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The aim of this study was to investigate the chemical space and interactions of natural compounds with sulfotransferases (SULTs) using ligand- and structure-based in silico methods. An in-house library of natural ligands (hormones, neurotransmitters, plant-derived compounds and their metabolites) reported to interact with SULTs was created. Their chemical structures and properties were compared to those of compounds of non-natural (synthetic) origin, known to interact with SULTs. The natural ligands interacting with SULTs were further compared to other natural products for which interactions with SULTs were not known. Various descriptors of the molecular structures were calculated and analyzed. Statistical methods (ANOVA, PCA, and clustering) were used to explore the chemical space of the studied compounds. Similarity search between the compounds in the different groups was performed with the ROCS software. The interactions with SULTs were additionally analyzed by docking into different experimental and modeled conformations of SULT1A1. Natural products with potentially strong interactions with SULTs were outlined. Our results contribute to a better understanding of chemical space and interactions of natural compounds with SULT enzymes and help to outline new potential ligands of these enzymes. | Sulfur Group Transferases |
BACKGROUND: Low adult immunization rates leave adults at risk from infectious disease, and the resulting complications of vaccine-preventable diseases. Standing orders protocols (SOPs) for adult immunization have not been implemented widely in clinics serving adult patients. Our purpose was to evaluate the impact of SOPs on adult immunization rates and identify challenges to sustaining adult immunization coverage rates after implementation of SOPs. METHODS: Baseline adult vaccination rates were calculated for the year prior to SOPs implementation in 5 diverse clinics. Vaccines included in the implemented standing orders included Tdap, influenza, pneumococcal, human papillomavirus, herpes zoster, and hepatitis B. Adult vaccination rates were tracked for 1 year after SOPs implementation. RESULTS: Sites generally sustained modest gains in coverage rates (4%-8% increase) after SOP implementation, but greater success was found in practices that used SOPs as a foundation on which additional interventions were built. Challenges to increasing coverage rates included prioritization of acute and chronic conditions over adult vaccination, Medicare Part D reimbursement policies, electronic medical record issues related to data reporting and programming for patient alerts, and the lack of interoperability between the state immunization information system (missing patient vaccination history) and electronic medical record. CONCLUSIONS: SOPs may provide a good starting point for increasing adult immunization coverage rates. Using additional interventions, quality-based metrics, or incentives could lead to sustained adult immunization prioritization. | Standing Orders |
To identify thyroid hormone-sensitive neuronal populations in the forebrain, we studied the effects of thyroid hormone deficiency and replacement on the expression of RC3 messenger RNA (mRNA) in the rat brain by in situ hybridization. RC3/neurogranin is a brain-specific, calmodulin-binding, protein kinase C substrate that has been implicated in postsynaptic events involving calcium as a second messenger. We have previously shown that RC3 mRNA and protein concentrations are thyroid hormone dependent in developing and adult rats. In normal developing rats, RC3 expression occurs in two phases. Before postnatal day 10 (P10), RC3 mRNA was detected mainly in layers II/III and V of cerebral cortex and the CA fields of the hippocampus. From P10 to P15, it decreased in layer V and increased in layer VI, the retrosplenial cortex, the caudate-putamen nucleus, and the dentate gyrus. Expression in the caudate followed a lateral to medial gradient. Thyroid hormone deficiency interfered with the late phase of RC3 expression, such that developing hypothyroid rats showed lower RC3 expression in layer VI, the retrosplenial cortex, the dentate gyrus, and the caudate, and increased expression in layer V. These changes were reverted by T4 treatment. Adult- onset hyperthyroidism also reversibly decreased hybridization in the striatum. In contrast to other molecular targets of thyroid hormone in the brain, such as myelin genes, expression of RC3 was also affected by long term hypothyroidism in the absence of hormone replacement, indicating that thyroid hormone is a required factor for the cell-specific control of RC3 expression. In addition to identifying thyroid hormone-sensitive neurons, our results suggest that one action of thyroid hormone during brain development is the timely coordination of gene expression among phenotypically different, region-specific neuronal populations. | Neurogranin |
PURPOSE OF REVIEW: Myoclonus, one of the most common involuntary movement disorders, poses particular challenges for the treating physician. The evaluation of a patient with myoclonus depends completely on the clinical history and examination, supported when necessary by electrophysiology, neuroimaging and selected genetic and laboratory testing. The sudden, shock-like jerks which define myoclonus may be highly disabling, and when they persist, often require treatment. RECENT FINDINGS: In a paper published in this journal, we reviewed the published trials of antimyoclonic agents, and formulated a treatment algorithm based on the available evidence. In the current paper, we present our approach for evaluating patients with myoclonus, and suggest practical guidelines for treating patients based on the pre-2000 literature and on studies published in the last 2 years. The newer medications which are being used in management of myoclonus are levetiracetam and gamma-hydroxybutyric acid. Levetiracetam is especially useful for posthypoxic myoclonus and gamma-hydroxybutyric acid for alcohol-sensitive myoclonus. A combination of medications is often needed to obtain adequate control of symptoms. Botulinum toxin is also being introduced for focal myoclonus with encouraging results. SUMMARY: There are no approved medications for myoclonus, and most therapies are borrowed from the antiepileptic and psychiatric armamentarium. Nonetheless, there is a logic to the choice and dosing of antimyoclonic drugs, and we hope that by applying a few simple principles, neurologists will approach the care of these patients with confidence. | Myoclonus |
Floods determine river behaviour in time and space. Yet quantitative measures of discharge variability from geological stratigraphy are sparse, even though they are critical to understand landscape sensitivity to past and future environmental change. Here we show how storm-driven river floods in the geologic past can be quantified, using Carboniferous stratigraphy as an exemplar. The geometries of dune cross-sets demonstrate that discharge-driven disequilibrium dynamics dominated fluvial deposition in the Pennant Formation of South Wales. Based on bedform preservation theory, we quantify dune turnover timescales and hence the magnitude and duration of flow variability, showing that rivers were perennial but prone to flashy floods lasting 4-16 h. This disequilibrium bedform preservation is consistent across 4 Ma of stratigraphy, and coincides with facies-based markers of flooding, such as mass-preservation of woody debris. We suggest that it is now possible to quantify climate-driven sedimentation events in the geologic past, and reconstruct discharge variability from the rock record on a uniquely short (daily) timescale, revealing a formation dominated by flashy floods in perennial rivers. | Floods |
OBJECTIVE: Vein of Galen Malformations (VoGM) are rare vascular malformations, typically seen in pediatric age groups. Even more rarely, VoGM's may be seen later in adulthood. In this case report and systematic review, we provide a thorough description of the current literature as well as provide a case example exploring the diagnosis, imaging, treatment, and management of VoGM in adults. METHODS: In accordance with PRISMA guidelines, we performed a systematic literature search for all relevant cases and case series of VoGM in adult patients. The reference list of all articles were reviewed for additional relevant cases. Articles were included if they described a VoGM of a patient over the age of 18 years old and published in English. 149 articles were originally identified and 26 described cases met our inclusion criteria. RESULTS: In our literature review we found 26 patients that met our inclusion criteria. We found 14 male patients and 12 female patients. The mean age at presentation was 37.2 years (median=34 years, SD= 13.6 years). The most common presenting symptoms of patient were headache (n = 9), seizure (n = 6), and vomiting (n = 4). Of the 12 cases which clearly reported the subtype of VoGM, the choroidal type was more frequently seen (n = 10) compared to the mural type (n = 2). In 3 patients, the VoGM was thrombosed at time of diagnosis. Of the 26 patients, endovascular treatment was performed most frequently (n = 8) but some received microsurgical treatment (n = 4) or were treated conservatively (n = 6). Other treatment modalities included (ventriculoperitoneal shunt, ventriculostomy) (n = 5). In 3 cases treatment was not specified. In comparison to VoGM seen in pediatric or neonatal populations, VoGM in adults generally resulted in more favorable outcomes with only 2 patients reported to have passed away following treatment. CONCLUSION: VoGM remains a rare finding amongst the adult population. Hence, we described the clinical presentation, treatment modalities, and outcomes of the cases described in the English literature. Perhaps due to the rate of thrombosis and the unique angioarchitecture seen in adult VoGM patients, outcomes were generally more favorable than those described in the literature in pediatric or neonate VoGM patients. | Vein of Galen Malformations |
Antero- and retrograde cargo transport through the Golgi requires a series of membrane fusion events. Fusion occurs at the cis- and trans-side and along the rims of the Golgi stack. Four functional SNARE complexes have been identified mediating lipid bilayer merger in the Golgi. Their function is tightly controlled by a series of reactions involving vesicle tethering and SM proteins. This network of protein interactions spatially and temporally determines the specificity of transport vesicle targeting and fusion within the Golgi. | Transport Vesicles |
Valgus slip of the capital femoral epiphysis is a known but extremely rare form of a slipped capital femoral epiphysis. After the first report in 1926 up to the present, approximately 44 cases have been reported. We report two cases of valgus slip of the capital femoral epiphysis with a comprehensive review of the existing literature and the precautions that are needed while planning surgical management of these patients. Awareness of this condition is essential to make a prompt diagnosis and plan the appropriate management. | Bone Retroversion |
The aim of the study was to verify differences between age groups of female judo matches in time-motion and technical-tactical analysis. The sample was composed of pre-cadet (13-14 years, n = 148), cadet (15-16 years, n = 228), junior (17-19 years, n = 104) and senior (>20 years, n = 237) groups. The time-motion indicators consisted of total combat time, standing combat time, displacement without contact, gripping time, total time of techniques, groundwork combat time and pause time, per match and by each combat/pause cycle. Technical and tactical variables were also collected. The one-way analysis of variance and a post hoc test were conducted, P </= 0.05. Cadets, with a median of 7 (2, 12), had a number of combat/pause cycles different from junior, with 3 (1, 8.5). Regarding time-motion per match and per cycle, senior had longer total combat time, standing combat time and gripping time than other groups. Senior presented lower frequency of leg techniques than pre-cadet, cadet and junior. Time-motion and technical-tactical variables effects in female judo athletes emphasise the difference between seniors and other groups. | Task Performance and Analysis |
Heat stress is an important issue in dairy cattle feeding management affecting summer health and economic efficiency. This experiment combined 16S rDNA sequencing(3,864,982 tags, 30 sequencing data), metagenomic sequencing(1,269,441,128 reads, 18 sequencing data), metabolomics analysis(72 sequencing data) and blood index analysis. Ten cows in each animal type (growing heifers, heifers, and lactating cows) were selected for sample collection in April and August. Here, we characterized both the changes in metabolites, rumen microbial communities and their functional potential and the effects of heat stress on serum biochemical, immune, oxidative stress, and hormonal indices derived from rumen fluid and serum samples from cows during different growth stages and in different climates. The generated data expand the resources for the rumen microbiome related to heat stress and age and provide useful datasets for research on developing therapeutic strategies to achieve high summer milk production in cows. These datasets will help researchers study the effects of heat stress on the physiological metabolism of Holstein cows and the time-dependent changes associated with growth stages. | DNA, Ribosomal |
BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p (interaction) = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (OR(ordinal): 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508). | Atorvastatin |
Thermolysis of [(H)(BPI)Pt(CH(3))][OTf] (BPI = 1,3-bis(2-(4-tert-butyl)pyridylimino)isoindole) to release methane and form (BPI)Pt(OTf) is reported. Kinetic, mechanistic, and computational studies point to an unusual anion-assisted pathway that obviates the need for a higher oxidation state intermediate to couple the metal-bound methyl group with the ligand-bound hydrogen. Leveraging this insight, a triflimide derivative of the (BPI)Pt complex was shown to activate benzene, highlighting the role of the counteranion in controlling the activity of these complexes. | Platinum |
In a continuation of our attempts to elucidate the prolactin release inhibiting pharmacophore within the ergoline structure, we have prepared several derivatives of 3-phenylpiperidine. These congeners have been evaluated for inhibition of prolactin release in vivo and are for the most part inactive." | Prolactin Release-Inhibiting Factors |
