Miracle-dz/UniFAR-FTUs huggingface dataset:
Phospholipid retention in the absence of asymmetry strengthens the outer membrane permeability barrier to last-resort antibiotics

Significance The outer membrane of Gram-negative bacteria prevents the entry of many antibiotics and limits treatment options for Gram-negative infections. This unique membrane is effective due to its asymmetric lipid composition, with the glycolipid lipid A [LPS or lipooligosaccharide (LOS)] in the outer leaflet at the cell surface and glycerophospholipids in the inner leaflet. Furthering our understanding of how outer membrane asymmetry is maintained is critical for the development of novel therapeutics to target multidrug-resistant bacteria. Here, we used a Gram-negative bacterium without LOS to probe for factors that impact cell-envelope maintenance in the absence of LOS. Our approach enabled us to explore fundamental mechanisms of cell-envelope biology and expand our holistic view of the asymmetrical, Gram-negative outer membrane. The outer membrane of Gram-negative bacteria is a critical barrier that prevents entry of noxious compounds. Integral to this functionality is the presence of lipopolysaccharide (LPS) or lipooligosaccharide (LOS), a molecule that is located exclusively in the outer leaflet of the outer membrane. Its lipid anchor, lipid A, is a glycolipid whose hydrophobicity and net negative charge are primarily responsible for the robustness of the membrane. Because of this, lipid A is a hallmark of Gram-negative physiology and is generally essential for survival. Rare exceptions have been described, including Acinetobacter baumannii, which can survive in the absence of lipid A, albeit with significant growth and membrane permeability defects. Here, we show by an evolution experiment that LOS-deficient A. baumannii can rapidly improve fitness over the course of only 120 generations. We identified two factors which negatively contribute to fitness in the absence of LOS, Mla and PldA. These proteins are involved in glycerophospholipid transport (Mla) and lipid degradation (PldA); both are active only on mislocalized, surface-exposed glycerophospholipids. Elimination of these two mechanisms was sufficient to cause a drastic fitness improvement in LOS-deficient A. baumannii. The LOS-deficient double mutant grows as robustly as LOS-positive wild-type bacteria while remaining resistant to the last-resort polymyxin antibiotics. These data provide strong biological evidence for the directionality of Mla-mediated glycerophospholipid transport in Gram-negative bacteria and furthers our knowledge of asymmetry-maintenance mechanisms in the context of the outer membrane barrier.
Evaluation of out-patient prescriptions in rural part of central Gujarat

Background: The prescription error is a failure in the prescription writing process leading to wrong instructions about the identity of the recipient, the identity of the drug, the formulation, dose, route, timing, frequency, and duration of administration. This study is an effort directed to find errors in prescription writing and interventions to improve on such error-prone practices of prescription writing. Methods: This was a cross-sectional, observational study conducted to analyze the prescription writing errors in the outpatient department in the rural area of Anand district of Central Gujarat. Prescriptions were collected from two nearby rural areas of Anand city-Petlad and Anklav. The prescription copies so-obtained were analyzed as per the WHO guidelines for “Prescription Writing Errors. ” Results: Overall, 191 prescriptions were collected from both rural areas in the study. The highest number of prescriptions was collected from general practitioners, followed by surgeons and gynecologists. Name, qualification, and address of prescribers were mentioned in all the prescriptions while registration number was mentioned only in 14.10% of prescriptions. The esoteric symbol was mentioned in 63% of prescriptions. Prescribers signed their prescription only in 48% of prescriptions. A total of 420 drugs were prescribed to the patients in the study. All but one drug were prescribed by brand name. Dosage form and route of administration of drugs were mentioned in >60% of drugs. Conclusion: Most medical schools provide some training in prescribing to medical undergraduates; however, this training is perceived to be suboptimal by medical students and junior doctors. Such training programs are the need of the hour.
Changes in Simultaneous Liver-kidney Transplant Allocation Policy May Impact Postliver Transplant Outcomes

