Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutations of Tau Protein in Frontotemporal Dementia Promote Aggregation of Paired Helical Filaments by Enhancing Local β-Structure*

The microtubule-associated protein tau is a natively unfolded protein in solution, yet it is able to polymerize into the ordered paired helical filaments (PHF) of Alzheimer's disease. In the splice isoforms lacking exon 10, this process is facilitated by the formation of β-structure around the hexapeptide motif PHF6 (306VQIVYK311) encoded by exon 11. We have investigated the structural requirements for PHF polymerization in the context of adult tau isoforms containing four repeats (including exon 10). In addition to the PHF6 motif there exists a related PHF6* motif (275VQIINK280) in the repeat encoded by the alternatively spliced exon 10. We show that this PHF6* motif also promotes aggregation by the formation of β-structure and that there is a cross-talk between the two hexapeptide motifs during PHF aggregation. We also show that two of the tau mutations found in hereditary frontotemporal dementias, ΔK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for β-structure around the hexapeptide motifs.
Relationship between hypercoagulable state and erythrocyte phosphatidylserine exposure in splenectomized haemoglobin E/β‐thalassaemic patients *

Summary. Small pulmonary arterial thromboses can occur following splenectomy of patients with haemoglobin E/β‐thalassaemia (Hb E/β‐thal). We compared plasma markers of coagulation activation in vivo and red blood cell (RBC) markers of procoagulant activity in 15 Hb E/β‐thal patients who were not splenectomized (NS), 15 who had been splenectomized (S), and 15 normal controls (NC). Levels of plasma thrombin–antithrombin III complex (TAT) were significantly higher in the S group than in either the NS or the NC groups, and levels of prothrombin fragment 1.2 (F 1.2) were significantly higher in the S than in the NC group. Diluted Russell's viper venom clotting times were significantly shorter when RBCs from group S patients were added to the assay compared with RBCs from the NC group. Phosphatidylserine (PS) expression (% of annexin V‐positive RBCs) on the outer leaflet of RBC membrane of both ‘larger’‐ and ‘smaller’‐sized RBCs was significantly higher for the S than the NC group. The RBC PS expression of the S and the NS groups, respectively, accounted for 25·3% (P = 0·174) and 6·3% (P = 0·675) of the variation in plasma TAT levels. Our findings indicated that, when compared with NC, splenectomized patients with Hb E/β‐thal were in a chronic low‐grade hypercoagulable state associated with increased numbers of circulating PS exposed RBCs. This condition may have a role in the risk of these patients for pulmonary arterial thromboses.
An Ultrasonographic Evaluation of Gallbladder Emptying in Patients with Cholelithiasis

Impaired gallbladder emptying producing biliary stasis may provide potent carcinogen, which comes in contact with gallbladder mucosa for a prolonged period, inducing carcinogenesis. The aim was to study gallbladder emptying pattern in cholelithiasis. Postprandial gallbladder emptying was measured ultrasonographically in terms of fasting volume (FV), postprandial residual volume at 30 minutes (PP30), 60 minutes (PP60), and 90 minutes (PP90), residual fraction, and ejection volume (EV) in 58 patients with gallstones. Patients were divided into two groups of poor and good contractors on the basis of 50% maximal postprandial gallbladder emptying. Malonaldehyde level was estimated in 15 patients with cholelithiasis. Twenty-nine patients (50%) were poor contractors. The FV in patients with cholelithiasis (mean, 30.08 mL) was larger than the controls (mean, 17.55 mL) and the difference was statistically significant (p < 0.02). The FV in the cholelithiasis group correlated significantly with the PP30 (r = 0.85, p < 0.001), PP60 (r = 0.85, p < 0.001), PP90 (r = 0.78, p < 0.001), and EV (r = 0.65, p < 0.001). Ejection volume was significantly less in poor contractors (p <0.001). Residual fraction was significantly higher in poor contractors (p < 0.001). The biliary malonaldehyde in poor contractors (2.27 &mgr;mol/mL) was higher than in good contractors (1.78 &mgr;mol/mL), but the difference was statistically not significant. Significantly larger volumes of PP30, PP60, PP90, and residual fraction and a low EV indicate poor contraction leading to biliary stasis.
Association between C-reactive protein and insulin resistance in a Japanese population: the Minoh Study.

