Miracle-dz/UniFAR-FTUs huggingface dataset:
A Rationally Engineered Anti-HIV Peptide Fusion Inhibitor with Greatly Reduced Immunogenicity

ABSTRACT Peptides derived from the C-terminal heptad repeat 2 (HR2) region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very efficient HIV-1 fusion inhibitors. We previously developed innovative gene therapeutic approaches aiming at the direct in vivo production of C peptides from genetically modified host cells and found that T cells expressing membrane-anchored or secreted C peptides are protected from HIV-1 infection. However, an unwanted immune response against such antiviral peptides may significantly impair clinical efficacy and pose safety risks to patients. To overcome this problem, we engineered a novel C peptide, V2o, with greatly reduced immunogenicity and excellent antiviral activity. V2o is based on the chimeric C peptide C46-EHO, which is derived from the HR2 regions of HIV-2EHO and HIV-1HxB2 and has broad anti-HIV and anti-simian immunodeficiency virus activity. Antibody and major histocompatibility complex class I epitopes within the C46-EHO peptide sequence were identified by in silico and in vitro analyses. Using rational design, we removed these epitopes by amino acid substitutions and thus minimized antigenicity and immunogenicity considerably. At the same time, the antiviral activity of the deimmunized peptide V2o was preserved or even enhanced compared to that of the parental C46-EHO peptide. Thus, V2o is an ideal candidate, especially for those novel therapeutic approaches for HIV infection that involve direct in vivo production of antiviral C peptides.
A Randomized Controlled Trial Assessing the Effects of Raltegravir Intensification on Endothelial Function in Treated HIV Infection

Objectives:To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated HIV-infected individuals. Design:Randomized, double-blinded, placebo-controlled study. Methods:Fifty-six subjects with treatment-mediated viral suppression for at least 1 year were randomized to add 400 mg of raltegravir twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function [as assessed by flow-mediated vasodilation (FMD) of the brachial artery] from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence. Results:At baseline, the median CD4+ T-cell count was 498 cells/mm3, nadir CD4+ T-cell count was 191 cells/mm3, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group: +0.032% per week, placebo group: +0.023% per week; P = 0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4+ T-cell count and current abacavir use were associated with lower hyperemic velocity. Conclusions:The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713).
Evaluation of thromboelastography in two factor XII-deficient cats

Case summary The current report describes thromboelastography (TEG) findings in two cats with factor XII (FXII) deficiency. The first cat was diagnosed with bilateral perinephric pseudocysts; hemostatic testing was performed prior to performing renal aspirates. The second cat was healthy; hemostatic testing was performed prior to inclusion into a research project. Both cats had markedly prolonged partial thromboplastin times and hypocoagulable TEG tracings when samples were activated with kaolin. However, when tissue factor (TF) was used to activate the sample, both cats had normal-to-hypercoagulable TEG tracings. The cats each had a subnormal FXII level. Relevance and novel information TEG is becoming widely used to investigate hemostasis in veterinary patients, and TEG results in cats with FXII deficiency have not been previously reported. FXII deficiency is the most common hereditary hemostatic defect in cats. While FXII deficiency does not lead to in vivo hemorrhagic tendencies, it can lead to marked prolongation in activated partial thromboplastin and activated clotting times, and cannot be differentiated from true hemorrhagic diatheses without measuring individual factor activity. With the increased use of TEG to evaluate hemostasis in veterinary patients, it is important to recognize the effects of FXII deficiency on this testing modality. The finding of a hypocoagulable kaolin-activated TEG tracing and a concurrent normal TF-activated TEG tracing in samples should prompt clinicians to consider ruling out FXII deficiency.
Calretinin inputs are confined to motoneurons for upward eye movements in monkey

Motoneurons of extraocular muscles are controlled by different premotor pathways, whose selective damage may cause directionally selective eye movement disorders. The fact that clinical disorders can affect only one direction, e.g., isolated up‐/downgaze palsy or up‐/downbeat nystagmus, indicates that up‐ and downgaze pathways are organized separately. Recent work in monkey revealed that a subpopulation of premotor neurons of the vertical eye movement system contains the calcium‐binding protein calretinin (CR). With combined tract‐tracing and immunofluorescence, the motoneurons of vertically pulling eye muscles in monkey were investigated for the presence of CR‐positive afferent terminals. In the oculomotor nucleus, CR was specifically found in punctate profiles contacting superior rectus and inferior oblique motoneurons, as well as levator palpebrae motoneurons, all of which participate in upward eye movements. Double‐immunofluorescence labeling revealed that CR‐positive terminals lacked the γ‐aminobutyric acid (GABA)‐synthesizing enzyme glutamate decarboxylase, which is present in inhibitory afferents to all motoneurons mediating vertical eye movements. Therefore, CR‐containing afferents are considered to be excitatory. In conclusion, a strong CR input is confined to motoneurons mediating upgaze, which derive from premotor pathways mediating saccades and smooth pursuit, but not from secondary vestibulo‐ocular neurons in the magnocellular part of the medial vestibular nucleus. The functional significance of CR in these connections is unclear, but it may serve as a useful marker to locate upgaze pathways in the human brain. J. Comp. Neurol. 521:3154–3166, 2013. © 2013 Wiley Periodicals, Inc.
Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

