Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification and Characterization of the First Class of Potent Bacterial Acetyl-CoA Carboxylase Inhibitors with Antibacterial Activity*

The multisubunit acetyl-CoA carboxylase, which catalyzes the first committed step in fatty acid biosynthesis, is broadly conserved among bacteria. Its rate-limiting role in formation of fatty acids makes this enzyme an attractive target for the design of novel broad-spectrum antibacterials. However, no potent inhibitors have been discovered so far. This report describes the identification and characterization of highly potent bacterial acetyl-CoA carboxylase inhibitors with antibacterial activity for the first time. We demonstrate that pseudopeptide pyrrolidine dione antibiotics such as moiramide B inhibit the Escherichia coli enzyme at nanomolar concentrations. Moiramide B targets the carboxyltransferase reaction of this enzyme with a competitive inhibition pattern versus malonyl-CoA (Ki value = 5 nm). Inhibition at nanomolar concentrations of the pyrrolidine diones is also demonstrated using recombinantly expressed carboxyltransferases from other bacterial species (Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa). We isolated pyrrolidine dione-resistant strains of E. coli, S. aureus, and Bacillus subtilis, which contain mutations within the carboxyltransferase subunits AccA or AccD. We demonstrate that such mutations confer resistance to pyrrolidine diones. Inhibition values (IC50) of >100 μm regarding an eukaryotic acetyl-CoA carboxylase from rat liver indicate high selectivity of pyrrolidine diones for the bacterial multisubunit enzyme. The natural product moiramide B and synthetic analogues show broad-spectrum antibacterial activity. The knowledge of the target and the availability of facile assays using carboxyltransferases from different pathogens will enable evaluation of the antibacterial potential of the pyrrolidine diones as a promising antibacterial compound class acting via a novel mode of action.
Bayesian Deep Generative Models for Semi-Supervised and Active Learning

Despite the recent successes in machine learning, there remain many open challenges. Arguably one of the most important and interesting open research problems is that of data efficiency. Supervised machine learning models, and especially deep neural networks, are notoriously data hungry, often requiring millions of labeled examples to achieve desired performance. However, labeled data is often expensive or difficult to obtain, hindering advances in interesting and important domains. What avenues might we pursue to increase the data efficiency of machine learning models? One approach is semi-supervised learning. In contrast to labeled data, unlabeled data is often easy and inexpensive to obtain. Semi-supervised learning is concerned with leveraging unlabeled data to improve performance in supervised tasks. Another approach is active learning: in the presence of a labeling mechanism (oracle), how can we choose examples to be labeled in a way that maximizes the gain in performance? In this thesis we are concerned with developing models that enable us to improve data efficiency of powerful models by jointly pursuing both of these approaches. Deep generative models parameterized by neural networks have emerged recently as powerful and flexible tools for unsupervised learning. They are especially useful for modeling high-dimensional and complex data. We propose a deep generative model with a discriminative component. By including the discriminative component in the model, after training is complete the model is used for classification rather than variational approximations. The model further includes stochastic inputs of arbitrary dimension for increased flexibility and expressiveness. We leverage the stochastic layer to learn representations of the data which naturally accommodate semi-supervised learning. We develop an efficient Gibbs sampling procedure to marginalize the stochastic inputs while inferring labels. We extend the model to include uncertainty in the weights, allowing us to explicitly capture model uncertainty, and demonstrate how this allows us to use the model for active learning as well as semi-supervised learning. I would like to dedicate this thesis to my loving wife, parents, and sister .
Structural and compositional changes associated with chlorine inactivation of polioviruses

Chlorine inactivation of polioviruses resulted in the loss of viral ribonucleic acid, converting the viruses from 156S particles to 80S particles. However, it was found that virus inactivation occurred before the ribonucleic acid was released from the virions. Extraction of ribonucleic acid from partially inactivated virus suspensions indicated that chlorine inactivation was due to degradation of the ribonucleic acid before release and that ribonucleic acid loss was a secondary event. The empty 80S capsids had the same isoelectric point and ability to attach to host cells as infective virions. Thus, no major capsid conformational changes occurred during chlorine inactivation.
Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

SUMMARY Twenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger.
Sources of Errors in Rainfall Measurements by Polarimetric Radar: Variability of Drop Size Distributions, Observational Noise, and Variation of Relationships between R and Polarimetric Parameters

