Miracle-dz/UniFAR-FTUs huggingface dataset:
The Dual Nature of Nek9 in Adenovirus Replication

ABSTRACT To successfully replicate in an infected host cell, a virus must overcome sophisticated host defense mechanisms. Viruses, therefore, have evolved a multitude of devices designed to circumvent cellular defenses that would lead to abortive infection. Previous studies have identified Nek9, a cellular kinase, as a binding partner of adenovirus E1A, but the biology behind this association remains a mystery. Here we show that Nek9 is a transcriptional repressor that functions together with E1A to silence the expression of p53-inducible GADD45A gene in the infected cell. Depletion of Nek9 in infected cells reduces virus growth but unexpectedly enhances viral gene expression from the E2 transcription unit, whereas the opposite occurs when Nek9 is overexpressed. Nek9 localizes with viral replication centers, and its depletion reduces viral genome replication, while overexpression enhances viral genome numbers in infected cells. Additionally, Nek9 was found to colocalize with the viral E4 orf3 protein, a repressor of cellular stress response. Significantly, Nek9 was also shown to associate with viral and cellular promoters and appears to function as a transcriptional repressor, representing the first instance of Nek9 playing a role in gene regulation. Overall, these results highlight the complexity of virus-host interactions and identify a new role for the cellular protein Nek9 during infection, suggesting a role for Nek9 in regulating p53 target gene expression. IMPORTANCE In the arms race that exists between a pathogen and its host, each has continually evolved mechanisms to either promote or prevent infection. In order to successfully replicate and spread, a virus must overcome every mechanism that a cell can assemble to block infection. On the other hand, to counter viral spread, cells must have multiple mechanisms to stifle viral replication. In the present study, we add to our understanding of how the human adenovirus is able to circumvent cellular roadblocks to replication. We show that the virus uses a cellular protein, Nek9, in order to block activation of p53-regulated gene GADD45A, which is an important player in stress response and p53-mediated cell cycle arrest. Importantly, our study also identifies Nek9 as a transcriptional repressor.
Bioinformatic Inference of Specific and General Transcription Factor Binding Sites in the Plant Pathogen Phytophthora infestans

Plant infection by oomycete pathogens is a complex process. It requires precise expression of a plethora of genes in the pathogen that contribute to a successful interaction with the host. Whereas much effort has been made to uncover the molecular systems underlying this infection process, mechanisms of transcriptional regulation of the genes involved remain largely unknown. We performed the first systematic de-novo DNA motif discovery analysis in Phytophthora. To this end, we utilized the genome sequence of the late blight pathogen Phytophthora infestans and two related Phytophthora species (P. ramorum and P. sojae), as well as genome-wide in planta gene expression data to systematically predict 19 conserved DNA motifs. This catalog describes common eukaryotic promoter elements whose functionality is supported by the presence of orthologs of known general transcription factors. Together with strong functional enrichment of the common promoter elements towards effector genes involved in pathogenicity, we obtained a new and expanded picture of the promoter structure in P. infestans. More intriguingly, we identified specific DNA motifs that are either highly abundant or whose presence is significantly correlated with gene expression levels during infection. Several of these motifs are observed upstream of genes encoding transporters, RXLR effectors, but also transcriptional regulators. Motifs that are observed upstream of known pathogenicity-related genes are potentially important binding sites for transcription factors. Our analyses add substantial knowledge to the as of yet virtually unexplored question regarding general and specific gene regulation in this important class of pathogens. We propose hypotheses on the effects of cis-regulatory motifs on the gene regulation of pathogenicity-related genes and pinpoint motifs that are prime targets for further experimental validation.
Journal of Quantitative Analysis in Sports A Point-Mass Mixture Random Effects Model for Pitching Metrics

A plethora of statistics have been proposed to measure the effectiveness of pitchers in Major League Baseball. While many of these are quite traditional (e.g., ERA, wins), some have gained currency only recently (e.g., WHIP, K/BB). Some of these metrics may have predictive power, but it is unclear which are the most reliable or consistent. We address this question by constructing a Bayesian random effects model that incorporates a point mass mixture and fitting it to data on twenty metrics spanning approximately 2,500 players and 35 years. Our model identifies FIP, HR/ 9, ERA, and BB/9 as the highest signal metrics for starters and GB%, FB%, and K/9 as the highest signal metrics for relievers. In general, the metrics identified by our model are independent of team defense. Our procedure also provides a relative ranking of metrics separately by starters and relievers and shows that these rankings differ quite substantially between them. Our methodology is compared to a Lasso-based procedure and is internally validated by detailed case studies.
Patient Adherence Improves Glycemic Control

