Miracle-dz/UniFAR-FTUs huggingface dataset:
Discovery of Novel Inhibitors of the Tautomerase Activity of Macrophage Migration Inhibitory Factor (MIF)

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine associated with multiple diseases, including neurodegenerative disorders. With the ultimate goal of providing novel chemotypes as starting points for development of disease-modifying therapeutics for neurodegeneration, we endeavored to screen the GSK compound collection for MIF inhibitors using a miniaturized, activity-based kinetic assay. The assay monitors the increase in absorbance at 320 nm resulting from keto-to-enol tautomerization of 4-hydroxyphenylpyruvate, a reaction catalyzed by MIF. We ran a full-diversity screen evaluating the inhibitory activity of 1.6 million compounds. Primary hits were confirmed and retested in an orthogonal assay measuring tautomerization of l-dopachrome methyl ester by the decrease in absorbance at 475 nm in kinetic mode. Selected compounds were progressed to medium-throughput mode-of-inhibition studies, which included time dependence, enzyme concentration dependence, and reversibility of their inhibitory effect. With these results and after inspection of the physicochemical properties of compounds, 17 chemotypes were prioritized and progressed to further stages of validation and characterization to better assess their therapeutic potential.
Restoration of vision IV: role of compensatory soma swelling of surviving retinal ganglion cells in recovery of vision after optic nerve crush.

PURPOSE Diffuse axonal injury following partial optic nerve crush (ONC) leads to severe visual deficits from which rats can partially recover within 2-3 weeks. To evaluate tbc role of surviving retinal ganglion cells (RGCS) in recovery, we have observed their morphology repeatedly in vivo with ICON-microscopy and correlated cell size changes with recovery of vision which we observed in parallel in the same animals. METHODS After rats had learned a visual contrast discrimination task using an automated, computer-based test, RGCs were labeled retrogradely with fluorescent beads. Animals then received either no lesion, a complete axotomy or bilateral mild, moderate or severe ONC. Before surgery and for 40 days post-operatively, ROC number and soma size was repeatedly quantified every five days with tbc in vivo confocal neuroimaging method (Sabel et al., Nature med. 3, 1997, p. 244). In parallel, visual function was quantified with the contrast-discrimination task. RESULTS After ONC about 70 % of the ROCs died after having undergone a fast and massive soma swelling. The extent of cell death was independent of crush severity. RGCs surviving the injury did not change their body size over time in the severe group and these animals also did not recover their vision. In contrast, after a mild or moderate crush, about half of the surviving RGCs experienced a slow and moderate, "compensatory" cell soma swelling and the rats showed partial recovery of vision. Both the number of RGCs showing such compensatory soma swelling and the extent of the swelling correlated highly (r = 0.96) with recovery of contrast discrimination performance at post-operative days 23 and 38. CONCLUSIONS Depending en the time course and extent, soma swelling after neurotrauma may be associated either with cell death or recovery of function. Because of the very high correlation between extent of recovery and amount of soma swelling, moderate soma swelling contributes in a prominent way to recovery of vision. We believe that these cells provide an important structural substrate for neuronal tissue repair and therefore term these cells "compensatory neurons".
Neurodegeneration in Mice Resulting From Loss of Functional Selenoprotein P or Its Receptor Apolipoprotein E Receptor 2

Selenoprotein P (Sepp1) is involved in selenium homeostasis. Mice with a deletion of Sepp1, replacement of it by the shortened form Sepp1&Dgr;240-361, or deletion of its receptor apolipoprotein E receptor 2 develop severe neurologic dysfunction when fed low-selenium diet. Because the brainstems of Sepp1−/− mice had been observed to contain degenerated axons, a study of these 3 strains was made under selenium-deficient and high-selenium (control) conditions. Selenium-deficient wild-type mice were additional controls. Serial sections of the brain were evaluated with amino cupric silver degeneration and anti-glial fibrillary acidic protein stains. All 3 strains with altered Sepp1 metabolism developed severe axonal injury when fed selenium deficient diet. This injury was mitigated by high-selenium diet and was absent from selenium-deficient wild-type mice. Injury was most severe in Sepp1−/− mice, with staining in at least 6 brain regions. Injury in Sepp1&Dgr;240-361 and apolipoprotein E receptor 2−/− mice was less severe and occurred only in areas injured in Sepp1−/− mice, suggesting a common selenium-related etiology. Affected brain regions were primarily associated with auditory and motor functions, consistent with the clinical signs. Those areas have high metabolic rates. We conclude that interference with Sepp1 function damages auditory and motor areas, at least in part by restricting selenium supply to the brain regions.
Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese.

