones for proper development of the central nervous system (CNS). Because IGF-1 exhibits neuroprotective and myelinogenetic effects, it possesses therapeutic potential in treating neurodegenerative demyelinating diseases such as multiple sclerosis (MS). However, IGF actions are largely dependant on high-affinity regulatory IGF binding proteins (IGFBPs), which are likely to interfere with therapeutic attempts at elevating IGF-1 levels in the CNS. In particular, IGFBP-2 plays a dominant role in IGF regulation in the CNS and is upregulated in several pathological conditions, including MS. The question remains as to whether IGFBPs should be considered "interfering" components of IGF treatment strategies or might possibly be utilized to clinical advantage. This review discusses our current understanding of biological functions of IGFBP-2 in the CNS and its implications in the demyelinating disease MS." | Insulin-Like Growth Factor Binding Protein 2 |
Simazine is a soil-active herbicide that has been applied worldwide in agricultural soils, being the second most commonly detected herbicide in groundwater and surface waters. Although its use has been restricted in many countries of Europe, it is still applied in many locations around the world in orchards, vineyards and forestry. Therefore, it is important to study its fate and transport in the environment. This paper investigates simazine transport in undisturbed bare soils from a vineyard at the Casablanca valley, Chile. In the study site, shallow groundwater tables (<1.0 m depth) and high simazine levels (>15 mug L(-1)) in the groundwater were observed and thus, there is potential for simazine to be transported further away through the saturated zone. The soils from the study site were characterized and the hydrodynamic transport parameters were determined. Column leaching experiments showed that the two-site chemical non-equilibrium model correctly represented simazine transport. It was found that 36.3% of the adsorption sites achieve instantaneous equilibrium and that the first-order kinetic rate of the non-equilibrium sites was 6.2 x 10(-3) h(-1). Hydrus 2D was used to predict the transport of simazine in the study site under natural field conditions. Simulation results showed that simazine concentrations at depths shallower than 2.1 m are above the maximum contaminant level of 4 mug L(-1) (defined by the U.S. Environmental Protection Agency). The timing of herbicide application was found to be important on simazine leaching and the main processes involved in simazine transport were degradation and adsorption, which accounted for 95.78 and 4.19% of the simulated mass of pesticide, respectively. A qualitative agreement in the timing and magnitude of simazine concentration was obtained between the simulations and the field data. Therefore, the model utilized in this investigation can be used to predict simazine transport and is a valuable tool to assess agricultural practices to minimize environmental impacts of simazine. | Simazine |
In vitro assays for cytochrome P450 enzymes developed from plant-derived microsomal extracts have not been used extensively for the characterization and quantification of enzyme activities in plant tissues. We describe here an in vitro assay for abscisic acid (ABA) 8'-hydroxylase that was developed using microsomes extracted from (+)-ABA-induced corn suspension cultures. This assay may be useful for further characterization and monitoring of ABA 8'-hydroxylase activities in germinating seeds, seedlings, and other tissues. Additionally, the optimization protocols provided here may be adapted towards improving in vitro enzyme assays for other cytochrome P450 enzymes expressed in plants. | Microsomes |
This study investigated for the first time maximum force production, shortening velocity (Vmax) and power output in permeabilised single muscle fibres at 12 degrees C from lion, Panthera leo (Linnaeus 1758), and caracal, Caracal caracal (Schreber 1776), and compared the values with those from human cyclists. Additionally, the use and validation of previously frozen tissue for contractile experiments is reported. Only type IIx muscle fibres were identified in the caracal sample, whereas type IIx and only two type I fibres were found in the lion sample. Only pure type I and IIa, and hybrid type IIax fibres were identified in the human samples - there were no pure type IIx fibres. Nevertheless, compared with all the human fibre types, the lion and caracal fibres were smaller (P<0.01) in cross-sectional area (human: 6194+/-230 mum(2), lion: 3008+/-151 mum(2), caracal: 2583+/-221 mum(2)). On average, the felid type IIx fibres produced significantly greater force (191-211 kN m(-2)) and ~3 times more power (29.0-30.3 kN m(-2) fibre lengths s(-1)) than the human IIax fibres (100-150 kN m(-2), 4-11 kN m(-2) fibre lengths s(-1)). Vmax values of the lion type IIx fibres were also higher than those of human type IIax fibres. The findings suggest that the same fibre type may differ substantially between species and potential explanations are discussed. | Lions |