An alginate fraction, 04S2P, was isolated from the brown seaweed Sargassum fusiforme and was structurally characterized by the ratio (M/G) of beta-d-mannuronic acid residues (M) to alpha-l-guluronic acid residues (G) via (1)H and (13)C NMR spectroscopy. When compared to commercial alginate (Alg) and alginates from other brown algae, 04S2P has a higher M/G ratio of 9.0:1.0 as determined by a modified high-performance liquid chromatography method after pre-column derivatization with PMP. Furthermore, the sulfated polysaccharides 04S2P-S and Alg-S were prepared by the chlorosulfonic acid-pyridine method. Both C-2 and/or C-3 of M and G residues of 04S2P-S were substituted by sulfate groups, with C-3 of M residues preferentially substituted. Their effects on tube formation of HMEC-1 cells were examined, and the results indicated that the sulfated Alg, Alg-S, exhibited a strong anti-angiogenic effect on HMEC-1 cells. The anti-tumor activity of native and sulfated alginates was tested on five different tumor cell lines. Alg-S demonstrated significant anti-tumor effects on the Bel7402, SMMC7721, and HT-29 cell lines, whereas 04S2P-S showed a distinct anti-tumor effect only on the Bel7402 cell line. | Glucuronic Acid |
High enantiomeric excesses (ee's) of l-amino acids, including non-proteinogenic amino acid isovaline (Iva), were discovered in the Murchison meteorite, but the detailed molecular mechanism responsible for the observed ee of amino acids remains elusive and inconsistent, because Iva has an inverted circular dichroism (CD) spectrum with respect to alpha-H amino acids, e.g., alanine. To address this issue, we resort to accurate ab initio calculations for amino acids and their precursors in the Strecker synthesis. We evaluated their photolysis-induced ee in the range 5-11 eV including the Lyman alpha emission line (Lyalpha), the typical intensive 10.2 eV radiation ascribed to the early phase of galactic evolution. We show that only the aminonitrile precursors are characterized by positive ee in the Lyalpha region, explaining why right-handed circularly polarized Lyalpha (R-CP-Lyalpha) induces homologous l-amino acids. This study shows that the homochirality of amino acids is produced at the aminonitrile precursors stage. | Meteoroids |
RATIONALE: Preliminary results suggest a potential benefit of agents that enhance gamma-aminobutyric acid (GABA) neurotransmission in treating posttraumatic stress disorder (PTSD). OBJECTIVES: It is the aim of this study to evaluate the effect of a selective GABA reuptake inhibitor (SGRI), tiagabine, in patients with PTSD. METHODS: Twenty-nine adult outpatients with PTSD were treated with open-label tiagabine for 12 weeks. Those who responded to treatment (i.e., demonstrated at least minimal clinical improvement) were randomly assigned to double-blind treatment with either tiagabine or matching placebo. Efficacy assessments included measures of PTSD, anxiety, depression, sleep quality, resilience, and disability. Safety evaluation included changes in vital signs and weight and treatment-emergent adverse events. RESULTS: In subjects completing open-label treatment (n=19), significant improvement was observed on all outcome measures (P<0.05) and the treatment was well tolerated. Eighteen subjects responded and were randomized into the double-blind phase. Following randomization, benefits of treatment were generally upheld, but there was no greater incidence of relapse in the placebo group. However, continued treatment with tiagabine was associated with a greater trend toward likelihood of remission than if one was switched to placebo (P<0.08). CONCLUSIONS: These findings suggest a possible role for the SGRI tiagabine in the treatment of PTSD. As the role of GABAergic drugs in PTSD is poorly defined, larger, randomized, double-blind, placebo-controlled trials are needed. | GABA Uptake Inhibitors |
The results of measurement and dynamics of intra-abdominal pressure obtained in 129 patients with acute destructive pancreatitis are presented. It was revealed that in 78% cases the pancreatonecrosis is accompanied by increase in intra-abdominal pressure (IAP); the intra-abdominal hypertension have developed in 9,3% patients. The prolonged intra-abdominal hypertension in the patients with progressive pancreatonecrosis requires the performance of laparotomy, which contributes to decrease in intra-abdominal pressure. The dependence between IAP value and dissemination of pancreatogenic inflammatory process in abdominal cavity and retroperitoneal space as well as between IAP level and condition gravity according to APACHE II scale was revealed. | Abdominal Cavity |
A novel erm(44) gene variant, erm(44)(v), has been identified by whole-genome sequencing in a Staphylococcus saprophyticus isolate from the skin of a healthy person. It has the particularity to confer resistance to macrolides and lincosamides but not to streptogramin B when expressed in S. aureus The erm(44)(v) gene resides on a 19,400-bp genomic island which contains phage-associated proteins and is integrated into the chromosome of S. saprophyticus. | Streptogramins |
Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization. | Pyrithiamine |
As of January 1, 1993 a huge market, encompassing more than 325 million people, has been established with the unification of the 12 member states in the European Community. During the last 10 years, the pharmaceutical wholesaling sector has therefore been involved in an intense restructuring process. But, there is a considerable scientific gap in the knowledge of pharmaceutical wholesaling. In view of the uncertain situation and the scarcity of structured information, the purpose of this article is to examine current and future trends in the European pharmaceutical wholesaling sector. We reviewed the literature and identified three major areas of interest; general threats to traditional full-line wholesaling, wholesalers' response to these threats, and the new Glaxo distribution scheme. The current and expected importance of these areas were assessed with the help of a survey, encompassing 20 experts in this field. Based on the review and the survey, we conclude that there are many serious threats to traditional wholesaling, the major ones being governmental pressures to lower the already relatively low gross margins, manufacturers contemplating taking over the drug distribution process themselves and increasing international competition. The major responses to these threats are to become a truly international player (via mergers, acquisitions and joint ventures), or being able to provide the customers with detailed management information through computerised networks. In order to survive the next 5-10 years, companies have to be very alert to the changing competitive situation. | Economics, Pharmaceutical |
A 15-year-old female cockatiel (Nymphicus hollandicus) undergoing long term management for hepatopathy died and underwent necropsy. Microscopic findings were consistent with chronic liver disease characterized by distorted hepatic architecture, fibrosis and biliary proliferation. The additional finding of large intranuclear inclusion bodies within hepatocytes and renal tubular epithelium prompted diagnostic next generation sequencing. The assembled sequences isolated from pooled kidney and liver were related to siadenoviruses. The genus Siadenovirus, within the family Adenoviridae, includes several species of viruses that pathogenically infect avian species including hemorrhagic enteritis virus of turkeys and marble spleen virus of pheasants. Siadenoviruses have previously been reported in seven psittacine species: a plum-headed parakeet (Psittacula cyanocephala), an umbrella cockatoo (Cacatua alba) budgerigars (Melopsittacus undulates), an eastern rosella (Platycercus eximius), a scarlet chested parrot (Neophema splendida), a cockatiel (Nymphicus hollandicus), and a red-crowned parakeet (Cyanoramphus novaezelandiae). This report describes a novel siadenovirus in a cockatiel that is highly identical to budgerigar adenovirus 1 and distinct from PsAdV-2 in cockatiels. We report the clinical pathologic, gross, and histopathologic findings in a cockatiel with chronic hepatitis and a novel siadenovirus, PsAdV-5. The sequencing data is presented with a phylogenetic analysis. | Siadenovirus |
In 2011 a working group of the European Society for the Study of Tourette syndrome (ESSTS) developed the first European Guidelines for Tourette syndrome (TS) published in the ECAP journal. After a decade ESSTS now presents updated guidelines, divided into four sections: Part I: assessment, Part II: psychological interventions, Part III: pharmacological treatment and Part IV: deep brain stimulation (DBS). In this paper, we summarise new developments described in the guidelines with respect to assessment and treatment of tics. Further, summary findings from a recent survey conducted amongst TS experts on these same topics are presented, as well as the first European patient representative statement on research. Finally, an updated decision tree is introduced providing a practical algorithm for the treatment of patients with TS. Interestingly, in the last decade there has been a significant shift in assessment and treatment of tics, with more emphasis on non-pharmacological treatments. | Tourette Syndrome |
We report on a 3-month-old girl with culture-confirmed infant botulism caused by a rare double toxin-producing Clostridium botulinum type Ba. This case was not related to honey-feeding. The clinical course was prolonged, with minimal spontaneous improvement at onset, and a period of fluctuating motor weakness and nasogastric feeding dependence afterward. Neurophysiologic studies produced normal results. Human botulism immune globulin was administered empirically on day 23 of presentation, with rapid full recovery. This case highlights the importance of pursuing diagnoses of infant botulism despite normal results of neurophysiologic testing and no history of honey-feeding. Our case also demonstrates a favorable response to human botulism immune globulin, despite the relatively late treatment. | Clostridium botulinum type B |
PURPOSE: To define the rule according to which crystalloid solutions characterized by different strong ion difference (SID) modify the acid-base variables of human plasma. METHODS: With a previously validated software, we computed the effects of diluting human plasma with crystalloid solutions ([SID] 0-60, 10 mEq/l stepwise). An equation was derived to compute the diluent [SID] required to maintain the baseline pH unchanged, at constant PCO(2) and at every dilution fraction. The results were experimentally tested using fresh frozen plasma, re-warmed at 37 degrees C, equilibrated at PCO(2) 35 and 78 mmHg, at baseline and after the infusion of crystalloid solutions with 0, 12, 24, 36, 48 mEq/l [SID]. RESULTS: The mathematical analysis showed that the diluent [SID] required to maintain unmodified the baseline pH equals the baseline bicarbonate concentration, [HCO(3)(-)], assuming constant PCO(2) throughout the process. The experimental data confirmed the theoretical analysis. In fact, at the baseline [HCO(3)(-)] of 18.3 +/- 0.3 mmol/l (PCO(2) 35 mmHg) the pH was 7.332 +/- 0.004 and remained 7.333 +/- 0.003 when the diluting [SID] was 18.5 +/- 0.0 mEq/l. At baseline [HCO(3)(-)] of 19.5 +/- 0.3 mmol/l (PCO(2) 78 mmHg) the pH was 7.010 +/- 0.003 and remained 7.004 +/- 0.003 when the diluting [SID] was 19.1 +/- 0.1 mEq/l. At both PCO(2) values infusion with [SID] lower or greater than baseline [HCO(3)(-)] led pH to decrease or increase, respectively. CONCLUSIONS: The baseline [HCO(3)(-)] dictates the pH response to crystalloid infusion. If a crystalloid [SID] equals baseline [HCO(3)(-)], pH remains unchanged at constant PCO(2), whereas it increases or decreases if the [SID] is greater or lower, respectively. | Hydrogen-Ion Concentration |
Genome evolution in bacterial endosymbionts is notoriously extreme: the combined effects of strong genetic drift and unique selective pressures result in highly reduced genomes with distinctive adaptations to hosts [1-4]. These processes are mostly known from animal endosymbionts, where nutritional endosymbioses represent the best-studied systems. However, eukaryotic microbes, or protists, also harbor diverse bacterial endosymbionts, but their genome reduction and functional relationships with their hosts are largely unexplored [5-7]. We sequenced the genomes of four bacterial endosymbionts from three species of diplonemids, poorly studied but abundant and diverse heterotrophic protists [8-12]. The endosymbionts come from two bacterial families, Rickettsiaceae and Holosporaceae, that have invaded two families of diplonemids, and their genomes have converged on an extremely small size (605-632 kilobase pairs [kbp]), similar gene content (e.g., metabolite transporters and secretion systems), and reduced metabolic potential (e.g., loss of energy metabolism). These characteristics are generally found in both families, but the diplonemid endosymbionts have evolved greater extremes in parallel. They possess modified type VI secretion systems that could function in manipulating host metabolism or other intracellular interactions. Finally, modified cellular machinery like the ATP synthase without oxidative phosphorylation, and the reduced flagellar apparatus present in some diplonemid endosymbionts and nutritional animal endosymbionts, indicates that intracellular mechanisms have converged in bacterial endosymbionts with various functions and from different eukaryotic hosts across the tree of life. | Holosporaceae |
A Malaysian family with congenital insensitivity to pain with anhydrosis was diagnosed based on clinical symptoms of chronic ulcers, joint deformities, malunited fractures, anhydrosis, and learning disabilities. We detected a compound heterozygous mutation in exon 16: V709L from the mother and G718S from the father. Two novel mutations were identified: at amino acid 709, a change of G to C at nucleotide 2209 (approximately 2209G to C) causing a valine to leucine substitution (V709L), and at amino acid 718, a change of G to A at nucleotide 2236 (approximately 2236G to A) causing a glycine to serine substitution (G718S). Polymorphisms identified were at nucleotides approximately 2113G to C and approximately 2176T to C. | Hypohidrosis |
T-cell lymphoblastic lymphoma (T-LLy) and T-cell acute lymphoblastic leukemia (T-ALL) have historically been considered a spectrum of the same disease. However, recent evidence demonstrating differential responses to chemotherapy raise the possibility that T-LLy and T-ALL are distinct clinical and biologic entities. Here, we examine differences between the 2 diseases and use illustrative cases to highlight key recommendations on how to best treat patients with newly diagnosed and relapsed/refractory T-LLy. We discuss results of recent clinical trials incorporating use of nelarabine and bortezomib, choice of induction steroid, role of cranial radiotherapy, and risk stratification markers to identify patients at highest risk of relapse and to further refine current treatment strategies. Because prognosis for relapsed or refractory T-LLy patients is poor, we discuss ongoing investigations incorporating novel therapies, including immunotherapeutics, into upfront and salvage regimens and the role of hematopoietic stem cell transplantation." | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma |
