Miracle-dz/UniFAR-FTUs huggingface dataset:
A Specific Two-pore Domain Potassium Channel Blocker Defines the Structure of the TASK-1 Open Pore*

Two-pore domain potassium (K2P) channels play a key role in setting the membrane potential of excitable cells. Despite their role as putative targets for drugs and general anesthetics, little is known about the structure and the drug binding site of K2P channels. We describe A1899 as a potent and highly selective blocker of the K2P channel TASK-1. As A1899 acts as an open-channel blocker and binds to residues forming the wall of the central cavity, the drug was used to further our understanding of the channel pore. Using alanine mutagenesis screens, we have identified residues in both pore loops, the M2 and M4 segments, and the halothane response element to form the drug binding site of TASK-1. Our experimental data were used to validate a K2P open-pore homology model of TASK-1, providing structural insights for future rational design of drugs targeting K2P channels.
Viral hepatitis screening in transgender patients undergoing gender identity hormonal therapy

Background and aim Viral hepatitis is a global health issue and can lead to cirrhosis, liver failure, and hepatocellular carcinoma. Guidelines for viral hepatitis screening in the transgender population do not exist. Transgender patients may be at higher risk for contracting viral hepatitis due to socioeconomic and behavioral factors. The aim of this study was to measure the quality of screening, prevalence, and susceptibility of viral hepatitis, and to identify barriers to screening in transgender patients undergoing gender identity hormonal therapy. Methods LGBTQ-friendly clinic visits from transgender patients older than 18 years in New York City from 2012 to 2015 were reviewed. Results Approximately 13% of patients were screened for any viral hepatitis on initial consultation. Screening rates for hepatitis C virus (HCV), hepatitis B virus (HBV), and hepatitis A virus (HAV) at any point were 27, 22, and 20%. HAV screening was performed in 28% of the female to male (FtM) patients and 16% of male to female (MtF) (P<0.05) patients. HBV screening was performed in 30% of FtM patients and 18% of MtF patients (P<0.05). Thirty-one percent of FtM, 24% of MtF, and 17% of genderqueer patients were tested for HCV (P>0.05). Prevalence of HCV, HBV, and HIV in FtM was 0, 0, and 0.44% and that in MtF was 1.78, 0.89, and 1.78%, respectively. Percentage of patients immune to hepatitis A in FtM and MtF subgroups were 55 and 47% (P>0.05). Percentage of patients immune to HBV in FtM and MtF subgroups were 54 and 48% (P>0.05). Conclusion This study indicates a significant lack of hepatitis screening in the transgender population and a concerning proportion of patients susceptible to disease.
Bacterial etiology of acute diarrhea in children under five years of age.

BACKGROUND Diarrheal diseases are major problem of developing countries. Though precise data on childhood mortality associated with diarrheal diseases in Nepal is not available, it has been estimated that approximately 25% of child death are associated with diarrheal disease, particularly acute diarrhea. The purpose of this study was to assess the incidence of bacterial pathogens causing acute diarrhea in children under 5 years of age. METHODS A total of 525 children with acute diarrhea in a children's hospital of Kathmandu, Nepal were enrolled between April 2011 to September 2011. Feacal specimens for culture were inoculated to the several media. The organisms were identified by different biochemical tests and serotyping. Their antibiotic sensitivity tests were performed by Kirby-Bauer's disc diffusion method as recommended by CLSI. RESULTS Out of total 525 enrolled cases bacterial infection was found to be 46 (8.8%). Bacterial infection was found to be of highest, 36 (78.3%) in the age group between 6-24 months. Among the total enrolled cases the prevalence of Shigella species was 24 (4.6%) followed by Escherichia coli 12 (2.3%) and Salmonella species 10 (1.9%). Chloramphenicol and Tetracycline showed efficacy in 9 (90.0%) isolates of Salmonella species, Gentamycin showed efficacy in 22 (91.7%) isolates of Shigella species and Chloramphenicol showed 100% efficacy against Escherichia coli whereas 7 (70.0%) isolates of Salmonella species were resistant to ampicillin in vitro. MDR was highest 7 (70.0%) in Salmonella species. CONCLUSIONS The bacterial pathogens were found to be a significant cause of acute diarrhea. The most common causative organism for acute diarrhea were Shigella spp. Awareness of improving hygiene and infectious diseases may reduce the burden of infection.
Feasibility of withholding antibiotics in selected febrile neutropenic cancer patients.

