Chemoenzymatic Synthesis of Pleiogenone A: An Antiproliferative Trihydroxyalkylcyclohexenone Isolated from Pleiogynium timorense.
The first total synthesis of polyhydroxylated cyclohexenone 1, isolated from Pleiogynium timorense and named pleiogenone A, is reported that also serves as a proof of structure and absolute configuration. Enzymatic dihydroxylation of benzoic acid with R. eutrophus B9 provided enantiomerically pure diene diol 6. Elaboration of the carboxylate moiety to the alkyl side chain was followed by singlet oxygen cycloaddition to furnish an endoperoxide whose reduction with thiourea led to cyclitol 19. Several protective operations were required before oxidation and the final extension of the side chain by a Wittig reaction. After final deprotection of the acetonide functionality the desired pleiogenone A (1) was obtained in 14 operations from benzoic acid.


A new classification of impacted proximal humerus fractures based on the morpho-volumetric evaluation of humeral head bone loss with a 3D model.
This study aimed to classify the pathomorphology of impacted proximal humeral fractures according to the control volume theory, with the intention to introduce a severity index to support surgeons in decision making. In total, 50 proximal humeral fractures were randomly selected from 200 medical records of adult patients treated from 2009 to 2016. Four nonindependent observers used 2 different imaging modalities (computed tomography scans plus volume rendering; 3D model) to test the classification reliability. A fracture classification system was created according to the control volume theory to provide simple and understandable patterns that would help surgeons make quick assessments. The impacted fractures table was generated based on an evaluation of the calcar condition, determined by the impairment of a defined volumetric area under the cephalic cup and the humeral head malposition. In addition to the main fracture pattern, the comminution degree (low, medium, high), providing important information on fracture severity, could also be evaluated. From 3D imaging, the inter- and intraobserver reliability revealed a k value (95% confidence interval) of 0.55 (0.50-0.60) and 0.91 (0.79-1.00), respectively, for the pattern code, and 0.52 (0.43-0.76) and 0.91 (0.56-0.96), respectively, for the comminution degree. The new classification provides a useful synoptic framework for identifying complex fracture patterns. It can provide the surgeon with useful information for fracture analysis and may represent a good starting point for an automated system.


The effects of putative non-adrenergic, non-cholinergic autonomic transmitters on isolated strips from the stomach of the rainbow trout. Salmo gairdneri.
1. The effects of some putative non-adrenergic, non-cholinergic transmitters have been studied on longitudinal and circular smooth muscle from the stomach of the rainbow trout, Salmo gairdneri. 2. ATP, adenosine and vasoactive intestinal polypeptide (VIP) on certain occasions inhibited the activity of the stomach smooth muscle; ATP and adenosine only circular muscle. VIP both longitudinal and circular muscle. 3. Neurotensin produced a contraction, which in strips from the cardiac stomach in most cases occurred after the exposure to the peptide; this might be a rebound contraction after an inhibition which could not be recorded with the experimental set-up. 4. Bombesin, 5-hydroxytryptamine and substance P produced dose-dependent contractions over a wide dose range. Somatostatin and enkephalin contracted the preparations only in the highest doses tested (10(-9) moles, 10(-8) moles). 5. Atropine did not reduce or abolish the response to any of the substances tested, indicating that their effects are not via cholinergic neurons, which innervate the smooth muscle. 6. Of the substances tested ATP, adenosine, VIP and neurotensin may be involved in the inhibitory vagal non-adrenergic, non-cholinergic innervation of the rainbow trout stomach.


D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking.
Alleles of the human dopamine D(4) receptor (D(4)R) gene (DRD4.7) have repeatedly been found to correlate with novelty seeking, substance abuse, pathological gambling, and attention-deficit hyperactivity disorder (ADHD). If these various psychopathologies are a result of attenuated D(4)R-mediated signaling, mice lacking D(4)Rs (D(4)KO) should be more impulsive than wild-type (WT) mice and exhibit more novelty seeking. However, in our study, D(4)KO and WT mice showed similar levels of impulsivity as measured by delay discounting performance and response inhibition on a Go/No-go test, suggesting that D(4)R-mediated signaling may not affect impulsivity. D(4)KO mice were more active than WT mice in the first 5 min of a novel open field test, suggesting greater novelty seeking. For both genotypes, more impulsive mice habituated less in the novel open field. These data suggest that the absence of D(4)Rs is not sufficient to cause psychopathologies associated with heightened impulsivity and novelty seeking.


Corticoids augment nuclear binding capacity for triiodothyronine in bullfrog tadpole tail fins.
The effect of aldosterone and corticosterone on T3 binding to the nuclear fraction of the tail fin of bullfrog tadpoles was investigated in vitro. Both corticoids (10(-7) - 10(-5) M) added to the incubation medium increased T3 binding in a dose-dependent manner. The aldosterone-induced increase in T3-binding was blocked by cycloheximide, an inhibitor of protein synthesis, and actinomycin D, an inhibitor of RNA synthesis. Scatchard analysis revealed that 10(-6) M aldosterone and corticosterone increased the maximum binding capacity for T3 by 60 and 41%, respectively, and that the corticoids did not alter the value of the dissociation constant. The significance of the finding is discussed in relation to metamorphosis.


Prolactin (PRL) mRNA from human decidua differs from pituitary PRL mRNA but resembles the IM-9-P3 lymphoblast PRL transcript.
The expression of the human prolactin (hPRL) gene is normally restricted to the anterior pituitary and the decidualized endometrium of the uterus. The human B-lymphoblastoid cell line IM-9-P3 ectopically expresses a PRL mRNA which is about 150 nucleotides larger than its pituitary counterpart even though the mature protein products appear identical. In the present study we show that human decidual and IM-9-P3 PRL mRNAs are similar in size, both being elongated relative to the pituitary transcript. The size difference persisted after removal of the 3' end poly(A) tract, whereas the PRL precursors synthesized in a cell-free translation system using mRNAs from the three tissues showed identical apparent molecular weights upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The elongation could therefore not be attributed to differences in the protein coding region or in the degree of polyadenylation and is suggested to reside in the 5' untranslated region of the molecule.


[Prevention of feral rabies in the province of Rome].
This summary briefly describes the work carried out in recent years by the staff of the Province of Rome for prevention of sylvatic rabies.


COVID-19 and trade credit speed of adjustment.
This paper examines the extent to which COVID-19 affects corporate trade credit policy. We find that COVID-19 significantly accelerates US firms' convergency speed toward the target trade credit. In addition, we find that firms subject to higher ex-ante operational risk tend to adjust trade credit toward the target faster than those with fewer risk exposures. Overall, our evidence is consistent with the risk avoidance explanation for trade credit policy changes in the presence of adverse shocks.


Lipoprotein (a) stimulates mitogen activated protein kinase in human mesangial cells.
Evidence suggests an important role of elevated serum lipoproteins in the progression of renal glomerulosclerosis. We report here that lipoprotein (a) (Lp(a)) increased phosphorylation and activity of mitogen activated protein kinase (MAPK) in human mesangial cells. When protein kinase C (PKC) was depleted by long-term incubation with the phorbol 12-O-myristate 13-acetate the effect of Lp(a) on MAPK activation was completely inhibited. Forskolin, a stimulator of the adenylyl cyclase, and dibutyryl-cAMP reduced the effect of Lp(a) on MAPK phosphorylation and activation. We conclude that Lp(a) stimulates the MAPK cascade via activation of PKC and that activation of protein kinase A counteracts Lp(a) induced MAPK activation in human mesangial cells.


AI-predicted mpMRI image features for the prediction of clinically significant prostate cancer.
To evaluate the feasibility of using mpMRI image features predicted by AI algorithms in the prediction of clinically significant prostate cancer (csPCa). This study analyzed patients who underwent prostate mpMRI and radical prostatectomy (RP) at the Affiliated Hospital of Jiaxing University between November 2017 and December 2022. The clinical data collected included age, serum prostate-specific antigen (PSA), and biopsy pathology. The reference standard was the prostatectomy pathology, and a Gleason Score (GS) of 3 + 3 = 6 was considered non-clinically significant prostate cancer (non-csPCa), while a GS ≥ 3 + 4 was considered csPCa. A pre-trained AI algorithm was used to extract the lesion on mpMRI, and the image features of the lesion and the prostate gland were analyzed. Two logistic regression models were developed to predict csPCa: an MR model and a combined model. The MR model used age, PSA, PSA density (PSAD), and the AI-predicted MR image features as predictor variables. The combined model used biopsy pathology and the aforementioned variables as predictor variables. The model's effectiveness was evaluated by comparing it to biopsy pathology using the area under the curve (AUC) of receiver operation characteristic (ROC) analysis. A total of 315 eligible patients were enrolled with an average age of 70.8 ± 5.9. Based on RP pathology, 18 had non-csPCa, and 297 had csPCa. PSA, PSAD, biopsy pathology, and ADC value of the prostate outside the lesion (ADCprostate) varied significantly across different ISUP grade groups of RP pathology (P < 0.001). Other clinical variables and image features did not vary significantly across different ISUP grade groups (P > 0.05). The MR model included PSAD, the ratio of ADC value between the lesion and the prostate outside the lesion (ADClesion/prostate), the signal intensity ratio of DWI between the lesion and the prostate outside the lesion (DWIlesion/prostate), and the ratio of DWIlesion/prostate to ADClesion/prostate. The combined model included biopsy pathology, ADClesion/prostate, mean signal intensity of the lesion on DWI (DWIlesion), DWI signal intensity of the prostate outside the lesion (DWIprostate), and signal intensity ratio of DWI between the lesion and the prostate outside the lesion (DWIlesion/prostate). The AUC of the MR model (0.830, 95% CI 0.743, 0.916) was not significantly different from that of biopsy pathology (0.820, 95% CI 0.728, 0.912, P = 0.884). The AUC of the combined model (0.915, 95% CI 0.849, 0.980) was higher than that of the biopsy pathology (P = 0.042) and MR model (P = 0.031). The aggressiveness of prostate cancer can be effectively predicted using AI-extracted image features from mpMRI images, similar to biopsy pathology. The prediction accuracy was improved by combining the AI-extracted mpMRI image features with biopsy pathology, surpassing the performance of biopsy pathology alone.