Human pluripotent stem cells (hPSCs) can acquire non-random genomic variation during culture. Some of these changes are common in tumours and confer a selective growth advantage in culture. Additionally, there is evidence that reprogramming of human induced pluripotent stem cells (hiPSCs) introduces mutations. This poses a challenge to both the safety of clinical applications and the reliability of basic research using hPSCs carrying genomic variation. A number of methods are available for monitoring the genomic integrity of hPSCs, and a balance between practicality and sensitivity must be considered in choosing the appropriate methods for each use of hPSCs. Adjusting protocols by which hPSCs are derived and cultured is an evolving process that is important in minimising acquired genomic variation. Assessing genetic variation for its potential impact is becoming increasingly important as techniques to detect genome-wide variation improve." | Induced Pluripotent Stem Cells |
Purpose. To determine the incidence of neurologic complications of cerebral angiography in children with moyamoya syndrome (MMS) as compared to children without MMS. Materials and methods. One-hundred-ninety consecutive cerebral angiograms obtained in 152 children were evaluated. Sixty of these angiograms were obtained in 40 children with MMS. Patients underwent neurologic evaluation prior to and after the procedure. For this study, a neurologic complication was defined as any new focal neurologic deficit or alteration in mental status occurring during the procedure or within the ensuing 24 hours. Results. There were 2 neurologic complications within 24 hours of angiography, one in the MMS group and one in the non-MMS group. One patient with MMS became mute following angiography. The symptom resolved within 12 hours. One patient without MMS being examined postoperatively for residual arteriovenous malformation developed intracranial hemorrhage requiring reexploration 12 hours after the angiogram. Using a two-tail Fisher's exact test, there was no significant statistical difference in the ischemic (P = 0.3) or hemorrhagic (P = 1.0) complication rates between the group of patients with MMS and the non-MMS groups. Conclusion. The risk of a neurologic complication from cerebral angiography in children with MMS is low and not statistically different from the risk in children with other cerebrovascular disorders. | Cerebral Angiography |
Lincosamide inactivation nucleotidylation (Lin) enzyme determined by the pBI109PGL plasmid of Staphylococcus epidermidis exhibits high level resistance to lincomycin but sensitivity to clindamycin by standard susceptibility methods. Substrate profile determination showed clindamycin to be a better substrate for the enzyme than lincomycin. In cultures of the plasmid-harboring strain, the level of clindamycin decreased below the inhibitory concentration in the first 4 hours of incubation but the level of lincomycin persisted longer. The initial extended inhibitory effect of clindamycin is due to better membrane penetrating ability, resulting in a higher intracellular concentration than that of lincomycin. Moreover, energy-dependent reduction in clindamycin uptake, probably due to active efflux of clindamycin but not of lincomycin, was observed. A therapeutic effect of clindamycin is not expected in infections caused by Lin-producer strains because the bacteriostatic effect of the drug is rapidly eliminated after administration. | Lincosamides |
The first total synthesis of syringalide B, 2-(4-hydroxyphenyl)ethyl 4-O-[(E)-feruloyl]-beta-D-glucopyranoside, is described. The hydroxyl groups were protected with allyloxycarbonyl (Aoc) and allyl groups, which successfully prevent the migration of the feruloyl group during the deblocking procedure. | Glucosides |
The strategy of the Silk Road Economic Belt in China has promoted the urban development of the backward regions in the west, but it might also cause serious eco-environmental concerns. Studying the coupling relationship between urbanization and the eco-environment (UEE) is essential to promote the sustainable development in backward regions. This study developed a combined method of coupling coordination degree (CCD) model, linear regression, and gray relational analysis (GRA) model to investigate the spatio-temporal coupling relationship and the influencing factors between UEE in Ningxia Hui Autonomous Region (NHAR), a typical backward region along the Silk Road Economic Belt. Results show that (1) the economic urbanization and eco-environmental pressure made the largest contribution to the system of urbanization and eco-environment, respectively. (2) The overall CCD in NHAR showed a linear upward trend from 2001 to 2018, while the CCD of each district presented significant spatial difference. The CCDs in the more developed northern regions were generally higher than those in southern mountainous regions. (3) Furthermore, population factors were the main mechanism imposing stress on the eco-environment, and the factors of eco-environmental status had higher restrictive effect on urban development in NHAR. This study could provide theoretical basis for investigating the interaction between UEE in backward regions, which might enable policymakers to formulate targeted sustainable development plans. | Spatio-Temporal Analysis |
While the phenomena described under the terms transitivism and appersonation are well known, they have not been studied in detail either from the descriptive or from the psychopathological standpoints. Here only a brief reference is made to the descriptive data. An account of the psychopathological hypotheses on which an explanation of the phenomena is based is followed by a discussion of the relevance of the clinical manifestations for a theory of psychosis. | Cathexis |
Sialoglycoconjugates form the outermost layer of animal cells and play a crucial role in cellular communication processes. An essential step in the biosynthesis of sialylated glycoconjugates is the activation of sialic acid to the monophosphate diester CMP-sialic acid. Only the activated sugar is transported into the Golgi apparatus and serves as a substrate for the linkage-specific sialyltransferases. Interference with sugar activation abolishes sialylation and is embryonic lethal in mammals. In this chapter we focus on the enzyme catalyzing the activation of sialic acid, the CMP-sialic acid synthetase (CMAS), and compare the enzymatic properties of CMASs isolated from different species. Information concerning the reaction mechanism and active site architecture is included. Moreover, the unusual nuclear localization of vertebrate CMASs as well as the biotechnological application of bacterial CMAS enzymes is addressed." | N-Acylneuraminate Cytidylyltransferase |
This chapter presents a method called PolyA-iEP that has been developed for the prediction of polyadenylation sites. More precisely, PolyA-iEP is a method that recognizes mRNA 3'ends which contain polyadenylation sites. It is a modular system which consists of two main components. The first exploits the advantages of emerging patterns and the second is a distance-based scoring method. The outputs of the two components are finally combined by a classifier. The final results reach very high scores of sensitivity and specificity. | RNA, Messenger |
Phylogenetic analyses of small viral K(+) channels suggests that they did not originate from their hosts, but instead could be the source of the postulated pore precursor in the evolution of K(+) channels. | Potassium Channels |
CONTEXT: To investigate the effects of steroid injection (STE), prolotherapy (PRO), and exercise therapy in the treatment of partial tears of the supraspinatus. DESIGN: A retrospective cohort study. METHODS: A total of 64 patients with clinically and radiologically diagnosed partial-thickness supraspinatus tear who received either a cortisone injection (STE), dextrose PRO, or physical therapy combined with home-based exercise therapy were included. Main outcome measures were patients' visual analog scale scores, Western Ontario Rotator Cuff (WORC) Index scores, and the Shoulder Pain and Disability Index scores at the baseline, 3 weeks, and 3 months. RESULTS: The effect of group, time, and group-time interaction on visual analog scale, WORC, and Shoulder Pain and Disability Index scores was statistically significant (P < .001). Visual analog scale and Shoulder Pain and Disability Index scores were the lowest in the STE group at week 3, and the lowest in the PRO group at month 3 (P < .001). WORC scores of the STE group were the highest at week 3 (P < .001). At month 3, WORC scores of STE and PRO groups were similar (P = .089), but significantly higher than exercise therapy. CONCLUSIONS: Corticosteroids provide a fast pain-relieving effect and improvement in function in partial-thickness rotator cuff tears, but these effects diminish over time, whereas PRO provides a long-lasting effect. | Prolotherapy |
Pyrrole-imidazole polyamides are ligands that bind in the minor groove of DNA with high affinity and sequence selectivity. Molecules of this class have been shown to disrupt specific transcription factor-DNA interactions and to inhibit basal and activated transcription from various RNA polymerase II and III promoters. A set of eight-ring hairpin-motif pyrrole-imidazole polyamides has been designed to bind within the binding site for the human cytomegalovirus (CMV) UL122 immediate early protein 2 (IE86). IE86 represses transcription of the CMV major immediate early promoter (MIEP) through its cognate cis recognition sequence (crs) located between the TATA box and the transcription initiation site. The designed polyamides bind to their target DNA sequence with nanomolar affinities and with a high degree of sequence selectivity. The polyamides effectively block binding of IE86 protein to the crs in DNase I footprinting experiments. A mismatch polyamide, containing a single imidazole to pyrrole substitution, and also a polyamide binding to a site located 14 base pairs upstream of the repressor binding site, do not prevent IE86 binding to the crs. IE86-mediated transcriptional repression in vitro is relieved by a match polyamide but not by a mismatch polyamide. Transcription from a DNA template harboring a mutation in the crs is not affected either by IE86 protein or by the match polyamides. These results demonstrate that this new class of small molecules, the pyrrole-imidazole polyamides, are not only effective inhibitors of basal and activated transcription, but also can be used to activate transcription by blocking the DNA-binding activity of a repressor protein. | Enzyme Repression |
BACKGROUND: The ECG features of Andersen-Tawil syndrome (ATS) patients with KCNJ2 mutations (ATS1) have not been systematically assessed. This study aimed to define ECG features of KCNJ2 mutation carriers, to determine whether characteristic T-U-wave patterns exist, and to establish whether T-U patterns predict the ATS1 genotype. METHODS AND RESULTS: In phase I, evaluation of T-U morphology in ECGs of 39 KCNJ2 mutation carriers identified characteristic T-U patterns: prolonged terminal T downslope, wide T-U junction, and biphasic and enlarged U waves. In phase II, ATS1 genotype prediction by T-U pattern was evaluated in the next 147 ECGs (57 other KCNJ2 mutation carriers, 61 unaffected family members, and 29 ATS patients without KCNJ2 mutations), with a sensitivity of 84% and specificity of 97%. Characteristic T-U patterns were present in 91% (87/96), in whom an enlarged U wave was predominant (73%). In phase III, QTc, QUc, and T- and U-wave duration/amplitude were compared in the 96 ATS1, 29 non-KCNJ2 ATS, and 75 normal subjects. In ATS1 patients, QUc, U-wave duration and amplitude, and QTc were all increased (P<0.001), but median QTc and interquartile range (IQR) were just 440 ms (IQR, 28 ms) compared with 420 ms (IQR, 20 ms) in normal subjects and 425 ms (IQR, 48 ms) in ATS non-KCNJ2 patients. CONCLUSIONS: In ATS1 patients, gene-specific T-U-wave patterns resulting from decreased IK1 owing to KCNJ2 mutations can aid diagnosis and direct genotyping. The normal QTc, distinct ECG, and other clinical features distinguish ATS1 from long-QT syndrome, and it is best designated as ATS1 rather than LQT7. | Andersen Syndrome |
miRNA-132/212 are small regulators of gene expression with a function that fulfills a vital function in diverse biological processes including neuroprotection of cells with prolonged longevity in neurons and the cardiovascular system. In neurons, miRNA-132 appears to be essential for controlling differentiation, development, and neural functioning. Indeed, it also universally promotes axon evolution, nervous migration, plasticity as well, it is suggested to be neuroprotective against neurodegenerative diseases. Moreover, miRNA-132/212 disorder leads to neural developmental perturbation, and the development of degenerative disorders covering Alzheimer's, Parkinson's, and epilepsy's along with psychiatric perturbations including schizophrenia. Furthermore, the cellular mechanisms of the miRNA-132/212 have additionally been explored in cardiovascular diseases models. Also, the miRNA-132/212 family modulates cardiac hypertrophy and autophagy in cardiomyocytes. The protective and effective clinical promise of miRNA-132/212 in these systems is discussed in this review. To sum up, the current progress in innovative miRNA-based therapies for human pathologies seems of extreme concern and reveals promising novel therapeutic strategies. | Molecular Targeted Therapy |
The effects of polychlorinated biphenyls (PCBs) on development and reproduction are well documented. However, very little is known about the effects of PCBs on sexual behavior. In this study, we examined the effects of two commercial PCB mixtures, Aroclor 1221 (A1221) and Aroclor 1254 (A1254), on the development of female sexual behavior and of the incertohypothalamic dopaminergic cells (A11 and A13) in Long-Evans rats. Neonatal exposure to A1254 significantly reduced sexual receptivity and reduced the female's latency to approach a male after an intromission. Neonatal treatment with A1221 did not affect female sexual behavior nor did treatment of adult females with A1221 or A1254. Since sexual behavior is affected by dopamine and since PCBs have been reported to alter dopamine content in the brain, we examined the effects of A1221 or A1254 on dopaminergic cells in the incertohypothalamic region of neonatally exposed rats. None of the treatments significantly affected the number of A11 or A13 neurons that were immunoreactive for tyrosine hydroxylase (TH) or the expression of Fos (i.e., the product of the immediate early gene c-fos) in these dopaminergic neurons. Therefore, the disruption of behavior induced by neonatal treatment with A1254 does not appear to be mediated by toxic effects of the mixture on incertohypothalamic dopaminergic systems. | Polychloroterphenyl Compounds |