PURPOSE To investigate the feasibility of withholding antibiotics and early discharge for patients with chemotherapy-induced neutropenia and fever at low risk of bacterial infection by a new risk assessment model. PATIENTS AND METHODS Outpatients with febrile neutropenia were allocated to one of three groups by a risk assessment model combining objective clinical parameters and plasma interleukin 8 level. Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk. Based on their interleukin-8 level, remaining patients were allocated to low or medium risk for bacterial infection. Medium-risk and high-risk patients received standard antibiotic therapy, whereas low-risk patients did not receive antibiotics and were discharged from hospital after 12 hours of a febrile observation. End points were the feasibility of the treatment protocol. RESULTS Of 196 assessable episodes, 76 (39%) were classified as high risk, 84 (43%) as medium risk, and 36 (18%) as low risk. There were no treatment failures in the low-risk group (95% CI, 0% to 10%). Therefore, sensitivity of our risk assessment model was 100% (95% CI, 90% to 100%), the specificity, positive, and negative predictive values were 21%, 13%, and 100%, respectively. Median duration of hospitalization was 3 days in the low-risk group versus 7 days in the medium- and high-risk groups (P < .0001). The incremental costs of the experimental treatment protocol amounted to a saving of 471 (US $572) for every potentially low-risk patient. CONCLUSION This risk assessment model appears to identify febrile neutropenic patients at low risk for bacterial infection. Antibiotics can be withheld in well-defined neutropenic patients with fever.
A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) is a chronic illness associated with substantial morbidity; it often requires long-term medication. The best-studied therapeutic agent in the treatment of this disorder is the tricyclic antidepressant clomipramine. Since other tricyclic antidepressants appear to lack efficacy in OCD, that of clomipramine has been linked to its potent effects on serotonin. Consequently, agents that selectively inhibit serotonin reuptake have been the focus of several large-scale, placebo-controlled studies of OCD. Their efficacy in OCD is the focus of our review. DATA SOURCES MEDLINE search (1966 to present) of OCD treatment with clomipramine or SSRI antidepressant medication using the key words obsessive-compulsive disorder, serotonin reuptake inhibitors, clomipramine, and pharmacology. STUDY FINDINGS The selective serotonin reuptake inhibitors fluoxetine, sertraline, fluvoxamine, and paroxetine have, in separate multicenter trials, demonstrated efficacy and tolerability in the treatment of OCD. In contrast, clomipramine, though efficacious, is often associated with substantial adverse events, particularly anticholinergic side effects. While 2 recent meta-analyses support the superior efficacy of clomipramine over selective serotonin reuptake inhibitors in the treatment of OCD, 5 of 6 head-to-head comparisons of either fluoxetine or fluvoxamine versus clomipramine have found similar efficacy but a lower incidence of side effects with the selective serotonin reuptake inhibitor. A recently completed multicenter, 12-week, double-blind trial of paroxetine versus clomipramine versus placebo showed paroxetine to be as effective as clomipramine. With significantly fewer dropouts due to adverse effects than clomipramine, paroxetine was also associated with superior tolerability. CONCLUSION The suggestion that selective serotonin reuptake inhibitors possess efficacy similar to that of clomipramine, but have a superior side effect profile, may have important implications for patients with OCD who require long-term treatment.
Dynamics of the folded and unfolded villin headpiece (HP35) measured with ultrafast 2D IR vibrational echo spectroscopy

A series of two-dimensional infrared vibrational echo experiments performed on nitrile-labeled villin headpiece [HP35-(CN)2] is described. HP35 is a small peptide composed of three alpha helices in the folded configuration. The dynamics of the folded HP35-(CN)2 are compared to that of the guanidine-induced unfolded peptide, as well as the nitrile-functionalized phenylalanine (PheCN), which is used to differentiate the peptide dynamic contributions to the observables from those of the water solvent. Because the viscosity of solvent has a significant effect on fast dynamics, the viscosity of the solvent is held constant by adding glycerol. For the folded peptide, the addition of glycerol to the water solvent causes observable slowing of the peptide’s dynamics. Holding the viscosity constant as GuHCl is added, the dynamics of unfolded peptide are much faster than those of the folded peptide, and they are very similar to that of PheCN. These observations indicate that the local environment of the nitrile in the unfolded peptide resembles that of PheCN, and the dynamics probed by the CN are dominated by the fluctuations of the solvent molecules, in contrast to the observations on the folded peptide.
Computed tomography angiography reveals stenosis and aneurysmal dilation of an aberrant right subclavian artery causing systemic blood pressure misreading in an old Pekinese dog

