Miracle-dz/UniFAR-FTUs huggingface dataset:
Protonation and pK changes in protein–ligand binding

Abstract Formation of protein–ligand complexes causes various changes in both the receptor and the ligand. This review focuses on changes in pK and protonation states of ionizable groups that accompany protein–ligand binding. Physical origins of these effects are outlined, followed by a brief overview of the computational methods to predict them and the associated corrections to receptor–ligand binding affinities. Statistical prevalence, magnitude and spatial distribution of the pK and protonation state changes in protein–ligand binding are discussed in detail, based on both experimental and theoretical studies. While there is no doubt that these changes occur, they do not occur all the time; the estimated prevalence varies, both between individual complexes and by method. The changes occur not only in the immediate vicinity of the interface but also sometimes far away. When receptor–ligand binding is associated with protonation state change at particular pH, the binding becomes pH dependent: we review the interplay between sub-cellular characteristic pH and optimum pH of receptor–ligand binding. It is pointed out that there is a tendency for protonation state changes upon binding to be minimal at physiologically relevant pH for each complex (no net proton uptake/release), suggesting that native receptor–ligand interactions have evolved to reduce the energy cost associated with ionization changes. As a result, previously reported statistical prevalence of these changes – typically computed at the same pH for all complexes – may be higher than what may be expected at optimum pH specific to each complex. We also discuss whether proper account of protonation state changes appears to improve practical docking and scoring outcomes relevant to structure-based drug design. An overview of some of the existing challenges in the field is provided in conclusion.
Hyperpolarisation‐activated inward current in isolated sheep mesenteric lymphatic smooth muscle

1 Freshly isolated sheep lymphatic smooth muscle cells were studied using the perforated patch‐clamp technique. Hyperpolarisation with constant‐current pulses caused a time‐dependent rectification evident as a depolarising ‘sag’ followed by an anode‐break overshoot at the end of the pulse. Both sag and overshoot were blocked with 1 mM Cs+. 2 Cells were voltage clamped at −30 mV and stepped to −120 mV in 10 mV steps of 2 s duration. Steps negative to −60 mV evoked a slowly activating, non‐inactivating inward current which increased in size and rate of activation with increasing hyperpolarisation. 3 The slowly activating current was reduced in Na+‐free bathing solution but enhanced when the extracellular K+ concentration was increased to 60 mM. The current was significantly reduced by 1 mM Cs+ and 1 μM ZD7288 but not by 1·8 mM Ba2+. 4 The steady‐state activation curve of the underlying conductance showed a threshold at −50 mV and half‐maximal activation at −81 mV. Neither threshold nor half‐maximal activation was significantly affected by increasing the external K+ concentration to 60 mM. 5 The frequency of spontaneous contractions and fluid propulsion in isolated cannulated segments of sheep mesenteric lymphatics were decreased by 1 mM Cs+ and by 1 μM ZD7288. 6 We conclude that sheep lymphatics have a hyperpolarisation‐activated inward current similar to the If seen in sinoatrial node cells of the heart. Blockade of this current slows spontaneous pumping in intact lymphatic vessels suggesting that it is important in normal pacemaking.
Who votes and why? An empirical analysis reflecting the 2015 general election in Tanzania