I estimate per nucleotide rates of spontaneous mutations of different kinds in humans directly from the data on per locus mutation rates and on sequences of de novo nonsense nucleotide substitutions, deletions, insertions, and complex events at eight loci causing autosomal dominant diseases and 12 loci causing X‐linked diseases. The results are in good agreement with indirect estimates, obtained by comparison of orthologous human and chimpanzee pseudogenes. The average direct estimate of the combined rate of all mutations is 1.8×10−8 per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are ∼25 times more common than all other mutations, deletions are ∼three times more common than insertions, complex mutations are very rare, and CpG context increases substitution rates by an order of magnitude. There is only a moderate tendency for loci with high per locus mutation rates to also have higher per nucleotide substitution rates, and per nucleotide rates of deletions and insertions are statistically independent on the per locus mutation rate. Rates of different kinds of mutations are strongly correlated across loci. Mutational hot spots with per nucleotide rates above 5×10−7 make only a minor contribution to human mutation. In the next decade, direct measurements will produce a rather precise, quantitative description of human spontaneous mutation at the DNA level. Hum Mutat 21:12–27, 2002. Published 2002 Wiley‐Liss, Inc.
Stereotype Susceptibility in Children: Effects of Identity Activation on Quantitative Performance

A growing body of research indicates that the activation of negative stereotypes can impede cognitive performance in adults, whereas positive stereotypes can facilitate cognitive performance. In two studies, we examined the effects of positive and negative stereotypes on the cognitive performance of children in three age groups: lower elementary school, upper elementary school, and middle school. Very young children in the lower elementary grades (kindergarten-grade 2) and older children in the middle school grades (grades 6–8) showed shifts in performance associated with the activation of positive and negative stereotypes; these shifts were consistent with patterns previously reported for adults. The subtle activation of negative stereotypes significantly impeded performance, whereas the subtle activation of positive stereotypes significantly facilitated performance. Markedly different effects were found for children in the upper elementary grades (grades 3–5). These results suggest that the development of stereotype susceptibility is a critical domain for understanding the connection between stereotypes and individual behavior.
Magnetic Resonance Angiography in Infrapopliteal Arterial Disease: Prospective Comparison of 1.5 and 3 Tesla Magnetic Resonance Imaging

Purpose:To prospectively determine the accuracy of 1.5 Tesla (T) and 3 T magnetic resonance angiography (MRA) versus digital subtraction angiography (DSA) in the depiction of infrageniculate arteries in patients with symptomatic peripheral arterial disease. Patients and Methods:A prospective 1.5 T, 3 T MRA, and DSA comparison was used to evaluate 360 vessel segments in 10 patients (15 limbs) with chronic symptomatic peripheral arterial disease. Selective DSA was performed within 30 days before both MRAs. The accuracy of 1.5 T and 3 T MRA was compared with DSA as the standard of reference by consensus agreement of 2 experienced readers. Signal-to-noise ratios (SNR) and signal-difference-to-noise ratios (SDNRs) were quantified. Results:No significant difference in overall image quality, sufficiency for diagnosis, depiction of arterial anatomy, motion artifacts, and venous overlap was found comparing 1.5 T with 3 T MRA (P > 0.05 by Wilcoxon signed rank and as by Cohen k test). Overall sensitivity of 1.5 and 3 T MRA for detection of significant arterial stenosis was 79% and 82%, and specificity was 87% and 87% for both modalities, respectively. Interobserver agreement was excellent k > 0.8, P < 0.05) for 1.5 T as well as for 3 T MRA. SNR and SDNR were significantly increased using the 3 T system (average increase: 36.5%, P < 0.032 by t test, and 38.5%, P < 0.037 respectively). Conclusions:Despite marked improvement of SDNR, 3 T MRA does not yet provide a significantly higher accuracy in diagnostic imaging of atherosclerotic lesions below the knee joint as compared with 1.5 T MRA.
Histopathologic subtype of hippocampal sclerosis and episodic memory performance before and after temporal lobectomy for epilepsy