A 14-year-old dog weighing 4 kg presented with hypotension only in the right forelimb. Thoracic radiography revealed a round soft tissue opacity near the aortic arch and below the second thoracic vertebra on a lateral view. Three-dimensional computed tomography angiography clearly revealed stenosis and aneurysmal dilation of an aberrant right subclavian artery. Stenosis and aneurysm of an aberrant subclavian artery should be included as a differential diagnosis in dogs showing a round soft tissue opacity near the aortic arch and below the thoracic vertebra on the lateral thoracic radiograph.
Pharmacology and therapeutic potential of Euphorbia hirta (Syn: Euphorbia pilulifera)- A review

-The phytochemical screening of Euphorbia hirta revealed that the plant contained reducing sugars, terpenoids, alkaloids, steroids, tannins, proteins, fats, oils, gums, mucilages, glycoside, saponin, coumarin, cardiac glycosides, anthroquinones, flavanoids and phenolic compounds. The previous pharmacological studies showed that Euphorbia hirta exerted antioxidant, antimicrobial, sedative anxiolytic, antiepileptic, antiinflammatory, analgesic, antipyretic, antihistaminic, antiasthmatic, antidiabetic, anticancer, wound healing, gastrointestinal, diuretic, antiparasitic, immunological, hepatoprotective, galactogenic, angiotensin converting enzyme inhibiting and anti-dipsogenic activities. The current review discussed the chemical constituents, pharmacological and therapeutic potential of Euphorbia hirta.
New Microsatellite Multiplex PCR for Candida albicans Strain Typing Reveals Microevolutionary Changes

ABSTRACT Five new microsatellite loci were described and characterized for use as molecular markers for the identification and genetic differentiation of Candida albicans strains. Following the typing of 72 unrelated clinical isolates, the analysis revealed that they were all polymorphic, presenting from 5 to 30 alleles and 8 to 46 different genotypes. The discriminatory power obtained by combining the information generated by three microsatellites used in a multiplex PCR amplification strategy was 0.99, the highest ever reported. The multiplex PCR was later used to test a total of 114 C. albicans strains, including multiple isolates from the same patient collected from different body locations and along episodes of vulvovaginal infections. Three different scenarios for strain relatedness were identified: (i) different isolates that were revealed to be the same strain, (ii) isolates that were the same strain but that apparently underwent a process of microevolution, and (iii) isolates that corresponded to different strains. Analysis of the microevolutionary changes between isolates from recurrent infections indicated that the genotype alterations observed could be the result of events that lead to the loss of heterozygosity (LOH). In one case of recurrent infection, LOH was observed at the CAI locus, and this could have been related to exposure to fluconazole, since such strains were exposed to this antifungal during treatment. The analysis of microsatellites by a multiplex PCR strategy was found to be a highly efficient tool for the rapid and accurate differentiation of C. albicans strains and adequate for the identification of fine microevolutionary events that could be related to strain microevolution in response to environmental stress conditions.
Early postoperative outcomes after pancreaticoduodenectomy in the elderly.