BACKGROUND: Activation of hepatic stellate cells (HSCs) to a myofibroblastic phenotype is a key event in liver fibrosis. Identification of transcription factors with activities that are modulated during HSC activation will improve our understanding of the molecular events controlling HSC activation. AIMS: To determine if changes in E-box DNA binding activity occur during in vitro and in vivo activation of rat and human HSCs and to investigate mechanisms underlying any observed changes. METHODS: Nuclear extracts were prepared from rat HSCs isolated and cultured from normal and carbon tetrachloride injured rat livers and from HSCs isolated from human liver. EMSA analysis of E-box DNA binding activity was performed on nuclear extracts to determine changes during HSC activation. Western and northern blot analysis of MyoD and Id1 basic helix-loop-helix (bHLH) proteins was performed to confirm expression in HSC. RESULTS: HSC activation was associated with inducible expression of two low mobility E-box binding complexes that were immunoreactive with an anti-MyoD antibody. MyoD mRNA expression was found at similar levels in freshly isolated and activated HSCs; in contrast, MyoD protein expression was elevated in activated HSCs. Activation of rat HSCs was accompanied by reduced expression of the inhibitory bHLH protein Id1. CONCLUSIONS: In vitro and in vivo activation of rat and human HSCs is accompanied by induction of MyoD binding to E-box DNA sequences which appears to be mechanistically associated with elevated MyoD protein expression and reduced expression of the inhibitory Id1 protein. Clarification of the role of MyoD and Id1 proteins in HSC activation and liver fibrogenesis is now required. | E-Box Elements |
Lipidomics and metabolomics are nowadays widely used to provide promising insights into the pathophysiology of cellular stress disorders. Our study expands, with the use of a hyphenated ion mobility mass spectrometric platform, the understanding of the cellular processes and stress due to microgravity. By lipid profiling of human erythrocytes, we annotated complex lipids such as oxidized phosphocholines, phosphocholines bearing arachidonic in their moiety, as well as sphingomyelins and hexosyl ceramides associated with microgravity conditions. Overall, our findings give an insight into the molecular alterations and identify erythrocyte lipidomics signatures associated with microgravity conditions. If the present results are confirmed in future studies, they may help to develop suitable treatments for astronauts after return to Earth. | Lipidomics |
OBJECTIVE: Non-invasive spectral analysis of fetal heart rate variability is a promising new field of fetal monitoring. To validate this method properly, we studied the relationship between gestational age and the influence of fetal rest-activity state on spectral estimates of fetal heart rate variability. DESIGN: Prospective longitudinal study. SETTING: Tertiary care teaching hospital. POPULATION: Forty healthy women with an uneventful singleton pregnancy. METHODS: Non-invasive fetal electrocardiogram measurements via the maternal abdomen were performed at regular intervals between 14 and 40 weeks of gestation and processed to detect beat-to-beat fetal heart rate. Simultaneous ultrasound recordings were performed to assess fetal rest-activity state. MAIN OUTCOME MEASURES: Absolute and normalized power of fetal heart rate variability in the low (0.04-0.15 Hz) and high (0.4-1.5 Hz) frequency band were obtained, using Fourier Transform. RESULTS: 14% of all measurements and 3% of the total amount of abdominal data (330 segments) was usable for spectral analysis. During 21-30 weeks of gestation, a significant increase in absolute low and high frequency power was observed. During the active state near term, absolute and normalized low frequency power were significantly higher and normalized high frequency power was significantly lower compared with the quiet state. CONCLUSIONS: The observed increase in absolute spectral estimates in preterm fetuses was probably due to increased sympathetic and parasympathetic modulation and might be a sign of autonomic development. Further improvements in signal processing are needed before this new method of fetal monitoring can be introduced in clinical practice. | Heart Rate, Fetal |