Induction and expression of mutations in mammalian cells in the absence of DNA synthesis and cell division.
The induction of mutations by the alkylating agent ethyl methanesulfonate (EMS) was determined with Chinese hamster ovary cells maintained in serum-free medium to arrest DNA synthesis and cell division. The arrested cultures were treated with EMS and maintained in serum-free medium for various time intervals post-treatment before serum containing medium was added to initiate DNA synthesis and cell division. The concentration-dependent increase in 6-thioguanine-resistant mutants in the arrested cultures was similar to that found with exponentially dividing cultures when serum was added to the arrested cultures immediately after the EMS treatment; the time course of phenotypic expression was also similar with both cultures. In addition, maintenance of the arrested cultures in serum-free medium for up to 18 days post-treatment resulted in no change in the mutant frequency. This suggests that the mutagenic damage is not removed in these arrested cultures. Furthermore, maintenance of the arrested state for increasing time intervals before serum addition results in decreases in the time necessary for maximum phenotypic expression. Cultures maintained in serum-free medium for 16 days after mutation treatment show complete expression of the mutations with no need for subculture. This last result suggests that the mutagenic damage induced by EMS in Chinese hamster ovary cells is not removed and that this damage results in both the induction and expression of mutation in the absence of DNA replication.


Histone demethylase JMJD3 at the intersection of cellular senescence and cancer.
Cellular senescence is defined by an irreversible growth arrest and is an important biological mechanism for suppression of tumor formation. Although deletion/mutation to DNA sequences is one mechanism by which cancer cells can escape senescence, little is known about the epigenetic factors contributing to this process. Histone modifications and chromatin remodeling related to the function of a histone demethylase, jumonji domain-containing protein 3 (JMJD3; also known as KDM6B), play an important role in development, tissue regeneration, stem cells, inflammation, and cellular senescence and aging. The role of JMJD3 in cancer is poorly understood and its function may be at the intersection of many pathways promoted in a dysfunctional manner such as activation of the senescence-associated secretory phenotype (SASP) observed in aging.


Bilateral internuclear ophthalmoplegia related to chronic toluene abuse.
A 36-year-old woman exhibited slurred speech, progressive ataxia, blurred vision, and oscillopsia. Examination showed dysconjugate torsional nystagmus and bilateral internuclear ophthalmoplegia (INO). Further investigation revealed evidence of chronic toluene abuse. The neurologic findings in toluene abuse and the causes of bilateral INO are discussed.


The effect of vitamins C and E on biomarkers of oxidative stress depends on baseline level.
Oxidative stress is elevated in obesity, and may be a major mechanism for obesity-related diseases. Nonsmokers (n=396) were randomized to 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Treatment effect was examined in multiple regression analyses using an intention-to-treat approach. Vitamin C (P=0.001) and vitamin E (P=0.043) reduced plasma F2-isoprostanes. In the overall sample, changes from baseline were +6.8, -10.6, and -3.9% for placebo, vitamin C, and vitamin E groups, respectively. However, a significant interaction with baseline F2-isoprostane was found. When baseline F2-isoprostane was >50 microg/mL, vitamin C reduced F2-isoprostane by 22% (P=0.01). Vitamin E reduced it by 9.8% (P=0.46). Below that cut point, neither treatment produced further reductions. F2-isoprostane>50 microg/mL was strongly associated with obesity, and was present in 42% of the sample. Change in malondialdehyde concentration was minimal. These findings suggest a role for vitamin C in reducing lipid peroxidation. Future research on effects of vitamins C or E on plasma F2-isoprostane should limit participants to those with baseline levels >50 mug/mL. Further studies are needed to establish whether treatment with vitamins C or E in persons with concentrations above that cut point could slow the development of cardiovascular disease.


A behavioral analysis of diaphragmatic breathing and its effects on peripheral temperature.
Three young women volunteers were trained through instructional feedback in two breathing procedures: diaphragmatic, derived from Eastern meditative techniques, and thoracic, involving opposite maneuvers. A single-subject reversal design was employed. Physiograph recordings of diaphragmatic expansion and mouth breathing provided the basis for feedback. Peripheral (digital) temperature was time-sampled at 1-min intervals and linear regression lines were fitted to the data. Temperature decreased throughout "normal" (baseline) breathing, probably due to warm outdoor and cool indoor temperatures. For two subjects, temperature during diaphragmatic breathing was generally stable; temperature during thoracic breathing showed significant decreases and did not differ from normal breathing. Within-session reversals showed dramatic changes in temperature as a function of breathing technique, which were maintained at follow-up, for these subjects. Temperature was more labile and decreased regardless of breathing procedure for the third subject. These data support a relationship between respiratory and vasomotor activity, and suggest that breathing strategy may be an uncontrolled variable in temperature biofeedback. It is further suggested that diaphragmatic breathing may facilitate temperature biofeedback or other types of relaxation training.


Submaximal angioplasty and staged stenting for severe posterior circulation intracranial stenosis: a technique in evolution.
Severe medically refractory intracranial stenosis portends a grave prognosis. Recent advances in stent technology have enabled clinicians to treat these lesions. Evidence in the coronary literature suggests that stenting without predilation angioplasty is as safe and effective as stenting immediately preceded by predilation angioplasty for the treatment of severely stenotic lesions. Because of marked differences in vessel histology and differences in the sensitivity of the cerebral and coronary vascular beds to embolic insult, direct stenting of severe intracranial stenoses may be more prone to neurological complications than a conventional or staged stenting procedure. We reviewed our clinical experience with conventional, direct, and staged stenting for high-grade stenoses involving the posterior intracranial circulation. We also reviewed the literature and experimental data supporting the rationale for staged stenting. In our experience, no permanent neurological morbidity was identified in four patients treated with a staged approach. In contrast, one of three patients with conventional stenting of the basilar artery and two of four patients treated with direct basilar stenting had permanent neurological sequelae. For patients with high-grade posterior circulation intracranial stenoses involving the perforator-rich zones of the basilar artery, staged stenting may reduce procedure-related morbidity. A staged approach allows for plaque stabilization resulting from post-angioplasty fibrosis, which may protect patients from "snow-plowing," embolic shower of debris, or dissection. Further clinical, in vivo, and histological investigation is warranted.


Low entropic cost of binding confers high selectivity on an allosteric ERK2 inhibitor.
Extracellular signal-regulated kinase 2 (ERK2), a mitogen-activated protein kinase (MAPK), plays an essential role in physiological cellular processes and is a drug target for treating cancers and type 2 diabetes. A previous in silico screening study focusing on an allosteric site that plays a crucial role in substrate anchoring conferred an ERK2 inhibitor (compound 1). In this report, compound 1 was found to show high selectivity toward ERK2 compared with the nearest off-target p38α MAPK, and the crystal structure revealed that compound 1 binds to the allosteric site of ERK2. Fragment molecular orbital calculations based upon this crystal structure provided the structural basis to improve potency of compound 1 derivatives. Further computational studies uncovered that the low entropic cost of binding conferred the high selectivity of compound 1 toward ERK2 over p38α MAPK. These findings demonstrate the feasibility of developing potent and selective ERK2 inhibitors.


Receptors for insulin and CCK in the acinar pancreas: relationship to hormone action.
These studies, therefore, allow a model of how CCK and insulin regulate the acinar pancreas in a coordinated manner (Fig. 27). CCK, after its secretion by gut cells, interacts with a specific receptor on the cell surface and then increases intracellular free Ca2+. Ca2+, in turn (1) interacts with the secretory granules leading to zymogen release, (2) stimulates protein synthesis, and (3) increases glucose transport. The model is supported on the finding of specific high affinity CCK receptors on acini and by the localization of CCK to the plasma membrane in EM autoradiographs. Insulin, secreted from the pancreatic islets, also interacts with a specific receptor on the cell surface. Either via a messenger generated by this reaction, or via insulin's subsequent direct interaction with intracellular organelles, such as the Golgi-endoplasmic reticulum, protein synthesis is initiated and glucose transport is increased. Then a series of events is initiated to increase cell growth, amylase content, and sensitivity to CCK. These studies, therefore, indicate that the control of acinar cell function is a product of cooperative intrahormonal interactions.


Presence of SH2 domains of phospholipase C gamma 1 enhances substrate phosphorylation by increasing the affinity toward the epidermal growth factor receptor.
src homology region 2 and 3 (SH2 and SH3) domains are conserved noncatalytic regions originally described in cytoplasmic tyrosine kinases and subsequently identified in phospholipase C gamma 1 (PLC gamma 1), GTPase-activating protein of ras, and other signaling proteins. Although numerous studies indicate that SH2 domains promote protein-protein interactions by specific binding to tyrosine phosphorylated proteins, the function of SH3 domains is not known. The SH2 domain of PLC gamma 1 binds to certain tyrosine-phosphorylated growth factor receptors, and following phosphorylation on Tyr783 the enzymatic activity of PLC gamma 1 is enhanced, leading to phosphatidylinositol hydrolysis. To determine the functional role of the SH2 domain(s) on substrate phosphorylation in quantitative terms, we have expressed in Escherichia coli PLC gamma 1 constructs encoding the region containing Tyr783 and Tyr771, their two flanking SH2 domains and the SH3 domain, and five different deletion mutants of this region. These six proteins were purified and subjected to quantitative phosphorylation by the epidermal growth factor receptor (EGFR). Analysis of the kinetics of substrate phosphorylation revealed similar Vmax for the phosphorylation of the various mutant proteins. However, the affinity was enhanced for substrates containing SH2 domains: from S0.5 (average apparent Km) of 110 microM to S0.5 of 20 microM with the addition of a single SH2 domain and S0.5 of 3-4 microM for mutants containing two SH2 domains. The presence of the SH3 domain did not influence the apparent Km of substrate phosphorylation. These results demonstrate that the presence of the SH2 domain in PLC gamma 1 lowers the apparent Km (increases the affinity) of substrate phosphorylation by the EGFR, thereby facilitating PLC gamma 1 phosphorylation and activation.


Hydrolysis of oligosaccharides from distillers grains using organic-inorganic hybrid mesoporous silica catalysts.
The use of propylsulfonic acid-functionalized mesoporous silica as a catalyst for the hydrolysis of oligosaccharides released by hydrothermal pretreatment of distiller's grains was examined in batch reactor studies. The effectiveness of the catalyst system for oligosaccharide hydrolysis was found to improve significantly with increased reaction temperature. This higher temperature operation allowed for more selective recovery of glucose, but was detrimental to arabinose recovery since significant degradation occurred. Xylose recovery efficiency improved with increasing temperature, but the higher temperature led to increased degradation. Using a model feed, solubilized proteins were found to deactivate the organic-inorganic hybrid catalyst, but a simple pretreatment with activated silica was found to alleviate the deactivation.