OBJECTIVE To investigate the association between C-reactive protein (CRP) and insulin resistance. MATERIALS AND METHODS This study included 1,624 Japanese participants (652 men and 972 women) aged 40 to 69 years who were non-diabetics or did not have medication for hypertension or dyslipidemia, a history of cardiovascular disease or CRP levels >10 mg/l. Serum CRP level, fasting glucose level, and fasting insulin level were measured, and the degree of insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Categories of CRP were defined by the following tertiles: <0.25 mg/l, 0.25-0.59 mg/l, and > or = 0.60 mg/l. RESULTS Elevated CRP levels were associated with increased fasting insulin levels, fasting glucose levels, and HOMA-IR in both men and women. Although the adjustment for body mass index in addition to age, cigarette smoking, and alcohol consumption attenuated the associations between CRP and fasting insulin, fasting glucose, and HOMA-IR, elevated CRP levels were associated with increased insulin levels and HOMA-IR in both sexes. Stratified analyses by CRP level and obesity showed that obesity status was associated with increased fasting insulin levels, fasting glucose levels, and HOMA-IR in both sexes and that fasting insulin levels, fasting glucose levels, and HOMA-IR were higher among obese individuals than among non-obese individuals at the same level of CRP. CONCLUSION These results suggest a possible role of subclinical inflammation in insulin resistance and glucose intolerance in Japanese, but it only partly explains the link between obesity and impaired glucose homeostasis.
A new tarkadectine primate from the Eocene of Inner Mongolia, China: phylogenetic and biogeographic implications

Tarka and Tarkadectes are Middle Eocene mammals known only from the Rocky Mountains region of North America. Previous work has suggested that they are members of the Plagiomenidae, an extinct family often included in the order Dermoptera. Here we describe a new primate, Tarkops mckennai gen. et sp. nov., from the early Middle Eocene Irdinmanha Formation of Inner Mongolia, China. The new taxon is particularly similar to Tarka and Tarkadectes, but it also displays many features observed in omomyids. A phylogenetic analysis based on a data matrix including 59 taxa and 444 dental characters suggests that Tarkops, Tarka and Tarkadectes form a monophyletic group—the Tarkadectinae—that is nested within the omomyid clade. Within Omomyidae, tarkadectines appear to be closely related to Macrotarsius. Dermoptera, including extant and extinct flying lemurs and plagiomenids, is recognized as a clade nesting within the polyphyletic group of plesiadapiforms, therefore supporting the previous suggestion that the relationship between dermopterans and primates is as close as that between plesiadapiforms and primates. The distribution of tarkadectine primates on both sides of the Pacific Ocean basin suggests that palaeoenvironmental conditions appropriate to sustain primates occurred across a vast expanse of Asia and North America during the Middle Eocene.
Pathway enrichment analysis approach based on topological structure and updated annotation of pathway

Abstract Pathway enrichment analysis has been widely used to identify cancer risk pathways, and contributes to elucidating the mechanism of tumorigenesis. However, most of the existing approaches use the outdated pathway information and neglect the complex gene interactions in pathway. Here, we first reviewed the existing widely used pathway enrichment analysis approaches briefly, and then, we proposed a novel topology‐based pathway enrichment analysis (TPEA) method, which integrated topological properties and global upstream/downstream positions of genes in pathways. We compared TPEA with four widely used pathway enrichment analysis tools, including database for annotation, visualization and integrated discovery (DAVID), gene set enrichment analysis (GSEA), centrality‐based pathway enrichment (CePa) and signaling pathway impact analysis (SPIA), through analyzing six gene expression profiles of three tumor types (colorectal cancer, thyroid cancer and endometrial cancer). As a result, we identified several well‐known cancer risk pathways that could not be obtained by the existing tools, and the results of TPEA were more stable than that of the other tools in analyzing different data sets of the same cancer. Ultimately, we developed an R package to implement TPEA, which could online update KEGG pathway information and is available at the Comprehensive R Archive Network (CRAN): https://cran.r‐project.org/web/packages/TPEA/.
Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han.

OBJECTIVE Experimental and clinical data suggested that brain-derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) is characterized by declined cognitive function and has a high probability of evolving into AD. The aim of this study was to investigate serum BDNF concentrations in aMCI patients and determine whether there is an association of the BDNF gene Val66Met polymorphism with aMCI, cognitive function, and serum BDNF. METHOD Between April 2005 and January 2006, the present study recruited 99 aMCI patients who met diagnostic criteria for MCI proposed by the Mayo Clinic Alzheimer's Disease Research Center and 99 matched healthy controls from a population-based sample. All subjects underwent extensive assessment of cognitive function, measurement of serum BDNF by an enzyme-linked immunosorbent assay, and genotyping of the BDNF gene Val66Met polymorphism. RESULTS The serum concentrations of BDNF in aMCI patients (median [interquartile range] = 4.37 [2.35-6.40] ng/mL) were significantly lower than those of healthy controls (4.98 [3.50-7.33] ng/mL) (z = -2.449, p = .014). There were significant positive correlations between serum BDNF and scores on delayed recall in the Auditory Verbal Learning Test, which reflects episodic memory (r = 0.264, p = .008). No significant differences were found for either the genotype or allele distribution of BDNF Val66Met polymorphism between aMCI patients and control subjects. The BDNF Val66Met polymorphism was not associated with serum BDNF or cognitive function in aMCI patients. CONCLUSIONS This study suggests that reduced BDNF levels may play a role in the pathophysiology of aMCI, and the BDNF gene Val66Met polymorphism may not be an important factor in susceptibility to aMCI.
Women in novel occupational roles: mental health trends in the UK Armed Forces.