Abstract Using a set of long-term disdrometric data and of actual radar measurements from the McGill S-band operational polarimetric radar, several sources of errors in rain measurement with polarimetric radar are explored in order to investigate their relative importance and the feasibility of a polarimetric technique for estimating R in the context of the McGill S-band operational radar that performs a full volume scan of 24 plan position indicators (PPIs) every 5 min. The sources of errors considered are the variability of drop size distributions (DSDs), observational noise, and systematic variation of the relationships between R and polarimetric parameters at different climate regimes. Additional polarimetric parameters dramatically reduce the effect of the DSD variability on rain estimates by radar. The effectiveness of various multiparameter relationships is investigated. The relationships from the literature that are derived from the DSD model and measured DSDs at a different climate regime differ .
Illuminating the Evolutionary History of Chlamydiae

Chlamydiae are the major cause of preventable blindness and sexually transmitted disease. Genome analysis of a chlamydia-related symbiont of free-living amoebae revealed that it is twice as large as any of the pathogenic chlamydiae and had few signs of recent lateral gene acquisition. We showed that about 700 million years ago the last common ancestor of pathogenic and symbiotic chlamydiae was already adapted to intracellular survival in early eukaryotes and contained many virulence factors found in modern pathogenic chlamydiae, including a type III secretion system. Ancient chlamydiae appear to be the originators of mechanisms for the exploitation of eukaryotic cells.
Regenerative medicine and connective tissues: cartilage versus tendon

Progress in medicine over recent decades has notably increased life expectancy in the Western world. Such advance implies that the treatment of degenerative processes associated with ageing has become one of the major tasks of current medicine and therapeutics. High expectation relies on stem cell research in order to apply cell therapies to ameliorate degenerative processes, remarkably those concerning the circulatory, locomotor and nervous systems. However, the skeletal connective tissues have revealed that cell plasticity is a factor of major importance in regenerative therapies. Most evidence indicates that connective tissue cells of cartilage, tendons, ligaments and fascia share common progenitors during their differentiation, which are regulated by a number of director genes and a panel of miRNAs coupled with transforming growth factor‐β signalling. Furthermore, we know that not only stem cells but also differentiated cells from these tissues may dedifferentiate and redifferentiate, even one into another. Hence, modulation of cell plasticity might be a potential target for regenerative therapies in the future. In this review, we highlight classical concepts about the properties and differentiation of the connective tissues and their relation with recent advances in the study of stem cells, significant for regenerative medicine, paying special attention to cartilage and tendons. Copyright © 2011 John Wiley & Sons, Ltd.
Unbalanced Regressions and the Predictive Equation

Predictive return regressions with persistent regressors are typically plagued by (asymptotically) biased/inconsistent estimates of the slope, non-standard or potentially even spurious statistical inference, and regression unbalancedness. We alleviate the problem of unbalancedness in the theoretical predictive equation by suggesting a data generating process, where returns are generated as linear functions of a lagged latent I(0) risk process. The observed predictor is a function of this latent I(0) process, but it is corrupted by a fractionally integrated noise. Such a process may arise due to aggregation or unexpected level shifts. In this setup, the practitioner estimates a misspecified, unbalanced, and endogenous predictive regression. We show that the OLS estimate of this regression is inconsistent, but standard inference is possible. To obtain a consistent slope estimate, we then suggest an instrumental variable approach and discuss issues of validity and relevance. Applying the procedure to the prediction of daily returns on the S&P 500, our empirical analysis confirms return predictability and a positive risk-return trade-off.
Experiential Avoidance as an Emotion Regulatory Function: An Empirical Analysis of Experiential Avoidance in Relation to Behavioral Avoidance, Cognitive Reappraisal, and Response Suppression

The purpose of the present study was to empirically test the suggestion that experiential avoidance in an emotion regulation context is best understood as an emotion regulatory function of topographically distinct strategies. To do this we examined whether a measure of experiential avoidance could statistically account for the effects of emotion regulation strategies intervening at different points of the emotion-generative process as conceptualized by Gross' (1998) process model of emotion regulation. The strategies under examination were behavioral avoidance, cognitive reappraisal, and response suppression. The specific hypotheses to be tested were (1) that behavioral avoidance, cognitive reappraisal, and response suppression would statistically mediate the differences in measures of psychological well-being between a clinical and nonclinical sample, but that (2) these indirect effects would be reduced to nonsignificant levels when controlling for differences in experiential avoidance. The results provide clear support for the first hypothesis with regard to all the studied strategies. In contrast to the second hypothesis, the results showed the predicted outcome pattern only for the response-focused strategy “response suppression” and not for cognitive reappraisal or behavioral avoidance. The results are interpreted and discussed in relation to theories on experiential avoidance and emotion regulation.
Nonmalignant mortality among workers in six Norwegian aluminum plants.