Heart failure is the end-stage of all cardiovascular diseases with a ~25% 5-year survival rate, and insufficient mitochondrial energy production to meet myocardial demand is the hallmark of heart failure. Mitochondrial components involved in the regulation of ATP production remain to be fully elucidated. Recently, roles of 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in the pathophysiological processes of heart diseases have emerged, implicated by evidence that mitochondrial CNPase proteins are associated with mitochondrial integrity under metabolic stress. In this study, a zebrafish heart failure model was established, by employing antisense morpholino oligonucleotides and the CRISPR-Cas9 gene-editing system, which recapitulates heart failure phenotypes including heart dysfunction, pericardial edema, ventricular enlargement, bradycardia, and premature death. The translational implications of CNPase in the pathophysiological process of heart failure were tested in a pressure overload-induced heart hypertrophy model, which was carried out in rats through transverse abdominal aorta constriction (TAAC). AAV9-mediated myocardial delivery of CNPase mitigated the hypertrophic response through the specific hydrolysis of 2'-3'-cyclic nucleotides, supported by the decrease of cardiac hypertrophy and fibrosis, the integrity of mitochondrial ultrastructure, and indicators of heart contractility in the AAV9-TAAC group. Finally, the biometrics of a mitochondrial respiration assay carried out on a Seahorse cellular energy analyzer demonstrated that CNPase protects mitochondrial respiration and ATP production from AngII-induced metabolic stress. In summary, this study provides mechanistic insights into CNPase-2',3'-cyclic nucleotide metabolism that protects the heart from energy starvation and suggests novel therapeutic approaches to treat heart failure by targeting CNPase activity." | 2',3'-Cyclic-Nucleotide Phosphodiesterases |
T cell-intrinsic regulation, such as anergy, adaptive tolerance and exhaustion, is central to immune regulation. In contrast to Type 1 and Type 17 settings, knowledge of the intrinsic fate and function of Th2 cells in chronic Type 2 immune responses is lacking. We previously showed that Th2 cells develop a PD-1/PD-L2-dependent intrinsically hypo-responsive phenotype during infection with the filarial nematode Litomosoides sigmodontis, denoted by impaired functionality and parasite killing. This study aimed to elucidate the transcriptional changes underlying Th2 cell-intrinsic hypo-responsiveness, and whether it represents a unique and stable state of Th2 cell differentiation. We demonstrated that intrinsically hypo-responsive Th2 cells isolated from L. sigmodontis infected mice stably retained their dysfunctional Th2 phenotype upon transfer to naive recipients, and had a divergent transcriptional profile to classical Th2 cells isolated prior to hypo-responsiveness and from mice exposed to acute Type 2 stimuli. Hypo-responsive Th2 cells displayed a distinct transcriptional profile to exhausted CD4+ T cells, but upregulated Blimp-1 and the anergy/regulatory-associated transcription factors Egr2 and c-Maf, and shared characteristics with tolerised T cells. Hypo-responsive Th2 cells increased mRNA expression of the soluble regulatory factors Fgl2, Cd38, Spp1, Areg, Metrnl, Lgals3, and Csf1, and a subset developed a T-bet+IFN-gamma+ Th2/Th1 hybrid phenotype, indicating that they were not functionally inert. Contrasting with their lost ability to produce Th2 cytokines, hypo-responsive Th2 cells gained IL-21 production and IL-21R blockade enhanced resistance to L. sigmodontis. IL-21R blockade also increased the proportion of CD19+PNA+ germinal centre B cells and serum levels of parasite specific IgG1. This indicates a novel regulatory role for IL-21 during filarial infection, both in controlling protection and B cell responses. Thus, Th2 cell-intrinsic hypo-responsiveness is a distinct and stable state of Th2 cell differentiation associated with a switch from a classically active IL-4+IL-5+ Th2 phenotype, to a non-classical dysfunctional and potentially regulatory IL-21+Egr2+c-Maf+Blimp-1+IL-4loIL-5loT-bet+IFN-gamma+ Th2 phenotype. This divergence towards alternate Th2 phenotypes during chronicity has broad implications for the outcomes and treatment of chronic Type 2-related infections and diseases. | Th2 Cells |
Molar incisor hypomineralization is a developmental defect of dental enamel associated with rapid caries progression. In order to discover whether molar incisor hypomineralization predisposes to dental caries, a cross-sectional cohort study was conducted in a sample of 414 children aged between eight and nine years. It was found that 24.2% of the children presented molar incisor hypomineralization. Of these, 72% had a mild form and 28% a severe form. Caries prevalence was greater among the children with severe form (60.7%) than in those with mild form (43.1%) or no molar incisor hypomineralization (45.5%). The caries indices were higher in out molar incisor hypomineralization (1.18) or with mild form (1.08). The tooth-surface caries ratio was significantly higher in surfaces with severe hypomineralization than in those with no hypomineralization or mild hypomineralization. A linear regression model showed that cariogenic food intake and the presence of severe molar incisor hypomineralization were significantly associated with DMFS. Consequently, an association was found to exist between dental caries and the presence of surfaces affected by severe molar incisor hypomineralization, which should be considered a risk factor within the multifactorial etiology of caries. | Dental Enamel Hypoplasia |