Elatine is a genus in which, flower and seed characteristics are the most important diagnostic features; i.e. seed shape and the structure of its cover found to be the most reliable identification character. We used a combination of classic discriminant methods by combining with deep learning techniques to analyze seed morphometric data within 28 populations of six Elatine species from 11 countries throughout the Northern Hemisphere to compare the obtained results and then check their taxonomic classification. Our findings indicate that among the discriminant methods, Quadratic Discriminant Analysis (QDA) had the highest percentage of correct matching (mean fit-91.23%); only the deep machine learning method based on Convolutional Neural Network (CNN) was characterized by a higher match (mean fit-93.40%). The QDA method recognized the seeds of E. brochonii and E. orthosperma with 99% accuracy, and the CNN method with 100%. Other taxa, such as E. alsinastrum, E. trianda, E. californica and E. hungarica were matched with an accuracy of at least 95% (CNN). Our results indicate that the CNN obtains remarkably more accurate classifications than classic discriminant methods, and better recognizes the entire taxa pool analyzed. The least recognized species are E. macropoda and E. hexandra (88% and 78% match). | Discriminant Analysis |
Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum. | Histone Demethylases |
We report the first synthesis of the unnatural enantiomer of desmosterol (ent-desmosterol). The sterol nucleus was constructed enantiospecifically, followed by stepwise addition of the side chain. Beginning with ent-androst-4-ene-3,17-dione, ent-desmosterol was synthesized in 13 steps and 20% yield. Protected ent-desmosterol was subjected to catalytic deuteration to afford ent-deuterocholesterol. Ent-desmosterol and ent-deuterocholesterol will be used to study the importance of sterol absolute configuration for sterol-lipid interactions in biophysical studies and in biological systems. | Dehydrocholesterols |
The wide diversity of articles in this issue reveals an explosion of evidence for the mechanisms of prediction in the visual system. When thought of as visual priors, predictive mechanisms can be seen as tightly interwoven with incoming sensory data. Prediction is thus a fundamental and essential aspect not only of visual perception but of the actions that are guided by perception. | Saccades |
Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs. | Skin Diseases, Papulosquamous |
Cervicitis is an extremely common gynecological disease and can be induced by diverse factors such as Neisseria gonorrhoeae, Chlamydia trachomatis, and Mycoplasma genitalium infections. Long-term unhealed cervicitis may lead to a series of diseases including endometritis, salpingitis, pelvic inflammatory disease, and chorioamnionitis. However, the pathogenesis of cervicitis remains unknown. Ainsliaea fragrans Champ. (AFC) has been widely used in clinical treatment of cervicitis. In the present study, we performed an integrative investigation involving histopathology analysis and non-target plasma metabolomics analysis in a cervicitis rat model induced by phenol mucilage, using ultra-performance liquid chromatography coupled with a tandem quadrupole time-of-flight mass spectrometry approach. Based on the integrative investigation, marked metabolomic differences were identified between the cervicitis and control groups using multivariate analysis. As a result, 32 potential biomarkers were identified in the response to cervicitis, and were involved in arachidonic acid metabolism, linoleic acid metabolism, primary bile acid biosynthesis, taurine and hypotaurine metabolism, pantothenate and CoA biosynthesis, and glycerophospholipid metabolism. After treatment, a total of 27 potential biomarkers exhibited altered levels in the AFC group compared to the model group, and 12 metabolites including 1-stearoylglycerophosphoinositol, bolasterone, lysoPC(16:0), lysoPC(20:4), lysoPC(P-16:0), lysoPC(P-18:0), lysoPC(P-18:1), stearoylcarnitine, taurine, lysoPC(17:0), 20-hydroxyeicosatetraenoic acid, and 1-arachidonoylglycerophosphoinositol returned to their normal levels. This study suggested that the therapeutic mechanism of AFC is related to those altered endogenous metabolites. | Uterine Cervicitis |
BACKGROUND: Despite its widespread uses in Chinese and European medicine, Styphnolobium japonicum (Chinese scholar tree, formerly Sophora japonicum) has not been extensively investigated for its potential to protect against neurodegenerative processes and to promote resistance to oxidative stress. In this study, we evaluated the neuroprotective activities of a hydroalcoholic extract from Chinese scholar tree fruits that could be possibly linked to its antioxidant properties using Caenorhabditis elegans as a well-established in vivo model. METHODS: Survival rate in mutant daf-16 and skn-1 worms, stressed by the pro-oxidant juglone and treated with the extract, was tested. Localization of the transcription factors SKN-1 and DAF-16, and expression of gst-4 were measured. For evaluation of neuroprotective effects, formation of polyglutamine (polyQ40) clusters, alpha-synuclein aggregates, loss of amphid sensilla (ASH) neuronal function, and amyloid beta (Abeta) accumulation (as markers for Huntington's, Parkinson's, and Alzheimer's) was examined. RESULTS: The extract, which contains substantial amounts of phenolic phytochemicals, showed an increase in the survival rate of worms challenged with juglone in daf-16 mutants but not in skn-1 mutants. The transcription factor SKN-1 was activated by the extract, while DAF-16 was not affected. Upon application of the extract, a significant decline in GST-4 levels, polyQ40 cluster formation, number of lost ASH sensory neurons, alpha-synuclein aggregation, and paralysis resulting from Abeta accumulation was observed. CONCLUSIONS: Styphnolobium japonicum fruit extract activated the SKN-1/Nrf2 pathway, resulting in oxidative stress resistance. It revealed promising pharmacological activities towards treatment of Huntington's, Parkinson's, and Alzheimer's diseases. Polyphenolics from Styphnolobium japonicum may be a promising route towards treatment of CNS disorders, but need to be tested in other in vivo systems. | Sophora japonica |
Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the alpha subunit of the stimulatory G protein (Gsalpha), a key component of the PTH/PTHrP signaling pathway. Since its first description, different studies unveiled, beside the molecular basis for PHP, the existence of different subtypes and of diseases in differential diagnosis associated with genetic alterations in other genes of the PTH/PTHrP pathway. The clinical and molecular overlap among PHP subtypes and with different but related disorders make both differential diagnosis and genetic counseling challenging. Recently, a proposal to group all these conditions under the novel term inactivating PTH/PTHrP signaling disorders (iPPSD)" was promoted and, soon afterwards, the first international consensus statement on the diagnosis and management of these disorders has been published. This review will focus on the major and minor features characterizing PHP/iPPSDs as a group and on the specificities as well as the overlap associated with the most frequent subtypes." | Pseudohypoparathyroidism |
An undescribed species of freshwater ostracod belonging to the genus Pseudostrandesia Savatenalinton and Martens, 2009 was collected from two pet shops in the Kanto region of central Japan. This species, herein named Pseudostrandesia tenebrarum sp. nov., is similar to four species previously reported from Southeast Asia, but can be distinguished by carapace and appendage features. It is the second species of the genus for which males are known. Of the nine previously described species in the genus, one is exclusively known from Turkey, and the others are found in Southeast Asia and the vicinity, one of which is also recorded in India and east China. There are two scenarios to explain the existence of Pseudostrandesia tenebrarum sp. nov. in pet shops in Japan: it is either native to Japan but has yet to be discovered in its natural habitat, or it is an alien species, perhaps unwittingly imported with plants or fish for the pet trade. We review the likelihood of both scenarios, and conclude that although there is insufficient evidence to be sure, it is potentially an alien species in Japan. The most likely origin is Southeast Asia, as evidenced by its close morphological resemblance to particular Southeast Asian species. Juveniles as well as adults were recovered, indicating that this species is reproducing in the pet trade, supporting the notion that it has invasive potential to areas outside of its natural range. The description and report of this species highlights a possible introduction of an alien species to Japan, and facilitates further monitoring. | Crustacea |
The Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurological disorder characterized by progressive pontobulbar palsy associated with sensorineural deafness. Fifty-eight cases have been reported in just over 100 years. The female to male ratio is approximately 3:1. The age of onset of the initial symptom varies from infancy to the third decade. The syndrome most frequently presents with sensorineural deafness, which is usually progressive and severe. Lower cranial nerve involvement and lower and upper motor neuron limb signs are common neurological features. Other features include respiratory compromise (the most frequent non-neurological finding), limb weakness, slurring of speech, facial weakness, and neck and shoulder weakness. Optic atrophy, retinitis pigmentosa, macular hyperpigmentation, autonomic dysfunction, epilepsy may occur. The etiopathogenesis of the condition remains elusive. Approximately 50% of cases are familial, of which autosomal recessive is suggested. The remaining cases are sporadic. The diagnosis is usually based on the clinical presentation. Investigations (neurophysiological studies, magnetic resonance imaging of the brain, muscle biopsy, cerebrospinal fluid examination) are done to exclude other causes or to confirm the clinical findings. The differential diagnoses include the Fazio-Londe syndrome, amyotrophic lateral sclerosis, Nathalie syndrome, Boltshauser syndrome and Madras motor neuron disease. Treatment with steroids or intravenous immunoglobulin may result in temporary stabilization of the syndrome. However, the mainstays of management are supportive and symptomatic treatment, in particular assisted ventilation and maintenance of nutrition via gastrostomy. The clinical course of BVVL is variable and includes gradual deterioration (almost half of cases), gradual deterioration with stable periods in between (a third of cases) and deterioration with abrupt periods of worsening (just under a fifth of cases). After the initial presentation, one third of patients survive for ten years or longer. | Bulbar Palsy, Progressive |
OBJECTIVE: To compare the effects between concentrated-dose and non-concentrated-dose pralidoxime chloride on respiratory muscle paralysis(RMP) in acute organophosphorus pesticide poisoning(AOPP). METHODS: 76 cases of RMP due to AOPP were involved in a retrospective study. All the patients were poisoned through ingestion. According to the administered dose of pralidoxime chloride within the first three days after the onset, the patients were divided into two groups: Group A consisted 30 patients; they were given pralidoxime chloride 10.0-25.8 grams (with an average of 11.4 grams) everyday in the first three days after the onset. Group B included 46 patients; the dose of pralidoxime chloride used daily in the first three days ranged from 3.3 to 8.6 grams (average 6.3). RESULTS: The curative rate and the death rate in group A were 73.3% and 26.7% respectively, while those in group B were 21.7% and 78.3% respectively. The curative rate in group A was significantly higher than that in group B (chi 2 = 19.83, P < 0.005). CONCLUSION: Concentrated-dose pralidoxime chloride was more effective than non-concentrated-dose for patients with RMP due to AOPP and this kind of administration could remarkably improve the prognosis in such patients. | Pralidoxime Compounds |
Acute kidney injury (AKI) is defined by changes in serum creatinine and urine output (UO). Significant limitations exist regarding accurate ascertainment of urine output even within the intensive care unit. We sought to evaluate an automated urine output collections system and compare it to nursing measurements. We prospectively collected urine output using an electronic urine monitoring system and compared it to charted hourly UO in 44 patients after cardiac surgery at a single university hospital ICU. We calculated UO and oliguria rates and compared them to data from the sensor and from nursing charting. A total of 187 hourly UO measurements were obtained and on average, UO was reported 47 min late, with a median of 18 min, and a maximum of almost 6 h. Patients had a mean hourly UO of 76.3 ml over the observation period. Compared to manual measurements by study personnel, nurses significantly overestimated hourly UO by 19.9 ml (95% CI: 10.3; 29.5; p = < 0.001). By contrast, the mean difference between the UO measured with the sensor and by study personnel was 2.29 ml (95% CI: - 6.7; 11.3), p = 0.61. Electronic UO monitoring is significantly more accurate than nurse-performed manual measurements in actual intensive care patients. Furthermore, timely ascertainment of UO is difficult to achieve with manual technique, resulting in important delays in detecting oliguria perhaps leading to missed cases of AKI. | Oliguria |