This paper empirically provides answers to very central questions towards. understanding elections and voting behaviour in the context of democratic systems: who votes and why. The paper analyses the aspects of voters turn out decline to characterize who are still turning out to vote and what propels them to vote as reflected in the 2015 General Election based on a study conducted in Morogoro, Tanzania. A questionnaire administered through Computer Aided Personal Interviewing (CAPI) platform was used JOr data collection from 240 randomly drawn respondents from Jour randomly selected wards (Kichangani, Tungi, Mazimbu and Mil Mpya) . from Morogoro urban which was purposively selected. A Discrete Choice Framework and R(117(10171 Utility Approach were employed to determine .factors that cted voters to go for election or not using a Logit model. Data analysis and processing were done using the Statistical Package for Social Sciences (SPSS) computer software. The study found that; older people were more likely to vote compared to younger people; single citizens were 11101e likely to vote compared to married ones, people in the informal sector were more likelv to vote than citizens who were formally emploved, males were more likely to vote than females; Christians were more likely to vote than Mu.slints; those affiliated to political party were more likely to vote than non party members; citizens who attended to election campaign were more likely to vote than none-attendees, and citizen living near the polling station were more likely to vote compared to citizens living further away. The reasons JOu voting included: exercising democracy (67.5 i',"), exercising the right of each citizen aged IS years and above (95%), holding elected leaders accountable (60%), to get leaders of their choice (80 %), another 62.5% were enticed to tote due to the pC1. 101"117(111Ce past leaders in relation to meeting development goals in the respective area. Another reason for voting was. .stated as, exposure to information 017 voting (77.5%). The study recommends the need to emphasize participation in voting among the females, . formally employed, and younger citizens who had become eligible for voting.
Sulcal variability, stereological measurement and asymmetry of Broca's area on MR images

Leftward volume asymmetry of the pars opercularis and pars triangularis may exist in the human brain, frequently referred to as Broca's area, given the functional asymmetries observed in this region with regard to language expression. However, post‐mortem and magnetic resonance imaging (MRI) studies have failed to consistently identify such a volumetric asymmetry. In the present study, an analysis of the asymmetry of sulco‐gyral anatomy and volume of this anterior speech region was performed in combination with an analysis of the morphology and volume asymmetry of the planum temporale, located within the posterior speech region, in 50 healthy subjects using MRI. Variations in sulcal anatomy were documented according to strict classification schemes and volume estimation of the grey matter within the brain structures was performed using the Cavalieri method of stereology. Results indicated great variation in the morphology of and connectivity between the inferior frontal, inferior precentral and diagonal sulci. There were significant inter‐hemispheric differences in the presence of (1) the diagonal sulcus within the pars opercularis, and (2) horizontal termination of the posterior Sylvian fissure (relative to upward oblique termination), both with an increased leftward incidence. Double parallel inferior precentral sulci and absent anterior rami of the Sylvian fissure prevented stereological measurements in five subjects. Therefore volumes were obtained from 45 subjects. There was a significant leftward volume asymmetry of the pars opercularis (P = 0.02), which was significantly related to the asymmetrical presence of the diagonal sulcus (P < 0.01). Group‐wise pars opercularis volume asymmetry did not exist when a diagonal sulcus was present in both or neither hemispheres. There was no significant volume asymmetry of the pars triangularis. There was a significant leftward volume asymmetry of the planum temporale (P < 0.001), which was significantly associated with the shape of the posterior Sylvian fissure as a unilateral right or left upward oblique termination was always associated with leftward or rightward volume asymmetry respectively (P < 0.01). There was no relationship between volume asymmetries of the anterior and posterior speech regions. Our findings illustrate the extent of morphological variability of the anterior speech region and demonstrate the difficulties encountered when determining volumetric asymmetries of the inferior frontal gyrus, particularly when sulci are discontinuous, absent or bifid. When the intrasulcal grey matter of this region is exhaustively sampled according to strict anatomical landmarks, the volume of the pars opercularis is leftward asymmetrical. This manuscript illustrates the importance of simultaneous consideration of brain morphology and morphometry in studies of cerebral asymmetry.
Burnout Rates in Pediatric Emergency Medicine Physicians