Although the absence of intervening sequences (IVSs) within the 23S rRNA genes in Campylobacter lari isolates has been described, there are apparently no reports regarding correlations between the nucleotide sequences of 23S rRNA genes and erythromycin (Ery) susceptibility in C. lari isolates. Here, we determined the minimum inhibitory concentrations of 35 C. lari isolates [n = 19 for urease-positive thermophilic Campylobacter (UPTC); n = 16 urease-negative (UN) C. lari] obtained from Asia, Europe, and North America. We found that the 18 isolates were resistant to the Ery (defined as >==8 mug/mL), and three isolates, UPTC A1, UPTC 92251, and UPTC 504, showed increased resistance (16 mug/mL). No correlations between the IVSs in the helix 45 region within the 23S rRNA gene sequences and Ery resistance were identified in the C. lari isolates examined. In addition, no point mutations occurred at any expected or putative position within the V domain in the isolates. In conclusion, antibiotic resistance against the macrolide erythromycin is mediated through an alternative pathway to that described above. | Campylobacter lari |
For DNA viruses, the immediate-early (IE) proteins are generally essential regulators that manipulate the host machinery to support viral replication. Recently, IE1, an IE protein encoded by white spot syndrome virus (WSSV), has been demonstrated to function as a transcription factor. However, the target genes of IE1 during viral infection remain poorly understood. Here, we explored the host target genes of IE1 using RNAi coupled with transcriptome sequencing analysis. A total of 429 differentially expressed genes (DEGs) were identified from penaeid shrimp, of which 284 genes were upregulated and 145 genes were downregulated after IE1 knockdown. GO and KEGG pathway enrichment analysis revealed the identified DEGs are significantly enriched in the minichromosome maintenance (MCM) complex and DNA replication, indicating that IE1 plays a critical role in DNA replication control. In addition, it was found that Penaeus vannamei MCM complex genes were remarkably upregulated after WSSV infection, while RNAi-mediated knockdown of PvMCM2 reduced the expression of viral genes and viral loads at the early infection stage. Finally, we demonstrated that overexpression of IE1 promoted the expression of MCM complex genes as well as cellular DNA synthesis in insect High-Five cells. Collectively, our current data suggest that the WSSV IE1 protein is a viral effector that modulates the host DNA replication machinery for viral replication. | Nimaviridae |
The tripartite-motif (TRIM) family of proteins represents one of the largest classes of putative single protein RING-finger E3 ubiquitin ligases. The members of this family are characterized by an N-terminal TRIM motif containing one RING-finger domain, one or two zinc-finger domains called B boxes (B1 box and B2 box), and a coiled-coil region. The TRIM motif can be found in isolation or in combination with a variety of C-terminal domains, and based on C-terminus, TRIM proteins are classified into 11 distinct groups. Because of the complex nature of TRIM proteins, they are implicated in a variety of cellular functions and biological processes, including regulation of cell proliferation, cell division and developmental processes, cancer transformation, regulation of cell metabolism, autophagocytosis, modification of chromatin status, regulation of gene transcription, post-translational modifications, and interactions with pathogens. Here, we demonstrate the specific activities of TRIM family proteins that contribute to the cancer stem cell phenotype. A growing body of evidence demonstrates that several TRIM members guarantee the acquisition of stem cell properties and the ability to sustain stem-like phenotype by cancer cells using distinct mechanisms. For other members, further work is needed to understand their full contribution to stem cell self-renewal. Identification of TRIM proteins that possess the potential to serve as therapeutic targets may result in the development of new therapeutic strategies. Finally, these strategies may result in the disruption of the machinery of stemness acquisition, which may prevent tumor growth, progression, and overcome the resistance to anticancer therapies. | Cell Self Renewal |