Background. Previous simultaneous liver-kidney (SLK) transplant allocation was based on serum creatinine, a metric that disadvantaged women relative to men. A recent SLK transplant policy change uses estimated glomerular filtration rate (eGFR), which accounts for sex-based differences in creatinine. Methods. To understand the impact of this new policy, we analyzed nonstatus 1 adults listed for liver transplantation (LT) from May 2007 to July 2014, excluding those with exceptions. We defined patients who met the new SLK policy as having an eGFR <60 mL/min for 90 days, with a final eGFR <30 mL/min. Results. Of 40979 candidates, 1683 would have met only the new criteria (N-SLK), 2452 would have met only the old criteria (O-SLK), and 1878 would have met both criteria (B-SLK). Compared to those in the B-SLK or O-SLK groups, those in the N-SLK group were significantly more likely to be female (52% versus 36% versus 39%, P < 0.001). Cox-regression analysis demonstrated that in adjusted analysis those in the N-SLK group were significantly less likely to die postliver transplant (hazard ratio [HR], 0.0; P < 0.001). Further, in Cox regression subgroup analyses, both in women (HR 0.04; P < 0.001) and in men (HR, 0.02, P < 0.001) those in the N-SLK group who underwent liver transplant were significantly less likely to die postliver transplant, even after adjustment for confounders. Conclusions. We anticipate that implementation of the new SLK policy will increase the proportion of women and decrease the proportion of men who are listed for SLK but may not improve posttransplant survival. Our data highlight the need for monitoring of SLK outcomes after implementation of the new policy.
Recent research trends and updates on nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), together with metabolic syndrome and obesity, has shown a rapid increase in prevalence worldwide and is emerging as a major cause of chronic liver disease and liver transplantation. Among the various phenotypes of NAFLD, nonalcoholic steatohepatitis (NASH) is highly likely to progress to development of end-stage liver disease and cardiometabolic disease, resulting in liver-related and non-liver–related mortality. Nonetheless, there is no standardized pharmacotherapy against NASH and many drugs are under development in ongoing clinical trials. To develop a successful anti-NASH drug, it is necessary to select an appropriate target population and treatment outcomes depending on whether the mode of action is anti-metabolic, anti-inflammatory or anti-fibrotic. Recently, innovative surrogate markers have been investigated to replace hard outcomes such as liver histology and mortality and reduce the clinical trial duration. Currently, several drugs with fast track designation are being tested in phase III clinical trials, and many other drugs have moved into phase II clinical trials. Both lean NAFLD and typical obese NAFLD have been extensively studied and genetic variants such as PNPLA3 and TM6SF2 have been identified as significant risk factors for lean NAFLD. In the near future, noninvasive biomarkers and effective targeted therapies for NASH and associated fibrosis are required to develop precision medicine and tailored therapy according to various phenotypes of NAFLD.
Oral Alpha, Beta, and Gamma HPV Types and Risk of Incident Esophageal Cancer

Background: Several studies have examined association between human papillomaviruses (HPV) and esophageal cancer, but results have been inconsistent. This is the first prospective study to investigate associations between α, β and γ HPV detection in the oral cavity and risk of esophageal cancer. Methods: We conducted a nested case–control study among 96,650 cancer-free participants in the American Cancer Society Cancer Prevention Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident esophageal cancer cases (n = 125) were identified during an average 3.9 years of follow-up. Three controls per case (n = 372) were selected and matched on age, sex, race/ethnicity, and time since mouthwash collection. α, β, and γ HPV DNA in oral samples were detected using a next-generation sequencing assay. Conditional logistic regression models were used to estimate OR and 95% confidence intervals (CIs), adjusting for smoking and alcohol consumption. Statistical significance was evaluated using permutation test. Results: Prevalence of oral α, β, and γ HPV was 18.4%, 64.8%, and 42.4% in cases and 14.3%, 55.1%, and 33.6% in controls, respectively. Oral HPV16 detection was not associated with esophageal cancer (OR = 0.54, 95% CI, 0.1–4.84) and none of the esophageal squamous cell carcinoma cases (n = 28) were HPV16 positive. Some oral HPV types were more common in cases than controls; however, none of the associations were statistically significant. Conclusions: Although HPVs in the oral cavity are very common, this study showed no evidence of association between oral HPVs and esophageal cancer. Impact: Oral HPVs may not contribute to risk of esophageal cancer. Cancer Epidemiol Biomarkers Prev; 27(10); 1168–75. ©2018 AACR.
The latest FAD – Faecal antibody detection in cattle. Protocol and results from three UK beef farms naturally infected with gastrointestinal nematodes