COVID-19-associated-mucormycosis: possible role of free iron uptake and immunosuppression.
COVID-19-associated-mucormycosis, commonly referred to as the "Black Fungus," is a rare secondary fungal infection in COVID-19 patients prompted by a group of mucor molds. Association of this rare fungal infection with SARS-CoV-2 infection has been declared as an endemic in India, with minor cases in several other countries around the globe. Although the fungal infection is not contagious like the viral infection, the causative fungal agent is omnipresent. Infection displays an overall mortality rate of around 50%, with many other secondary side effects posing a potential threat in exacerbating COVID-19 mortality rates. In this review, we have accessed the role of free iron availability in COVID-19 patients that might correlate to the pathogenesis of the causative fungal agent. Besides, we have analyzed the negative consequences of using immunosuppressive drugs in encouraging this opportunistic fungal infection.


The outcomes and prognostic factors of patients with hepatocellular carcinoma and Child-Turcotte-Pugh class B.
The Child-Turcotte-Pugh (CTP) score is widely used for assessing the liver's functional reserve in patients with advanced chronic liver disease (ACLD) and hepatocellular carcinoma (HCC). This study aims to explore the outcomes of patients with HCC and CTP class B and to investigate the prognostic accuracy of prediction models for ACLD in these patients. We retrospectively enrolled 1143 patients with HCC and CTP class B between 2007 and 2022. We divided the patients into three subgroups based on their CTP scores: CTP-B7, CTP-B8, and CTP-B9. We compared the corrected Akaike information criterion among each mortality prediction model, including the CTP score, albumin-bilirubin (ALBI) score, modified ALBI score, the model for end-stage liver disease (MELD), and MELD 3.0. Among the enrolled patients, 576 (50.3%) were in the CTP-B7 group, 363 (31.8%) were in the CTP-B8 group, and 204 (17.9%) were in the CTP-B9 group. After a median follow-up of 4.6 months (interquartile range IQR 1.8-17.2 months), 963 patients died, and the 5-year overall survival (OS) rate was 11.4%. The 5-year OS rates were 11.6%, 13.6%, and 8.3% in the CTP-B7, CTP-B8, and CTP-B9 groups, respectively. Patients in the CTP-B7 group and CTP-B8 group had comparable OS ( p = 0.089), both of which were better than those in the CTP-B9 group ( p < 0.001). Furthermore, the MELD 3.0 score had the lowest corrected akaike information criteria value and provided a more accurate mortality prediction than the MELD score, ALBI grade, modified ALBI grade, and CTP score. Patients in the CTP-B7 and CTP-B8 groups had comparable OS, both of which were better than those in the CTP-B9 group. Moreover, MELD 3.0 provided the most accurate mortality prediction in patients with HCC and CTP class B.


Downregulation of hsa-miR-203 in peripheral blood and wound margin tissue by negative pressure wound therapy contributes to wound healing of diabetic foot ulcers.
Negative pressure wound therapy (NPWT) has been widely used in the treatment of chronic wounds, including diabetic foot ulcers (DFU) as the severe manifestation of diabetic foot. Hsa-miR-203 is proven to be correlated with the severity of DFU. To investigate whether NPWT influences hsa-miR-203 levels in persons with DFU, we detected hsa-miR-203 levels in peripheral plasma and wound margin tissue from the following patients: type 2 diabetic (T2D) patients with DFU (DFU group), T2D patients without DFU (NDFU group), patients with chronic skin ulcer and normal glucose tolerance (SUC group), and healthy volunteers with normal glucose tolerance (NC group). All patients in SUC group received NPWT. As contrast, some of patients in DFU group received NPWT (NPWT group) while others chose routine dressing therapy (non-NPWT group). In vitro experiments were also performed to determine influences of negative pressure on cell proliferation and migration of HaCaT cells (human keratinocytes). Results showed that before NPWT, levels of hsa-miR-203 in peripheral plasma (P-miR-203) and wound margin tissue (T-miR-203) of DFU group were obviously increased compared to SUC group while expression of P-miR-203 decreased in NDFU group compared with NC group. After NPWT, levels of P-miR-203 and T-miR-203 in DFU and SUC group were significantly lower than before. Changes of P-miR-203 and T-miR-203 after NPWT were positively correlated with 4-week ulcer healing rate in NPWT and SUC group. In vitro, negative pressure lowered the expression of hsa-miR-203, enhancing cell proliferation and migration in HaCaT cells via up-regulation of p63 protein. Meanwhile, the effects of negative pressure on cells were remarkable reduced by high-glucose intervention. Our study suggests that NPWT promotes DFU healing by reducing the expression of hsa-miR-203 in peripheral blood and wound tissue. The changes of hsa-miR-203 in peripheral blood and wound tissue may be related to the therapeutic effect of NPWT.


ProCS15: a DFT-based chemical shift predictor for backbone and Cβ atoms in proteins.
We present ProCS15: a program that computes the isotropic chemical shielding values of backbone and Cβ atoms given a protein structure in less than a second. ProCS15 is based on around 2.35 million OPBE/6-31G(d,p)//PM6 calculations on tripeptides and small structural models of hydrogen-bonding. The ProCS15-predicted chemical shielding values are compared to experimentally measured chemical shifts for Ubiquitin and the third IgG-binding domain of Protein G through linear regression and yield RMSD values of up to 2.2, 0.7, and 4.8 ppm for carbon, hydrogen, and nitrogen atoms. These RMSD values are very similar to corresponding RMSD values computed using OPBE/6-31G(d,p) for the entire structure for each proteins. These maximum RMSD values can be reduced by using NMR-derived structural ensembles of Ubiquitin. For example, for the largest ensemble the largest RMSD values are 1.7, 0.5, and 3.5 ppm for carbon, hydrogen, and nitrogen. The corresponding RMSD values predicted by several empirical chemical shift predictors range between 0.7-1.1, 0.2-0.4, and 1.8-2.8 ppm for carbon, hydrogen, and nitrogen atoms, respectively.


Stacking interaction study of trans-resveratrol (trans-3,5,4'-trihydroxystilbene) in solution by Nuclear Magnetic Resonance and Fourier Transform Infrared Spectroscopy.
Interactions between aromatic rings or other unsaturated systems, including pi-stacking and face-to-edge complexes, are the origin of many phenomena in both organic and biological chemistry. It is well known that these interactions play an important role in the stabilization of the stereo-structure of DNA and the tertiary structure of many proteins.Trans-resveratrol (trans-3,5,4'-trihydroxystilbene, trans-RSV) is a phytoalexin found in Vitis sp. and in many other plants and food products and has received much attention because of its possible positive health benefits. In this work, the pi-stacking interaction of trans-RSV was studied by nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy. In particular, the proton chemical shift dependence of the RSV concentration in the range 2 x 10(-2) - 1 x 10(-5) M and temperature were analysed. Moreover, the dynamics of the supramolecular aggregates were studied by nuclear spin relaxation data.


Multi-Probe RFA vs. Single-Probe MWA in an Ex Vivo Bovine Liver Model: Comparison of Volume and Shape of Coagulation Zones.
To compare the volumes and shapes of the coagulation zone (CZ) of a multi-probe RFA system (three RFA electrodes) and a single-probe MWA system from the same vendor in an ex vivo bovine liver model. A total of 48 CZs were obtained in bovine liver specimens with three different ablation system configurations (single-probe MWA vs. multi-probe RFA with 20 mm inter-probe distance [confluent CZ] vs. multi-probe RFA with 50 mm inter-probe distance [three individual CZs]) at 4, 6, 8, and 10 min ablation time using a fixed ablation protocol. Ablation diameters were measured and ellipticity indices (EIs) and volumes calculated. Calculations for all systems/configurations were compared. Volumes and diameters increased with ablation time for all configurations. At 4 and 6 min ablation time volumes obtained with the RFA 50 mm setup, and at 8 and 10 min with the RFA 20 mm setup were the largest at 26.5 ± 4.1 mL, 38.1 ± 5.8 mL, 46.3 ± 4.9 mL, 48.4 ± 7.3 mL, respectively. The single-probe MWA could not reach the volumes of the RFA setups for any of the ablation times evaluated. EI were very similar and almost round for RFA 20 mm and single-probe MWA, and differed significantly to the more ovoid ones for the RFA 50 mm configuration. The multi-probe RFA system employing three electrodes achieved significantly larger ablation volumes in both configurations (confluent CZ and three individual CZs) per time as compared with a single-probe MWA system in this ex vivo bovine liver model.


A novel acyl-CoA-binding protein from bovine liver. Effect on fatty acid synthesis.
Bovine liver was shown to contain a hitherto undescribed medium-chain acyl-CoA-binding protein. The protein co-purifies with fatty-acid-binding proteins, but was, unlike these proteins, unable to bind fatty acids. The protein induced synthesis of medium-chain acyl-CoA esters on incubation with goat mammary-gland fatty acid synthetase. The possible function of the protein is discussed.


Nifedipine suppressed atherosclerosis in cholesterol-fed rabbits but not in Watanabe heritable hyperlipidemic rabbits.
We studied the effects of nifedipine, a calcium antagonist, on atherosclerosis in cholesterol-fed rabbits and Watanabe heritable hyperlipidemic rabbits (WHHL rabbits). Japanese White rabbits were fed 120g of 2% cholesterol rabbit chow daily, and WHHL rabbits were fed standard rabbit chow. In each experiment, the rabbits were divided into two groups. Twenty milligrams of nifedipine was given orally twice a day to the nifedipine group, and the control group was given a placebo in the same way. The rabbits were sacrificed at the end of the 12th week in the case of cholesterol-fed rabbits, and the 20th week in the case of WHHL rabbits. Among the cholesterol-fed rabbits, the percentage of aortic intimal surface area covered by atherosclerotic lesions (AS%) was 25.9 +/- 7.6% (mean +/- S.D.) in the nifedipine group (n = 7), and 55.6 +/- 22.8% in the placebo group (n = 8) (p less than 0.01). The cholesterol content of thoracic and abdominal aorta in the nifedipine group was lower than those in the placebo group (p less than 0.05). Among the WHHL rabbits, the AS% was 33.4 +/- 14.1% in the nifedipine group (n = 5), and 27.0 +/- 11.7% in the placebo group (n =6) (n.s.). The aortic cholesterol and calcium contents also showed no significant differences between the two groups. We concluded that nifedipine suppressed atherosclerosis in cholesterol-fed rabbits but not in WHHL rabbits. The different responses suggest that the effect of nifedipine could be mediated by low density lipoprotein receptors or that the early exposure to hyperlipidemic serum from birth might affect cell functions of WHHL rabbits.