Objective Burnout is a syndrome in which a reduced sense of personal accomplishment, depersonalization, and emotional exhaustion develop in response to prolonged stress. It is well known that physicians suffer high rates of burnout; emergency medicine physicians experience significantly increased rates of burnout, whereas physicians in other specialties, like pediatrics, may be spared. Pediatric emergency medicine physicians are on the frontline of care for the critically ill child, which could put them at high risk for burnout. This study evaluates the rate of burnout in pediatric emergency medicine physicians. Methods We conducted a survey assessing burnout using a sample of pediatric emergency medicine physicians who subscribe to an open Listserv server maintained by Brown University. Burnout was measured using a validated instrument, the Maslach Burnout Inventory-Human Services Survey, which was distributed by e-mail to the study group. Results Respondents averaged a score of 9 (95% confidence interval [CI], 8–10), 23 (95% CI, 21–25), and 39 (95% CI, 38–40) in the subscales of depersonalization, emotional exhaustion, and personal accomplishment, respectively. This placed our cohort into the average range for all subscales. The percentage of respondents who scored in the high levels of burnout (moderate to high scores in both depersonalization and emotional exhaustion and low to moderate scores in personal accomplishment) was 25% (95% CI, 18–32). Conclusions Unlike previous literature showing burnout prevalence in excess of 60% in emergency medicine physicians and 38% in pediatricians, our pediatric emergency medicine physicians fared better with only 25% (95% CI, 18–32), showing elevated levels of burnout.
Toll-Like Receptor 4 Gene (TLR4), but Not TLR2, Polymorphisms Modify the Risk of Tonsillar Disease Due to Streptococcus pyogenes and Haemophilus influenzae

ABSTRACT Tonsillar disease (recurrent tonsillitis and/or tonsillar hypertrophy) is one of the most common human disorders, with Streptococcus pyogenes (group A beta-hemolytic streptococcus [GAS]) and Haemophilus influenzae representing the most common pathogens. Until now, no study has investigated why some individuals are more susceptible to tonsillar infections caused by specific bacteria than others. The aim of this study was to uncover possible associations between common Toll-like receptor gene (TLR) polymorphisms and tonsillar disease. The TLR2-R753Q, TLR4-D299G, and TLR4-T399I polymorphisms were determined in a cohort of 327 patients subjected to tonsillectomy due to recurrent tonsillitis (n = 245) and tonsillar hypertrophy (n = 82) and 245 healthy bone marrow donors. Associations of the aforementioned polymorphisms with the isolated bacterial strains after tonsillectomy were also investigated. Interestingly, carriers of the TLR4 polymorphisms displayed an approximately 3-fold increased risk for GAS infections (for TLR4-D299G, odds ratio [OR] = 2.81, 95% confidence interval [CI] = 1.16 to 6.79, P = 0.038; for TLR4-T399I, OR = 3.01, 95% CI = 1.29 to 7.02, P = 0.023), and this association was more profound in patients with recurrent tonsillitis. On the contrary, the presence of the TLR4-T399I polymorphism was associated with a 2-fold decreased risk of Haemophilus influenzae carriage (OR = 0.38, 95% CI = 0.15 to 0.96, P = 0.038). In the end, no significant differences were observed, considering the genotype and allele frequencies of the above-mentioned polymorphisms, between patients and controls. Our findings indicate that, regarding tonsillar infections, TLR4 polymorphisms predispose individuals to GAS infection, while they are protective against Haemophilus influenzae infection. This result further elucidates the role that host immune genetic variations might play in the susceptibility to common infections and tonsillar disease.
Understanding the career development and employability of information technology students

Purpose The purpose of this paper is to understand the career development and employability needs of undergraduate information technology (IT) students at an Australian University, and their relation to students’ career interest. While many factors and stakeholders contribute to student career development, this study focused specifically on the student experience. Social cognitive career theory (SCCT) is used as an approach to understand the students’ needs of career development and employability. Design/methodology/approach An online survey was completed by 126 IT students to record information about students’ career development and employability background and needs. Findings The results demonstrate that SCCT helps understand the factors that impact on IT students’ career development, with their outcome expectations and self-efficacy informed by prior studies in IT and their need for access to “IT professionals” to contribute towards their career interest. In addition, IT students rely on academic achievement and experiential learning, rather than career resources, to guide their career development and employability. Research limitations/implications The data collected in this study are limited to one discipline (IT) at one university, which necessarily limits the generalisability of the specific results. Practical implications Career development is a complex, life-stage-dependant and discipline-specific process that varies for every decision maker. This research makes an important contribution in presenting the IT student experience and demonstrates how an appropriate career development model can help understand students’ needs. This outcome will help educators better support IT students to build the career interest. Originality/value This study explored the often-overlooked student experience of career development, providing valuable insight into IT students’ needs.
Effects of glucose, free fatty acids or arginine load on the GH‐releasing activity of ghrelin in humans