Eryptosis is a coordinated non-lytic cell death of erythrocytes characterized by cell shrinkage, cell membrane scrambling, Ca(2+) influx, ceramide accumulation, oxidative stress, activation of calpain and caspases. Physiologically, it aims at removing damaged or aged erythrocytes from circulation. A plethora of diseases are associated with enhanced eryptosis, including metabolic diseases, cardiovascular pathology, renal and hepatic diseases, hematological disorders, systemic autoimmune pathology, and cancer. This makes eryptosis and eryptosis-regulating signaling pathways a target for therapeutic interventions. This review highlights the eryptotic signaling machinery containing several protein kinases and its small molecular inhibitors with a special emphasis on casein kinase 1alpha (CK1alpha), a serine/threonine protein kinase with a broad spectrum of activity. In this review article, we provide a critical analysis of the regulatory role of CK1alpha in eryptosis, highlight triggers of CK1alpha-mediated suicidal death of red blood cells, cover the knowledge gaps in understanding CK1alpha-driven eryptosis and discover the opportunity of CK1alpha-targeted pharmacological modulation of eryptosis. Moreover, we discuss the directions of future research focusing on uncovering crosstalks between CK1alpha and other eryptosis-regulating kinases and pathways. | Eryptosis |
A two-way-crossover bioavailability study was completed with 15 healthy male volunteers to evaluate the relative bioavailability of an orally administered controlled-release (CR) formulation of albuterol as compared to the immediate-release (IR) formulation of albuterol. The CR formulation of albuterol used in this study was based mechanistically on the elementary osmotic pump. Each subject received one 8 mg CR tablet every 12 h for 8 consecutive days and one 4 mg IR tablet every 6 h for 8 consecutive days, with 7 days separating each phase. During day 8 of dosing, hourly blood samples (0-12 h) were collected after the morning dose and three additional samples were obtained 16, 20 and 24 h following this dose. Plasma concentrations were measured using a gas chromatography-mass spectrometry procedure. No statistically significant differences were observed in mean steady-state values for Cmax, Cmin, AUC(0-12 h) and peak-to-trough fluctuations (PTF) in comparing the two dosage formulations. Mean steady state Tmax values were 2.6 and 6.0 h for the TR and CR formulations, respectively. It was concluded that twice daily administration of the controlled-release formulation of albuterol provides an alternative to four times daily administration of conventional (immediate-release) albuterol tablets. | Albuterol |
OBJECTIVES: Analyse clinical and bone metabolism features in a case series of patients with multiple vertebral fractures after discontinuation of denosumab (DMab). METHODS: An observational descriptive study analysing data from ten patients with multiple vertebral fractures after DMab discontinuation that were admitted to our rheumatology department between 2015 and 2018. RESULTS: There were a total of 49 spontaneous fractures after an average of 6 DMab doses and 10.9 months from discontinuation. Ninety percent had already received treatment other than DMab 7 of 10 oral bisphosphonates. After discontinuation, CTX and P1NP remained elevated and mean T-score for femoral neck and lumbar spine was lower than before treatment. The most affected vertebrae were L3, L5, D6, D7, D9 and D11. CONCLUSION: This report of ten new cases suffering multiple vertebral fractures early after discontinuation of DMab highlights the emerging concern on the subject in the scientific community and the need to clarify its pathogenic mechanism, and to support by solid evidence the new recommendations on its management. | Fractures, Multiple |
This review summarizes the most relevant information on PBDEs' occurrence and their impacts in cetaceans at global scale, with special attention on the species with the highest reported levels and therefore the most potentially impacted by the current and continuous release of these substances. This review also emphasizes the anthropogenic and environmental factors that could increase concentrations and associated risks for these species in the next future. High PBDE concentrations above the toxicity threshold and stationary trends have been related to continuous import of PBDE-containing products in cetaceans of Brazil and Australia, where PBDEs have never been produced. Non-decreasing levels documented in cetaceans from the Northwest Pacific Ocean might be linked to the increased e-waste import and ongoing production and use of deca-BDE that is still allowed in China. Moreover, high levels of PBDEs in some endangered species such as beluga whales (Delphinapterus leucas) in St. Lawrence Estuary and Southern Resident killer whales (Orcinus Orca) are influenced by the discharge of contaminated waters deriving from wastewater treatment plants. Climate change related processes such as enhanced long-range transport, re-emissions from secondary sources and shifts in migration habits could lead to greater exposure and accumulation of PBDEs in cetaceans, above all in those species living in the Arctic. In addition, increased rainfall could carry greater amount of contaminants to the marine environment, thereby, enhancing the exposure and accumulation especially for coastal species. Synergic effects of all these factors and ongoing emissions of PBDEs, expected to continue at least until 2050, could increase the degree of exposure and menace for cetacean populations. In this regard, it is necessary to improve current regulations on PBDEs and broader the knowledge about their toxicological effects, in order to assess health risks and support regulatory protection for cetacean species. | Halogenated Diphenyl Ethers |
