Miracle-dz/UniFAR-FTUs huggingface dataset:
The bacterial ribonuclease P holoenzyme requires specific, conserved residues for efficient catalysis and substrate positioning

RNase P is an RNA-based enzyme primarily responsible for 5′-end pre-tRNA processing. A structure of the bacterial RNase P holoenzyme in complex with tRNAPhe revealed the structural basis for substrate recognition, identified the active site location, and showed how the protein component increases functionality. The active site includes at least two metal ions, a universal uridine (U52), and P RNA backbone moieties, but it is unclear whether an adjacent, bacterially conserved protein loop (residues 52–57) participates in catalysis. Here, mutagenesis combined with single-turnover reaction kinetics demonstrate that point mutations in this loop have either no or modest effects on catalytic efficiency. Similarly, amino acid changes in the ‘RNR’ region, which represent the most conserved region of bacterial RNase P proteins, exhibit negligible changes in catalytic efficiency. However, U52 and two bacterially conserved protein residues (F17 and R89) are essential for efficient Thermotoga maritima RNase P activity. The U52 nucleotide binds a metal ion at the active site, whereas F17 and R89 are positioned >20 Å from the cleavage site, probably making contacts with N−4 and N−5 nucleotides of the pre-tRNA 5′-leader. This suggests a synergistic coupling between transition state formation and substrate positioning via interactions with the leader.
Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes

The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.
Assessment of adherence to the statistical components of consolidated standards of reporting trials statement for quality of reports on randomized controlled trials from five pharmacology journals

Background: The Consolidated Standards of Reporting Trials (CONSORT) statement is a device to standardize reporting and improve the quality of controlled trials. However, little attention is paid to the statistical components in the CONSORT checklist. The present study evaluates the randomized controlled trials [RCTs] published in five high impact pharmacology journals with respect to its statistical methods. Methods: Randomized Controlled Trials [RCTs] published in the years 2013 & 2014 in five pharmacology journals with high impact factor, The Journal of Clinical Pharmacology (JCP), British Journal of Clinical Pharmacology (BJCP), European Journal of Clinical Pharmacology (EJCP), Journal of Pharmacology & Pharmacotherapeutics (JPP) and Indian Journal of Pharmacology (IJP) were assessed for adherence to the statistical components of CONSORT statement. Results: Of the 174 RCTs analysed, 103 described the method of sample size calculation. Of the five journals, maximum reports in JCP (34/50) and minimum in IJP (13/31) adhered to the CONSORT checklist [item 7a-sample size calculation]. Most reports mentioned the statistical methods used for analysis of data. (171/174) as per the checklist [item 12=statistical methods used]. Analysis of variance (ANOVA) was the most commonly used test (88/174). The software used for statistical analysis was mentioned in 111 RCTs and SPSS was used more frequently (58/111). The exact p value was stated in 108 reports. Certain errors in statistical analysis were also noted (40/174). Conclusion: These findings show inconsistencies and non- adherence to the statistical components of the CONSORT statement especially with respect to sample size calculation. Special attention must be paid to the statistical accuracy of the reports.
Event-related potentials and the study of memory retrieval: A critical review

Memory retrieval has been extensively investigated by a variety of techniques and methodological approaches. The present article reports a critical review on the research investigating this subject by means of event-related potentials (ERP). The main goal is to elucidate the key contributions of this technique regarding episodic memory retrieval, as well as to perform a critical analysis taking into account its major advantages and limitations in the framework of current cognitive neuroscience. Considerations concerning its theoretical contributions and implementation in national universities are also discussed.
Fast Eigenspace Approximation using Random Signals

We focus in this work on the estimation of the first $k$ eigenvectors of any graph Laplacian using filtering of Gaussian random signals. We prove that we only need $k$ such signals to be able to exactly recover as many of the smallest eigenvectors, regardless of the number of nodes in the graph. In addition, we address key issues in implementing the theoretical concepts in practice using accurate approximated methods. We also propose fast algorithms both for eigenspace approximation and for the determination of the $k$th smallest eigenvalue $\lambda_k$. The latter proves to be extremely efficient under the assumption of locally uniform distribution of the eigenvalue over the spectrum. Finally, we present experiments which show the validity of our method in practice and compare it to state-of-the-art methods for clustering and visualization both on synthetic small-scale datasets and larger real-world problems of millions of nodes. We show that our method allows a better scaling with the number of nodes than all previous methods while achieving an almost perfect reconstruction of the eigenspace formed by the first $k$ eigenvectors.
Stochastic Multiple Choice Learning for Training Diverse Deep Ensembles