objective Ghrelin, a 28 amino acid peptide purified from the stomach and showing a unique structure with an n‐octanoyl ester in serine‐3 residue, is a natural ligand of the GH secretagogue (GHS) receptor (GHS‐R) and strongly stimulates GH secretion. In humans, ghrelin is more potent than growth hormone‐releasing hormone (GHRH) and non‐natural GHS such as hexarelin. Moreover, ghrelin shows a true synergism with GHRH, has no interaction with hexarelin and, similarly to non‐natural GHS, is partially refractory to the inhibitory effect of exogenous somatostatin (SS). Despite this evidence, the mechanisms underlying the GH‐releasing effect of ghrelin in humans have not been fully clarified.
Psychiatric illness in the next of kin of patients who die in the intensive care unit*

Objectives:To determine the rates of psychiatric illness in next of kin following the death of a relative in a medical intensive care unit. Design:Cross-sectional survey. Setting:A university teaching hospital, New Haven, CT. Patients:Forty-one next of kin who had served as primary surrogate decision makers before the death of their loved one in the intensive care unit 3–12 months previously. Interventions:Structured Clinical Interviews for DSM-IV and the Inventory of Complicated Grief–Revised were used to determine prevalence of psychiatric illness. Formal questionnaires were used to evaluate key features of the intensive care unit experience. Bivariate statistics were used to identify factors associated with the presence of psychiatric illness. Measurements and Main Results:Following 107 patient deaths, 51 next of kin were successfully contacted and 41 (80%) agreed to study participation. Thirty-four percent (95% confidence interval, 20% to 51%) met criteria for at least one psychiatric illness: major depressive disorder (27%), generalized anxiety disorder (10%), panic disorder (10%), or complicated grief disorder (5%). Disorders were more common in spouses than other kinship relations (63% vs. 16%, p = .002), those experiencing additional stressors after the loss (53% vs. 21%, p = .03), those who said the patient was ill <5 yrs (45% vs. 8%, p = .03), and those who said the patient’s physician was not comforting (71% vs. 23%, p = .02). Conclusions:In a cohort of bereaved next of kin of patients who died in the intensive care unit, we identified a high prevalence of psychiatric illness, particularly major depressive disorder. More work is needed to identify those at risk for psychiatric illness so that appropriate interventions may be targeted.
Time to virological failure of 3 classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group.

OBJECTIVE The purpose of the present study was to determine the prevalence and incidence of virological triple drug-class failure (TCF) and to summarize the clinical outcome for patients who started receiving highly active antiretroviral therapy (HAART). METHODS The present study is an observational longitudinal study of 3496 treatment-experienced (TE) and treatment-naive (TN) patients monitored from the time they started receiving HAART (baseline) until TCF occurred (as determined on the basis of viral loads), until AIDS was newly diagnosed, or until death. RESULTS Four hundred forty-five patients (12.7%) had TCF; 370 (16.6%) of 2230 patients were TE, and 75 (5.9%) of 1266 patients were TN. At 6 years after starting HAART, 21.4% of TE and 11.2% of TN patients had TCF (P<.0001). The prevalence of TCF at or after 2002 was 15.5% in TE patients and 4.8% in TN patients. TN patients had a 32% annual increase in the incidence of TCF (95% confidence interval [CI], 14%-54%; P<.0001); at 5 years after starting HAART, the rate was comparable for TE and TN patients (3.3 and 3.4 cases/100 person-years of follow-up [PYFU], respectively). The incidence of new cases of AIDS or death was 2.7 cases/100 PYFU in patients who did not experience TCF and 5.0 cases/100 PYFU in patients who did experience TCF, an estimated 36% increase with each category of TCF (95% CI, 19%-56%; P<.0001). CONCLUSION The prevalence of TCF was low after patients started receiving HAART, particularly among TN patients. Despite the influx of patients who had started receiving HAART more recently, the prevalence of TCF increased over calendar time. Patients with TCF had a higher incidence of newly diagnosed AIDS or death. Treatment of patients with TCF deserves further investigation.
Legislative Representation, Bargaining Power and the Distribution of Federal Funds: Evidence from the US Congress