OBJECTIVES This study investigated the associations between exposure to fluorides and polycyclic aromatic hydrocarbons (PAH) and mortality from nonmalignant diseases among workers in the Norwegian primary aluminum industry. METHODS Mortality among 10,857 men, employed for more than 3 years in 1 of 6 aluminum plants, was investigated from 1962 to 1996, giving 239,246 person-years during follow-up. Ajob-exposure matrix covering all 6 plants was used to estimate the individual exposure to total fluorides and particulate PAH. The observed cause-specific deaths were compared with expected figures calculated from national rates. Dose-response relations were investigated by internal comparisons using Poisson regression and by stratified analyses for standardized mortality ratio. Potential confounding by smoking was investigated in subanalyses restricted to 3 of the plants for which information on smoking habits was accessible. RESULTS Mortality from circulatory disease was slightly lower than expected [SMR 0.95, 95% confidence interval (95%CI) 0.9-1.0], while there was an increased mortality from asthma, emphysema, and chronic bronchitis combined, SMR 1.2 (95% CI 1.0-1.5). Mortality from these diseases was associated with cumulative exposure to fluorides. The rate ratio in the internal analysis rose steadily to 2.5 (95% CI 1.5-4.3) for the upper exposure category. No association was observed between cumulative fluoride exposure or PAH exposure and circulatory mortality. CONCLUSIONS The study showed an association between exposure to potroom emissions measured by fluorides and mortality from asthma, emphysema, and chronic bronchitis combined.
Validation of Preexisting Reference Intervals: Can the Procedure be Applied to Canine Hemostasis?

The de novo establishment of reference intervals (RIs) for all variables is beyond the capabilities of many small laboratories. Thus, recent international recommendations propose procedures to adopt RIs established by “donor” laboratories after validation in “receiving” laboratories. The objective of the current study was to use recently published RIs of canine hemostasis tests as possible donor values and evaluate the validation procedure with randomized sets of values obtained in another study of canine RI determination of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, and antithrombin (AT). The preanalytical, analytical, and demographic conditions of the donor and receiving laboratories were first compared. To represent new reference individuals, 25 validation sample sets of 20 results of the receiving laboratory were randomly selected for each variable and compared with the RI of the donor laboratory. Validation was rejected in all cases for APTT and AT. Donor RI could be validated in 14 of 25 cases for fibrinogen and in 4 of 25 cases for PT. When preanalytical and analytical differences existed between donor and receiving laboratories, validation procedures consistently rejected preexisting RI. When the differences are smaller, the variability of the results obtained in the validation sample sets tested may be responsible for validations or rejections, which can lead to further misinterpretations of results from patients. Validation of a preexisting reference interval is certainly an interesting option for small laboratories, but progressive determination of the laboratory's own reference interval is probably a better long-term solution.
World‐wide epidemiology of HBeAg‐negative chronic hepatitis B and associated precore and core promoter variants

Hepatitis B is a serious disease that is endemic in many parts of the world. A significant proportion of patients with chronic hepatitis B (CHB) are infected with a variant form of the hepatitis B virus (HBV) which decreases or abolishes the production of hepatitis B e‐antigen (HBeAg). The purpose of this literature review is to describe the epidemiology of HBeAg‐negative CHB (e‐CHB) worldwide. A literature search was conducted to identify studies pertaining to e‐CHB and underlying variants (precore and core promoter). Fifty studies were included in our analysis. The median prevalence of e‐CHB among patients with chronic HBV infection was 33% in the Mediterranean, 15% in Asia Pacific, and 14% in the USA and Northern Europe. The pre core stop codon variant was detected in a median of 60% (range 0–100%) of HBeAg‐negative patients overall, 92% in the Mediterranean, 50% in Asia Pacific and 24% in the USA and Northern Europe. There were very few data on the prevalence of core promoter variants outside Asia where the median prevalence among HBeAg‐negative patients was 77%. This literature review revealed that e‐CHB is more common than previously suspected and that it is present worldwide with marked variations in the prevalence of associated HBV variants across different geographical regions. Additional research using population based samples of adequate size based on a consensus definition of e‐CHB and using standardized HBV DNA assays is needed to better estimate the true prevalence of e‐CHB and its associated HBV variants.
Feature selection in power transformer fault diagnosis based on dissolved gas analysis

Dissolved gas analysis is an important test to diagnose the condition of a power transformer. Based on key gases, various features are recommended for the purpose of fault classification. A feature selection method can be used to reduce the number of features by excluding less useful or irrelevant features. Selecting useful features not only reduces the computational complexity, but also enhances the classification performance. The novelty of this paper is to use various techniques of feature selection, including Student's t-test, Kolmogorov-Smirnov test and Kullback Leibler Divergence test, to rank features' order based on discriminative power of different features. The ordered features are tested with the K-Nearest Neighbour classification algorithm to evaluate their importance based on fault classification accuracy.
Antidiabetic effects of hesperidin and naringin in type 2 diabetic rats.