Many practical perception systems exist within larger processes that include interactions with users or additional components capable of evaluating the quality of predicted solutions. In these contexts, it is beneficial to provide these oracle mechanisms with multiple highly likely hypotheses rather than a single prediction. In this work, we pose the task of producing multiple outputs as a learning problem over an ensemble of deep networks -- introducing a novel stochastic gradient descent based approach to minimize the loss with respect to an oracle. Our method is simple to implement, agnostic to both architecture and loss function, and parameter-free. Our approach achieves lower oracle error compared to existing methods on a wide range of tasks and deep architectures. We also show qualitatively that the diverse solutions produced often provide interpretable representations of task ambiguity.
Incidence and Symptoms of High Altitude Illness in South Pole Workers: Antarctic Study of Altitude Physiology (ASAP)

Introduction Each year, the US Antarctic Program rapidly transports scientists and support personnel from sea level (SL) to the South Pole (SP, 2835 m) providing a unique natural laboratory to quantify the incidence of acute mountain sickness (AMS), patterns of altitude related symptoms and the field effectiveness of acetazolamide in a highly controlled setting. We hypothesized that the combination of rapid ascent (3 hr), accentuated hypobarism (relative to altitude), cold, and immediate exertion would increase altitude illness risk. Methods Medically screened adults (N = 246, age = 37 ± 11 yr, 30% female, BMI = 26 ± 4 kg/m2) were recruited. All underwent SL and SP physiological evaluation, completed Lake Louise symptom questionnaires (LLSQ, to define AMS), and answered additional symptom related questions (eg, exertional dyspnea, mental status, cough, edema and general health), during the 1st week at altitude. Acetazolamide, while not mandatory, was used by 40% of participants. Results At SP, the barometric pressure resulted in physiological altitudes that approached 3400 m, while T °C averaged -42, humidity 0.03%. Arterial oxygen saturation averaged 89% ± 3%. Overall, 52% developed LLSQ defined AMS. The most common symptoms reported were exertional dyspnea-(87%), sleeping difficulty-(74%), headache-(66%), fatigue-(65%), and dizziness/lightheadedness-(46%). Symptom severity peaked on days 1-2, yet in >20% exertional dyspnea, fatigue and sleep problems persisted through day 7. AMS incidence was similar between those using acetazolamide and those abstaining (51 vs. 52%, P = 0.87). Those who used acetazolamide tended to be older, have less altitude experience, worse symptoms on previous exposures, and less SP experience. Conclusion The incidence of AMS at SP tended to be higher than previously reports in other geographic locations at similar altitudes. Thus, the SP constitutes a more intense altitude exposure than might be expected considering physical altitude alone. Many symptoms persist, possibly due to extremely cold, arid conditions and the benefits of acetazolamide appeared negligible, though it may have prevented more severe symptoms in higher risk subjects.
Efficiency Optimization of a Step-Down Switched Capacitor Converter for Subthreshold

In this brief, an efficient voltage scalable switched capacitor converter (SCC) for 1.1 V battery-powered digital system is presented. The SCC employs a binary resolution technique to preserve high efficiency at load voltages down to sub-200 mV while keeping the efficiency high. The proposed converter can be configured into four topologies to support subthreshold output levels of 0.18-0.6 V. The converter is designed in a standard lowpower 40-nm CMOS TSMC process. Simulation results show that the efficiency of the SCC can be improved by 10%-11% in the vicinity of VDD=200 mV as compared to one using a conventional approach. An optimization strategy for designing multi-topology SCC is presented to improve the effectiveness of the circuit and to preserve efficiency over large load voltages.
Yeast Transcription Elongation Factor Spt5 Associates with RNA Polymerase I and RNA Polymerase II Directly*

Spt5 is a transcription factor conserved in all three domains of life. Spt5 homologues from bacteria and archaea bind the largest subunit of their respective RNA polymerases. Here we demonstrate that Spt5 directly associates with RNA polymerase (Pol) I and RNA Pol II in yeast through its central region containing conserved NusG N-terminal homology and KOW domains. Deletion analysis of SPT5 supports our biochemical data, demonstrating the importance of the KOW domains in Spt5 function. Far Western blot analysis implicates A190 of Pol I as well as Rpb1 of Pol II in binding Spt5. Three additional subunits of Pol I may also participate in this interaction. One of these subunits, A49, has known roles in transcription elongation by Pol I. Interestingly, spt5 truncation mutations suppress the cold-sensitive phenotype of rpa49Δ strain, which lacks the A49 subunit in the Pol I complex. Finally, we observed that Spt5 directly binds to an essential Pol I transcription initiation factor, Rrn3, and to the ribosomal RNA. Based on these data, we propose a model in which Spt5 is recruited to the rDNA early in transcription and propose that it plays an important role in ribosomal RNA synthesis through direct binding to the Pol I complex.
Transductive multi-label ensemble classification for protein function prediction