While representation in the U.S. House is based upon state population, each state has an equal number (two) of U.S. Senators. Thus, relative to the state delegations in the U.S. House, small population states are provided disproportionate bargaining power in the U.S. Senate. This paper provides new evidence on the role of this small state bargaining power in the distribution of federal funds using data on projects earmarked in appropriations bills between 1995 and 2003. Relative to earmarks secured in House appropriations bills, Senate earmarks exhibit a small state advantage that is both economically and statistically significant. The paper also examines two theoretically-motivated channels through which this small state advantage operates: increased proposal power through appropriations committee representation and the lower cost of securing votes due to smaller federal tax shares. Taken together, these two channels explain over 80 percent of the measured small state bias. Finally, a welfare analysis demonstrates the inefficiency of hte measured small state bias.
Aplicaciones docentes de la Economía del Comportamiento a la Economía Pública

This work aims to present the main elements of a teaching experience consisting in elaborating a didactic unit on applications of Behavioural Economics to Public Economic. Particularly, the article surveys the implications for public policy of considering economic agents who are not non-completely self-interested, do not behave in perfectly rational way and suffer from self-control problems. The main applications discussed here refer to the convenience of using monetary incentives in some circumstances, the design of saving and pension policy and drug use and public policy
Screening of differential promoter hypermethylated genes in primary oral squamous cell carcinoma.

BACKGROUND Promoter hypermethylation leads to altered gene functions and may result in malignant cellular transformation. Thus, identification of biomarkers for hypermethylated genes could be useful for diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC). OBJECTIVES To screen hypermethylated genes with a microarray approach and to validate selected hypermethylated genes with the methylation-specific polymerase chain reaction (MSPCR). MATERIALS AND METHODS Genome-wide analysis of normal oral mucosa and OSCC tissues was conducted using the Illumina methylation microarray. The specified differential genes were selected and hypermethylation status was further verified with an independent cohort sample of OSCC samples. Candidate genes were screened using microarray assay and run by MSPCR analysis. RESULTS TP73, PIK3R5, and CELSR3 demonstrated high percentages of differential hypermethylation status. CONCLUSIONS Our microarray screening and MSPCR approaches revealed that the signature candidates of differentially hypermethylated genes may possibly become potential biomarkers which would be useful for diagnostic, prognostic and therapeutic targets of OSCC in the near future.
Incidence, risk factors and outcome of histological transformation in follicular lymphoma

Histological transformation (HT) into diffuse large B‐cell lymphoma (DLBCL) was documented in 37 of the 281 (13%; 95% CI, 9–18) follicular lymphoma (FL) patients treated at our institute from 1979 to 2007. HT occurred at a median of 2·75 years from initial FL diagnosis and HT rate was 15% at 10 years and 26% at 14 years, with a plateau from that point onward. Patients with bulky or extranodal disease, or those diagnosed before 1990 had a significantly higher risk of HT. When initial treatment strategies were taken into account, a reduced HT risk was seen in the patients initially managed with a ‘watch and wait’ policy, while the risk appeared significantly increased in the small subset of 18 patients initially managed with rituximab plus chemotherapy (P = 0·0005). HT was associated with a significantly shorter cause‐specific survival (P = 0·0002). Predictors of survival after HT were the Follicular Lymphoma International Prognostic Index at diagnosis, as well as age and performance status at the time of HT. Our data confirm the adverse clinical outcome of FL after HT. In keeping with previous isolated reports, our findings suggest that there is a subgroup of patients in whom HT may not occur.