Postnatal development of serotonin in adrenal medullary cells.
The ontogeny of serotonin in the chromaffin cells of the adrenal medulla in rats from 1 to 48 days of age was studied using immunocytochemical and biochemical methods. Using indirect antibody enzyme PAP method on glycol methacrylate embedded sections, serotonin-immunostaining was evident as distinct granules in medullary cells already at one day of age. Serotonin was present in cells prior to complete maturation as was evident by immunostaining in medullary cells which had not yet migrated into a central medulla and in mitotic cells. However, no immunostaining was observed in the chromaffin precursor cells which were evident through 8 days of age or in ganglion cells. A progressive increase in the number of immunoreactive cells and the amount of serotonin-immunostaining per cell was observed between 1 and 12 days of age. After 12 days of age the serotonin-immunostaining appeared adultlike in distribution. Quantitative determination of the adrenal serotonin content by HPLC-EC substantiated the immunocytochemical observations. While serotonin was present at a concentration of approximately 10 mumoles/kg adrenal weight, the total content increased progressively with age (1.24 +/- 0.01 X 10(-11) moles at one day to 10.00 +/- 1.00 X 10(-11) moles at 48 days of age). Dopamine, norepinephrine and epinephrine were measured and also increase with age. In conclusion, like the catecholamines, serotonin is already present in adrenal medullary cells at day one neonatally and the indoleamine and catecholamines show essentially a parallel development.


HDL cholesterol in cardiovascular diseases: the good, the bad, and the ugly?
Atherosclerotic cardiovascular diseases are the leading cause of death in developed and developing countries. HDL-raising therapeutic modalities (such as cholesterol ester transferase protein (CETP) inhibitors) are being developed to combat these diseases. However, recent setback of two CETP inhibitors (Torcetrapib and Dalcetrapib) has highlighted the importance of measuring qualitative functionality of HDL particles, rather than focusing quantitatively on HDL cholesterol serum concentrations. It has been known that, HDL from patients with coronary artery disease (CAD) (i.e., HDL(CAD)) limits the anti-inflammatory and endothelial repair properties of normal HDL, due to the activation of lectin-like oxidized LDL receptor-1 (LOX-1), thereby causing failure in endothelial nitric oxide (NO) production. A more recent study (Immunity 2013; 38: 754-768) also demonstrates that HDL from patients with chronic kidney dysfunction (CKD) (i.e., HDL(CKD)), unlike its healthy counterpart (i.e., HDL(Healthy)), promotes superoxide production, reduces NO bioavailability and raises blood pressure via toll-like receptor-2 (TLR-2) activation. This study provides novel insights into understanding why HDL-raising agents failed to demonstrate beneficial effects on cardiovascular mortality in large clinical trials and why CKD accelerates the development of atherosclerosis in CAD patients. Further research is warranted to elucidate whether HDL(CKD) and HDL(CAD) participate in other cellular processes in atherosclerosis, such as foam cell formation, the proliferation and migration of smooth muscle cells, and most importantly, plaque destabilization.


[Hipersensibility to red tattoo ink, review of a case].
The hypersensitivity reaction associated with tattoo ink and its management represent a growing challenge, despite having precedents in diagnostic and treatment experience in other reports or case series in recent decades, no one has been found homogeneous offer that is effective and safe. Therefore, a review is presented with what has been described in pathophysiological theories, as well as therapeutic proposals and the response found in related cases that have been reported to date. 30-year-old male, with dermatosis located on the right upper extremity, affecting the inner side of the forearm and the outer side of the arm, unilateral, asymmetric, monomorphic in appearance, made up of an artificial macula, caused by red ink (tattoo), with development of papular-like lesions in original trace, pruritic, referred evolution time of one month. Tattoo completion time of 5 and 2 years on the outer side of the right arm and inner side of the ipsilateral forearm, respectively. According to antecedents in other reports and case series, including the experience of our patient, there is no proven efficacy with the use of topical immunomodulators, in turn, patients who shows complete improvement until the elimination of the allergen, either from excisional or laser.


Dynameric asymmetric membranes for directional water transport.
Hydrophilic/hydrophobic dynamers prepared via template partial phase segregation have been used in the formation of asymmetric membranes for directional water transport.


Cell-specific envelope glycosylation distinguishes FIV glycoproteins produced in cytopathically and noncytopathically infected cells.
Feline immunodeficiency virus (FIV) infection induces syncytium formation and cell death in primary feline astrocyte cultures but persistently and noncytopathically infects Crandell feline kidney cells (CrFK). Because viral envelope glycoproteins are implicated in cell fusion events we evaluated the astrocyte-produced FIV surface glycoprotein for properties that might distinguish it from that produced in CrFK cells. The surface glycoprotein from astrocytes migrated faster on SDS-PAGE and contained more Endo H-sensitive oligosaccharides than that from CrFK, although the precursor and deglycosylated envelope glycoproteins from both cells were the same size. Castanospermine treatment of infected astrocytes, which blocks glucose trimming from oligosaccharide side chains of glycoproteins, both obliterated the mobility difference between astrocyte- and CrFK-produced FIV surface glycoproteins and prevented syncytium in infected astrocyte cultures. These results demonstrate the importance of the infected cell type in viral envelope protein glycosylation and implicate cell type-specific carbohydrate structures on retroviral glycoproteins as mediators of cell fusion.


Telehealth-supported level 2 pediatric home polysomnography.
The gold standard for diagnosis of pediatric obstructive sleep apnea (OSA) is level 1 polysomnography (PSG). At our centre, some children are selected for unattended level 2 home sleep apnea testing (HSAT) with telehealth support, and we sought to review this home service. A retrospective audit was conducted from 2013 to 2020. All level 2 HSAT reports in children aged 5-18 years referred for suspected OSA were analyzed. American Academy of Sleep Medicine-compliant portable PSG acquisition equipment with electroencephalogram was used. The primary outcome was the proportion of technically successful tests achieved, and of these, the percentage with potential underestimation of diagnostic category. Secondary outcomes included sleep quality and parental acceptance by nonvalidated service-specific questionnaire. Data were analyzed using descriptive and inferential statistics. χ2 tests were used for categorical variables. There were 233 (139 male, 59.6%) patients studied between 2013 and 2020 (7 years). The mean age was 10.8 (standard deviation 3.6) years. Sixty-seven patients (28.8%) had comorbidities. Technically successful studies were obtained in almost 90% (209/233) and failed studies occurred in just over 10% (24/233). One failed study still achieved a diagnosis. There was no significant difference between failed studies set up by hospital-in-the-home nurses compared with sleep scientists (P = .2). Overall, an accurate diagnosis was made in 80% (167/209) of patients, with potential for underestimation in 20% (42/209). Six hours or more of sleep was obtained in 89.5%. Parental questionnaires revealed 89.3% perceived high-level care, 91% perceived increased convenience, and 76% perceived good/excellent telehealth support. Telehealth-supported pediatric HSAT achieves technical success in almost 90% of patients investigated for OSA, with 89.5% achieving ≥ 6 hours sleep duration and excellent family acceptability. Griffiths A, Mukushi A, Adams A-M. Telehealth-supported level 2 pediatric home polysomnography. J Clin Sleep Med. 2022;18(7):1815-1821.


Path to posttraumatic growth: The role of centrality of event, deliberate and intrusive rumination, and self blame in women victims and survivors of intimate partner violence.
Increased interest in positive changes in the aftermath of traumatic events led researchers to examine assumptions about the process of posttraumatic growth (PTG). However, existing studies often use samples from mixed trauma survivors and investigate separate factors and their associations with growth. Therefore, the purpose of the current study was to examine the path from centrality of event to PTG involving intrusive and deliberate rumination and self-blame as a coping strategy in women survivors of intimate partner violence (IPV). The study sample consisted of 200 women with a history of IPV (ages 18-69, M = 44.79, SD = 12.94). Results of the path analysis indicated that higher centrality of event was related to higher levels of intrusive rumination which was positively related to self-blame and deliberate rumination eventually leading to PTG. Indirect effects from centrality of event to PTG through intrusive and deliberate rumination, and from intrusive to deliberate rumination through self-blame were examined. This study gave support to some theoretical assumptions of the process of PTG and pointed out problematic areas of investigation of coping strategies in this process.


Patient safety concerns arising from test results that return after hospital discharge.
Failure to relay information about test results pending when patients are discharged from the hospital may pose an important patient-safety problem. Few data are available on the epidemiology of test results pending at discharge or on physician awareness of these results. To determine the prevalence, characteristics, and physician awareness of potentially actionable laboratory and radiologic test results returning after hospital discharge. Cross-sectional study. Two tertiary care academic hospitals. 2644 consecutive patients discharged from hospitalist services from February to June 2004. The main outcomes were the prevalence and characteristics of potentially actionable test results returning after hospital discharge, awareness of these results by inpatient and primary care physicians, and satisfaction of inpatient physicians with current systems for follow-up on test results. The authors prospectively collected data on test results pending at the time of discharge and, as results returned after discharge, surveyed hospitalists, junior residents, and primary care physicians about those results that were potentially actionable according to a physician-reviewer. A total of 1095 patients (41%) had 2033 test results return after discharge. Of these results, 191 (9.4% [95% CI, 8.0% to 11.0%]) were potentially actionable. Surveys were sent regarding 155 results, and 105 responses were returned. Of the 105 results in the surveys with responses, physicians had been unaware of 65 (61.6% [CI, 51.3% to 70.9%]); of these 65, they agreed with physician-reviewers that 24 (37.1% [CI, 25.7% to 50.2%]) were actionable and 8 (12.6% [CI, 6.4% to 23.3%]) required urgent action. Inpatient physicians were dissatisfied with their systems for following up on test results returning after discharge. The authors were unable to determine whether physicians' lack of awareness of test results returning after discharge was associated with adverse outcomes. Many patients are discharged from hospitals with test results still pending, and physicians are often unaware of potentially actionable test results returning after discharge. Further work is needed to design better follow-up systems for test results returning after hospital discharge.


Lymphomas of the upper GI tract: the role of radiotherapy.
The most common site of extra-nodal non-Hodgkin's lymphoma (NHL) is the gastrointestinal tract, of which the stomach is the most common site. With the exception of extra-nodal marginal zone lymphoma of gastric mucosa-associated lymphoid tissue (MALT), where excellent long term results can be achieved by radiotherapy, the published literature lacks high quality studies evaluating the role, optimal dose and technique of such treatment in the management of gastro-intestinal lymphoma. Non-randomised studies support organ preservation and a role for local radiotherapy in gastric lymphoma.


Approach to Abnormal Chest Computed Tomography Contrast Enhancement in the Hospitalized Patient.
This article describes an approach to analyzing the distribution of intravenous contrast on chest computed tomography and illustrates the various pathologies and pitfalls that may be encountered by the imager, especially in the hospitalized patient. Understanding normal and abnormal distribution of intravenous contrast can be used as a clue to detect alterations in physiology and flow.