Advances in biotechnology have made available multitudes of heterogeneous proteomic and genomic data. Integrating these heterogeneous data sources, to automatically infer the function of proteins, is a fundamental challenge in computational biology. Several approaches represent each data source with a kernel (similarity) function. The resulting kernels are then integrated to determine a composite kernel, which is used for developing a function prediction model. Proteins are also found to have multiple roles and functions. As such, several approaches cast the protein function prediction problem within a multi-label learning framework. In our work we develop an approach that takes advantage of several unlabeled proteins, along with multiple data sources and multiple functions of proteins. We develop a graph-based transductive multi-label classifier (TMC) that is evaluated on a composite kernel, and also propose a method for data integration using the ensemble framework, called transductive multi-label ensemble classifier (TMEC). The TMEC approach trains a graph-based multi-label classifier for each individual kernel, and then combines the predictions of the individual models. Our contribution is the use of a bi-relational directed graph that captures relationships between pairs of proteins, between pairs of functions, and between proteins and functions. We evaluate the ability of TMC and TMEC to predict the functions of proteins by using two yeast datasets. We show that our approach performs better than recently proposed protein function prediction methods on composite and multiple kernels.
On Markov Chains for Independent Sets

Random independent sets in graphs arise, for example, in statistical physics, in the hardcore model of a gas. In 1997, Luby and Vigoda described a rapidly mixing Markov chain for independent sets, which we refer to as the Luby? Vigoda chain. A new rapidly mixing Markov chain for independent sets is defined in this paper. Using path coupling, we obtain a polynomial upper bound for the mixing time of the new chain for a certain range of values of the parameter ? This range is wider than the range for which the mixing time of the Luby? Vigoda chain is known to be polynomially bounded. Moreover, the upper bound on the mixing time of the new chain is always smaller than the best known upper bound on the mixing time of the Luby? Vigoda chain for larger values of ? (unless the maximum degree of the graph is 4). An extension of the chain to independent sets in hypergraphs is described. This chain gives an efficient method for approximately counting the number of independent sets of hypergraphs with maximum degree two, or with maximum degree three and maximum edge size three. Finally, we describe a method which allows one, under certain circumstances, to deduce the rapid mixing of one Markov chain from the rapid mixing of another, with the same state space and stationary distribution. This method is applied to two Markov chains for independent sets, a simple insert/delete chain, and the new chain, to show that the insert/delete chain is rapidly mixing for a wider range of values of ? than was previously known.
Induction of Strain-Transcending Antibodies Against Group A PfEMP1 Surface Antigens from Virulent Malaria Parasites

Sequence diversity in pathogen antigens is an obstacle to the development of interventions against many infectious diseases. In malaria caused by Plasmodium falciparum, the PfEMP1 family of variant surface antigens encoded by var genes are adhesion molecules that play a pivotal role in malaria pathogenesis and clinical disease. PfEMP1 is a major target of protective immunity, however, development of drugs or vaccines based on PfEMP1 is problematic due to extensive sequence diversity within the PfEMP1 family. Here we identified the PfEMP1 variants transcribed by P. falciparum strains selected for a virulence-associated adhesion phenotype (IgM-positive rosetting). The parasites transcribed a subset of Group A PfEMP1 variants characterised by an unusual PfEMP1 architecture and a distinct N-terminal domain (either DBLα1.5 or DBLα1.8 type). Antibodies raised in rabbits against the N-terminal domains showed functional activity (surface reactivity with live infected erythrocytes (IEs), rosette inhibition and induction of phagocytosis of IEs) down to low concentrations (<10 µg/ml of total IgG) against homologous parasites. Furthermore, the antibodies showed broad cross-reactivity against heterologous parasite strains with the same rosetting phenotype, including clinical isolates from four sub-Saharan African countries that showed surface reactivity with either DBLα1. 5 antibodies (variant HB3var6) or DBLα1. 8 antibodies (variant TM284var1). These data show that parasites with a virulence-associated adhesion phenotype share IE surface epitopes that can be targeted by strain-transcending antibodies to PfEMP1. The existence of shared surface epitopes amongst functionally similar disease-associated P. falciparum parasite isolates suggests that development of therapeutic interventions to prevent severe malaria is a realistic goal.
Delay-Independent Stability of Reset Control Systems