BACKGROUND There is uncertainty about whether women in the military have more psychological symptoms than men and whether psychological symptoms have increased over time. The aims of this study were to assess changes in psychological symptoms in military women over time, to compare them with men, and assess the effect of deployment. METHODS Two cross-sectional studies based on random samples of the Armed Forces were used to assess the effects of deployment to the Gulf and Iraq Wars. We selected for the analyses all the women and a 20% random sample of men who completed a questionnaire stratified by rank. We assessed psychological distress, number of symptoms, post-traumatic stress reaction (PTSR), chronic fatigue and alcohol misuse. RESULTS There has been an increase in psychological symptoms, including alcohol misuse, in those not deployed to the Gulf or Iraq Wars, especially in women. The odds ratios for PTSR [5.82 (95% CI: 1.27-26.71)], multiple symptoms [8.49 (1.97-36.65)] and alcohol misuse [6.20 (2.09-18.37)] were higher in women than in men in the non-deployed samples. Psychological distress and chronic fatigue was more common in women, and alcohol misuse, was more common in men. In women, psychological symptoms were positively associated with deployment in the Gulf War, but not the Iraq War. CONCLUSION Psychological symptoms in the Armed Forces have increased over time regardless of gender, in those not deployed. The association between gender and psychological symptoms has not changed over time. The deployment effect in women is similar to that described in men.
COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention.

OBJECTIVE The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that step-down combination therapy with prednisolone, methotrexate, and sulfasalazine (SSZ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis (RA). The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time, and to determine which baseline factors could predict outcome. METHODS All patients had participated in the 56-week COBRA trial. During followup, they were seen by their own rheumatologists and were also assessed regularly by study nurses; no treatment protocol was specified. Disease activity, radiologic damage, and functional ability were the primary outcome domains. Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method. Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat, starting with data obtained at the last visit of the COBRA trial (56 weeks after baseline). RESULTS At the beginning of followup, patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score (DAS28) and a significantly lower median radiologic damage (Sharp) score compared with those in the SSZ monotherapy group. The functional ability score (Health Assessment Questionnaire [HAQ]) was similar in both groups. During the 4-5 year followup period, the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group. The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group. After adjustment for differences in treatment and disease activity during followup, the between-group difference in the rate of radiologic progression was 3.7 points per year. The HAQ score did not change significantly over time. Independent baseline predictors of radiologic progression over time (apart from treatment allocation) were rheumatoid factor positivity, Sharp score, and DAS28. CONCLUSION An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy.
Correlation of Overexpression of Efflux Pump Genes with Antibiotic Resistance in Escherichia coli Strains Clinically Isolated from Urinary Tract Infection Patients

ABSTRACT Escherichia coli is one of the most common pathogens in urinary tract infections (UTIs), and antibiotic resistance in E. coli is becoming a serious problem in treating UTI. Efflux system overexpression is reported to contribute to E. coli resistance to several antibiotics. This study investigated the correlation of antibiotic susceptibilities with the overexpression of the efflux pump genes such as marA, yhiU, yhiV, and mdfA and with risk factors for antibiotic resistance in E. coli isolated from UTI patients. We examined the expression level of efflux pump genes using quantitative real-time reverse transcription-PCR (qRT-PCR). We also tested the in vitro susceptibilities to 12 kinds of antibiotics in 64 clinical strains of E. coli isolated from UTI patients. By multivariate analyses we revealed significant relationships between the overexpression of (i) marA and MICs of cefepime (FEP) and nalidixic acid (NAL), (ii) yhiV and MICs of minocycline (MIN), and (iii) mdfA and MICs of sitafloxacin (STX). In our investigation of the efflux pump genes, risk factors such as gender and the previous use of fluoroquinolones correlated with the overexpression of marA, and indwelling catheter use correlated with the overexpression of mdfA. In conclusion, we demonstrated that the increased expression of efflux pump genes such as marA and mdfA can lead to fluoroquinolone resistance in E. coli. These results contribute to our knowledge of the efflux system and raise the possibility of developing new agents, such as efflux pump inhibitors (EPIs), to antibiotic-resistant E. coli.
Association between anesthesiologist experience and mortality after orthotopic liver transplantation