Exercise quantity-dependent muscle hypertrophy in adult zebrafish (Danio rerio).
Exercise is very important for maintaining and increasing skeletal muscle mass, and is particularly important to prevent and care for sarcopenia and muscle disuse atrophy. However, the dose-response relationship between exercise quantity, duration/day, and overall duration and muscle mass is poorly understood. Therefore, we investigated the effect of exercise duration on skeletal muscle to reveal the relationship between exercise quantity and muscle hypertrophy in zebrafish forced to exercise. Adult male zebrafish were exercised 6 h/day for 4 weeks, 6 h/day for 2 weeks, or 3 h/day for 2 weeks. Flow velocity was adjusted to maximum velocity during continual swimming (initial 43 cm/s). High-speed consecutive photographs revealed that zebrafish mainly drove the caudal part. Additionally, X-ray micro computed tomography measurements indicated muscle hypertrophy of the mid-caudal half compared with the mid-cranial half part. The cross-sectional analysis of the mid-caudal half muscle revealed that skeletal muscle (red, white, or total) mass increased with increasing exercise quantity, whereas that of white muscle and total muscle increased only under the maximum exercise load condition of 6 h/day for 4 weeks. Additionally, the muscle fiver size distributions of exercised fish were larger than those from non-exercised fish. We revealed that exercise quantity, duration/day, and overall duration were correlated with skeletal muscle hypertrophy. The forced exercise model enabled us to investigate the relationship between exercise quantity and skeletal muscle mass. These results open up the possibility for further investigations on the effects of exercise on skeletal muscle in adult zebrafish.


Clinical efficacy of diclofenac sodium on postsurgical inflammation after intraocular lens implantation.
We investigated the anti-inflammatory effects of 0.1% diclofenac sodium on anterior inflammation after cataract surgery. Fibrin precipitation after surgery in patients without systemic or ocular disease was markedly less when diclofenac sodium ophthalmic solution was used in combination with topical corticosteroids. There was also a reduction in fibrin precipitation in other patients, especially in those with diabetes mellitus, primary angle-closure glaucoma, and exfoliation syndrome. In conclusion, diclofenac sodium was shown to be clinically useful as a topical preparation to suppress inflammation after cataract surgery.


Quorum sensing in different subcommunities becomes the key factor affecting the humification of the aerobic composting system with sauerkraut fermentation wastewater.
Aerobic composting is an effective and harmless method to treat Sauerkraut fermentation wastewater (SFW). Given the limited understanding of the effect of quorum sensing (QS) on humification in subcommunities under acidic environments, a large-scale analysis was conducted to identify features that impact the response of QS to humification in different subcommunities. The results showed that the addition of SFW directly affected humification in subcommunities A and C, and the abundances of functional genes related to carbon fixation and carbon degradation were significantly increased at 7 and 15 d, respectively. In addition, subcommunity B indirectly affected humus production but regulated carbon metabolic pathways such as glycolysis/gluconeogenesis and pentose phosphate by QS with subcommunities B. These findings provide a novel perspective for analysing the regulation of humification in aerobic composting and suggest that composting has potential applications in organic wastewater treatment.


Recycling of waste lithium-ion batteries via a one-step process using a novel deep eutectic solvent.
Deep eutectic solvents (DESs) possess excellent solubility and selectivity, making them suitable for extracting valuable metals and serving as a green alternative in the recycling process. This work introduces a low-viscosity DES consisting of dimethylthetin, oxalic acid, and water for the comprehensive recovery of cathode materials from LIBs. Leaching parameters such as ratio (1:1), leaching temperature (60 °C), and reaction time (15 min) for were systematically optimized, resulting in a selective separation efficiency of 99.98 % for lithium ions. Furthermore, in-situ regeneration of the precursor can be achieved during the leaching process. Charge-discharge tests indicate that the initial charge and discharge capacities of the regenerated battery are 166.8 mAh/g and 138.4 mAh/g, respectively. The DES demonstrates stability and can be easily recycled by replenishing the consumed components. This proposed strategy facilitates the reintroduction of nonrenewable resources into the supply chain and reduces the environmental impact of heavy metals, aligning with the principles of a circular economy.


The cost of hospitalisation for youth self-harm: differences across age groups, sex, Indigenous and non-Indigenous populations.
To report the comparative rates, average length of stay and cost per episode of hospital management for self-harm in three age cohorts: 15-19 years, 20-24 years and 25-29 years; by sex and indigeneity. A secondary data analysis of the Australian Institute of Health and Welfare (AIHW) dataset between 1st January 2014 and 31st December 2014 inclusive. Cost per episode of hospitalised self-harm and rates by age group, sex and Indigenous status. The rate of hospitalised self-harm among Australian youth was 254.0 per 100,000 population. This rate resulted in an annual cost to the healthcare system of AU$55 million or an average cost per episode of $4649 (95% CI $4488:$4810). Hospitalised self-harm was 21 times higher than the rate of suicide (11,820 episodes of hospitalised self-harm/564 suicides). Indigenous youth had on average a 1.4 times higher rate of hospitalised self-harm and 2.2 times higher rate of suicide than non-Indigenous counterparts. When controlling for age and sex, the average cost per episode was significantly lower for Indigenous youth compared to non-Indigenous youth, estimated marginal means $4538 and $4954, respectively (p < 0.001). Hospitalised self-harm among Australian youth resulted in a substantial cost to the healthcare system. This cost is only part of the overall burden associated with self-harm. The rate of hospitalised self-harm was significantly higher in Indigenous youth, but the associated cost per episode was significantly lower.


Platinum in PM2.5 of the metropolitan area of Mexico City.
The increase in platinum (Pt) in the airborne particulate matter with size ≤2.5 µm (PM2.5) in urban environments may be interpreted as result of the abrasion and deterioration of automobile catalyst. Nowadays, about four million vehicles in Mexico City use catalytic converters, which means that their impact should be considered. In order to evaluate the contribution of Pt to environmental pollution of the metropolitan area of Mexico City (MAMC), airborne PM2.5 was collected at five different sites in the urban area (NW, NE, C, SW, SE) in 2011 during April (dry-warm season), August (rainy season) and December (dry-cold season). Analytical determinations were carried out using a ICP-MS with a collision cell and kinetic energy discrimination. The analytical and instrument performance was evaluated with standard road dust reference material (BCR-723). Median Pt concentration in the analyzed particulate was is 38.4 pg m(-3) (minimal value 1 pg m(-3) maximal value 79 pg m(-3)). Obtained Pt concentrations are higher than those reported for other urban areas. Spatial variation shows that SW had Pt concentration significantly higher than NW and C only. Seasonal variation shows that Pt median was higher in rainy season than in both dry seasons. A comparison of these results with previously reported data of PM10 from 1991 and 2003 in the same studied area shows a worrying increase in the concentration of Pt in the air environment of MAMC.


Base-Controlled Diastereoselective Synthesis of Either anti- or syn-β-Aminonitriles.
Deprotonation of secondary alkane nitriles with nBuLi and addition to aryl imines gives kinetic anti-β-aminonitriles. Use of LHMDS allows reversible protonation of the reaction intermediate to give syn-β-aminonitriles. The pure diastereosiomers can be isolated in good yields, and the mechanism was elucidated.


Pregnancy and Systemic Lupus Erythematosus.
As SLE onset is often in young adulthood, pregnancy is common and is usually successful. Pregnancy, though, is considered high-risk due to a combination of maternal (lupus flare, diabetes, pre-eclampsia) and fetal (miscarriage, intrauterine fetal demise, preterm birth, intrauterine growth restriction, congenital heart block) risks. Pregnancy should be planned for a time of good control of SLE (on allowable medications). The antimalarial hydroxychloroquine should be continued. The only permitted immunosuppressive drugs are azathioprine and tacrolimus. Of the antiphospholipid antibodies, only the lupus anticoagulant has been associated with adverse pregnancy outcomes in the largest prospective multicenter study, Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE). Management of antiphospholipid syndrome in pregnancy is low molecular weight heparin and aspirin, although only 75% of pregnancies are successful.


Communicating the Issue of Underwater Noise Pollution: The Deaf as a Fish Project.
Aquatic noise pollution is largely ignored by the lay public. How experts communicate this issue is critical to move public opinion. In 2010, the Cassa di Risparmio di Gorizia (CaRiGO) bank sponsored the Deaf as a Fish project that included local underwater noise monitoring, a boat census, a pamphlet for nonexperts, and some seminars and public meetings. This project allowed us to raise interest in this issue. Using accurate and understandable language in a light-humored setting goes far toward cultivating trust from a public audience that can be intimidated or suspicious of complicated scientific messaging.


A microcomputer system for on-line collection of blood flow and related physiological data.
A multi-disciplinary approach is described for the development of a microcomputer based on-line data collection system for blood flow experiments. Well designed software provides a flexible approach to data collection, which is particularly suited to blood flow research laboratories. The choice of well supported hardware ensures ease of development with minimum time and cost.


Induction of Hypersensitivity with Purified Beta-Lactoglobulin as a Mouse Model of Cow's Milk Allergy.
Cow's milk allergy is one of the most prevalent food allergies in both children and adults. As dairy products are common dietary ingredients and the prevalence of chronic conditions is on the rise, milk allergy is a growing public health concern. To elucidate underlying mechanisms and develop therapeutic strategies, reliable animal models are essential research tools. Sensitization to a milk protein is the principal procedure for establishing animal models of cow's milk allergy. However, the methods of sensitization vary from laboratory to laboratory, using different milk proteins with different amounts, routes, and durations of allergen exposure during sensitization of varying sex and strains of mice, likely resulting in diverse immunological and physical responses. Furthermore, the sources and potential impurities of milk protein may also produce variable responses. Thus, standardization of sensitization protocol is important, particularly when results are compared across studies. Here, we describe a method to generate a mouse model of cow's milk allergy using purified β-lactoglobulin as the milk allergen with cholera toxin as an adjuvant in a 5-week oral sensitization protocol.


[Analysis on prevalence and epidemic risk of animal plague in different ecological plague foci in Inner Mongolia Autonomous Region].
The risk of plague epidemics and relapse of various types of plague foci persists in Inner Mongolia Autonomous Region. For Marmota sibirica plague foci, the animal plague has not been found but antibody has been detected positive. Nowadays, Marmota sibirica has been increasing in population and distribution in China. In bordering countries Mongolia and Russia, the animal plague has been continuously prevalent. For Spermophilus dauricus plague foci, the animal plague has been taken place now and then. Compared to the above foci, the animal plague is most prevalent in Meriones unguiculatus plague foci and frequently spread to humans. Due to higher strain virulence and historical disaster in Marmota sibirica plague foci and Spermophilus dauricus plague foci, plague prevention and control should be strengthened on these foci. In addition to routine surveillance, epidemic dynamics need to be further monitored in these two foci, in order to prevent their relapse and spread to humans.