Reset control systems have potential advantages to overcome fundamental limitations of LTI compensation. However, since a reset compensator may destabilize a stable base LTI system, stability needs to be guaranteed in advance for a proper practical application of reset control. This works extends previous stability results of reset control systems to consider the case of LTI plants with time-delays. Stability independent of the delay criteria are developed both by means of LMIs and in the frequency domain by using the KYP Lemma
Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM) at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg). A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel) has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (p<0.0001) was found between automated analysis and the above standard evaluation methods. This correlation establishes automated analysis as a novel end-point measure of BLM-induced lung fibrosis in mice, which will be very valuable for future preclinical drug explorations.
In vitro transcription of PrfA‐dependent and  ‐independent genes of Listeria monocytogenes

In vitro transcription starting from the promoters of the Listeria monocytogenes genes hly, plcA, actA, mpl, prfA and iap has been studied. Whereas transcription from Phly, PplcA and PactA is strictly PrfA‐dependent, that from Piap, PprfA1/2 and, unexpectedly, also from Pmpl is independent. Initiation of in vitro transcription at all tested promoters except PprfA requires high concentrations of ATP but not GTP. The nucleotides required in higher concentrations for efficient in vitro transcription are always included in the first three nucleotides of the corresponding transcript. RNA polymerase prepared from L. monocytogenes cultured either in rich culture medium (RNAPBHI), exposed to heat shock conditions (RNAP48) or conditioned in minimal essential medium (RNAPMEM) shows significant differences in the transcription efficiencies when transcription is initiated at these promoters. Transcription starting from the PrfA‐dependent promoters PactA and Phly is enhanced with RNAP48 and RNAPMEM (in relation to Piap–mediated transcription), while transcription from the other promoters is reduced when compared with RNAPBHI. These data suggest that in vivo transcription of the genes actA and hly may not function optimally with RNA polymerase loaded with the vegetative sigma factor 43, but may require a modified RNA polymerase, possibly loaded with an alternative sigma factor.
Ecology and evolution of viruses infecting uncultivated SUP05 bacteria as revealed by single-cell- and meta-genomics

Viruses modulate microbial communities and alter ecosystem functions. However, due to cultivation bottlenecks, specific virus–host interaction dynamics remain cryptic. In this study, we examined 127 single-cell amplified genomes (SAGs) from uncultivated SUP05 bacteria isolated from a model marine oxygen minimum zone (OMZ) to identify 69 viral contigs representing five new genera within dsDNA Caudovirales and ssDNA Microviridae. Infection frequencies suggest that ∼1/3 of SUP05 bacteria is viral-infected, with higher infection frequency where oxygen-deficiency was most severe. Observed Microviridae clonality suggests recovery of bloom-terminating viruses, while systematic co-infection between dsDNA and ssDNA viruses posits previously unrecognized cooperation modes. Analyses of 186 microbial and viral metagenomes revealed that SUP05 viruses persisted for years, but remained endemic to the OMZ. Finally, identification of virus-encoded dissimilatory sulfite reductase suggests SUP05 viruses reprogram their host's energy metabolism. Together, these results demonstrate closely coupled SUP05 virus–host co-evolutionary dynamics with the potential to modulate biogeochemical cycling in climate-critical and expanding OMZs. DOI: http://dx.doi. org/10.7554/eLife.03125. 001
Prevalence of Ascaridia galli in some Poultry Farms of District Mardan

| This study was conducted from September 2013 to march 2014 to find out the prevalence of A. galli in some poultry farms of district Mardan. During this period total of about 751 chicken intestines were collected and examined for the presence of A. galli. In these 751 about 161 were infected and the overall prevalence rate of A. galli was about 21.44%. In this study total 360 local chicken were examined in which 90(25%) were infected. 221 layer chicken were examined in which 41(18.55%) were infected and about 170 broiler of which 30(17.64%) were infected. The overall study show that A. galli is the most common and highly prevalent nematode in the chicken of district Mardan. The study also shows that A. galli is common health problem in both free ranging and poultry chicken so suggest the need of proper poultry management.