Abstract Antibodies at gastrointestinal mucosal membranes play a vital role in immunological protection against a range of pathogens, including helminths. Gastrointestinal health is central to efficient livestock production, and such infections cause significant losses. Fecal samples were taken from 114 cattle, across three beef farms, with matched blood samples taken from 22 of those animals. To achieve fecal antibody detection, a novel fecal supernatant was extracted. Fecal supernatant and serum samples were then analysed, using adapted enzyme-linked immunosorbent assay protocols, for levels of total immunoglobulin (Ig)A, IgG, IgM, and Teladorsagia circumcincta-specific IgA, IgG, IgM and IgE (in the absence of reagents for cattle-specific nematode species). Fecal nematode egg counts were conducted on all fecal samples. Assays performed successfully and showed that IgA was the predominant antibody in fecal samples, whereas IgG was predominant in serum. Total IgA in feces and serum correlated within individuals (0.581, P = 0.005), but other Ig types did not. Results support the hypothesis that the tested protocols are an effective method for the non-invasive assessment of cattle immunology. The method could be used as part of animal health assessments, although further work is required to interpret the relationship between results and levels of infection and immunity.
Validation of yoga module for children with intellectual disabilities

Background: Children with developmental disabilities generally experience more pain than the normal children due to chronic systemic conditions associated with their disability. Description of pain is generally difficult in children and more so in children with intellectual disabilities (IDs). Yoga has been regarded as a kind of physical activity as well as a pain management strategy. Previous studies have reported the beneficial role of yoga in enhancing physical and psychomotor abilities of IDs; however, a validated yoga module (YM) for IDs is unavailable. The present study is aimed at developing a validated YM for children with IDs. Materials and Methods: The content validity of YM for children with IDs was assessed by a panel of 22 experienced yoga experts. The YM for children with IDs was developed in the form of tailor-made yoga practices that were supported by classical texts and research evidence. A total of 32 practices were included in the YM, and each practice was discussed and rated as (i) not essential, (ii) useful but not essential, and (iii) essential. The content validitity ratiowas calculated using Lawshe's formula. Results: Data analysis showed that out of 32 YM practices, 31 indicated significant content validity (cutoff value: 0.42, as calculated by applying Lawshe's formula for the CVR). Conclusions: The present study suggests that the YM for children with IDs is valid with good content validity. However, future randomized controlled trials must determine the feasibility and efficacy of the developed YM for children with IDs.
Combination of peripheral blood mononuclear cell miR-19b-5p, miR-221, miR-25-5p, and hypertension correlates with an increased heart failure risk in coronary heart disease patients

Objective: The aim of this study was to explore the differences in microRNA (miRNA) profiles in peripheral blood mononuclear cells (PBMCs) between coronary heart disease (CHD) patients with and without heart failure (HF) and to assess the values of differentially expressed miRNAs (DEMs) regarding HF risk in CHD patients. Methods: Six CHD patients with HF and six age- and gender-matched CHD patients without HF were enrolled in the exploration stage, and 44 CHD patients with HF and 42 age- and gender-matched CHD patients without HF were recruited in the validation stage. Peripheral blood samples were collected from all the participants, and PBMCs were separated for miRNA detection. miRNA microarray and quantitative polymerase chain reaction were performed to assess the miRNA expression. Results: In the exploration stage, heat map analysis showed that CHD patients with HF could be distinguished from those without HF using PMBC miRNA expressions; 63 downregulated DEMs and 84 upregulated DEMs in PBMCs were identified in CHD patients with HF using volcano map, and top 8 DEMs were selected based on their p values. In the validation stage, PBMC miR-221, miR-19b-5p, and miR-25-5p were found to be markedly dysregulated in CHD patients with HF. Multiple logistic regression analysis showed PBMC miR-221, miR-19b-5p, miR-25-5p, and hypertension to be the independent predictive factors for HF in CHD patients. A receiver operating characteristic curve demonstrated that area under curve of the combination of miR-221, miR-19b-5p, miR-25-5p, and hypertension was 0.871 (95% CI: 0.794-0.944). Conclusion: CHD patients with and without HF could be differentiated according to PBMC miRNA profiles, and the combination of PBMC miR-19b-5p, miR-221, miR-25-5p, and hypertension correlates with an increased HF risk in CHD patients.
Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia

Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different “omics,” clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental “virtual” liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal–fetal–placental immune interactions in preeclampsia. The description of these novel pathways in the “molecular phase” of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.
Evolution of Preferences in Multiple Populations