The central protein of the four component sulfur oxidizing (Sox) enzyme system of Paracoccus pantotrophus, SoxYZ, carries at the SoxY subunit the covalently bound sulfur substrate which the other three proteins bind, oxidize, and release as sulfate. SoxYZ of different preparations resulted in different specific thiosulfate-oxidizing activities of the reconstituted Sox enzyme system. From these preparations SoxYZ was activated up to 24-fold by different reductants with disodium sulfide being the most effective and yielded a uniform specific activity of the Sox system. The activation comprised the activities with hydrogen sulfide, thiosulfate, and sulfite. Sulfide-activation decreased the predominant beta-sheet character of SoxYZ by 4%, which caused a change in its conformation as determined by infrared spectroscopy. Activation of SoxYZ by sulfide exposed the thiol of the C-terminal Cys-138 of SoxY as evident from alkylation by 4-acetamido-4'-maleimidylstilbene-2,2'-disulfonic acid. Also, SoxYZ activation enhanced the formation of the Sox(YZ)2 heterotetramer as evident from density gradient gel electrophoresis. The tetramer was formed due to an interprotein disulfide between SoxY to yield a SoxY-Y dimer as determined by combined high pressure liquid chromatography and mass spectrometry. The significance of the conformational change of SoxYZ and the interprotein disulfide between SoxY-Y is discussed. | Paracoccus pantotrophus |
Data on litter size, weaning weights at 60, 90, and 120 d, postweaning gains from weaning to 120 or 365 d of age, fleece weight, and fiber diameter from Targhee, Suffolk, and Polypay flocks participating in the U.S. National Sheep Improvement Program were used to estimate genetic parameters for litter size and genetic relationships between early-life traits and future litter size. Records on 7,591 lambings by 3,131 Targhee ewes, 10,295 lambings by 5,038 Suffolk ewes, and 6,061 lambings by 2,709 Polypay ewes were used. Heritability estimates for litter size ranged from .09 to .11 across breeds; repeatability ranged from .09 to .13. Additive genetic effects on litter size were generally positively, and occasionally significantly, correlated with animal additive genetic effects on weaning weights and postweaning gains. Genetic correlations (r(a)) ranged from .08 to .48 in Targhee and from .17 to .43 in Suffolk but were close to 0 in Polypay (-.14 to .09). Additive maternal effects on weaning weight were positively associated with litter size in Suffolk and Polypay; this correlation was negative (-.23 to -.35), but not significant, in Targhee. Fleece weight was not strongly associated with litter size; (r(a) = -.09 to .21). However, fiber diameter had a significant undesirable correlation with litter size (.30) in Targhee. Estimates of phenotypic correlations of litter size with early-life traits were uniformly small (-.02 to .08). Thus, although occasional genetic antagonisms between litter size and early-life traits were observed in these data, none appeared large enough to prevent simultaneous genetic improvement in both traits. | Litter Size |
BACKGROUND: The majority of stress-sensitive genes responds to cold and high light in the same direction, if plants face the stresses for the first time. As shown recently for a small selection of genes of the core environmental stress response cluster, pre-treatment of Arabidopsis thaliana with a 24 h long 4 degrees C cold stimulus modifies cold regulation of gene expression for up to a week at 20 degrees C, although the primary cold effects are reverted within the first 24 h. Such memory-based regulation is called priming. Here, we analyse the effect of 24 h cold priming on cold regulation of gene expression on a transcriptome-wide scale and investigate if and how cold priming affects light regulation of gene expression. RESULTS: Cold-priming affected cold and excess light regulation of a small subset of genes. In contrast to the strong gene co-regulation observed upon cold and light stress in non-primed plants, most priming-sensitive genes were regulated in a stressor-specific manner in cold-primed plant. Furthermore, almost as much genes were inversely regulated as co-regulated by a 24 h long 4 degrees C cold treatment and exposure to heat-filtered high light (800 mumol quanta m(- 2) s(- 1)). Gene ontology enrichment analysis revealed that cold priming preferentially supports expression of genes involved in the defence against plant pathogens upon cold triggering. The regulation took place on the cost of the expression of genes involved in growth regulation and transport. On the contrary, cold priming resulted in stronger expression of genes regulating metabolism and development and weaker expression of defence genes in response to high light triggering. qPCR with independently cultivated and treated replicates confirmed the trends observed in the RNASeq guide experiment. CONCLUSION: A 24 h long priming cold stimulus activates a several days lasting stress memory that controls cold and light regulation of gene expression and adjusts growth and defence regulation in a stressor-specific manner. | Gene Expression |
We used a beta-lactamase-producing (beta L+) strain of Streptococcus faecalis that also had high levels of resistance to all aminoglycosides to induce experimental endocarditis in rats. The rats were treated for five or 10 days with procaine penicillin, vancomycin, gentamicin, rifampin, or ciprofloxacin (alone or in various combinations), or with penicillin plus clavulanic acid. The levels of penicillin in serum and vegetations declined rapidly in the beta L+-infected rats treated with procaine penicillin alone, unlike the sustained levels of penicillin in either beta L- -infected rats treated with procaine penicillin or beta L+-infected rats treated with penicillin plus clavulanic acid. For the beta L+-infected rats, the enterococcal counts in vegetations were significantly reduced (greater than 3 log10 cfu/g) only by vancomycin and by penicillin plus clavulanic acid. The efficacy of the latter regimen probably resulted from the inhibition of penicillin inactivation by clavulanic acid in vegetations infected with the beta L+ strain. Our in vivo findings document the biologic significance of beta-lactamase production. | Penicillin G Procaine |
The oral lesions in 50 habitual snuff-dippers were graded on a four-point scale. The patients' tobacco and drinking habits were studied by means of a questionnaire. From each patient a biopsy was taken for histomorphological and histochemical analysis. A correlation between snuff habits and the clinical degrees was found, as well as between the snuff habits and certain superficial and deeply located cell changes. The incidence of keratinized lesions, sialadenitis and slight dysplasia (based on subjective evaluation under a light microscope) was higher than previously reported. Presence of dysplastic changes could not be predicted by means of the parameters which characterise the snuff habit or from the clinical grade. The histomorphological and histochemical results were interpreted as showing that the mucosa react to snuff inducing hyperplasia in the basal cell layers. In the surface layer indications of lethal damage were found. The overall stromal reaction to snuff was weak. However, the salivary glands and excretory ducts exhibited degenerative changes which were found to be more severe than the pathological changes in the surface epithelium. | Mouth Diseases |
Frozen section evaluation of head and neck squamous cell carcinoma (SCC) is critical for margin status and subsequent patient therapy. In this study, we retrospectively reviewed the rate of frozen-permanent section discrepancies in blocks with two frozen section levels compared to >/= three levels in oral cavity and oropharyngeal SCCs. A search of the cases with both intraoperative frozen sections and corresponding permanent sections for SCCs in the oral cavity and oropharynx was performed. Frozen sections and permanent slides were compared. The nature of discrepancies was assigned to one of the following: change in diagnosis, margin status, or distance of the tumor from the margin. The cause of the discrepancy was designated as one of the following: block sampling, gross sampling, interpretation, or technical error. The pathologist experience, frozen section technical experience, and intraoperative impact of each discrepancy were also evaluated. A total of 654 frozen and corresponding permanent blocks were assessed. For 532 of the frozen section blocks, two levels were cut, while 122 frozen section blocks had >/= three levels. Thirty-five frozen-permanent section discrepancies were observed (5.4% of all blocks). Among these, 2.5% had a possible or definitive intraoperative impact. The percentage of discrepancies in the >/= three levels group (5.7%) was slightly higher than the two-level group (5.3%), and this difference was not statistically significant. For the two-level group, the overall block sampling error rate was 4.5%. This was not significantly different from the 4.1% block sampling error rate seen in the >/= three levels group. The rate of block sampling discrepancy did not show significant differences based on attending or frozen section technical experience. A change in margin distance (closer margin detected on permanent) occurred in 4% of the blocks and involved 16% of the patients. This review of oral cavity and oropharynx SCCs frozen/permanent section discrepancies shows that the error rate is not significantly different depending on the number of levels cut. The results suggest that always performing more than two frozen section levels may not yield a decreased discrepancy rate. A change in margin distance occurred quite frequently, but only in rare cases it had a definitive impact on the intraoperative management. Given the importance of correct intraoperative diagnosis in patient management, additional levels may be warranted depending on the clinical scenario. | Margins of Excision |
We recently demonstrated a contributing role of spinal cord infiltrating CD4+ T lymphocytes in the maintenance of mechanical hypersensitivity in a rodent model of neuropathic pain, spinal nerve L5 transection (L5Tx). It has been demonstrated that microglia play a role in the etiology of pain states. We hypothesized that infiltrating CD4+ T lymphocytes communicate with microglia via a CD40-CD154 interaction. Here, we investigated the role of CD40 in the development of mechanical hypersensitivity post-L5Tx. CD40 KO mice displayed significantly decreased mechanical sensitivity compared with WT mice starting from day 5 post-L5Tx. Using bone marrow chimeric mice, we further identified a pro-nociceptive role of CNS microglial CD40 rather than the peripheral leukocytic CD40. Flow cytometric analysis determined a significant increase of CD40+ microglia in the ipsilateral side of lumbar spinal cord post-L5Tx. Further, spinal cord proinflammatory cytokine (IL-1beta, IL-6, IL-12, and TNF-alpha) profiling demonstrated an induction of IL-6 in both WT and CD40 KO mice post-L5Tx prior to the increase of microglial CD40 expression, indicating a CD40-independent induction of IL-6 following L5Tx. These data establish a novel role of microglial CD40 in the maintenance of nerve injury-induced behavioral hypersensitivity, a behavioral sign of neuropathic pain. | CD40 Antigens |
Steroid-5alpha-reductases (SRD5alpha) and steroid-5beta-reductase (SRD5beta) represent a convergence in evolution: they share similar biological functions, but do not have a common ancestor. In vertebrates, SRD5alpha and SRD5beta are involved in C-19 and C-21 steroid biosynthesis, bile acid biosynthesis and erythropoiesis. We compare and contrast the history, evolution, tissue distribution, enzyme characteristics and biological functions of SRD5alpha and SRD5beta and suggest possible future directions for research efforts. Both, the unique and overlapping roles that SRD5alpha and SRD5beta play in steroid hormone metabolism, are indicated. We also present the phylogeny of the SRD5alpha. The main SRD5alpha subfamilies obtained include, not only the well-known SRD5alpha type 1, type 2 and type 3, but also the synaptic glycoprotein (GPSN2)/trans-2,3-enoly-CoA reductase group. Phylogenetic analysis indicated that a eukaryotic ancestor likely underwent duplication events to generate these three subfamilies (type 1/2, type 3 and GPSN2 ancestors); both SRD5alpha type 1/2 and GPSN2 subfamilies may have evolved by ancient duplication events at the early stage of vertebrate and chordate evolution. | Oxidoreductases |
The global phenomenon of mangrove encroachment into saltmarshes has been observed across five continents. It has been proposed that this encroachment is driven in part by rising atmospheric CO(2) concentration and reduced salinity in saltmarshes resulting from rising sea levels enhancing the establishment success of mangrove seedlings. However, this theory is yet to be empirically tested at the community-level. In this study, we examined the effect of CO(2) and salinity on seedling growth of two mangrove species, Aegiceras corniculatum and Avicennia marina, grown individually and in a model saltmarsh community in a glasshouse experiment. We found that the shoot (210%) and root (91%) biomass of the saltmarsh species was significantly greater under elevated CO(2). As a result, both mangrove species experienced a stronger competitive effect from the saltmarsh species under elevated CO(2). Nevertheless, A. marina seedlings produced on average 48% more biomass under elevated CO(2) when grown in competition with the saltmarsh species. The seedlings tended to allocate this additional biomass to growing taller suggesting they were light limited. In contrast, A. corniculatum growth did not significantly differ between CO(2) treatments. However, it had on average 36% greater growth under seawater salinity compared to hypersaline conditions. Avicennia marina seedlings were not affected by salinity. From these results, we suggest that although CO(2) and salinity are not universal drivers determining saltmarsh-mangrove boundaries, it is likely that rising atmospheric CO(2) concentration and reduced salinity associated with sea level rise will enhance the establishment success of mangrove seedlings in saltmarshes, which may facilitate mangrove encroachment in the future. | Salinity |
The affinity of anti-BSA antibody was measured daily in rabbits with acute immune complex disease. Affinity values increased with time (r = 0.87: p less than 0.01). Antibody affinity before antigen elimination was 5.3 +/- 0.7 X 10(5)M-1 (Mean +/- SEM, n = 19); affinity after antigen elimination was 9.6 +/- 1.4 X 10(5)M-1 (n = 7). (p less than 0.01: Student's t-test). At the time serum creatinine was elevated antibody affinity was low averaging 7.6 +/- 1.24 X 10(5)M-1 (n = 9). These findings support the hypothesis that complexes of low affinity antibody and antigen may participate in acute immune complex injury. | Immune Complex Diseases |
Burns are the second most common cause of death in childhood. More than half of pediatric burns are partial-thickness scald burns; the majority occur in the kitchen. Generally, minor burns may be treated on an outpatient basis, while moderate burns are treated in a community hospital. Children with major burns should be transferred to a regional burn unit as soon as possible after stabilization, provision of fluids and, if necessary, intubation. | Burns |