BACKGROUND: Transcription factor GA-binding protein (GABP) is suggested to be involved in the formation of the neuromuscular junctions by regulating the transcription of synapse genes. Interestingly, neurons and podocytes share molecular and functional similarities that led us to investigate the expression and function of GABP in podocytes and its role in transcriptional regulation of nephrin, the key molecule of the podocyte slit diaphragm that is essential for normal glomerular ultrafiltration. METHODS: The expression and localization of GABP in the rat and human kidney as well as in human embryonic kidney A293 cells and undifferentiated and differentiated human podocytes were analysed by immunoblotting and immunostaining. The role of GABP in activating the nephrin promoter was investigated by reporter gene assay and site-directed mutagenesis of the GABP-binding elements, and the interaction of GABP with the nephrin promoter was analysed by chromatin immunoprecipitation. The function of GABP in podocytes was studied by knocking down GABPalpha in differentiated human podocytes using lentiviral shRNA targeting GABPalpha. RESULTS: GABP is expressed in the nuclei in rat and human glomeruli. In addition, in A293 cells and undifferentiated and differentiated human podocytes, GABP highly enriches in the nucleus. GABP activates and binds nephrin proximal promoter and Ets sites are essential for this activity. Knock-down of GABPalpha stimulates apoptosis in cultured podocytes. CONCLUSIONS: The results show that GABP is expressed in podocytes and is involved in the regulation of nephrin gene expression. Furthermore, GABP may be important in the maintenance of podocyte function by regulating apoptosis." | GA-Binding Protein Transcription Factor |
System B(0) activity accounts for the majority of intestinal and kidney luminal neutral amino acid absorption. An amino acid transport system, called ATB(0) (also known as ASCT2), with functional characteristics similar to those of system B(0), has been recently cloned. We generated polyclonal antibodies to human and rabbit ATB(0) COOH-terminal peptides and used Western blot analysis to detect ATB(0) protein in rabbit tissues, rabbit ileal brush-border membrane vesicles (BBMV), and HeLa cells transfected with plasmids containing ATB(0) cDNAs. Immunohistochemistry was used to localize ATB(0) in rabbit kidney and intestine. In Western blots of rabbit tissues, ATB(0) was a broad smear of 78- to 85-kDa proteins. In transfected HeLa cells, ATB(0) appeared as a smear consisting of 57- to 65-kDa proteins. The highest expression was found in the kidney. ATB(0) was enriched in rabbit ileal BBMV and in HeLa cells transfected with ATB(0) cDNAs. In the kidney and in the intestine, ATB(0) was confined to the brush-border membrane (BBM) of the proximal tubular cell and of the enterocyte, respectively. Tissue and intracellular distribution of ATB(0) protein parallels that of system B(0) activity. ATB(0) protein could be the transporter responsible for system B(0) in the BBM of epithelial cells." | Amino Acid Transport System ASC |
Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on beta-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual beta-cell function in type 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1beta + IFNgamma + TNFalpha) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several of the 11 candidate genes have overlapping biological functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment. | Genetic Load |
BACKGROUND: Elymus nutans Griseb., is an important alpine perennial forage of Pooideae subfamily with strong inherited cold tolerance. To get a deeper insight into its molecular mechanisms of cold tolerance, we compared the transcriptome profiling by RNA-Seq in two genotypes of Elymus nutans Griseb. the tolerant Damxung (DX) and the sensitive Gannan (GN) under cold stress. RESULTS: The new E. nutans transcriptomes were assembled and comprised 200,520 and 181,331 transcripts in DX and GN, respectively. Among them, 5436 and 4323 genes were differentially expressed in DX and GN, with 170 genes commonly expressed over time. Early cold responses involved numerous genes encoding transcription factors and signal transduction in both genotypes. The AP2/EREBP famliy of transcription factors was predominantly expressed in both genotypes. The most significant transcriptomic changes in the later phases of cold stress are associated with oxidative stress, primary and secondary metabolism, and photosynthesis. Higher fold expressions of fructan, trehalose, and alpha-linolenic acid metabolism-related genes were detected in DX. The DX-specific dehydrins may be promising candidates to improve cold tolerance. Twenty-six hub genes played a central role in both genotypes under cold stress. qRT-PCR analysis of 26 genes confirmed the RNA-Seq results. CONCLUSIONS: The stronger transcriptional differentiation during cold stress in DX explains its better cold tolerance compared to GN. The identified fructan biosynthesis, alpha-linolenic acid metabolism, and DX-specific dehydrin-related genes may provide genetic resources for the improvement of cold-tolerant characters in DX. Our findings provide important clues for further studies of the molecular mechanisms underlying cold stress responses in plants. | Elymus |