We study the evolution of preferences in a multi-population setting. Each individual has subjective preferences over potential outcomes, and chooses a best response based on his preferences and the information about the opponents' preferences. However, individuals' actual fitnesses are defined by material payoff functions. Following Dekel et al. (2007), we assume that individuals can observe their opponents' preferences with some fixed probability $p$, and derive necessary and sufficient conditions for stability for $p=1$ and $p=0$. We also check the robustness of our results against small perturbations on observability for the case of pure-strategy outcomes.
Phonetic Detail and Dimensionality in Sound-shape Correspondences: Refining the Bouba-Kiki Paradigm

Sound symbolism is the process by which speakers link phonetic features with meanings non-arbitrarily. For instance, speakers across languages associate non-words with rounded vowels, like bouba, with round shapes, and non-words without rounded vowels, like kiki, with spiky shapes. Researchers have posited that this link results from a cognitive association between sounds and visual or proprioceptive cues made in their production (e.g. sounds of rounded vowels cue the image of rounded lips, which is mapped to rounded shapes). However, non-words used in previous studies differ from one another along multiple phonetic dimensions, some showing no clear iconic mapping to shape. This study teases apart these features, finding that vowel backness, consonant voicing, and consonant place of articulation each elicit a sound symbolic effect, which is amplified when these dimensions are combined. This investigation also probes object properties that can be involved in sound symbolic association, bringing the “bouba-kiki” paradigm, typically involving the use of abstract shapes, into the realm of real-world objects. To shed light on ways that sound symbolism may operate in natural language, this study suggests that future research in this paradigm would benefit from consideration of both more detailed phonetic correlates and more refined object properties.
Does Mandated Corporate Social Responsibility Reduce Intrinsic Motivation ? Evidence from India ∗

We investigate the implementation of a 2014 Government of India mandate that requires companies to at least spend 2% of their profits on corporate social responsibility (CSR) activities. Firms that voluntarily engaged in CSR before the mandate reduce their spending significantly down to the suggested 2% level. Firms that did not actively engage in CSR before the mandate increase their spending marginally. CSR spending post mandate is highly sensitive to negative shocks to firm profits, but not to positive profit shocks. CSR spending post mandate is channeled to more opaque venues with limited third-party verification, relative to before the regulation. Our results are consistent with the hypothesis that regulatory intervention dampens managers’ intrinsic motivation to “do good”and, hence, could at times be counter-productive.
Response to Ioannis D. Evrigenis's review of Ruling Oneself Out: A Theory of Collective Abdications

In a book written more than four hundred years ago (Discourse on Voluntary Servitude, 1548), La Boétie conveyed his astonishment about people “acquiescing to their own servitude. ” Ruling Oneself Out restates the problem: why do groups legitimize the prospect of their political incapacity and, by way of consequence, the possibility of their servitude? I address this question by considering two parliamentary decisions of crucial historical significance: the parliamentary surrenders of constitutional authority in Germany (March 1933) and in France (July 1940). These events have paradigmatic value because they are clear-cut cases of collective abdications and because they lend themselves to explanations that seem as obvious as they are commonsensical. People abdicate because they face coercive pressures. They abdicate because they misjudge the consequences of their action. Or they abdicate because their ideology predisposes them to do so.
Earnings management in Brazil : a survey of the literature

This article reviews the recent academic literature on earnings management (EM) in Brazil. The objective is to identify the main research them es addressed in the Brazilian context and the results of interest to users and preparers of f inancial statements. It is hoped that this study will also be useful to researchers considering inve stigating the theme of earnings management, by providing an overview of the main discussions and methods usually employed. As a topic for academic research, earning s management is diversified and extensive, although relatively recent. The majority of Brazilian studies have been published in the past ten years, with a significant increase in academic production more recently, making this an opportune moment to reflect on the state of the art, summarize the evolution of knowledge and propose future research avenues.
End-to-end differentiable learning of protein structure

Predicting protein structure from sequence is a central challenge of biochemistry. Co‐evolution methods show promise, but an explicit sequence‐to‐structure map remains elusive. Advances in deep learning that replace complex, human‐designed pipelines with differentiable models optimized end‐to‐end suggest the potential benefits of similarly reformulating structure prediction. Here we report the first end‐to‐end differentiable model of protein structure. The model couples local and global protein structure via geometric units that optimize global geometry without violating local covalent chemistry. We test our model using two challenging tasks: predicting novel folds without co‐evolutionary data and predicting known folds without structural templates. In the first task the model achieves state‐of‐the‐art accuracy and in the second it comes within 1‐2Å; competing methods using co‐evolution and experimental templates have been refined over many years and it is likely that the differentiable approach has substantial room for further improvement, with applications ranging from drug discovery to protein design.