The International League Against Epilepsy (ILAE) proposed a classification system for hippocampal sclerosis (HS) based on location and extent of hippocampal neuron loss. The literature debates the usefulness of this classification system when studying memory in people with temporal lobe epilepsy (TLE) and determining memory outcome after temporal lobe resection (TLR). This study further explores the relationship between HS ILAE subtypes and episodic memory performance in patients with TLE and examines memory outcomes after TLR.
7-Methylxanthine Methyltransferase of Coffee Plants

Caffeine is synthesized through sequential three-step methylation of xanthine derivatives at positions 7-N, 3-N, and 1-N. However, controversy exists as to the number and properties of the methyltransferases involved. Using primers designed on the basis of conserved amino acid regions of tea caffeine synthase andArabidopsis hypothetical proteins, a particular DNA fragment was amplified from an mRNA population of coffee plants. Subsequently, this fragment was used as a probe, and four independent clones were isolated from a cDNA library derived from coffee young leaves. Upon expression in Escherichia coli, one of them was found to encode a protein possessing 7-methylxanthine methyltransferase activity and was designated as CaMXMT. It consists of 378 amino acids with a relative molecular mass of 42.7 kDa and shows similarity to tea caffeine synthase (35.8%) and salicylic acid methyltransferase (34.1%). The bacterially expressed protein exhibited an optimal pH for activity ranging between 7 and 9 and methylated almost exclusively 7-methylxanthine with low activity toward paraxanthine, indicating a strict substrate specificity regarding the 3-N position of the purine ring. K m values were estimated to be 50 and 12 μm for 7-methylxanthine and S-adenosyl-l-methionine, respectively. Transcripts of CaMXMT could be shown to accumulate in young leaves and stems containing buds, and green fluorescent protein fusion protein assays indicated localization in cytoplasmic fractions. The results suggest that, in coffee plants, caffeine is synthesized through three independent methylation steps from xanthosine, in which CaMXMT catalyzes the second step to produce theobromine.
ABO(H) Blood Group A and B Glycosyltransferases Recognize Substrate via Specific Conformational Changes*

The final step in the enzymatic synthesis of the ABO(H) blood group A and B antigens is catalyzed by two closely related glycosyltransferases, an α-(1→3)-N-acetylgalactosaminyltransferase (GTA) and an α-(1→3)-galactosyltransferase (GTB). Of their 354 amino acid residues, GTA and GTB differ by only four “critical” residues. High resolution structures for GTB and the GTA/GTB chimeric enzymes GTB/G176R and GTB/G176R/G235S bound to a panel of donor and acceptor analog substrates reveal “open,” “semi-closed,” and “closed” conformations as the enzymes go from the unliganded to the liganded states. In the open form the internal polypeptide loop (amino acid residues 177-195) adjacent to the active site in the unliganded or H antigen-bound enzymes is composed of two α-helices spanning Arg180-Met186 and Arg188-Asp194, respectively. The semi-closed and closed forms of the enzymes are generated by binding of UDP or of UDP and H antigen analogs, respectively, and show that these helices merge to form a single distorted helical structure with alternating α-310-α character that partially occludes the active site. The closed form is distinguished from the semi-closed form by the ordering of the final nine C-terminal residues through the formation of hydrogen bonds to both UDP and H antigen analogs. The semi-closed forms for various mutants generally show significantly more disorder than the open forms, whereas the closed forms display little or no disorder depending strongly on the identity of residue 176. Finally, the use of synthetic analogs reveals how H antigen acceptor binding can be critical in stabilizing the closed conformation. These structures demonstrate a delicately balanced substrate recognition mechanism and give insight on critical aspects of donor and acceptor specificity, on the order of substrate binding, and on the requirements for catalysis.
Factors Associated with Willingness to Respond to a Disaster: A Study of Healthcare Workers in a Tertiary Setting

Abstract Introduction: Due to recent disasters, disaster planners increasingly are focusing on healthcare worker preparedness and response in the event of a disaster. In this study, factors associated with pediatric healthcare workers’ willingness to respond are identified. Hypothesis: It was hypothesized that personal factors may affect a pediatric healthcare worker’s willingness to respond to work in the event of a disaster. Methods: Employees of a tertiary, pediatric care hospital in Los Angeles were asked to complete a brief, 24-question online survey to determine their willingness to respond in the event of a disaster. Information on demographics, employment, disaster-related training, personal preparedness, and necessary resources was collected. A logistic regression model was performed to derive adjusted odds ratios (OR) and their corresponding 95% confidence intervals (95% CI). Results: Eight hundred seventy-seven pediatric healthcare employees completed the survey (22% response rate). Almost 50% (n = 318) expressed willingness to respond in the event of a disaster. Men were more likely to be willing to respond to a disaster than were women (OR = 2.4; 95%CI = 1.6–3.6), and single/divorced/widowed employees were more willing to respond than married or partnered employees (OR = 1.5; 95%CI = 1.1–2.1). An inverse relationship was observed between number of dependents and willingness to respond (OR = 0.45; 95%CI = 0.25–0.80, ≥3 dependents compared to 0). An inverse dose response relationship between commuting distance and number of necessary resources (ptrend = 0.0485 and 0.0001, respectively) was observed. There was no association between previous disaster experience, disaster training, or personal preparedness and willingness to respond. Conclusions: Number of dependents and resources were major factors in willingness to respond. Healthcare facilities must clearly communicate their disaster plans as well as any provisions they may make for their employees’ families in order to improve willingness among hospital employees.
International policies on alcohol impaired driving: are legal blood alcohol concentration (BAC) limits in motorized countries compatible with the scientific evidence?

Borkenstein et al. (1974) study indicated that drivers with BACs of 0.05 to 0.09 per cent were twice as likely to crash as drivers with a zero BAC. Drivers with BACs from 0.10 to 0.14 per cent were ten times as likely to have a fatal crash in 1964. There have been numerous efforts during the history of motorized countries to control the consumption of alcohol and the problems associated with it through legislative mandate, it was not until the 1970s that acceptance of legal BAC (Blood Alcohol Concentration) limits laws became widespread. In particular, as more and more people drive automobiles, the number of traffic accidents involving drunken drivers has soared, and many of these are known to be related to the consumption of alcohol. Thus, legislators find themselves under increasing pressure to find a reasonable and fair solution to the question of alcohol impaired driving, as the scientific evidence about alcohol consumption level and psycho motor functions impairment came to clear. A landmark event in the development of policies regarding impaired driving was the establishment of the fact that consumption of alcohol does, in fact, increase the probability of traffic crashes. Legal limit laws specify a maximum permissible BAC limit for drivers. Currently, a BAC laws range from zero tolerance and 0.02 to 0.10% constitutes prima facie evidence in most countries for 'Driving under Influence of Alcohol. ' This latter standard is too permissive, as driving skills deteriorate and crash involvement risk increases beginning at 0.02%. There are consequences attached to setting a BAC limit so high that a 72 kg man can drink five bottles of beer and still be under legal limit. In this sense high legal BAC limit may influence people to make bad estimates of their relative risk of injury or death while driving. Provided there is adequate political will, millions of lives could be saved in the coming years. This review is an attempt to examine in detail the available information about legal BAC limit laws, and issue of considerable interest to both policy makers and the public.
Insulin‐like growth factor‐II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse

Podocytes are crucial for preventing the passage of albumin into the urine and, when lost, are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate, therefore pro‐survival mechanisms are critically important. Insulin‐like growth factor‐II (IGF‐II) is a potent survival and growth factor; however, its major function is thought to be in prenatal development, when circulating levels are high. IGF‐II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using conditionally immortalized human and ex vivo adult mouse cells of the glomerulus, we demonstrated the podocyte to be the major glomerular source and target of IGF‐II; it signals to this cell via the IGF‐I receptor via the PI3 kinase and MAPK pathways. Functionally, a reduction in IGF signalling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF‐II transgenic mouse that produces approximately 60% of IGF‐II due to a lack of the P2 promoter of this gene. Collectively, this work reveals the fundamental importance of IGF‐II in the mature podocyte for glomerular health across mammalian species. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
CanVasc Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitides

Objective. The Canadian Vasculitis research network (CanVasc) is composed of physicians from different medical specialties and researchers with expertise in vasculitis. One of its aims is to develop recommendations for the diagnosis and management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. Methods. Diagnostic and therapeutic questions were developed based on the results of a national needs assessment survey. A systematic review of existing non-Canadian recommendations and guidelines for the diagnosis and management of AAV and studies of AAV published after the 2009 European League Against Rheumatism/European Vasculitis Society recommendations (publication date: January 2009) until November 2014 was performed in the Medline database, Cochrane library, and main vasculitis conference proceedings. Quality of supporting evidence for each therapeutic recommendation was graded. The full working group as well as additional reviewers, including patients, reviewed the developed therapeutic recommendations and nontherapeutic statements using a modified 2-step Delphi technique and through discussion to reach consensus. Results. Nineteen recommendations and 17 statements addressing general AAV diagnosis and management were developed, as well as appendices for practical use, for rheumatologists, nephrologists, respirologists, general internists, and all other healthcare professionals more occasionally involved in the management of patients with AAV in community and academic practice settings. Conclusion. These recommendations were developed based on a synthesis of existing international guidelines, other published supporting evidence, and expert consensus considering the Canadian healthcare context, with the intention of promoting best practices and improving healthcare delivery for patients with AAV.