Complete pangenomics is crucial for understanding genetic diversity and evolution across the tree of life. Chromosome-scale, haplotype-resolved pangenomics allows complex structural variations, long-range interactions, and associated functions to be discerned in species populations. We explore the need for high-resolution pangenomes, discuss computational strategies for their development, and describe applications in biodiversity and human health. | Haplotypes |
OBJECTIVE: Petrosquamosal sinus (PSS) is an embryonic emissary vein of the temporal bone connecting the intracranial and extracranial venous networks, which is present in some variants of venous cerebral drainage. The aim of the present study was to analyze 20 cases of PSS and to present its clinical characteristics and implications. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE: By reviewing retrospective medical records and TBCT findings, a total of 20 PSS cases were found. Based on the shapes of PSS demonstrated on TBCT, PSS was classified into tortuous and straight types. The course and thickness of PSS were also investigated. The average thicknesses of PSS between tortuous and straight types were compared. RESULTS: The mean age of the patients was 54.1 +/- 16.2 years. The study group consisted of 7 male (35.0%) and 13 female (65.0%) patients. Eleven cases were found on the right side and 8 cases on the left side. The mean diameter of the bony canal that PSS courses on TBCT was 2.57 +/- 0.88 mm. Its maximal and minimal diameters were 4.2 and 0.7 mm. The average diameter of tortuous type PSSs (3.04 +/- 0.75 mm) was significantly larger compared with that of straight-type PSSs (2.09 +/- 0.76 mm) (p < 0.05). CONCLUSION: Preoperative identification of PSS using TBCT may be important for safe mastoid surgery. The presence of PSS should be identified with thorough examination of radiographic findings before mastoid surgery. | Cranial Sinuses |
Pathological fractures caused by osteolytic lesions seriously threaten the health of patients. Osteoclasts play important roles in bone resorption whose hyperfunction are closely related to osteolytic lesions. Studies on osteoclast differentiation and function assist in the prevention of excessive bone loss associated diseases. We screened a variety of natural compounds with anti-inflammatory effect and found that poria cocos polysaccharide (PCP) inhibited RANKL-induced osteoclast formation and bone resorption via TRAcP staining, immunofluorescence, RT-PCR and western blot. PCP down-regulated phosphorylation of STAT3, P38, ERK and JNK, and thus repressed the expression of NFAcT1 and c-Fos during RANKL-induced osteoclastogenesis. Besides, the expression of bone resorption related genes such as TRAcP and CTSK was suppressed by PCP. The results suggest that PCP can be invoked as a candidate for the treatment of osteolytic diseases by inhibiting osteoclastogenesis. | Wolfiporia |
Bacterial luciferase (Lux) catalyzes oxidation of reduced flavin mononucleotide (FMN) and aldehyde to form oxidized FMN and carboxylic acid via molecular oxygen with concomitant light generation. The enzyme is useful for various detection applications in biomedical experiments. Upon reacting with oxygen, the reduced FMN generates C4a-peroxy-FMN (FMNH-C4a-OO(-)) as a reactive intermediate, which is required for light generation. However, the mechanism and control of FMNH-C4a-OO(-) formation are not clear. This work investigated the reaction of FMNH-C4a-OO(-) formation in Lux using QM/MM methods. The B3LYP/6-31G*/CHARMM27 calculations indicate that Lux controls the formation of FMNH-C4a-OO(-) via the conserved His44 residue. The steps in intermediate formation are found to be as follows: (i) H(+) reacts with O(2) to generate (+)OOH. (ii) (+)OOH attacks C4a of FMNH(-) to generate FMNH-C4a-OOH. (iii) H(+) is transferred from FMNH-C4a-OOH to His44 to generate FMNH-C4a-OO(-) while His44 stabilizes FMNH-C4a-OO(-) by forming a hydrogen bond to an oxygen atom. This controlling key mechanism for driving the change from FMNH-C4a-OOH to the FMNH-C4a-OO(-) adduct is confirmed because FMNH-C4a-OO(-) is more stable than FMNH-C4a-OOH in the luciferase active site. | Flavins |
PURPOSE: The purpose of this study was to examine the precision and accuracy of the Fiske 110 Osmolarity System under different protocols to determine the possible applications of this device in tear film research and clinical practice. METHODS: Three separate studies were performed. In the first, Fiske 110 measurements were made on undiluted and diluted (1:1, 1:4, and 1:9 dilutions) standard samples of different osmolarity values: 50, 290, and 850 mOsm/kg and 297 and 338 mOsm/L. In the second study, measurements were made on different types of contact lens care solutions. Finally, in an agreement study, measurements were made in two sets of 60 subjects to compare TearLab versus Fiske 110 (using both 2- and 4-muL tear sample). RESULTS: Although osmolarity measurements for undiluted solutions differed statistically from reference standard values, all biases were in the tolerance range proposed by the manufacturer except for the 850-mOsm/kg solution. No significant differences from reference osmolarity values were observed for the 1:1 and 1:4 diluted 297- and 338-mOsm/L H2O solutions, respectively, although all diluted solutions showed a possible bias out of the range provided. Osmolarities for the soft contact lens solutions fell within the range 293 to 309 mOsm/kg with the exception of Opti-Free Express (225 mOsm/kg). In the agreement study, significant differences were observed between measurements obtained using the TearLab and both Fiske 110 procedures, although the Fiske 110 (4 muL) procedure was closer to the TearLab than the Fiske (2 muL) procedure. CONCLUSIONS: For undiluted solutions, the Fiske 110 shows good performance, making it a useful device for osmolarity measurements in lens care solutions or eye drops. A worse performance was observed for more diluted standard solution samples. When testing diluted samples, performance was acceptable for osmolarity values close to tear values. | Osmometry |
The influenza virus hemagglutinin (HA) is a well-characterized integral membrane glycoprotein composed of three identical subunits. We have analyzed the formation of mixed trimers in cells expressing two different HA gene products. The results show efficient and essentially random assembly of functional hybrid trimers provided that the HAs are from the same HA subtype. Trimerization is thus a posttranslational event, and subunits are recruited randomly from a common pool of monomers in the endoplasmic reticulum. Mixed trimers were not observed between HAs derived from different subtypes, indicating that the trimerization event is sequence specific. Mixed trimers containing mutant subunits were, moreover, used to establish that the acid-induced conformational change involved in the membrane fusion activity of HA is a highly cooperative event. | Hemagglutinins, Viral |
Public accommodation laws (PALs) are used to address discrimination against minorities. There is broad discussion about using such laws to either protect or prohibit access to sex-segregated spaces for transgender people. Health care facilities are subject to PALs, which affect rooming assignments and access to sex-segregated environments. Around the time that a Massachusetts transgender PAL went into effect in October 2016, the first author (EB) facilitated 18 professional trainings at 5 health care facilities in greater Boston. During these trainings, staff repeatedly brought up 2 areas of moral concern reflecting public conversations about transgender rights: risk posed by the presence of transwomen in sex-segregated spaces and feelings of unpreparedness for dealing with anti-trans bias. This article discusses the role of education in responding to gender panic in inpatient settings." | Health Services for Transgender Persons |
Cu-containing nitrite reductases that convert NO(2)(-) to NO are critical enzymes in nitrogen-based energy metabolism. Among organisms in the order Rhizobiales, we have identified two copies of nirK, one encoding a new class of 4-domain CuNiR that has both cytochrome and cupredoxin domains fused at the N terminus and the other, a classical 2-domain CuNiR (Br(2D) NiR). We report the first enzymatic studies of a novel 4-domain CuNiR from Bradyrhizobium sp. ORS 375 (BrNiR), its genetically engineered 3- and 2-domain variants, and Br(2D) NiR revealing up to ~ 500-fold difference in catalytic efficiency in comparison with classical 2-domain CuNiRs. Contrary to the expectation that tethering would enhance electron delivery by restricting the conformational search by having a self-contained donor-acceptor system, we demonstrate that 4-domain BrNiR utilizes N-terminal tethering for downregulating enzymatic activity instead. Both Br(2D) NiR and an engineered 2-domain variant of BrNiR (Delta(Cytc-Cup) BrNiR) have 3 to 5% NiR activity compared to the well-characterized 2-domain CuNiRs from Alcaligenes xylosoxidans (AxNiR) and Achromobacter cycloclastes (AcNiR). Structural comparison of Delta(Cytc-Cup) BrNiR and Br(2D) NiR with classical 2-domain AxNiR and AcNiR reveals structural differences of the proton transfer pathway that could be responsible for the lowering of activity. Our study provides insights into unique structural and functional characteristics of naturally occurring 4-domain CuNiR and its engineered 3- and 2-domain variants. The reverse protein engineering approach utilized here has shed light onto the broader question of the evolution of transient encounter complexes and tethered electron transfer complexes. ENZYME: Copper-containing nitrite reductase (CuNiR) (EC 1.7.2.1). DATABASE: The atomic coordinate and structure factor of Delta(Cytc-Cup) BrNiR and Br(2D) NiR have been deposited in the Protein Data Bank (http://www.rcsb.org/) under the accession code 6THE and 6THF, respectively. | Achromobacter cycloclastes |
Hypertension is one of the most common worldwide diseases that afflict humans. Angiotensin I converting enzyme (ACE) catalyzes the formation of vasoconstrictor, angiotensin II, and the inactivation of vasodilator, bradykinin. The influences of ACE on blood pressure make it an ideal target clinically and nutritionally in the treatment of hypertension. A number of animal food-derived peptides have been reviewed about their in vitro and in vivo ACE inhibitory activities. The aim of this review is to discuss the plant food-derived angiotensin I converting enzyme (ACE) inhibitory peptides from sources, production, purification, and structure to in vitro and in vivo activities." | Angiotensin-Converting Enzyme Inhibitors |
People with HIV (PWH) on antiretroviral therapy (ART) experience elevated rates of neurological impairment, despite controlling for demographic factors and comorbidities, suggesting viral or neuroimmune etiologies for these deficits. Here, we apply multimodal and cross-compartmental single-cell analyses of paired cerebrospinal fluid (CSF) and peripheral blood in PWH and uninfected controls. We demonstrate that a subset of central memory CD4+ T cells in the CSF produced HIV-1 RNA, despite apparent systemic viral suppression, and that HIV-1-infected cells were more frequently found in the CSF than in the blood. Using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), we show that the cell surface marker CD204 is a reliable marker for rare microglia-like cells in the CSF, which have been implicated in HIV neuropathogenesis, but which we did not find to contain HIV transcripts. Through a feature selection method for supervised deep learning of single-cell transcriptomes, we find that abnormal CD8+ T cell activation, rather than CD4+ T cell abnormalities, predominated in the CSF of PWH compared with controls. Overall, these findings suggest ongoing CNS viral persistence and compartmentalized CNS neuroimmune effects of HIV infection during ART and demonstrate the power of single-cell studies of CSF to better understand the CNS reservoir during HIV infection. | Viral Transcription |
A previously described method of quantifying cerebral contusions in man (the contusion index) caused by non-missile head injury has been modified and applied to a larger series of cases, and used to assess contusions in experimental head injuries. The initial findings in man have been confirmed, viz. that contusions are most severe in the frontal and temporal lobes; that contusions may be entirely absent in a patient dying as a result of a head injury; that there is no correlation between the severity of contusions and the nature of the injury; that the concept of contrecoup must continue to be questioned; that contusions are more severe in patients who have a fracture of the skull in comparison to those who do not; that contusions are more severe in patients who do not experience a lucid interval than in those who do; and that contusions are less severe in patients with diffuse axonal injury than in those who do not have diffuse axonal injury. The distribution of contusions in subhuman primates is similar to that seen in man, and they occur more frequently with short duration than with long duration acceleration. | Cercopithecinae |
Spatial proteomics has recently garnered significant interest, as it offers to provide unprecedented insight into biological processes in both health and disease, by connecting protein expression patterns from the subcellular level to the tissue or even organism level. These high-content approaches generally rely on a high degree of multiplexing, whereby multiple proteins can be detected simultaneously. The most versatile multiplexing approaches utilize antibodies to confer specificity for various intracellular proteins of interest. Therefore, these methods must be able to differentiate many antibodies at once. In this chapter, we describe a simple and rapid approach to labeling antibodies with distinct epitope tags in a site-specific manner. This allows multiple antibodies, even from the same host species, to be uniquely identified and detected and offers a simple approach for spatial proteomic applications. | Antibodies, Phospho-Specific |