BACKGROUND Single-institution case series suggest that elderly patients do as well as younger patients after pancreaticoduodenectomy. OBJECTIVES To compare morbidity and mortality after pancreaticoduodenectomy in patients older than 70 years vs younger patients. HYPOTHESIS Elderly patients have worse 30-day outcomes. DESIGN Retrospective cohort study. SETTING American College of Surgeons-National Surgical Quality Improvement Program hospitals. PATIENTS All patients who had a pancreaticoduodenectomy from January 1, 2005, to December 31, 2007, were identified. METHODS Multiple logistic regression models were developed to assess the association between age and 30-day outcomes. MAIN OUTCOME MEASURES Thirty-day postoperative morbidity and mortality. RESULTS Of the 2610 patients identified, 977 (37.4%) were elderly and 1633 (62.6%) were younger. Overall morbidity was 36.5%. Elderly patients had a higher likelihood of developing at least 1 morbidity (surgical site infection, wound disruption, outpatient pneumonia, unplanned intubation, pulmonary embolism, prolonged ventilation, acute renal failure, urinary tract infection, stroke, cardiac arrest, deep venous thrombosis, sepsis, or return to the operating room) compared with that of younger patients (40.7% vs 34.0%; odds ratio, 1.27; 95% confidence interval, 1.06-1.51; P = .01). Overall mortality was 2.7%. Elderly patients had a higher likelihood of mortality compared with that of younger patients (4.3% vs 1.7%; adjusted odds ratio, 2.01; 95% confidence interval, 1.18-3.43; P = .01). In patients who had at least 1 morbidity, mortality was 10.1% in the elderly compared with 4.1% in the younger patients (P = .002). CONCLUSIONS Advanced age is independently associated with morbidity and death following pancreaticoduodenectomy. In addition, the elderly have a higher mortality after a complication compared with that of younger patients, suggesting that advanced age may have a role in "failure to rescue. "
Effects of broiler litter and nitrogen fertilization on uptake of major nutrients by coastal bermudagrass

Land application of poultry litter provides essential nutrients for hybrid bermudagrass [Cynodon dactylon (L.) Pers. ] production, but ammonia (NH3) volatilization and N mineralization influence the amount of litter N available for plant uptake. Our objective was to determine the combination of broiler litter and fertilizer N, which maximizes the yields of forage and N, P, and K by ‘Coastal’ bermudagrass. Studies were conducted for 3 yr (1999–2001) in pastures at Newton and Mize, MS that differed widely in soil test P (STP) due to history of litter application (0 vs. 301 yr, respectively.). Litter rates of 0, 4.5, 8.9, 13.4, and 17.9 Mg ha 21 were obtained by up to four monthly (April–July) applications of 4.5 Mg ha 21 and were supplemented with ammonium nitrate (NH4–NO3) to provide the same total N in each treatment. At Newton, combining litter with fertilizer N increased forage yield by 10% in 1999, 25% in 2000, and 34% in 2001, as compared to fertilizer N. At Mize, K uptake increased as litter rate increased in 2001 only. These responses to litter were related to increased soil P and K at Newton, and increased soil N, P, and Ca at Mize. Averaged across years, maximum P uptake of about 40 kg ha 21 was obtained by applying 8.9 Mg litter 1 134 kg N ha 21 at Newton and 4.5 Mg litter 1 202 kg N ha 21 at Mize. Safe and effective management of major plant nutrients in broiler litter may require the use of commercial N fertilizer.
Histone H2A and H4 N-terminal Tails Are Positioned by the MEP50 WD Repeat Protein for Efficient Methylation by the PRMT5 Arginine Methyltransferase*

Background: PRMT5-MEP50 is an arginine methyltransferase with significant roles in development and cancer. Results: MEP50 binds to the histone fold domain and is essential for the efficient use of SAM by PRMT5. Conclusion: MEP50 is essential for methylation of histones H4 and H2A by PRMT5. Significance: The mechanism of histone methylation by PRMT5-MEP50 provides novel insight into methyltransferase mechanisms and therapeutic development. The protein arginine methyltransferase PRMT5 is complexed with the WD repeat protein MEP50 (also known as Wdr77 or androgen coactivator p44) in vertebrates in a tetramer of heterodimers. MEP50 is hypothesized to be required for protein substrate recruitment to the catalytic domain of PRMT5. Here we demonstrate that the cross-dimer MEP50 is paired with its cognate PRMT5 molecule to promote histone methylation. We employed qualitative methylation assays and a novel ultrasensitive continuous assay to measure enzyme kinetics. We demonstrate that neither full-length human PRMT5 nor the Xenopus laevis PRMT5 catalytic domain has appreciable protein methyltransferase activity. We show that histones H4 and H3 bind PRMT5-MEP50 more efficiently compared with histone H2A(1–20) and H4(1–20) peptides. Histone binding is mediated through histone fold interactions as determined by competition experiments and by high density histone peptide array interaction studies. Nucleosomes are not a substrate for PRMT5-MEP50, consistent with the primary mode of interaction via the histone fold of H3-H4, obscured by DNA in the nucleosome. Mutation of a conserved arginine (Arg-42) on the MEP50 insertion loop impaired the PRMT5-MEP50 enzymatic efficiency by increasing its histone substrate Km, comparable with that of Caenorhabditis elegans PRMT5. We show that PRMT5-MEP50 prefers unmethylated substrates, consistent with a distributive model for dimethylation and suggesting discrete biological roles for mono- and dimethylarginine-modified proteins. We propose a model in which MEP50 and PRMT5 simultaneously engage the protein substrate, orienting its targeted arginine to the catalytic site.
Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status.