SUMMARY This study was designed to investigate the effect of hesperidin and naringin on serum glucose, blood glycosylated hemoglobin and serum insulin levels in high fat fed (HFD)/streptozotocin (STZ)-induced type 2 diabetic rats. In addition, the effect on serum lipid profile, adiponectin and resistin levels, cardiac function parameters and liver and muscle glycogen contents was assessed. Hesperidin and naringin were orally and daily administered at a dose level of 50 mg/kg b.w. for 30 days to HFD/STZ type 2 diabetic rats. Both hesperidin and naringin supplementation potentially ameliorated the elevated levels of glucose, glycosylated hemoglobin, AST, LDH and CK-MB and the lowered serum insulin level and hepatic and muscle glycogen content of insulin resistant diabetic rats. Both compounds were also found to alleviate lipid profile and serum adiponectin and resistin levels. These results showed that hesperidin and naringin have potential antihyperglycemic and antidyslipidemic efficacies as well as cardiac function improving action in HFD/STZ-induced type 2 diabetic rats.
Effects of warming up, massage, and stretching on range of motion and muscle strength in the lower extremity

The effects of general warming up, massage, and stretching on ranges of motion (ROM) and strength of quadriceps and hamstring muscles were measured in eight male volunteers. Thigh muscle strength was not influenced by the experimental procedures. Stretching resulted in a significantly increased range of hip flexion/ extension, hip abduction, knee flexion, and ankle dor siflexion; the effect was significantly greater than that obtained by massage and warming up separately or combined. Only ankle dorsiflexion was influenced by massage or warming up, whereas stretching affected all muscle groups tested. Stretching was, therefore, superior to the other methods tested for increasing flexibility in the lower extremity.
Evidence for Impaired Hepatic Vitamin K1 Metabolism in Patients Treated with N-Methyl-Thiotetrazole Cephalosporins

Summary In 8 patients on no oral intake and with parenteral alimentation, administration of cephalosporins with N-methyl-thiotetrazole side chain (moxalactam, cefamandole), was associated with prolongation of prothrombin time, appearance in the circulation of descarboxy-prothrombin (counter immunoelectrophoresis and echis carinatus assay) and diminution of protein C. Acute administration of 10 mg vitamin Ki was followed by the transient appearance of vitamin K1 2,3-epoxide, indicating an impaired hepatocellular regeneration of vitamin K1 from the epoxide. Impaired hepatic vitamin K1 metabolism, tentatively ascribed to the N-methyl-thiotetrazole group, is one (but possibly not the only) cause of bleeding complications and depression of vitamin K1dependent procoagulants in patients treated with the new class of cephalosporins.
Nonlinear Koopman modes and power system stability assessment without models

Summary form only given. The loss of stability-an instability-can become a critical cause of emergent cascading outages leading to widespread blackouts. Penetration of renewable energy sources makes the problem of instability more urgent because of the highly fluctuating nature of such sources. Here we show a data-based approach to stability assessment of power systems without models. This approach is enabled by Koopman mode analysis for nonlinear dynamical systems, which detects an instability based on the properties of the point spectrum of the Koopman operator. We apply the technique to data on physical power flows sampled from the two major accidents, the 2011 Arizona-Southern California grid outage and the 2006 system disturbance of the European interconnected grid, and successfully detect unstable power flow patterns that govern the complex dynamics occurring during the accidents.
Theorizing the Pathways From Seeking and Scanning to Mammography Screening

This study combines insights from existing theories in mass communication and health communication, and builds an integrated model accounting for the mechanisms by which an individual’s acquisition of mammogram-related media information becomes associated with intentions to obtain a mammogram. Our model was largely supported by a survey with a nationally representative sample of American females between the ages of 40 and 70 years. As expected, seeking and scanning mammogram-related information from the media were both positively associated with reflective integration of media health information, which in turn was positively related to behavioral attitudes and perceived normative pressures. Attitudes and normative pressures were then positively linked to the intention to get a mammogram. Based on these findings, we offer some suggestions for future research in this area.