Epitranscriptomic marks: Emerging modulators of RNA virus gene expression.
Epitranscriptomics, the study of posttranscriptional chemical moieties placed on RNA, has blossomed in recent years. This is due in part to the emergence of high-throughput detection methods as well as the burst of discoveries showing biological function of select chemical marks. RNA modifications have been shown to affect RNA structure, localization, and functions such as alternative splicing, stabilizing transcripts, nuclear export, cap-dependent and cap-independent translation, microRNA biogenesis and binding, RNA degradation, and immune regulation. As such, the deposition of chemical marks on RNA has the unique capability to spatially and temporally regulate gene expression. The goal of this article is to present the exciting convergence of the epitranscriptomic and virology fields, specifically the deposition and biological impact of N7-methylguanosine, ribose 2'-O-methylation, pseudouridine, inosine, N6-methyladenosine, and 5-methylcytosine epitranscriptomic marks on gene expression of RNA viruses. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.


Long noncoding RNA CASC21 exerts an oncogenic role in colorectal cancer through regulating miR-7-5p/YAP1 axis.
Emerging evidences show that long non-coding RNAs (lncRNAs) are widely involved in various cell processes and tumor progression. The aim of this study was to investigate the role of new lncRNA homo sapiens cancer susceptibility 21 (CASC21) in the cancer biology of colorectal cancer and explore the underlying mechanism. We silenced the expression of CASC21 using siRNA interference in colorectal cancer cell lines HT29 and SW480, and the effects of CASC21 knockdown on cell proliferation, migration, invasion and apoptosis were assessed using CCK8, colony formation, wound-healing, Transwell and flow cytometry assays. Dual-luciferase reporter assay was performed to determine the relationship among CASC21, miR-7-5p and YAP1. Western blot analysis was used to examine expression of related proteins. By bioinformatics analysis, CASC21 was found to be significantly up-regulated in colorectal cancer tissues. Moreover, CASC21 knockdown displayed significant depression in cell viability, proliferation, migration, and invasion in colorectal cancer cells, as well as EMT process, while cell apoptosis was promoted by regulating the Bcl-2/Bax axis and Caspase cascade. Mechanistically, CASC21 could competently bind to miR-7-5p, resulting in increased YAP1 expression. Furthermore, up-regulation of YAP1 could rescue the inhibitory effects of CASC21 knockdown on EMT and cell invasion. Collectively, these results suggest that CASC21 functions as a ceRNA that plays an oncogenic role in the progression of colorectal cancer by regulating the miR-7-5p/YAP1 axis. LncRNA CASC21 might be a potential target for therapy of colorectal cancer.


Predictive value of adenosine 5'-monophosphate challenge in preschool children for the diagnosis of asthma 5 years later.
We evaluated the predictive values of preschool bronchial challenge with nebulized adenosine 5'-monophosphate (AMP) using the auscultation method for having asthma 5 years later. Preschool AMP challenge had a high negative (90%) and a moderate positive (67%) predictive value for asthma 5 years later. Positive predictive value increased with the age at which the challenge was performed. The degree of preschool response to AMP was associated with the severity of asthma at school age.


Occurrence and risks of antibiotics in an urban river in northeastern Tibetan Plateau.
There is a dearth of information on the occurrence and risks of antibiotics in the urban rivers from plateau areas. This study investigated 83 antibiotics in water and sediments of an urban river and effluents of sewage treatment plants (E-STPs) in Xining, Qinghai (northeastern Tibetan Plateau). Fifty-three antibiotics were detected, and the concentrations of individual antibiotics varied in the range of undetected (ND)-552 ng/L in water, ND-164 ng/g in sediments, and ND-3821 ng/L in E-STPs. Seasonal differences of antibiotic concentrations were significant for water samples (p < 0.05) but insignificant for sediments (p > 0.05). In urban area, E-STP is the main source of antibiotics in the river, while runoff from manured cropland contributes partially to antibiotics in the river in the suburban area. The antibiotic compositions in water were different from those in sediments, but were similar to those in E-STPs. Notably, because of strong solar radiation and long sunshine hours in the plateau area, low levels of quinolones, which are sensitive to photolysis, were observed in river water. Moreover, norfloxacin and enrofloxacin, observed in urban river from other regions of China, were not detected in the Huangshui River water. The occurrence of ofloxacin, erythromycin, roxithromycin, clarithromycin, and trimethoprim in E-STPs may induce a possible risk to antibiotic resistance evolution. Trimethoprim, anhydroerythromycin, sulfamethoxazole, sulfapyridine, and clindamycin in river water could pose low to medium risks to aquatic organisms. Further investigation on the occurrence and distribution of antibiotic resistance genes in the Huangshui River is urgently needed.


Data of the molecular dynamics simulations of mutations in the human connexin46 docking interface.
The structure of hCx26 derived from the X-ray analysis was used to generate a homology model for hCx46. Interacting connexin molecules were used as starting model for the molecular dynamics (MD) simulation using NAMD and allowed us to predict the dynamic behavior of hCx46wt and the cataract related mutant hCx46N188T as well as two artificial mutants hCx46N188Q and hCx46N188D. Within the 50 ns simulation time the docked complex composed of the mutants dissociate while hCx46wt remains stable. The data indicates that one hCx46 molecule forms 5-7 hydrogen bonds (HBs) with the counterpart connexin of the opposing connexon. These HBs appear essential for a stable docking of the connexons as shown by the simulation of an entire gap junction channel and were lost for all the tested mutants. The data described here are related to the research article entitled "The cataract related mutation N188T in human connexin46 (hCx46) revealed a critical role for residue N188 in the docking process of gap junction channels" (Schadzek et al., 2015) [1].


Improved immunomatrix methods to detect protein:protein interactions.
Immunoprecipitation (IP) and coimmunoprecipitation (co-IP) are key techniques for studying protein-protein interactions. These methods utilize immobilized Protein A or Protein G to isolate antibody-bound target antigens. The main disadvantage of traditional IP and co-IP is that the conditions used to elute the precipitated antigen also release the antibody thus contaminating the antigen and destroying the antibody support. To overcome these problems, we describe two methods to generate a reusable antibody support by cross-linking the antibody to immobilized Protein A or Protein G, or by coupling it directly to the resin (see Scheme 1). Antibody cross-linking can be done in 1 h while antibody coupling requires 4 h. IP or co-IP is accomplished by incubating the antibody resin with the protein sample. Washes and elutions are carried out in a spin column to reduce resin loss and decrease assay time. Target proteins are eluted with 0.1 M glycine (pH 2.8) and the resin-bound antibody is re-equilibrated in phosphate-buffered saline (PBS) for reuse. Our studies have demonstrated that the immobilization efficiency for the antibody coupling method was similar for several species of antibody. Furthermore, we illustrate that using both methods of antibody immobilization yield IP and co-IP results similar to traditional protocols but eliminate the antibody heavy and light chain contamination.


Use of puncture force measurement to investigate the conditions of blood vessel needle insertion.
Central venous catheterization involves venous puncture and catheter insertion for transfusions. Quantitative conditions that facilitate insertion of the needle, such as the angle and velocity of insertion, have not been clarified. We previously developed a robotic system for guiding the needle along a specified puncture path with high precision and are currently implementing a hardware design for a robotic system to assist in blood vessel puncture. In this study, we proposed the insertion angle and velocity for stopping the needle in a blood vessel, assuming that a robotic system such as ours is used during the procedure. We inserted a needle into a segment of porcine jugular vein and obtained the puncture reaction force. Evaluation indices were the magnitude of the sudden decrease in reaction force at the point at which the needle advances and the length of time that the needle is present within the vein. Results indicated that the conditions under which it was easiest to stop the needle inside the vein were an insertion angle range of 10-20 and an insertion velocity of 3mm/s.


Peritonitis before Peritoneal Dialysis Training: Analysis of Causative Organisms, Clinical Outcomes, Risk Factors, and Long-Term Consequences.
Peritonitis before peritoneal dialysis (PD) training (pretraining peritonitis [PTP]) is an uncommon event. The study aim was to examine the causative organisms, clinical outcomes, risk factors, and long-term consequences of PTP. In this single-center, retrospective, observational study involving all incident patients on PD who developed PTP between 1998 and 2012, we examined the causative organisms, primary response rate, complete cure rate, risk factors, and associations of PTP with peritoneal equilibration test (PET) and patient survival. For each patient in the PTP group, the patients who underwent catheter insertion immediately before and after the index case were identified as controls. Among 1252 incident patients on PD, 52 (4.2%) patients developed PTP, and 104 patients were identified as controls. The two groups were similar in age, sex distribution, comorbidities, and residual renal function, but the PTP group had significantly lower hemoglobin and serum albumin. Patients were followed up for a median of 37.5 months (interquartile range [IQR], 16.3-62.2 months). The most common causative organisms of PTP were Staphylococcus aureus (30.8%) and polymicrobial (21.2%); 25% had negative growth. The primary response and complete cure rates were 82.7% and 78.8%, respectively. In the PTP group, 7.7% of patients died, 9.6% of patients required catheter removal, and PD training was significantly delayed (median =42.0; IQR, 26.0-65.8 days versus 27.5; IQR, 23.0-35.0 days; P=0.01). Multivariate logistic regression analysis showed that serum albumin was the only predictor of PTP (adjusted odds ratio, 0.89 per 1-g/dl increase; 95% confidence interval, 0.82 to 0.97). There were no differences in PET results and dialysis adequacy (measured around 1 month after PD training). The PTP group had significantly worse patient survival (median =41.2; IQR, 21.8-60.5 months versus 55.8; IQR, 40.4-71.2 months; P=0.02). Technique failure occurred in 11.5% and 10.6% of patients in the PTP and control groups, respectively. S. aureus is the most common causative organism of PTP. Nutritional interventions in patients who are hypoalbuminemic before catheter insertion deserve additional study.