The metabolic syndrome is characterized by a clustering of cardiovascular risk factors including type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity. Elevated plasma insulin and urinary norepinephrine (noradrenaline) and reduced urinary epinephrine (adrenaline) excretion are associated with obesity in Caucasian populations. We examined the interrelationships between obesity, plasma insulin, and urinary catecholamine excretion in Chinese subjects with various components of the metabolic syndrome. A total of 577 Chinese subjects (aged 38 +/- 10 years; 68% with type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria and 32% healthy subjects) were studied, all of whom had a plasma creatinine less than 150 micromol/L. The blood pressure, height, weight, waist and hip circumference, and fasting plasma glucose, insulin, lipid, and creatinine levels were measured. A 24-hour urine sample was collected for measurement of albumin and catecholamine excretion. The body mass index (BMI) and waist circumference were used as measures of general and central obesity, respectively. The insulin resistance index was estimated by the calculated product of fasting plasma insulin and glucose concentrations. Patients with an increasing number of components of the metabolic syndrome (type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria) were more obese, hyperglycemic, dyslipidemic, and albuminuric and had higher blood pressure, plasma insulin, insulin resistance indices, and 24-hour urinary norepinephrine excretion but lower urinary epinephrine output (all P < .005). Increasing quintiles of BMI in the whole population or waist circumference in both sexes were associated with increasing trends for adverse lipid profiles, plasma insulin, insulin resistance indices, and urinary norepinephrine excretion but a decreasing trend for urinary epinephrine output (all P < .001). There were close associations between age, obesity, blood pressure, fasting plasma glucose, lipid, insulin, insulin resistance indices, and urinary catecholamine excretion. Using stepwise multiple regression analysis (all P < .001), 34% of the variability of the BMI and 45% of that of the waist circumference were independently related to gender (waist higher in males and BMI higher in females), increased plasma insulin, triglyceride, and urinary norepinephrine excretion, and decreased high-density lipoprotein (HDL) cholesterol and urinary epinephrine output. In Chinese subjects with different manifestations of the metabolic syndrome, hyperinsulinemia, insulin resistance, elevated norepinephrine, and reduced epinephrine excretion were closely associated with general and central obesity. Based on these findings, we postulate that complex interactions between the insulin and sympathoadrenal systems may lead to the development of obesity and the metabolic syndrome.
Protracted expression of serotonin transporter and altered thalamocortical projections in the barrelfield of hypothyroid rats

In humans, thyroid hormone deficiency during development causes severe neurological diseases but the underlying mechanisms are unclear. We have examined the effects of thyroid hormones on the development of somatosensory thalamocortical projections, by inducing hypothyroidism in rats by methimazole treatment at embryonic day 13 and subsequent thyroidectomy at postnatal day 6 (P6). Initial development of the thalamocortical projections and their tangential and laminar patterning were similar in normal and hypothyroid rats from birth to P4. The tangential spread of the thalamocortical arbors is reduced in hypothyroid rats after P4, paralleling the overall cortical atrophy. Anterograde tracing and single axon reconstructions indicate that thalamic afferents reached layer IV but that they had fewer and shorter branches, with a 42% reduction in the number of boutons. The transient serotonin (5‐HT) immunostaining and 5‐HT transporter (5‐HTT) expression were both prolonged by 5 days in hypothyroid rats. This does not reflect a delayed maturation of the thalamus because other transiently expressed genes such as the vesicular monoamine transporter and the 5‐HT1B receptor are not modified. Protracted 5‐HTT expression also occurred in other areas with transient expression, but no changes were observed in the raphe nuclei where the 5‐HTT is expressed permanently. Thus, thyroid hormones appear to be important in regulating the extinction of the 5‐HTT in nonserotoninergic neurons. The transient stabilization of 5‐HT reuptake in hypothyroid rats could affect the growth of thalamic axons. Our data stress the importance of maternal and foetal thyroid hormones for the normal development of sensory systems.
Deep-Sparse-Representation-Based Features for Speech Recognition

Features derived using sparse representation (SR)-based approaches have been shown to yield promising results for speech recognition tasks. In most of the approaches, the SR corresponding to speech signal is estimated using a dictionary, which could be either exemplar based or learned. However, a single-level decomposition may not be suitable for the speech signal, as it contains complex hierarchical information about various hidden attributes. In this paper, we propose to use a multilevel decomposition (having multiple layers), also known as the deep sparse representation (DSR), to derive a feature representation for speech recognition. Instead of having a series of sparse layers, the proposed framework employs a dense layer between two sparse layers, which helps in efficient implementation. Our studies reveal that the representations obtained at different sparse layers of the proposed DSR model have complimentary information. Thus, the final feature representation is derived after concatenating the representations obtained at the sparse layers. This results in a more discriminative representation, and improves the speech recognition performance. Since the concatenation results in a high-dimensional feature, principal component analysis is used to reduce the dimension of the obtained feature. Experimental studies demonstrate that the proposed feature outperforms existing features for various speech recognition tasks.
Kinetic Modeling Application to 18F-fluoroethylcholine Positron Emission Tomography in Patients with Primary and Recurrent Prostate Cancer Using Two-tissue Compartmental Model