We report copper(II) arsenite (CuAS)-integrated polymer micelles (CuAS-PMs) as a new class of Fenton-like catalytic nanosystem that can display reactive oxygen species (ROS)-manipulating anticancer therapeutic activity. CuAS-PMs were fabricated through metal-catechol chelation-based formation of the CuAS complex on the core domain of poly (ethylene glycol)-b-poly(3,4-dihydroxy-L-phenylalanine) (PEG-PDOPA) copolymer micelles. CuAS-PMs maintained structural robustness under serum conditions. The insoluble state of the CuAS complex was effectively retained at physiological pH, whereas, at endosomal pH, the CuAS complex was ionized to release arsenite and cuprous Fenton catalysts (Cu(+) ions). Upon endocytosis, CuAS-PMs simultaneously released hydrogen peroxide (H(2)O(2))-generating arsenite and Fenton-like reaction-catalyzing Cu(+) ions in cancer cells, which synergistically elevated the level of highly cytotoxic hydroxyl radicals (*OH), thereby preferentially killing cancer cells. Animal experiments demonstrated that CuAS-PMs could effectively suppress the growth of solid tumors without systemic in vivo toxicity. The design rationale of CuAS-PMs may provide a promising strategy to develop diverse oxidative stress-amplifying agents with great potential in cancer-specific therapy. | Arsenites |
The three-dimensional structure of Salmonella typhimurium orotate phosphoribosyltransferase (OPRTase) in complex with the ribose 5-phosphate donor alpha-D-5--phosphoribosyl-1-pyrophosphate (PRPP) and the nitrogenous base orotic acid has been solved and refined with X-ray diffraction data extending to 2.3 A resolution to a crystallographic R-factor of 18.7%. The complex was generated by carrying out catalysis in the crystal. Comparison of this structure with the previously reported structure of the orotidine 5'-monophosphate (OMP) complex [Scapin, G., Grubmeyer, C., and Sacchettini, J. C. (1994) Biochemistry 33, 1287-1294] revealed that the enzyme backbone undergoes only small movements. The most significant differences occur near the active site, at Ala71-Gly74, with the largest difference involving the side chains of Lys73, Val127-Ala133, the 5'-phosphate binding loop, and a long, solvent-exposed loop at the dimer interface. The position of the ribose moiety is, on the other hand, very different in the OMP and PRPP.orotate complexes, with its anomeric carbon moving approximately 7 A across the binding cavity. In the PRPP.orotate complex the highly conserved acidic side chain of Asp124 interacts with the ribose of PRPP, whereas there are no interactions of this aspartate with the substrate in the OMP complex. | Uridine Monophosphate |
During surgical procedures, abdominal swabs are routinely used to adsorb blood from the operation field and for the retention of tissues and organs. Due to the material characteristics, abdominal swabs exhibit a slight procoagulant activity, which is usually desirable and mostly harmless. However, during cardiac surgery with heart-lung machine (HLM) support, abnormal clot formation may result in life-threatening thromboembolic complications. Therefore, a simple clotting test (SCT) allowing in vitro detection of abdominal swabs with elevated hypercoagulant potency in the presence of heparinized human blood was developed and validated. In order to establish a SCT, heparinized human blood from 100 donors was incubated with five different cotton abdominal swabs for 30 min at 37 degrees C and then macroscopically analyzed. In a second study, 10 other swabs were screened with the established SCT (n=11) to confirm its suitability. Scanning electron microscopy, measurements of activated clotting times and thrombin-antithrombin were further performed. In the SCT, the results are dichotomized as negative (no detectable blood clot) and positive (blood clot formation). In the first study, three of the five tested abdominal swabs exhibited hypercoagulant potency in at least 25% of the donors. Calculations using the binomial distribution showed that blood of 11 donors is needed for routine testing with the SCT, which was confirmed in the second study using another 10 swabs. The established SCT can be used for detection of abdominal swabs with an elevated procoagulant potency, thereby minimizing the risk of thromboembolic complications during cardiac surgery with HLM support. | Equipment Failure Analysis |