BACKGROUND Most women with oestrogen receptor (ER) positive primary breast cancer receive adjuvant tamoxifen after surgery. The measurement of tumour biomarkers should allow better selection of patients for such treatment or for therapies such as aromatase inhibitors. PATIENTS AND METHODS Histopathological blocks of primary breast cancer patients who had been randomized to receive 2-years tamoxifen or no adjuvant therapy in two mature randomised clinical trials were retrieved. Immunohistochemical staining for ER, progesterone receptor (PgR), HER2 and epidermal growth factor receptor (EGFR) was undertaken. The primary endpoint was relapse free survival. RESULTS 813 patients were included in the study. Benefit from tamoxifen was seen in ER-positive patients [Relative risk (rr) 0.77, ci 0.63-0.93]. ER-negative patients also showed a strong trend to benefit from tamoxifen (rr 0.73, ci 0.52-1.02) which was largely confined to the PgR-positive group. Amongst the ER-positive group, PgR-positive and PgR-negative patients showed similar benefit (rr 0.81; ci 0.65-1.02 and 0.70; ci 0.49-0.99, respectively). Patients positive for HER2 did not benefit significantly (rr 1.14; ci 0.75-1.73) but this group was small. CONCLUSIONS Measurement of PgR status in ER-negative patients defines a group of patients that benefit from tamoxifen but would be excluded from tamoxifen therapy on the basis of ER status alone. The data are consistent with HER2 positive tumours being resistant to tamoxifen.
Autonomous agent response learning by a multi-species particle swarm optimization

An autonomous agent response learning (AARL) algorithm is presented in this paper. We proposed to decompose the award function into a set of local award functions. By optimizing this objective function set, the response function with maximum award can be determined. To tackle the optimization problem, a modified particle swarm optimization (PSO) called "multi-species PSO (MS-PSO)" is introduced by considering each objective function as a specie swarm. Two sets of experiments are provided to illustrate the performance of MS-PSO. The results show that it returns a more accurate response set within shorter duration by comparing with other PSO methods.
Simulated microgravity alters differentiation and increases apoptosis in human follicular thyroid carcinoma cells

This study focuses on the effects of simulated microgravity (0g) on the human follicular thyroid carcinoma cell line ML‐1. Cultured on a three‐dimensional clinostat, ML‐1 cells formed three‐dimensional MCTSs (MCTS diameter: 0.3±0.01 mm). After 24 and 48 h of clinorotation, the cells significantly decreased fT3 and fT4 secretion but up‐regulated the thyroid‐stimulating hormone‐receptor expression as well as the production of vimentin, vinculin, and extracellular matrix proteins (collagen I and III, laminin, fibronectin, chondroitin sulfate) compared with controls. Furthermore, ML‐1 cells grown on the clinostat showed elevated amounts of the apoptosis‐associated Fas protein, of p53, and of bax but showed reduced quantities of bcl‐2. In addition, signs of apoptosis became detectable, as assessed by terminal deoxynucleotidyl transferase‐mediated dUTP digoxigenin nick end labeling, 4′, 6‐diamidino‐2‐phenylindole staining, DNA laddering, and 85‐kDa apoptosis‐related cleavage fragments. These fragments resulted from enhanced 116‐kDa poly(ADP‐ribose)polymerase (PARP) activity and apoptosis. These observations suggest that clinorotation elevates intermediate filaments, cell adhesion molecules, and extracellular matrix proteins and simultaneously induces apoptosis in follicular thyroid cancer cells. In conclusion, our experiments could provide a regulatory basis for the finding that astronauts show low thyroid hormone levels after space flight, which may be explained by the increase of apoptosis in thyrocytes as a result of simulated 0g.