Although 18F-fludeoxyglucose-positron emission tomography (PET) is the most applied diagnostic method in tumor staging, its role in prostate cancer (PCA) is limited because glucose metabolism tends to be low unless PCA has high Gleason score. Alternatively, choline PET was introduced as a valuable imaging method. Kinetic analysis of PET acquisition has increasingly gained momentum as an investigative tool because it provides a non-invasive approach to obtain kinetic and metabolic data from tissues of interest including transport and metabolism of the administered material. In this regard, we sought to apply it in 18F-fluoroethylcholine (FECH)-PET/computed tomography (CT) in patients with PCA. 64 patients, the mean age 69 (range: 47-87 years) with primary/recurrent PCA were encompassed. They underwent 18F-FECH-PET started with a dynamic acquisition using a 20-frame each 30 s over the prostate region and followed at 1 h post-injection by a static whole body imaging. The kinetic evaluation of the data was performed using the software package PMOD (PMOD Technologies Ltd., Zürich, Switzerland). Significant increase in mean values for K1, K3, FD, standardized uptake value (SUV) and global influx in tumor tissue versus normal tissue (P < 0.05). Moderate but significant correlation (r: 0.28, P = 0.023) between SUV and K1. By contrast, no correlation between SUV and K3 (r: −0.08, P = 0.79). In patients with recurrent tumors, there is no significant difference in all kinetic parameters and SUV (P > 0.1) between the different types of recurrences. The kinetic analysis of dynamic FECH-PET provides a novel method in primary PCA diagnosis and could be of potential value in the delineation of tumor focus.
Whisker-related circuitry in the trigeminal nucleus principalis: Ultrastructure

Abstract Trigeminal (V) nucleus principalis (PrV) is the requisite brainstem nucleus in the whisker-to-barrel cortex model system that is widely used to reveal mechanisms of map formation and information processing. Yet, little is known of the actual PrV circuitry. In the ventral “barrelette” portion of the adult mouse PrV, relationships between V primary afferent terminals, thalamic-projecting PrV neurons, and gamma-aminobutyric acid (GABA)-ergic terminals were analyzed in the electron microscope. Primary afferents, thalamic-projecting cells, and GABAergic terminals were labeled, respectively, by Neurobiotin injections in the V ganglion, horseradish peroxidase injections in the thalamus, and postembedding immunogold histochemistry. Primary afferent terminals (Neurobiotin- and glutamate-immunoreactive) display asymmetric and multiple synapses predominantly upon the distal dendrites and spines of PrV cells that project to the thalamus. Primary afferents also synapse upon GABAergic terminals. GABAergic terminals display symmetric synapses onto primary afferent terminals, the somata and dendrites (distal, mostly) of thalamic-projecting neurons, and GABAergic dendrites. Thus, primary afferent inputs through the PrV are subject to pre- and postsynaptic GABAergic influences. As such, circuitry exists in PrV “barrelettes” for primary afferents to directly activate thalamic-projecting and inhibitory local circuit cells. The latter are synaptically associated with themselves, the primary afferents, and with the thalamic-projecting neurons. Thus, whisker-related primary afferent inputs through PrV projection neurons are pre- and postsynaptically modulated by local circuits.
Percutaneous Posterior Tibial Nerve Stimulation in Patients with Chronic Pelvic Pain: A Preliminary Study

Background: We evaluated the clinical effect of intermittent percutaneous posterior tibial nerve stimulation (PTNS) in patients with chronic pelvic pain (CPP). Methods: A total of 15 patients (10 women and 5 men, mean age 60.0 years, range 41–78) with CPP were enrolled in an open prospective clinical trial. The patients had 12 weekly outpatient treatment sessions, each lasting 30 min. All patients were evaluated by history, physical as well as urological examination, the Visual Analogue Scale (VAS) for pain and urgency, the International Prostate Symptom Score, and a 3-day frequency-volume chart. Results: After 12 weeks of PTNS, 9 (60%) and 3 patients (30%) had an improvement of >50% and 25–50% in the VAS score for pain, respectively. Six patients (40%) ended up with a mean VAS <3. Mean VAS for pain changed from 8.1 ± 0.2 at baseline to 4.1 ± 0.6 after 12 weeks of treatment (p < 0.01). Mean VAS for urgency changed from 4.5 ± 1.0 at baseline to 2.7 ± 0.7 after 12 weeks of treatment (p < 0.05). However, there was no statistically significant improvement in the International Prostate Symptom Score. There was no statistically significant difference in the number of voids and bladder volumes either. Conclusions: Our findings suggest that PTNS may improve pain symptoms for over half of the patients with CPP. Long-term follow-up studies are needed to verify these preliminary results.
Association between the subepidermal autoimmune blistering diseases linear IgA disease and the pemphigoid group and inflammatory bowel disease: two case reports and literature review