The cervical cap was used in artificial insemination (husband) in the home by 63 couples. An overall pregnancy rate of 19% occurred regardless of the duration of use, and a rate of 44% was associated with use for at least six months or until pregnancy occurred. Comparison of pregnancy rates between those in the program and those who dropped out and conceived without therapy revealed no statistical difference. | Insemination |
Attaining true quantitative data from WB requires that all the players involved in the procedure are quality controlled including the user. Appropriate protein extraction method, electrophoresis, and transfer of proteins, immunodetection of blotted protein by antibodies, and the ultimate step of imaging and analyzing the data is nothing short of a symphony. Like with any other technology in life-sciences research, Western blotting can produce erroneous and irreproducible data. We provide a systematic approach to generate quantitative data from Western blot experiments that incorporates critical validation steps to identify and minimize sources of error and variability throughout the Western blot process. | Immunoblotting |
In 2006, the Indonesian government decided to withhold avian flu samples from the World Health Organization. They argued that even though Indonesian samples were crucial to the development of vaccines, the results of vaccine research would be unaffordable for its citizens. Commentaries on the case varied from alleging blackmail to welcoming this strong stance against alleged exploitation. What is clear is that the concern expressed is related to benefit sharing. Benefit sharing requires resource users to return benefits to resource providers in order to achieve justice. One benefit sharing tool within health research is the duty to provide a health care intervention which has been proven to be beneficial (or alternative benefits) to research participants after a study has been concluded. This duty is generally known as a post-study obligation. It was enshrined in the Declaration of Helsinki in 2000 and re-emphasized in 2008. Yet, there are few, if any, examples of good practice. In this article, we analyse the obstacles to giving more bite to benefit sharing provisions in health research through ethical review. We conclude that the provision of post-study access to healthcare interventions is not a promising mechanism when monitored through research ethics committees. Alternative benefit provision is preferable if one focuses on achieving compliance. However, even the latter faces challenges, which we address in specific recommendations. | Helsinki Declaration |
Transcriptional regulation for the genes encoding alpha- and beta-chains of the high-affinity receptor for IgE (FcepsilonRI) have been analyzed in mast cells and regulatory mechanisms are beginning to be elucidated. Transcription factors GATA-1 and PU.1 cooperatively transactivate the alpha-chain gene, and three transcription factors, GATA-1, Oct-1, and MZF-1, are involved in regulation of beta-chain gene expression. No single nucleotide polymorphisms (SNPs) that are functionally related to the allergic diseases have been identified in coding regions of the alpha- and beta-chain genes in a definitive way. However, recent studies on SNPs in the promoter regions have revealed that these genes are probable candidates for new types of allergy-related genes whose transcription levels are affected by transcription factors which discriminate SNPs in the promoters. Another interesting finding on transcription factors functioning in mast cells is that the expression level of PU.1 determines cell fate between mast cells and monocytes. | Receptors, IgE |
Perioral dermatitis is a unique skin disorder of childhood. Its exact origin is unknown; it is probably an idiosyncratic response to exogenous factors such as the use of a topical fluorinated corticosteroid or other substances on the face. It is uncommon but not rare. The age of affected children has ranged from 7 months to 13 years, with the median being in the prepubertal period. Boys and girls, blacks and whites are equally affected. Clinical features include the following: (1) absence of systemic symptoms; (2) periorificial distribution (perioral, perinasal, periorbital); (3) skin lesions that consist of flesh colored or erythematous inflammed papules, micronodules, and rare pustules; and (4) variable pruritus. Laboratory tests are negative. Histologically, it is indistinguishable from rosacea; there is a superficial perifollicular granuloma consisting of epitheliod cells, and lymphohistiocytic infiltrate, with occasional giant cells. The disease waxes and wanes for weeks and months. Treatment consists of discontinuing topical fluorinated corticosteroid use if any, and using topical metronidazole alone or in combination with either oral tetracycline or erythromycin depending on the child's age. A low-potency topical steroid may also be used to suppress the inflammation and to wean off the strong steroid. Perioral dermatitis in childhood is probably a juvenile form of rosacea. | Dermatitis, Perioral |
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