Alzheimer's disease (AD) afflicts millions of people worldwide and is caused by accumulated amyloid beta and tau pathology. Progression of tau pathology in AD may utilize prion mechanisms of propagation in which pathological tau aggregates released from one cell are taken up by neighboring or connected cells and act as templates for their own replication, a process termed 'seeding'. We have used HEK293T cells to model various aspects of pathological tau propagation, including uptake of tau aggregates, induced seeding by exogenous aggregates, seeding caused by Lipofectamine-mediated delivery to the cell interior, and stable maintenance of aggregates in dividing cells. The factors that regulate these processes are not well understood, and we hypothesized that AD risk modifier genes might play a role. We identified 22 genes strongly linked to AD via meta-analysis of genome-wide association study (GWAS). We used CRISPR/Cas9 to individually knock out each gene in HEK293T cells and verified disruption using genomic sequencing. We then tested the effect of gene knockout in tau aggregate uptake, naked and Lipofectamine-mediated seeding, and aggregate maintenance in these cultured cell lines. GWAS gene knockouts had no effect in these models of tau pathology. With obvious caveats due to the model systems used, these results imply that the 22 AD risk modifier genes are unlikely to directly modulate tau uptake, seeding, or aggregate maintenance in a cell-autonomous fashion. | Genes, Modifier |
Ferrous fumarate (Fersamal) and ferrous carbonate (Ferrodic) may produce false-positive results with the orthotolidine tablet tests (Occultest and Hematest) if administered to patients being investigated for alimentary bleeding. Misleading results are also likely if the benzidine test is employed as a filter-paper procedure. Ferrous sulphate, gluconate, succinate, iron and ammonium citrate, and other preparations of iron have no influence on the modern tablet tests for occult alimentary bleeding. | Occult Blood |
Cryogenic electron microscopy (cryo-EM) enables structure determination of macromolecular objects and their assemblies. Although the techniques have been developing for nearly four decades, they have gained widespread attention in recent years due to technical advances on numerous fronts, enabling traditional microscopists to break into the world of molecular structural biology. Many samples can now be routinely analyzed at near-atomic resolution using standard imaging and image analysis techniques. However, numerous challenges to conventional workflows remain, and continued technical advances open entirely novel opportunities for discovery and exploration. Here, I will review some of the main methods surrounding cryo-EM with an emphasis specifically on single-particle analysis, and I will highlight challenges, open questions, and opportunities for methodology development. | Cryoelectron Microscopy |
This study examined the effects of a simultaneous ischemic preconditioning (IPC) and SHAM intervention to reduce the placebo effect due to a priori expectation on the performance of knee extension resistance exercise. Nine moderately trained men were tested in three different occasions. Following the baseline tests, subjects performed a first set of leg extension tests after the IPC (3 X 5 min 50 mmHg above systolic blood pressure) on right thigh and the SHAM (same as IPC, but 20 mmHg) on left thigh. After 48 hours, the subjects performed another set of tests with the opposite applications. Number of repetitions, maximal voluntary isometric contraction (MVIC) and perceptual indicators were analyzed. After IPC and SHAM intervention performed at the same time, similar results were observed for the number of repetitions, with no significant differences between conditions (baseline x IPC x SHAM) for either left (p = 0.274) or right thigh (p = 0.242). The fatigue index and volume load did not show significant effect size after IPC and SHAM maneuvers. In contrast, significant reduction on left tight MVIC was observed (p = 0.001) in SHAM and IPC compared to baseline, but not for right thigh (p = 0.106). Results from the current study may indicate that applying IPC prior to a set of leg extension does not result in ergogenic effects. The placebo effect seems to be related to this technique and its dissociation seems unlikely, therefore including a SHAM or placebo group in IPC studies is strongly recommended. | Ischemic Preconditioning |
A short-cut review was performed to evaluate whether irrigation or active blown air was the most effective treatment for CS gas irritation of the eyes. No published studies have answered this question. The clinical bottom line is that either treatment could be used to relieve eye symptoms after CS gas exposure." | o-Chlorobenzylidenemalonitrile |
Semen is collected and processed from a variety of animal species for use in artificial insemination breeding programmes. Because of the inherent nature of the semen collection process, bacterial contamination of the ejaculate is a common occurrence. Additionally, manipulation of the ejaculate during processing in the laboratory can expose the sample to possible introduction of bacterial contamination. If preventative measures at the stud fail to adequately control these risks, decreases in semen quality, dose longevity and fertility may occur. Multiple mammalian and non-mammalian sources have been identified as origins of contamination in the stud. Knowledge of these sources has aided the industries in developing strategies that help in controlling the introduction of contaminant bacteria in extended semen. A primary step in minimizing contamination is in the practice of good hygiene by stud personnel. Prudent general sanitation protocols should also be followed in the laboratory, animal housing and semen collection areas. Cleanliness and attention to the actual semen collection process can also aid in reducing bacterial load originating from the stud semen donor. Attentiveness to all of these steps significantly contributes to an overall reduction in the type and amount of bacterial contamination. However, their complete elimination still remains unavoidable. To address residual bacteria load in the sample, antimicrobials are commonly used in semen extenders intended to promote in vitro sperm longevity beyond that of a few hours. Current research by the animal industries continues in the selection and prudent use of antimicrobials that will lead to the success and sustainability of this modality in controlling bacterial contamination. | Semen Preservation |
Viral croup and epiglottitis are two major inflammatory causes of airway obstruction in children. Two conditions, spasmodic croup and membranous laryngotracheobronchitis, are also frequent causes of obstruction on an inflammatory basis. Rapid diagnosis and effective management are required to ensure an uncomplicated outcome. The pharmacologic treatment, role and timing of endoscopy, and airway management principles are discussed. | Croup |
BACKGROUND: The lack of non-invasive methods for detection of early micro-metastasis is a major cause of the poor prognosis of non-small cell lung cancer (NSCLC) brain metastasis (BM) patients. Herein, we aimed to identify circulating biomarkers based on proteomics for the early diagnosis and monitoring of patients with NSCLC BM. METHODS: Upregulated proteins were detected by secretory proteomics in the animal-derived high brain metastatic lung cancer cell line. A well-designed study composed of three independent cohorts was then performed to verify these blood-based protein biomarkers: the serum discovery and verification cohorts (n = 80; n = 459), and the tissue verification cohort (n = 76). Logistic regression was used to develop a diagnostic biomarker panel. Model validation cohort (n = 160) was used to verify the stability of the constructed predictive model. Changes in serum Cathepsin F (CTSF) levels of patients were tracked to monitor the treatment response. Progression-free survival (PFS) and overall survival (OS) were analysed to assess their prognostic relevance. RESULTS: CTSF and Fibulin-1 (FBLN1) levels were specifically upregulated in sera and tissues of patients with NSCLC BM compared with NSCLC without BM and primary brain tumour. The combined diagnostic performance of CTSF and FBLN1 was superior to their individual ones. CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of progression were detected earlier than the magnetic resonance imaging changes. Elevated expression of CTSF in NSCLC BM tissues was associated with poor PFS, and was found to be an independent prognostic factor. CONCLUSIONS: We report a novel blood-based biomarker panel for early diagnosis, monitoring of therapeutic response, and prognostic evaluation of patients with NSCLC BM. | Cathepsin F |
Indoor radon and its decay products are the primary sources of the population's exposure to background ionizing radiation. Radon decay products are one of the leading causes of lung cancer, with a higher lung cancer risk for smokers due to the synergistic effects of radon decay products and cigarette smoking. A total of 459 year-long radon measurements in 257 detached and semi-detached residential homes in southwest and south Greenland were carried out, and a dose assessment for adults was performed. The annual arithmetic and geometric means of indoor radon concentrations was 10.5 +/- 0.2 Bq m(-3) and 8.0 +/- 2.3 Bq m(-3) in Nuuk, 139.0 +/- 1.0 Bq m(-3) and 97.3 +/- 2.1 Bq m(-3) in Narsaq, and 42.1 +/- 0.7 Bq m(-3) and 22.0 +/- 3.1 Bq m(-3) in Qaqortoq. Arithmetic and geometric mean radon concentration of 79.0 Bq m(-3) and 50.3 Bq m(-3) were estimated for adult, person-weighted living in south Greenland. The total number of detached and semi-detached residential homes where indoor radon is exceeding 100 Bq m(-3), 200 Bq m(-3), and 300 Bq m(-3) is 37 homes (15.0%), 13 homes (5.2%), and 8 homes (3.2%), respectively. A positive correlation between indoor air radon concentrations and underlying geology was observed. The indoor radon contribution to the annual inhalation effective dose to an average adult was 0.5 mSv in Nuuk, 6.5 mSv in Narsaq, 2.0 mSv in Qaqortoq, and 4.0 mSv for south Greenland adult person weighted. The estimated annual average effective dose to adults in Narsaq is higher than the world's average annual effective dose of 1.3 mSv due to inhalation of indoor radon. Cost-efficient mitigation methods exist to reduce radon in existing buildings, and to prevent radon entry into new buildings. | Radon Daughters |
Thirty years of research have revealed the fundamental role of the ubiquitin-proteasome system in diverse aspects of cellular regulation in eukaryotes. The ubiquitin-protein ligases or E3s are central to the ubiquitin-proteasome system since they determine the specificity of ubiquitylation. The cullin-RING ligases (CRLs) constitute one large class of E3s that can be subdivided based on the cullin isoform and the substrate adapter. SCF complexes, composed of CUL1 and the SKP1/F-box protein substrate adapter, are perhaps the best characterized in plants. More recently, accumulating evidence has demonstrated the essential roles of CRL3 E3s, consisting of a CUL3 protein and a BTB/POZ substrate adaptor. In this Review, we describe the variety of CRL3s functioning in plants and the wide range of processes that they regulate. Furthermore, we illustrate how different classes of E3s may cooperate to regulate specific pathways or processes. | Cullin Proteins |
In two trials, 60 male commercial broilers were placed in each of eight environmentally controlled chambers receiving 0, 25, 50, or 75 ppm aerial ammonia from 1 to 28 days. Birds exposed to 25 ppm (lower concentration) ammonia gas developed ocular abnormalities but at a slower rate when compared with birds exposed to 50 and 75 ppm (higher concentrations). Birds exposed to higher concentrations also developed more severe lesions. With little atmospheric ammonia present after 28 days of the grow-out stage, the corneas indicated signs of healing. Lymphocytes and heterophils were seen in the iris at 49 days in ammonia-exposed birds even when ammonia exposure was terminated at 28 days. The lower ammonia concentrations resulted in abnormalities that were slight when compared with those seen at the higher ammonia concentrations. As measured by the incidence of inflammatory infiltrates in the trachea, lung, and air sacs, respiratory tract tissues did not appear to be affected by any tested level of aerial ammonia. The findings in this investigation represent the first report indicating that ammonia-induced uveitis in chickens clears rapidly after exposure to ammonia ceases. | Ammonia |
A case report and discussion of cutaneous odontogenic sinus tracts, frequently encountered but often misdiagnosed and mistreated, are presented. Awareness that periapical dental abscesses are the most common etiologic factor of cutaneous sinus tracts involving the face and neck will facilitate their early diagnosis and prevent needless treatment or anxiety for the patient. These lesions are often misinterpreted as chronic, resistant to therapy, pyogenic nodules, or granulomas. A high degree of suspicion is required for making the correct diagnosis, and dental roentgenographic studies should routinely be obtained in all such lesions. Permanent healing cannot be achieved unless the original site of infection is located and eradicated. | Oral Fistula |
The human myelin protein P2 is a membrane binding protein believed to maintain correct lipid composition and organization in peripheral nerve myelin. Its function is related to its ability to stack membranes, and this function can be enhanced by the P38G mutation, whereby the overall protein structure does not change but the molecular dynamics increase. Mutations in P2 are linked to human peripheral neuropathy. Here, the dynamics of wild-type P2 and the P38G variant were studied using quasielastic neutron scattering on time scales from 10 ps to 1 ns at 300 K. The results suggest that the mutant protein dynamics are increased on both the fastest and the slowest measured time scales, by increasing the dynamics amplitude and/or the portion of atoms participating in the movement. | Myelin P2 Protein |
Paramylon (beta-1,3-glucan) produced by Euglena gracilis displays antioxidant, antitumor, and hypolipidaemic functions. The biological properties of paramylon production by E. gracilis can be understood by elucidating the metabolic changes within the algae. In this study, the carbon sources in AF-6 medium were replaced with glucose, sodium acetate, glycerol, or ethanol, and the paramylon yield was measured. Adding 0.1260 g/L glucose to the culture medium resulted in the highest paramylon yield of 70.48 %. The changes in metabolic pathways in E. gracilis grown on glucose were assessed via non-targeted metabolomics analysis using ultra-high-performance liquid chromatography coupled to high-resolution quadrupole-Orbitrap mass spectrometry. We found that glucose, as a carbon source, regulated some differentially expressed metabolites, including l-glutamic acid, gamma-aminobutyric acid (GABA), and l-aspartic acid. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes further showed that glucose regulated the carbon and nitrogen balance through the GABA shunt, which enhanced photosynthesis, regulated the flux of carbon and nitrogen into the tricarboxylic acid cycle, promoted glucose uptake, and increased the accumulation of paramylon. This study provides new insights into E. gracilis metabolism during paramylon synthesis. | Euglena |