We report two patients with subepidermal autoimmune blistering diseases and inflammatory bowel disease (IBD) [one with linear IgA disease (LAD) and ulcerative colitis (UC), and the other with mucous membrane pemphigoid (MMP) and Crohn disease (CD)], and present a review of all previously reported cases. We reviewed the literature, and found 48 cases of patients with autoimmune blistering diseases and IBD. The blistering diseases were LAD (25 patients), bullous pemphigoid (BP) (21), MMP (1) and pemphigoid gestationis (1), while the IBD types comprised UC (40) and CD (8). We describe the clinical and immunopathological features and demographic characteristics of the patients. In all but one case, the diagnosis of IBD predated the development of the skin condition. The association was more common with LAD than BP. The immunopathogenesis of IBD and autoimmune blistering diseases is discussed and a link between them hypothesized, namely, that the presentation of multiple antigens to the immune system during the unregulated inflammation in the bowel wall results in excitation of the immune system and recognition of autologous antigens.
Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium.

OBJECTIVE To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. DATA SOURCES Forty research teams contributed data on APOE genotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. MAIN OUTCOME MEASURES Odds ratios (ORs) and 95% confidence intervals (CIs) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon4, and epsilon4/epsilon4 relative to the epsilon3/epsilon3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. RESULTS Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8). The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). The APOE epsilon4-AD association in Japanese subjects was stronger than in Caucasian subjects (epsilon3/epsilon4: OR=5.6, 95% CI=3.9-8.0; epsilon4/epsilon4: OR=33.1, 95% CI=13.6-80.5). The epsilon2/epsilon3 genotype appears equally protective across ethnic groups. We also found that among Caucasians, APOE genotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that the APOE epsilon4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex. CONCLUSIONS The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE epsilon4 and AD in African Americans requires clarification, and the attenuated effect of APOE epsilon4 in Hispanics should be investigated further.
Seroepidemiological study of Epstein‐Barr virus infection in Bangladesh

A seroepidemiological study was carried out on 502 sera to determine the prevalence of EBV infection in a group of Bangladeshi people (age range: 15 days–90 years). All sera were tested for IgG antibody to the EBV viral capsid antigen (VCA) by a commercially available enzyme linked immunosorbent assay (ELISA) and the negative sera were checked subsequently by indirect immunofluorescence (IF) methods. The prevalence of EBV infection in the study group was 81.27%. 42.37% of infants had antibodies to EBV by the age of 1 year. A significant rise in the percentage of seropositives between 0–1‐ and 1–2‐year‐old children was demonstrated, indicating a high rate of primary infection at these ages. The prevalence of IgG antibody to VCA was 87.93% in the 2–10 years age group and was sustained at over 85% thereafter. Higher ELISA values were more common both in the 0–2‐ and >25‐year age groups, the latter being statistically significant (P < 0.025). Similar higher values were also observed in females as compared to males (P = 0.05). Eighteen out of 109 negative sera and two equivocal sera by ELISA were found to be positive by indirect IF, indicating a negative predictive value of 82% for ELISA. The concordance between the two methods was 97% with ELISA proving to be less sensitive than indirect IF. It is concluded that the prevalence of EBV infection in Bangladeshi population is similar to that observed in other developing countries and that ELISA can be used for seroepidemiological surveys; however, the sera negative by ELISA should be checked routinely by indirect IF. © 1996 Wiley‐Liss, Inc.
Association of Efavirenz Hypersusceptibility with Virologic Response in ACTG 368, a Randomized Trial of Abacavir (ABC) in Combination with Efavirenz (EFV) and Indinavir (IDV) in HIV-Infected Subjects with Prior Nucleoside Analog Experience

Abstract Purpose: To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients. Method and Results: Rates of virologic failure were similar in the 2 arms at week 16 (p = .509). Treatment discontinuations were more common in the ABC arm (p = .001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistance mutation L74V was selected for in combination with the uncommonly occurring EFV-resistance mutations K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated. Conclusion: Premature treatment discontinuations in the ABC arm and the presence of EFV-HS HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance.