Miracle-dz/UniFAR-FTUs huggingface dataset:
Acetohydroxyacid synthase: a proposed structure for regulatory subunits supported by evidence from mutagenesis.

Valine inhibition of acetohydroxyacid synthase (AHAS) plays an important role in regulation of biosynthesis of branched-chain amino acids in bacteria. Bacterial AHASs are composed of separate catalytic and regulatory subunits; while the catalytic subunits appear to be homologous with several other thiamin diphosphate-dependent enzymes, there has been no model for the structure of the small, regulatory subunits (SSUs). AHAS III is one of three isozymes in Escherichia coli. Its large subunit (encoded by ilvI) by itself has 3-5 % activity of the holoenzyme and is not sensitive to inhibition by valine. The SSU (encoded by ilvH) associates with the large subunit and is required for full catalytic activity and valine sensitivity. The isolated SSU binds valine. The properties of several mutant SSUs shed light on the relation between their structure and regulatory function. Three mutant SSUs were obtained from spontaneous Val(R) bacterial mutants and three more were designed on the basis of an alignment of SSU sequences from valine-sensitive and resistant isozymes, or consideration of the molecular model developed here. Mutant SSUs N11A, G14D, N29H and A36V, when reconstituted with wild-type large subunit, lead to a holoenzyme with drastically reduced valine sensitivity, but with a specific activity similar to that of the wild-type. The isolated G14D and N29H subunits do not bind valine. Mutant Q59L leads to a valine-sensitive holoenzyme and isolated Q59L binds valine. T34I has an intermediate valine sensitivity. The effects of mutations on the affinity of the large subunits for SSUs also vary. D. Fischer's hybrid fold prediction method suggested a fold similarity between the N terminus of the ilvH product and the C-terminal regulatory domain of 3-phosphoglycerate dehydrogenase. On the basis of this prediction, together with the properties of the mutants, a model for the structure of the AHAS SSUs and the location of the valine-binding sites can be proposed.
Measuring disease activity in ankylosing spondylitis: patient and physician have different perspectives.

OBJECTIVE There is no "gold standard" to assess disease activity in patients with ankylosing spondylitis (AS). It is known that patients and physicians have different opinions about disease activity. The objective was therefore to investigate on which criteria patients with AS and physicians base their judgement on disease activity. METHODS A cohort of 203 AS out-patients fulfilling the modified New York criteria included in the ongoing long-term follow-up was analysed. The Assessment in Ankylosing Spondylitis (ASAS) International Working Group has established different domains relevant for outcome in AS. Each domain includes a number of instruments for making assessments, and all these instruments are included in the Outcome in Ankylosing Spondylitis International Study and were made every 6 months for 2 yr. Disease activity from the patient perspective as well as from the physician perspective was analysed using the patient's or the physician's global assessment of disease activity [visual analogue scale (VAS): 0 (best)-10 (worst)] by dichotomizing into "high disease activity" (VAS > or = 6.0) and "low disease activity" (VAS < or = 4.0). Data reduction by principal components analysis (PCA) was performed to distinguish factors capturing correlated instruments. Discriminant analysis with the factor loadings was performed to discriminate between a low and a high disease activity state from both the patient's and the physician's perspective. Multiple regression analysis on the discriminant scores was performed to prioritize the instruments. RESULTS PCA revealed four factors: spinal mobility, physician assessments, patient assessments and laboratory assessments (Cronbach's alpha 0.52-0.80; explained variance 61%). Discriminant function analysis showed that the factor "patient assessments" was most important (pooled correlation 0.85) in discriminating between a low and a high disease activity state as defined by the patient. The other three factors contributed marginally (pooled correlation <0.30). In contrast, the factors "physician's assessments" (pooled correlation 0.62), "spinal mobility" (pooled correlation 0.52) and "laboratory assessments" (pooled correlation 0.48) contributed most to the physician's perspective. The factor "patient assessments" did not contribute at all (pooled correlation 0.05). Multivariate analysis on the discriminant scores showed that the instruments "pain spine", "BASFI", "pain joints" and "BASDAI fatigue" explained more than 90% of variance in the case of the patient perspective. The instruments "cervical rotation", "swollen joint count", "CRP" and "intermalleolar distance" explained more than 90% of variance in case of physician perspective. CONCLUSION AS patients rate disease activity on the basis of complaints while physicians rate disease activity on the basis of instruments related to disease severity and inflammation.
ATP requirement for Prp5p function is determined by Cus2p and the structure of U2 small nuclear RNA

Stable addition of U2 small nuclear ribonucleoprotein (snRNP) to form the prespliceosome is the first ATP-dependent step in splicing, and it requires the DEXD/H box ATPase Prp5p. However, prespliceosome formation occurs without ATP in extracts lacking the U2 snRNP protein Cus2p. Here we show that Prp5p is required for the ATP-independent prespliceosome assembly that occurs in the absence of Cus2p. Addition of recombinant Cus2p can restore the ATP dependence of prespliceosome assembly, but only if it is added before Prp5p. Prp5p with an altered ATP-binding domain (Prp5-GNTp) can support growth in vivo, but only in a cus2 deletion strain, mirroring the in vitro results. Other Prp5 ATP-binding domain substitutions are lethal, even in the cus2 deletion strain, but can be suppressed by U2 small nuclear RNA mutations that hyperstabilize U2 stem IIa. We infer that the presence of Cus2p and stem IIa-destabilized forms of U2 small nuclear RNA places high demands on the ATP-driven function of Prp5p. Because Prp5p is not dispensable in vitro even in the absence of ATP, we propose that the core Prp5p function in bringing U2 to the branchpoint is not directly ATP-dependent. The positive role of Cus2p in rescuing mutant U2 can be reconciled with its antagonistic effect on Prp5 function in a model whereby Cus2p first helps Prp5p to activate the U2 snRNP for prespliceosome formation but then is displaced by Prp5p before or during the stabilization of U2 at the branchpoint.
Managing hepatitis B/HIV co-infected: adding entecavir to truvada (tenofovir disoproxil/emtricitabine) experienced patients

Background: Combination emtricitabine (FTC) or lamivudine (LAM) with tenofovir disoproxil (TDF) is the recommended first-line regime for treatment in chronic hepatitis B virus (HBV)/HIV co-infection. However, in those failing to suppress, few data exist regarding further management. In HBV/HIV co-infection, there are no published data describing outcomes when entecavir (ETV) is then added to TDF-based regimes in patients no longer suppressing their HBV. We report the first series of patients using ETV with truvada-based HAART in HBV/HIV co-infected patients with previous HBV therapy failure, including inadequate suppression. Methods: A prospective observational study. Results: Thirteen HIV/HBV co-infected patients (all male, hepatitis B e antigen positive and hepatitis B e antibody negative) were commenced on ETV in addition to background truvada. All patients were previously exposed to LAM or FTC and TDF (median 53 months, range 6–123). Seven patients had LAM monotherapy prior to TDF/LAM or FTC combination; the remaining six patients were exposed to FTC or LAM and TDF combination. Median time of follow-up was 74 weeks (range 16–159) and median HBV decline was 2.53 log10 IU/ml (range 1.28–7.36). Thirty-eight percent of patients achieved undetectable HBV DNA level by the end of the study and eight of 13 (62%) achieved normal alanine aminotransferase (ALT) levels with median reduction −28 U/l (range −152 to 37). TDF was stopped in one patient because of renal toxicity. ETV was well tolerated with no change of estimated glomerular filtration rate during the study. Conclusion: Entecavir can be considered in addition to TDF/FTC in HBV/HIV co-infected treatment-experienced patients failing to fully suppress their HBV viral load.
Further study of the control of place cell firing by intra‐apparatus objects

The angular positions of hippocampal place cell firing fields are accurately controlled by the position of a single salient cue card attached to the wall of a recording cylinder; when the card is rotated, fields rotate equally. In contrast, the control exerted by 3‐dimensional objects placed directly in the recording arena depends on their arrangement. When three objects lie on the vertices of an isosceles triangle near the center of the cylinder they rarely exert any control over the angular positions of firing fields. However, if the isosceles triangle is dilated so that its vertices are against the apparatus wall, the objects exert virtually ideal control over angular field position. Why do the objects gain control when they are against the cylinder wall? One possibility is that the asymmetry in the object set is more easily detected when the objects are far apart so that they provide a better polarizing cue. This hypothesis assumes that the identity of individual landmarks is not recognized by the place cell system whereas their geometric arrangement provides crucial information for controlling place field positions. If this is true, putting the 3 objects against the cylinder wall on the vertices of an equilateral triangle should cause a loss of stimulus control over the angular positions of firing fields. To the contrary, we found that the firing fields of most place cells (23/29) were accurately controlled by the equilateral object arrangement. Moreover, 5/6 of the uncontrolled cells were in a single animal. These results bolster our previous suggestion that the centrally placed objects fail to control place field positions because the computations necessary to form a stable reference frame are very difficult when the animal can go between stimuli. Hippocampus 1999;9:432–443. © 1999 Wiley‐Liss, Inc.
Correlation of Clinical Outcomes with Quantitative Polymerase Chain Reaction DNA Copy Number in Patients with Acute Retinal Necrosis

ABSTRACT Purpose: To correlate visual acuity outcomes and clinical features with quantitative PCR DNA copy number in patients with acute retinal necrosis (ARN). Methods: Retrospective, consecutive case series. Results: In total, 14 eyes of 13 patients were diagnosed with ARN, based on the American Uveitis Society criteria, and were followed for a mean of 324.5 days (median 250.5 days, SD ± 214 days). Anterior chamber fluid analyzed by quantitative PCR identified viral DNA in 11 of 14 eyes (78.5%). Varicella zoster virus (VZV) was identified in seven eyes (50%) and herpes simplex virus (HSV) in four eyes (28.5%). Mean DNA copy number was 7.9 × 106/mL (median 2.10 × 106/mL, range: 0–5.60 × 107/mL). Eyes with quantitative PCR DNA copy number of ≥5.0 × 106/mL (n = 6 eyes) had worse baseline visual acuity (logMAR 1.48 ± 0.71 vs 0.94 ± 0.76, p = 0.196) and final visual acuity (logMAR 2.10 ± 0.60 vs 0.82 ± 0.81, p = 0.007) compared with patients with a DNA copy number <5.0 × 106/mL (n = 8 eyes). Patients with a DNA copy number of ≥5.0 × 106/mL were more likely to have at least 5 clock hours of retinitis on funduscopic exam (p = 0.03) and developed retinal detachment more frequently (p = 0.08). Conclusions: Quantitative DNA copy number of ≥5.0 × 106/mL is associated with more extensive retinitis, worse visual acuity, and development of retinal detachment in patients with acute retinal necrosis.
Predictors of the Perception of Smoking Health Risks in Smokers With or Without Schizophrenia

ABSTRACT Objective: This study sought to examine the predictors of health risk perception in smokers with or without schizophrenia. Methods: The health risk subscale from the Smoking Consequences Questionnaire was dichotomized and used to measure health risk perception in smokers with (n = 67) and without schizophrenia (n = 100). A backward stepwise logistic regression was conducted using variables associated at the bivariate level to determine multivariate predictors. Results: Overall, 62.5% of smokers without schizophrenia and 40.3% of smokers with schizophrenia completely recognize the health risks of smoking (p ≤ .01). Multivariate predictors for smokers without schizophrenia included: sex (Exp (B) = . 3; p < . 05), Smoking Consequences Questionnaire state enhancement (Exp (B) = . 69; p < . 01), and craving relief (Exp (B) = 1.8; p < . 01). Among smokers with schizophrenia, predictors were education (Exp (B) = . 7; p < . 05), nicotine dependence (Exp (B) = . 5; p < . 01), motivation to quit (Exp (B) = 1.8; p < . 01), and Smoking Consequences Questionnaire craving relief (Exp (B) = 1.8; p < . 01). Conclusions: There was overlap and differences between predictors in smokers with and without schizophrenia. Commonly used techniques for education on the health consequences of cigarettes may work in smokers with schizophrenia, but intervention efforts specifically tailored to smokers with schizophrenia might be more efficacious.
Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return

Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect in which the pulmonary veins fail to enter the left atrium and drain instead into the right atrium or one of its venous tributaries. Although a genetic basis for TAPVR has long been recognized, no single gene involved in the pathogenesis of this disease has been identified to date. We previously reported a TAPVR patient bearing a de novo 10;21 balanced translocation. In this work, we cloned both translocation breakpoints from this patient and mapped the ANKRD1 gene, encoding a cardiac transcriptional regulator, 130 kb proximally to the breakpoint on chromosome 10. In situ hybridization analysis performed on murine embryos showed ANKRD1 expression in the developing pulmonary veins, suggesting a possible role for this gene in TAPVR pathogenesis. Moreover, ANKRD1 expression levels were found to be highly increased in lymphoblastoid cell lines derived from both the translocation‐bearing proband and a second independent sporadic TAPVR patient, suggesting that disruption of the normal ANKRD1 expression pattern is associated with TAPVR. Finally, a nonconservative missense mutation in the ANKRD1 gene was found in a third sporadic TAPVR patient. In vitro calpain‐mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac‐specific atrial natriuretic factor (ANF) promoter. Taken together, these results define ANKRD1 as a possible candidate gene for TAPVR pathogenesis. Hum Mutat 29(4), 468–474, 2008. © 2008 Wiley‐Liss, Inc.
Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis

Background: Ankylosing spondylitis (AS) and its early form account for up to 5% of all patients with chronic back pain. Interest has recently focused on shortening the delay of 5–10 years between the appearance of first symptoms and the diagnosis of AS, particularly because effective treatments have now become available. Referral parameters that are easy for doctors in primary care to apply to patients presenting with possible AS could contribute to earlier diagnosis. Methods: Orthopaedists and primary-care doctors were requested to refer patients with (1) chronic low back pain (duration >3 months) and (2) onset of back pain before <45 years of age to a specialist rheumatology outpatient clinic for further diagnostic investigation if at least one of the following screening parameters was present: (1) inflammatory back pain, (2) positive human leucocyte antigen B27, and (3) sacroiliitis detected by imaging. The final diagnosis was made according to expert opinion. Results: In total, 350 referred cases were analysed. A diagnosis of definite axial spondyloarthritis (axial SpA), comprising established AS and pre-radiographic axial SpA, could be made in 45.4% of all referred patients (of which 50.3% were classified as AS and 49.7% as preradiographic axial SpA), whereas 45.4% were classified as non-SpA and 9.1% as possible SpA. A diagnosis of definite axial SpA could be made in 34.2% if only one referral parameter was positive, and in 62.6% if there was >1 positive referral parameter. Conclusions: The proposed referral parameters have proven useful when applied in primary care in identifying patients with AS/pre-radiographic axial SpA among young to middle-aged patients with chronic low back pain.
Homocysteine-induced endoplasmic reticulum protein (herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies.

BACKGROUND Recent studies highlight the role of endoplasmic reticulum (ER) stress and aberrant protein degradation in the pathogenesis of neurodegenerative disorders. Herp which is encoded by the HERPUD 1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1) gene is a stress-response protein localized in the ER membrane of neurons and other cell types. Herp has been suggested to improve ER-folding, decrease ER protein load, and participate in ER-associated degradation (ERAD) of proteins. METHODS Based on microarray expression profiling results we have predicted an increased expression of HERPUD1 in the substantia nigra of Parkinson's disease (PD) patients. We have now used brain tissue of some of the same and additional cases of sporadic PD to localize Herp mRNA and protein in individual cell types. RESULTS We found expression of Herp in neurons and in glial cells including astrocytes. These findings were corroborated by in situ hybridization. Accumulation of Herp protein was also detected in the core of Lewy bodies suggesting a role in their formation. Hierarchical clustering analysis identified TWINKLE (PEO1) as the gene whose expression profile was most similar to that of Herp across the PD cohort. CONCLUSIONS The nigral glial cells that expressed Herp at a high level resembled TUNEL-positive glia. While some of these cells likely undergo degeneration, the strong up-regulation of Herp in glia could help to explain the inflammation-like changes observed in PD ("neuroinflammation") as it has been shown that the unfolded protein response serves as an important regulator of inflammatory genes in other organs.
Health Advice from Internet Discussion Forums: How Bad Is Dangerous?

Background Concerns over online health information–seeking behavior point to the potential harm incorrect, incomplete, or biased information may cause. However, systematic reviews of health information have found few examples of documented harm that can be directly attributed to poor quality information found online. Objective The aim of this study was to improve our understanding of the quality and quality characteristics of information found in online discussion forum websites so that their likely value as a peer-to-peer health information–sharing platform could be assessed. Methods A total of 25 health discussion threads were selected across 3 websites (Reddit, Mumsnet, and Patient) covering 3 health conditions (human immunodeficiency virus [HIV], diabetes, and chickenpox). Assessors were asked to rate information found in the discussion threads according to 5 criteria: accuracy, completeness, how sensible the replies were, how they thought the questioner would act, and how useful they thought the questioner would find the replies. Results In all, 78 fully completed assessments were returned by 17 individuals (8 were qualified medical doctors, 9 were not). When the ratings awarded in the assessments were analyzed, 25 of the assessments placed the discussion threads in the highest possible score band rating them between 5 and 10 overall, 38 rated them between 11 and 15, 12 rated them between 16 and 20, and 3 placed the discussion thread they assessed in the lowest rating band (21-25). This suggests that health threads on Internet discussion forum websites are more likely than not (by a factor of 4:1) to contain information of high or reasonably high quality. Extremely poor information is rare; the lowest available assessment rating was awarded only 11 times out of a possible 353, whereas the highest was awarded 54 times. Only 3 of 78 fully completed assessments rated a discussion thread in the lowest possible overall band of 21 to 25, whereas 25 of 78 rated it in the highest of 5 to 10. Quality assessments differed depending on the health condition (chickenpox appeared 17 times in the 20 lowest-rated threads, HIV twice, and diabetes once). Although assessors tended to agree on which discussion threads contained good quality information, what constituted poor quality information appeared to be more subjective. Conclusions Most of the information assessed in this study was considered by qualified medical doctors and nonmedically qualified respondents to be of reasonably good quality. Although a small amount of information was assessed as poor, not all respondents agreed that the original questioner would have been led to act inappropriately based on the information presented. This suggests that discussion forum websites may be a useful platform through which people can ask health-related questions and receive answers of acceptable quality.
The structure of common mental disorders.

BACKGROUND This report presents the results of confirmatory factor analyses of patterns of comorbidity among 10 common mental disorders in the National Comorbidity Survey, a national probability sample of US civilians who completed structured diagnostic interviews. METHODS Patterns of comorbidity among DSM-III-R mental disorders were analyzed via confirmatory factor analyses for the entire National Comorbidity Survey sample (N = 8098; age range, 15-54 years), for random halves of the sample, for men and women separately, and for a subsample of participants who were seeing a professional about their mental health problems. Four models were compared: a 1-factor model, a 2-factor model in which some disorders represented internalizing problems and others represented externalizing problems, a 3-factor variant of the 2-factor model in which internalizing was modeled as having 2 subfactors (anxious-misery and fear), and a 4-factor model in which the disorders represented separate affective, anxiety, substance dependence, and antisocial factors. RESULTS The 3-factor model provided the best fit in the entire sample. This result was replicated across random halves of the sample as well as across women and men. The substantial empirical intercorrelation between anxious-misery and fear (0.73) suggested that these factors were most appropriately conceived as subfactors of a higher-order internalizing factor. In the treatment sample, the 2-factor model fit best. CONCLUSIONS The results offer a novel perspective on comorbidity, suggesting that comorbidity results from common, underlying core psychopathological processes. The results thereby argue for focusing research on these core processes themselves, rather than on their varied manifestations as separate disorders.