Ganglioside GM3 in the plasma membranes suppresses cell growth by preventing the autophosphorylation of the epidermal growth factor receptor (EGFR). Biological studies have suggested that GM3 interacts with the transmembrane segment of EGFR. Further biophysical experiments are particularly important for quantitative evaluation of the peptide-glycolipid interplay in bilayer membranes using a simple reconstituted system. To examine these interactions in this way, we synthesized the transmembrane segment of EGFR bearing a nitrobenzoxadiazole fluorophore (NBD-TM) at the N-terminus. The affinity between EGFR and GM3 was evaluated based on Forster resonance energy transfer (FRET) between NBD-TM and ATTO594-labeled GM3 in bilayers where their non-specific interaction due to lateral proximity was subtracted by using NBD-labeled phospholipid. This method for selectively detecting the specific lipid-peptide interactions in model lipid bilayers disclosed that the lateral interaction between GM3 and the transmembrane segment of EGFR plays a certain role in disturbing the formation of active EGFR dimers. | G(M3) Ganglioside |
BACKGROUND: Environmental noise pollution is regarded as a general stressor. Noise levels frequently exceed recommended noise levels by the World Health Organization in hospitals, especially in the operation room. The aim of this systematic review was to assess the effects of noise pollution on patient outcome and performance by operation room staff. In addition, the perception and attitude toward playing music in the operation room, which can increase noise levels, were assessed as well. MATERIALS AND METHODS: A systematic literature search of the databases Embase, Medline Ovid, and Cochrane from date of database inception until October 16(th), 2020 using the exhaustive literature search method was performed. Prospective studies evaluating the effect of noise on the patient, surgeons, anesthesiologists, nurses, and other operation room staff, or perception and attitude toward playing music in the operation room, were included. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines and was registered with PROSPERO (ID: 208282). RESULTS: The literature search generated 4758 articles, and 22 prospective studies (3507 participants) were included. Three of the four studies that investigated the effect of noise on patient outcome reported a significant reduction of complication rate in surgical patients, when noise levels were lower. Six studies assessed the effect of noise in the operation room on the staff (1383 participants). Over half of the surveyed staff found noise levels to be a disturbing stressor and negatively impact performance. Although music increased decibel levels in the operation room, most surveyed staff was positively predisposed toward playing music during surgery, believing it to improve both individual and team performance. In general, music was not considered to be distracting or impairing communication. CONCLUSIONS: Higher noise levels seem to have a negative effect on patient outcome and adversely affect performance by members in the operation room. Further research is needed to assess whether this knowledge can benefit patient outcome and surgical performance. Notably, attitude of surgical team members toward music during surgery is generally regarded favorable. | Noise, Occupational |
Within the last decade, and in particular since 2012, research has greatly extended our understanding of the molecular basis of systemic mast cell activation disease (MCAD). Initial studies demonstrated that somatic mutations in the tyrosine kinase KIT led to the establishment of a clonal mast cell population. Recent studies, in particular those involving next generation sequencing analyses of advanced systemic mastocytosis, have revealed mutations in additional genes. The respective genes encode proteins for various signaling pathways, epigenetic regulators, the RNA splicing machinery, and transcription factors. Although almost all of the detected mutations are somatic in nature, transgenerational transmission of MCAD appears to be quite common. However, the molecular mechanisms underlying genetic predestination, e.g. germline mutations and the contribution of epigenetic processes, still await identification. The aim of the present review is to present and discuss available genetic findings, and to outline the relationship between adult-onset systemic MCAD and childhood-onset mastocytosis, often termed cutaneous mastocytosis, on the basis of current genetic data. Finally, the implications of increased knowledge of the molecular basis of MCAD in terms of diagnostics and therapy are discussed. | Leukemia, Mast-Cell |
BACKGROUND: Pituitary tumor transforming gene (PTTG), also known as securin, is highly expressed in various tumors including pituitary, thyroid, colon, ovary, testis, lung, and breast. An overexpression of PTTG enhances cell proliferation, induces cellular transformation in vitro, and promotes tumor development in nude mice. PTTG also inhibits separation of sister chromatids leading to aneuploidy and genetic instability. A great amount of work has been undertaken to understand the biology of PTTG and its expression in various tumors. However, mechanisms by which PTTG mediates its tumorigenic function are not fully understood. To utilize this gene for cancer therapy, identification of the downstream signaling genes regulated by PTTG in mediation of its tumorigenic function is necessary. For this purpose, we expressed PTTG in human embryonic kidney (HEK293) cells that do not express PTTG and analyzed the downstream genes using microarray analysis. RESULTS: A total of 22,277 genes printed on an Affymetrix HG-U133A 2.0 GeneChip array were screened with labeled cRNA prepared from HEK293 cells infected with adenovirus vector expressing PTTG cDNA (AdPTTG cDNA) and compared with labeled cRNA prepared from HEK293 cells infected with control adenovirus (control Ad) or adenovirus vector expressing GFP (AdGFP). Out of 22,277 genes, 71 genes were down-regulated and 35 genes were up-regulated with an FDR corrected p-value of < or = 0.05 and a fold change of > or =2. Most of the altered genes identified are involved in the cell cycle and cell apoptosis; a few are involved in mRNA processing and nitrogen metabolism. Most of the up-regulated genes belong to the histone protein family. CONCLUSION: PTTG is a well-studied oncogene for its role in tumorigenesis. In addition to its importance in regulation of the cell cycle, this gene has also been recently shown to play a role in the induction of cell apoptosis. The microarray analysis in the present study demonstrated that PTTG may induce apoptosis by down-regulation of oncogenes such as v-Jun and v-maf and up-regulation of the histone family of genes. | Genes, jun |
Recent studies described the great impact of a non-benzotriazolic family of coupling reagents based on ethyl 2-cyano-2-(hydroxyimino)acetate, Oxyma, as a powerful coupling methodology for peptide synthesis. Here we present the synthesis and evaluation of the derived phosphonium salts O-[(1-cyano-2-ethoxy-2-oxoethylidene)amino]-oxytri(pyrrolidin-1-yl) phosphonium hexafluorophosphate (PyOxP) and tetrafluoroborate (PyOxB). Both coupling reagents exhibited higher capacity to suppress racemization in various peptide models and enhanced solubility in DMF and DCM than benzotriazole-based reagents. In addition, the hexafluorophosphate analog PyOxP, combined excellent stability with outstanding efficiency in the assembly of demanding penta and decapeptides that include consecutive Aib residues. Cyclization models revealed the advantages of PyOxP, which rendered a higher percentage of cyclic material than other known potent phosphonium salts. | Pregnadienes |
The Ras-Raf-MEK-MAPK (mitogen-activated protein kinase)-signaling pathway plays a key role in the regulation of many cellular functions, including cell proliferation, differentiation and transformation, by transmitting signals from membrane receptors to various cytoplasmic and nuclear targets. One of the key components of this pathway is the serine/threonine protein kinase, Raf. The Raf family kinases (A-Raf, B-Raf and C-Raf) have been intensively studied since being identified in the early 1980s as retroviral oncogenes, especially with respect to the discovery of activating mutations of B-Raf in a large number of tumors which led to intensified efforts to develop drugs targeting Raf kinases. This also resulted in a rapid increase in our knowledge of the biological functions of the B-Raf and C-Raf isoforms, which may in turn be contrasted with the little that is known about A-Raf. The biological functions of A-Raf remain mysterious, although it appears to share some of the basic properties of the other two isoforms. Recently, emerging evidence has begun to reveal the functions of A-Raf, of which some are kinase-independent. These include the inhibition of apoptosis by binding to MST2, acting as safeguard against oncogenic transformation by suppressing extracellular signal-regulated kinases (ERK) activation and playing a role in resistance to Raf inhibitors. In this review, we discuss the regulation of A-Raf protein expression, and the roles of A-Raf in apoptosis and cancer, with a special focus on its role in resistance to Raf inhibitors. We also describe the scaffold functions of A-Raf and summarize the unexpected complexity of Raf signaling. | raf Kinases |
The coccygeal region has complex anatomy, much of which may contribute to or be the cause of coccyx region pain (coccydynia). This anatomy is well depicted at imaging, and management is often dictated by what structures are involved. Coccydynia is a common condition that is known to be difficult to evaluate and treat. However, imaging can aid in determining potential causes of pain to help guide management. Commonly, coccydynia (coccygodynia) occurs after trauma and appears with normal imaging features at static neutral radiography, but dynamic imaging with standing and seated lateral radiography may reveal pathologic coccygeal motion that is predictive of pain. In addition, several findings seen at cross-sectional imaging in patients with coccydynia can point to a source of pain that may be subtle and easily overlooked. Radiology can also offer a role in management of coccygeal region pain with image-guided pain management procedures such as ganglion impar block. In addition to mechanical coccyx pain, a host of other conditions involving the sacrococcygeal region may cause coccydynia, which are well depicted at imaging. These include neoplasm, infection, crystal deposition, and cystic formations such as pilonidal cyst. The authors review a variety of coccydynia causes, their respective imaging features, and common management strategies.((c))RSNA, 2020. | Coccyx |
PURPOSE: To compare the relative efficacy of supportive therapies (inotropes, vasopressors, and mechanical circulatory support [MCS]) for adult patients with cardiogenic shock complicating acute myocardial infarction. SOURCE: We conducted a systematic review and network meta-analysis and searched six databases from inception to December 2021 for randomized clinical trials (RCTs). We evaluated inotropes, vasopressors, and MCS in separate networks. Two reviewers performed screening, full-text review, and extraction. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to rate the certainty in findings. The critical outcome of interest was 30-day all-cause mortality. PRINCIPAL FINDINGS: We included 17 RCTs. Among inotropes (seven RCTs, 1,145 patients), levosimendan probably reduces mortality compared with placebo (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.33 to 0.87; moderate certainty), but primarily in lower severity shock. Milrinone (OR, 0.52; 95% CI, 0.19 to 1.39; low certainty) and dobutamine (OR, 0.67, 95% CI, 0.30 to 1.49; low certainty) may have no effect on mortality compared with placebo. With regard to MCS (eight RCTs, 856 patients), there may be no effect on mortality with an intra-aortic balloon pump (IABP) (OR, 0.94; 95% CI, 0.69 to 1.28; low certainty) or percutaneous MCS (pMCS) (OR, 0.96; 95% CI, 0.47 to 1.98; low certainty), compared with a strategy involving no MCS. Intra-aortic balloon pump use was associated with less major bleeding compared with pMCS. We found only two RCTs evaluating vasopressors, yielding insufficient data for meta-analysis. CONCLUSION: The results of this systematic review and network meta-analysis indicate that levosimendan reduces mortality compared with placebo among patients with low severity cardiogenic shock. Intra-aortic balloon pump and pMCS had no effect on mortality compared with a strategy of no MCS, but pMCS was associated with higher rates of major bleeding. STUDY REGISTRATION: Center for Open Science ( https://osf.io/ky2gr ); registered 10 November 2020. | Simendan |
Degradation of para-toluate by Rhodococcus opacus 1cp was investigated. Activities of the key enzymes of this process, catechol 1,2-dioxygenase and muconate cycloisomerase, are detected in this microorganism. Growth on p-toluate was accompanied by induction of two catechol 1,2-dioxygenases. The substrate specificity and physicochemical properties of one enzyme are identical to those of chlorocatechol 1,2-dioxygenase; induction of the latter enzyme was observed during R. opacus 1cp growth on 4-chlorophenol. The other enzyme isolated from the biomass grown on p-toluate exhibited lower rate of chlorinated substrate cleavage compared to the catechol substrate. However, this enzyme is not identical to the catechol 1,2-dioxygenase cloned in this strain within the benzoate catabolism operon. This supports the hypothesis on the existence of multiple forms of dioxygenases as adaptive reactions of microorganisms in response to environmental stress. | Catechol 1,2-Dioxygenase |
Bacterial wilt, caused by Ralstonia solanacearum, is one of the most devastating plant diseases, affecting some economically important Solanaceae crops. In contrast, Solanum torvum, also known as wild eggplant, does not wilt when infested with R. solanacearum. In order to describe the mechanism underlying the response of S. torvum, it was compared with the cultivated eggplant, S. melongena, when both were infected with the same R. solanacearum strain. No wilting occurred in S. torvum, although the bacteria colonised roots and stems in both species within the first 24 h. There were marked differences beyond 24 h, consisting of high bacterial mortality in S. torvum. Using the calli model, our investigations revealed an increase in cell wall monoamine oxidase activity in S. torvum after R. solanacearum inoculation, which did not occur in S. melongena. | Ralstonia |
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