The association of asthma, atopy and lung function with hormone replacement therapy and surgical cessation of menstruation in a population-based sample of English women.
Gynaecological surgery that may lead to cessation of menstruation is a major indication for the use of hormone replacement therapy (HRT) which in turn has been associated with asthma. Information on asthma-like symptoms, lung function and immunoglobulin E (IgE) sensitization to house dust mite (HDM) and on menstrual status and use of HRT was collected from 3724 women aged between 35 and 64 years living in England. Association of health outcomes with use of HRT and with surgery resulting in cessation of menstruation was examined in multivariable models. Over a third of women who had ever used HRT had undergone surgery resulting in cessation of menstruation. Current use of HRT was associated with frequent wheeze, particularly in lean women [body mass index (BMI) < 25; odds ratio (OR) 1.90; 95% confidence interval (CI) 1.17-3.05; BMI 25+; OR 1.02; 95% CI 0.69-1.51]. Wheeze was associated with the reporting of menstrual cessation that was due to surgery even if women denied ever using HRT (OR 1.55; 95% CI 1.09-2.20). There was some evidence that HRT use was associated with airway obstruction in leaner women but little evidence that it was associated with IgE sensitization to HDM. In this cross-sectional study use of HRT was associated with asthma-like symptoms, particularly in those who have lower BMI. A substantial proportion of women whose periods have stopped because of surgery use HRT but this does not fully explain their increased morbidity.


[The syndrome of solitary rectal ulcer. Problems of radiologic diagnosis].
The authors review 7 cases of syndrome of the solitary ulcer of the rectum, examined with barium enema. The radiological signs of this syndrome, rarely described in literature, are compared with those observed in this series.


Removal of parallel prefabricated posts: a clinical report.
The serrations on some parallel and vented prefabricated posts are continuous spirals. Occasionally removal is indicated. If attempts to loosen the post by mechanical vibration fail, the embedded portion may be removed by turning. Careful examination of the radiograph and the exposed portion of the post is needed to determine the proper direction of torque.


An electron microscopic study of Cytoecetes phagocytophila infection in Ixodes ricinus.
Tick-borne fever, caused by a rickettsia-like organism, Cytoecetes phagocytophila, is transmitted by the sheep tick Ixodes ricinus. An electron microscopic technique was developed to examine I ricinus for C phagocytophila infection. Infected and uninfected ticks were obtained from a laboratory maintained tick culture. All stages of I ricinus collected from one field site were examined; 44 per cent of nymphae and 32 per cent of adults were infected with C phagocytophila, but larvae were uninfected. This supports the previously held theory of transtadial, but not transovarial transmission of tick-borne fever.


Selective Targeted Cerebral Revascularization via Microscope Integrated Indocyanine Green Videoangiography Technology.
Protective or flow replacement bypass surgery has an important role in the management of complex middle cerebral artery (MCA) aneurysms. Protective bypass is useful when prolonged temporary arterial occlusion is needed for clip reconstruction. Flow replacement bypass is instead important when aneurysmal trapping is the treatment of choice in order to supply permanent collateral blood flow to the brain distal to the "trapped" vessel. In both cases, the identification of the correct recipient artery is an essential surgical step. When a superficial (cortical) artery is chosen as recipient, it indeed has to represent a distal branch of the involved (temporarily or permanently occluded) vessel.Here we describe a technique for selective-targeted revascularization based on the use of indocyanine green video angiography (ICG-VA), a microscope-integrated intraoperative tool nowadays known to provide real-time assessment of the cerebral circulation with distinct visualization of arterial, capillary and venous angiographic phases. The technique is founded on the analysis of differences in the timing of filling of M4 vessels seen on serial ICG-VAs. It enables reliable identification of the cortical recipient and eliminates the risk of erroneous revascularization of non-involved territories. The surgical decision-making of two patients treated for complex MCA aneurysms with selective-targeted bypass is presented.


Rivastigmine-DHA ion-pair complex improved loading in hybrid nanoparticles for better amyloid inhibition and nose-to-brain targeting in Alzheimer's.
Rivastigmine hydrogen tartrate (RIV-HT) is given orally for Alzheimer's disease. However, oral therapy shows low brain bioavailability, short half-life and gastrointestinal-mediated adverse effects. RIV-HT intranasal delivery can avoid these side effects, but its low brain bioavailability remains challenging. These issues could be solved with hybrid lipid nanoparticles with enough drug loading to enhance RIV-HT brain bioavailability while avoiding oral route side effects. The RIV-HT and docosahexaenoic acid (DHA) ion-pair complex (RIV:DHA) was prepared to improve drug loading into lipid-polymer hybrid (LPH) nanoparticles. Two types of LPH, i.e., cationic (RIV:DHA LPH(+ve)) and anionic LPH (RIV:DHA LPH(-ve)) were developed. The effect of LPH surface charge on in-vitro amyloid inhibition, in-vivo brain concentrations and nose-to-brain drug targeting efficiency were investigated. LPH nanoparticles showed concentration dependant amyloid inhibition. RIV:DHA LPH(+ve) demonstrated relatively enhanced Aβ1-42 peptide inhibition. The thermoresponsive gel embedded with LPH nanoparticles improved nasal drug retention. LPH nanoparticles gel significantly improved pharmacokinetic parameters compared to RIV-HT gel. RIV:DHA LPH(+ve) gel showed better brain concentrations than RIV:DHA LPH(-ve) gel. The histological examination of nasal mucosa treated with LPH nanoparticles gel showed that the delivery system was safe. In conclusion, the LPH nanoparticle gel was safe and efficient in improving the nose-to-brain targeting of RIV, which can potentially be utilized in managing Alzheimer's.


Design of oral intestinal-specific alginate-vitexin nanoparticulate system to modulate blood glucose level of diabetic rats.
Vitexin of Ficus deltoidea exhibits intestinal α-glucosidase inhibitory and blood glucose lowering effects. This study designs oral intestinal-specific alginate nanoparticulate system of vitexin. Nanospray-dried alginate, alginate/stearic acid and alginate-C18 conjugate nanoparticles were prepared. Stearic acid was adopted to hydrophobize the matrix and minimize premature vitexin release in stomach, whereas C-18 conjugate as immobilized fatty acid to sustain hydrophobic effect and drug release. Nanoparticles were compacted with polyethylene glycol (PEG 3000, 10,000 and 20,000). The physicochemical, drug release, in vivo blood glucose lowering and intestinal vitexin content of nanoparticles and compact were determined. Hydrophobization of alginate nanoparticles promoted premature vitexin release. Compaction of nanoparticles with PEG minimized vitexin release in the stomach, with stearic acid loaded nanoparticles exhibiting a higher vitexin release in the intestine. The introduction of stearic acid reduced vitexin-alginate interaction, conferred alginate-stearic acid mismatch, and dispersive stearic acid-induced particle breakdown with intestinal vitexin release. Use of PEG 10,000 in compaction brought about PEG-nanoparticles interaction that negated initial vitexin release. The PEG dissolution in intestinal phase subsequently enabled particle breakdown and vitexin release. The PEG compacted nanoparticles exhibited oral intestinal-specific vitexin release, with positive blood glucose lowering and enhanced intestinal vitexin content in vivo.


Evidence for maternal diet-mediated effects on the offspring microbiome and immunity: implications for public health initiatives.
Diets rich in saturated fats have become a staple globally. Fifty percent of women of childbearing age in the United States are obese or overweight, with diet being a significant contributor. There is increasing evidence of the impact of maternal high-fat diet on the offspring microbiome. Alterations of the neonatal microbiome have been shown to be associated with multiple morbidities, including the development of necrotizing enterocolitis, atopy, asthma, metabolic dysfunction, and hypertension among others. This review provides an overview of the recent studies and mechanisms being examined on how maternal diet can alter the immune response and microbiome in offspring and the implications for directed public health initiatives for women of childbearing age. IMPACT: Maternal diet is important in shaping the offspring microbiome and neonatal immune system. Reviews the current literature in the field and suggests potential mechanisms and areas of research to be targeted. Highlights the current scope of our knowledge of ideal nutrition during pregnancy and consideration for enhanced public health initiatives to promote well-being of the future generation.


Coherent combining of self-cleaned multimode beams.
A low intensity light beam emerges from a graded-index, highly multimode optical fibre with a speckled shape, while at higher intensity the Kerr nonlinearity may induce a spontaneous spatial self-cleaning of the beam. Here, we reveal that we can generate two self-cleaned beams with a mutual coherence large enough to produce a clear stable fringe pattern at the output of a nonlinear interferometer. The two beams are pumped by the same input laser, yet are self-cleaned into independent multimode fibres. We thus prove that the self-cleaning mechanism preserves the beams' mutual coherence via a noise-free parametric process. While directly related to the initial pump coherence, the emergence of nonlinear spatial coherence is achieved without additional noise, even for self-cleaning obtained on different modes, and in spite of the fibre structural disorder originating from intrinsic imperfections or external perturbations. Our discovery may impact theoretical approaches on wave condensation, and open new opportunities for coherent beam combining.


A method for detecting molecular transport within the cerebral ventricles of live zebrafish (Danio rerio) larvae.
The production and flow of cerebrospinal fluid performs an important role in the development and homeostasis of the central nervous system.However, these processes are difficult to study in the mammalian brain because the ventricles are situated deep within the parenchyma.In this communication we introduce the zebrafish larva as an in vivo model for studying cerebral ventricle and blood–brain barrier function. Using confocal microscopy we show that zebrafish ventricles are topologically similar to those of the mammalian brain.We describe a new method for measuring the dynamics of molecular transport within the ventricles of live zebrafish by means of the uncaging of a fluorescein derivative. Furthermore, we determine that in 5–6 days post-fertilization zebrafish, the dispersal of molecules in the ventricles is driven by a combination of ciliary motion and diffusion. The zebrafish presents a tractable system with the advantage of genetics, size and transparency for exploring ventricular physiology and for mounting large-scale high throughput experiments.


Hemihyperplasia with Ehlers-Danlos syndrome like skin changes.
Hemihyperplasia is a condition characterized by asymmetric overgrowth of one or more body parts. It may be an isolated finding or may be associated with various syndromes like Beckwith-Weidemann syndrome, Klippel-Trenaunay-Weber syndrome, Proteus syndrome etc. Pigmentary skin lesions and capillary malformations are commonly seen in cases of hemihyperplasia. We report a case of hemihyperplasia with associated skin hyperextensibility, varicose veins, skin fragility, easy bruising and papery scars, on the side of hyperplasia. This is the first report of association of isolated hemihyperplasia with skin changes similar to Ehlers-Danlos syndrome.


Effect of temperature on the toxicokinetics and gene expression of the pacific cupped oyster Crassostrea gigas exposed to cadmium.
In this study, we investigated the influence of temperature on the bioaccumulation and depuration of Crassostrea gigas exposed to Cd associated with its molecular responses. Oysters were acclimatized to different temperatures (10 °C, 15 °C, 20 °C, 25 °C, and 30 °C) for 14 d and then exposed to 10 μg/L Cd for 28 d, followed by a depuration period of 35 d. Oysters were sampled for chemical analysis by inductively coupled plasma mass spectrometry (ICP-MS) and for mRNA quantification by qPCR. In the digestive gland, gill, and mantle, the cadmium concentration at 10 °C was significantly lower than that at 25 °C and 30 °C in both the whole experiments. The use of a two-compartment model showed that the uptake rate k1 in the above three tissues increased with increasing temperatures ranging from 15 to 25 °C. The fastest elimination rates and shortest half-lives were observed at 15-25 °C. The induction of metallothionein (MT) only occurred in the digestive gland at 15 °C and 20 °C at the end of the accumulation phase. In the mantle and gills, the expression of P-glycoprotein (P-gp) was significantly induced at the end of the accumulation phase and significantly inhibited at the end of the depuration phase. In the digestive gland, the expression of P-gp was induced at the end of both the accumulation and depuration phases. Heat shock protein (hsp70) expression exhibited an overall increasing trend throughout the experiment.


Parasites at Risk - Insights from an Endangered Marsupial.
Parasites are the most abundant form of life on earth and are vital components of ecosystem health. Yet, it is only relatively recently that attention has been given to the risks of extinction that parasites face when their hosts, particularly wildlife, are endangered. In such circumstances, parasites that are host-specific with complicated life cycles are most at risk. Such extinction/coextinction events have been poorly documented, principally because of the difficulties of following such extinction processes in nature. Fortunately, we were presented with the rare opportunity to catalogue an endangered Australian marsupial's parasites; we present our near-complete catalogue here. We incorporate this catalogue into a predictive framework to understand which parasites might be most vulnerable to coextinction, which we hope will serve as a model for endangered hosts and their parasites elsewhere.


Smad signaling pathway is a pivotal component of tissue inhibitor of metalloproteinases-3 regulation by transforming growth factor beta in human chondrocytes.
Transforming growth factor beta (TGF-beta1) promotes cartilage matrix synthesis and induces tissue inhibitor of metalloproteinases-3 (TIMP-3), which inhibits matrix metalloproteinases, aggrecanases and TNF-alpha-converting enzyme implicated in articular cartilage degradation and joint inflammation. TGF-beta1 activates Akt, ERK and Smad2 pathways in chondrocytes. Here we investigated previously unexplored roles of specific Smads in TGF-beta1 induction of TIMP-3 gene by pharmacological and genetic knockdown approaches. TGF-beta1-induced Smad2 phosphorylation and TIMP-3 protein expression could be inhibited by the Smad2/3 phosphorylation inhibitors, PD169316 and SB203580 and by Smad2-specific siRNA. Specific inhibitor of Smad3 (SIS3) and Smad3 siRNA abolished TGF-beta induction of TIMP-3. Smad2/3 siRNAs also down regulated TIMP-3 promoter-driven luciferase activities, suggesting transcriptional regulation. SiRNA-driven co-Smad4 knockdown abrogated TIMP-3 augmentation by TGF-beta. TIMP-3 promoter deletion analysis revealed that -828 deletion retains the original promoter activity while -333 and -167 deletions display somewhat reduced activity suggesting that most of the TGF-beta-responsive, cis-acting elements are found in the -333 fragment. Chromatin Immunoprecipitation (ChIP) analysis confirmed binding of Smad2 and Smad4 with the -940 and -333 promoter sequences. These results suggest that receptor-activated Smad2 and Smad3 and co-Smad4 critically mediate TGF-beta-stimulated TIMP-3 expression in human chondrocytes and TIMP-3 gene is a target of Smad signaling pathway.


JTT-501, a novel oral antidiabetic agent, improves insulin resistance in genetic and non-genetic insulin-resistant models.
1. We investigated whether JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxa zolidinedione) would improve insulin resistance in genetic (Zucker fatty rats) and non-genetic (high-fat fed rats) rodent models of obesity. 2. JTT-501 (10-100 mg kg(-1) day(-1)) was administered orally to Zucker fatty rats for 7-21 days. In the high-fat fed rat model, JTT-501 (100 mg kg(-1) day(-1) was administered orally for 7 days. In both models, JTT-501 improved metabolic abnormalities by enhancing insulin action during the glucose tolerance test and the euglycaemic-hyperinsulinaemic clamp study. In ex vivo assays, JTT-501 ameliorated the impaired insulin-sensitive glucose oxidation and lipid synthesis in peripheral tissues. Furthermore, JTT-501 enhanced insulin receptor autophosphorylation in hindlimb muscle. 3. JTT-501 reduced serum leptin concentrations in both models, but did not affect body weight or epididymal fat weight. 4. Our observations indicate that JTT-501 improves the metabolic abnormalities in both genetic and non-genetic insulin-resistant models by enhancing insulin action in peripheral tissues. These effects of JTT-501 are due, at least in part, to enhanced insulin receptor autophosphorylation. In addition, JTT-501 is able to reduce serum leptin concentrations in hyperleptinaemia of the insulin-resistant model. We expect JTT-501 to show promise for treating non-insulin dependent diabetes mellitus patients with insulin resistance.


Foraging scent marks of bumblebees: footprint cues rather than pheromone signals.
In their natural habitat foraging bumblebees refuse to land on and probe flowers that have been recently visited (and depleted) by themselves, conspecifics or other bees, which increases their overall rate of nectar intake. This avoidance is often based on recognition of scent marks deposited by previous visitors. While the term 'scent mark' implies active labelling, it is an open question whether the repellent chemicals are pheromones actively and specifically released during flower visits, or mere footprints deposited unspecifically wherever bees walk. To distinguish between the two possibilities, we presented worker bumblebees (Bombus terrestris) with three types of feeders in a laboratory experiment: unvisited control feeders, passive feeders with a corolla that the bee had walked over on its way from the nest (with unspecific footprints), and active feeders, which the bee had just visited and depleted, but which were immediately refilled with sugar-water (potentially with specific scent marks). Bumblebees rejected both active and passive feeders more frequently than unvisited controls. The rate of rejection of passive feeders was only slightly lower than that of active feeders, and this difference vanished completely when passive corollas were walked over repeatedly on the way from the nest. Thus, mere footprints were sufficient to emulate the repellent effect of an actual feeder visit. In confirmation, glass slides on which bumblebees had walked on near the nest entrance accumulated hydrocarbons (alkanes and alkenes, C23 to C31), which had previously been shown to elicit repellency in flower choice experiments. We conclude that repellent scent marks are mere footprints, which foraging bees avoid when they encounter them in a foraging context.


Family arrangements, identity verification, and happiness.
We study how the family structural arrangements individuals inhabit, the cultural meanings that accompany these structures, and individuals' experiences of identity verification within these structures are related to their general happiness. We use data (N = 1304) from the 2014 General Social Survey Identity Module to study the normative and non-normative family arrangements in which individuals reside, their experience of verification of the parent/non-parent identity, and their happiness. We find that parent/non-parent identity verification is positively associated with happiness for normative family arrangements but not non-normative family arrangements. We discuss how social structural arrangements and a culture that supports them may assist the identity verifying outcome of happiness, while structural arrangements and a culture that is not as supportive of certain family forms may undermine the identity verifying outcome of happiness. The findings provide insights into how social structure and culture at the macro level coalesce with the identity verification process at the micro level in affecting the emotional tenor of people's lives.


RAGE binds C1q and enhances C1q-mediated phagocytosis.
RAGE, the multiligand receptor of the immunoglobulin superfamily of cell surface molecules, is implicated in innate and adaptive immunity. Complement component C1q serves roles in complement activation and antibody-independent opsonization. Using soluble forms of RAGE (sRAGE) and RAGE-expressing cells, we determined that RAGE is a native C1q globular domain receptor. Direct C1q-sRAGE interaction was demonstrated with surface plasmon resonance (SPR), with minimum K(d) 5.6 μM, and stronger binding affinity seen in ELISA-like experiments involving multivalent binding. Pull-down experiments suggested formation of a receptor complex of RAGE and Mac-1 to further enhance affinity for C1q. C1q induced U937 cell adhesion and phagocytosis was inhibited by antibodies to RAGE or Mac-1. These data link C1q and RAGE to the recruitment of leukocytes and phagocytosis of C1q-coated material.


Comparative analysis on the effect of the endoscopic versus conventional treatment for pilonidal sinus: A meta-analysis of controlled clinical trials.
Pilonidal sinus is a common disease in the sacrococcygeal region. Although many treatments have been described in recent years, the recurrence of each method remains high. Surgeons did not reach a consensus on the preferred approach for pilonidal sinus. We carried out a meta-analysis of controlled clinical trials comparing the outcomes of endoscopic treatment versus conventional treatment for pilonidal sinus disease in this study. We performed a systematic literature search, and we used electronic databases such as PubMed/Medline, Embase, and the Cochrane library to search for the relevant literature comparing endoscopic management to other conventional treatments for pilonidal sinus disease. The primary outcome parameters were operative time, recurrence, postoperative complications and pain, and total healing time. Six studies were included in the review. Endoscopic pilonidal sinus treatment had a lower overall complication rate than the conventional surgery group (risk ratio = 0.33 [0.19-0.58], P = .0001) and lower pain score with a weighted mean difference of -2.44 (95% confidence interval: (-3.96) to (-0.92), I2 = 99%, P = .002). There was no significant difference in recurrence (risk ratio = 0.75, 95% confidence interval [0.30-1.90],P = .55). Compared to the excision followed by the primary closure technique, the operation time, time to complete wound healing, and satisfaction were similar. Endoscopic pilonidal sinus treatment is a unique and potential method of sacrococcygeal pilonidal disease treatment. The foremost benefits of this technique are mild postoperative pain, lower complications rate, and return to routine for a shorter time. However, due to the limited number of articles, we need to conduct more rigorous large-sample prospective randomized controlled trials to clarify the efficiency of endoscopic treatment for pilonidal cysts.


Staging and evaluation of the patient with lymphoma.
Patients who have non-Hodgkin's lymphoma or Hodgkin lymphoma most often present for medical attention because of signs or symptoms referable to enlarged lymph nodes or other disease-related symptoms (such as fevers, night sweats or fatigue). Less often, enlarged lymph nodes or splenomegaly may be incidental findings during evaluation for other medical issues. Determination of the extent of disease and accurate assessment of responses are necessary for appropriate management. Newer technologies have improved the ability to evaluate patients and to conduct clinical trials, leading to more effective therapies. This article addresses the advances in staging and evaluation of patients who have lymphoma, specifically examining the use of positron emission tomography.


Correction: Phase 1 First-in-Human Dose Escalation and Dose Expansion Study of KLS-1 (64Zinc Aspartate) in Patients With Cancer and Neurodegenerative Diseases.
[This corrects the article DOI: 10.7759/cureus.29921.].