The anesthesiologist has been recognized as an integral member of the liver transplant team, and previous studies have demonstrated that inter‐anesthesiologist variability can be a driver of outcomes for high‐risk patients. We hypothesized that anesthesiologist experience, defined as the number of previous liver transplants performed at our institution, the Icahn School of Medicine at Mount Sinai, would be independently associated with outcomes for liver transplant patients. Eight hundred forty‐nine liver transplants performed between January 2003 and January 2013 with a total of 22 anesthesiologists were analyzed. Each transplant was assigned an incremental case number that corresponded to the number of transplants that the attending anesthesiologist had already performed at our institution. Several perioperative covariates were controlled for in the context of a generalized linear mixed effects model to detail the influence of threshold levels of the incremental case number on the primary outcome, 30‐day mortality, and a secondary outcome, 30‐day graft failure. Sensitivity analyses were conducted to confirm the robustness of these findings. An incremental case number ≤ 5 was associated with a significantly greater risk of 30‐day mortality (odds ratio = 2.24, 95% confidence interval = 1.11‐4.54, P = 0.025), and there was evidence suggestive of a greater risk of 30‐day graft failure (odds ratio = 1.93, 95% confidence interval = 0.95‐3.93, P = 0.071). Sensitivity analyses ruled out threats to the validity of these findings, including dropout effects and time trends in the overall performance of the transplantation unit. In conclusion, this study shows that an anesthesiologist's level of experience has a significant effect on outcomes for liver transplant recipients, with increased mortality and possibly graft failure during a provider's first 5 cases. These findings may indicate the need for increased training and supervision for anesthesiologists joining the liver transplant team. Liver Transpl 21:89‐95, 2015. © 2014 AASLD.
Impacts of altered precipitation regimes on soil communities and biogeochemistry in arid and semi‐arid ecosystems

Altered precipitation patterns resulting from climate change will have particularly significant consequences in water‐limited ecosystems, such as arid to semi‐arid ecosystems, where discontinuous inputs of water control biological processes. Given that these ecosystems cover more than a third of Earth's terrestrial surface, it is important to understand how they respond to such alterations. Altered water availability may impact both aboveground and belowground communities and the interactions between these, with potential impacts on ecosystem functioning; however, most studies to date have focused exclusively on vegetation responses to altered precipitation regimes. To synthesize our understanding of potential climate change impacts on dryland ecosystems, we present here a review of current literature that reports the effects of precipitation events and altered precipitation regimes on belowground biota and biogeochemical cycling. Increased precipitation generally increases microbial biomass and fungal:bacterial ratio. Few studies report responses to reduced precipitation but the effects likely counter those of increased precipitation. Altered precipitation regimes have also been found to alter microbial community composition but broader generalizations are difficult to make. Changes in event size and frequency influences invertebrate activity and density with cascading impacts on the soil food web, which will likely impact carbon and nutrient pools. The long‐term implications for biogeochemical cycling are inconclusive but several studies suggest that increased aridity may cause decoupling of carbon and nutrient cycling. We propose a new conceptual framework that incorporates hierarchical biotic responses to individual precipitation events more explicitly, including moderation of microbial activity and biomass by invertebrate grazing, and use this framework to make some predictions on impacts of altered precipitation regimes in terms of event size and frequency as well as mean annual precipitation. While our understanding of dryland ecosystems is improving, there is still a great need for longer term in situ manipulations of precipitation regime to test our model.
Protection against cyclophosphamide‐induced alopecia and inhibition of mammary tumor growth by topical 1,25‐dihydroxyvitamin D3 in mice

Twenty‐one‐day‐old BALB/c mice were shaved on the back to synchronize hair growth. On day 30 or 31, when at least 90% of mice exhibited hair regrowth in the shaved area, 1,25(OH)2D3 was applied topically to the shaved area daily for 5 days. On the 6th day, cyclophosphamide (Cytoxan, CTX) was injected i.p. to induce hair loss in the shaved area. Alopecia was induced in a dose‐dependent manner by CTX treatment within 1 to 2 weeks. This effect was reduced significantly if mice were pre‐treated with 1,25(OH)2D3, though only slight protection was observed in female mice. Interestingly, this 1,25(OH)2D3‐mediated protection against hair loss was attenuated in male mice but became more significant in female mice when they were inoculated with the EMT‐6 murine mammary tumor prior to treatment. More importantly, topical treatment with 1,25(OH)2D3 alone was able to inhibit EMT‐6 tumor growth in both male and female BALB/c mice. Furthermore, 1,25(OH)2D3 pre‐treatment also augmented the anti‐tumor effect of CTX. Our results demonstrate that topical application of 1,25(OH)2D3 can protect against CTX‐induced alopecia both in tumor‐free and in tumor‐bearing mice in a sex‐dependent manner. Moreover, 1,25(OH)2D3 was shown, either alone or in combination with CTX, to inhibit tumor growth. Int. J. Cancer 75:303–309, 1998. © 1998 Wiley‐Liss, Inc.