Purpose The purpose of this study was to assess the influence of appointment keeping and medication adherence on HbA1c. Methods A retrospective evaluation was performed in 1560 patients with type 2 diabetes who presented for a new visit to the Grady Diabetes Clinic between 1991 and 2001 and returned for a follow-up visit and HbA1c after 1 year of care. Appointment keeping was assessed by the number of scheduled intervening visits that were kept, and medication adherence was assessed by the percentage of visits in which self-reported diabetes medication use was as recommended at the preceding visit. Results The patients had an average age of 55 years, body mass index (BMI) of 32 kg/m2, diabetes duration of 4.6 years, and baseline HbA1c of 9.1%. Ninety percent were African American, and 63% were female. Those who kept more intervening appointments had lower HbA1c levels after 12 months of care (7.6% with 6-7 intervening visits vs 9.7% with 0 intervening visits). Better medication adherence was also associated with lower HbA1c levels after 12 months of care (7.8% with 76%-100% adherence). After adjusting for age, gender, race, BMI, diabetes duration, and diabetes therapy in multivariate linear regression analysis, the benefits of appointment keeping and medication adherence remained significant and contributed independently; the HbA1c was 0.12% lower for every additional intervening appointment that was kept (P= .0001) and 0.34% lower for each quartile of better medication adherence (P= .0009). Conclusion Keeping more appointments and taking diabetes medications as directed were associated with substantial improvements in HbA1c. Efforts to enhance glycemic outcomes should include emphasis on these simple but critically important aspects of patient adherence.
Where to put the image in an image caption generator

Abstract When a recurrent neural network (RNN) language model is used for caption generation, the image information can be fed to the neural network either by directly incorporating it in the RNN – conditioning the language model by ‘injecting’ image features – or in a layer following the RNN – conditioning the language model by ‘merging’ image features. While both options are attested in the literature, there is as yet no systematic comparison between the two. In this paper, we empirically show that it is not especially detrimental to performance whether one architecture is used or another. The merge architecture does have practical advantages, as conditioning by merging allows the RNN’s hidden state vector to shrink in size by up to four times. Our results suggest that the visual and linguistic modalities for caption generation need not be jointly encoded by the RNN as that yields large, memory-intensive models with few tangible advantages in performance; rather, the multimodal integration should be delayed to a subsequent stage.
Long Branch Effects Distort Maximum Likelihood Phylogenies in Simulations Despite Selection of the Correct Model

The aim of our study was to test the robustness and efficiency of maximum likelihood with respect to different long branch effects on multiple-taxon trees. We simulated data of different alignment lengths under two different 11-taxon trees and a broad range of different branch length conditions. The data were analyzed with the true model parameters as well as with estimated and incorrect assumptions about among-site rate variation. If length differences between connected branches strongly increase, tree inference with the correct likelihood model assumptions can fail. We found that incorporating invariant sites together with distributed site rates in the tree reconstruction (+I) increases the robustness of maximum likelihood in comparison with models using only . The results show that for some topologies and branch lengths the reconstruction success of maximum likelihood under the correct model is still low for alignments with a length of 100,000 base positions. Altogether, the high confidence that is put in maximum likelihood trees is not always justified under certain tree shapes even if alignment lengths reach 100,000 base positions.
The "End of Men" and Rise of Women in the High-Skilled Labor Market

We document a new finding regarding changes in labor market outcomes for high-skilled men and women in the US. Since 1980, conditional on being a college-educated man, the probability of working in a cognitive/high-wage occupation has fallen. This contrasts starkly with the experience for college-educated women: their probability of working in these occupations rose, despite a much larger increase in the supply of educated women relative to men. We show that one key channel capable of rationalizing these findings is a greater increase in the demand for female-oriented skills in cognitive/high-wage occupations relative to other occupations. Using occupation-level data, we find evidence that this relative increase in the demand for female skills is due to an increasing importance of social skills within such occupations. Evidence from both male and female wages is also indicative of an increase in the demand for social skills. Finally, we document how these patterns change across the early and latter portions of the period.
The effect of sevoflurane and ondansetron on QT interval and transmural dispersion of repolarization in children

This study evaluated the prolongation of QT interval by the combination of sevoflurane and ondansetron in pediatric patients. Additionally, transmural dispersion of repolarization as interval between the peak and end of the T wave (Tp‐e) and Tp‐e/QT ratio was also measured to assess the risk of ventricular arrhythmia.
Gene expression mediated by cis‐acting sequences of the Krüppel gene in response to the Drosophila morphogens bicoid and hunchback.

The initial expression of the gap gene Krüppel (Kr) occurs in a precisely bounded central region of the Drosophila blastoderm embryo. According to genetic analysis, the spatial limits of the Kr expression domain are controlled by the morphogenetic activities of the anterior organizer gene bicoid (bcd) and the anterior gap gene hunchback (hb). Using gene fusion analysis, we assayed for cis‐acting sequences of the Kr gene which mediate transcriptional activation and localized gene expression in response to trans‐acting factors. A 730 bp Kr control element drives gene expression in place of the endogenous Kr central domain. This cis‐acting element, Kr730, is composed of bcd and hb responsive sequences. They map into regions of multiple hb and bcd protein in vitro binding sites. A 142 bp core fragment containing one low affinity hb and five medium to strong bcd protein binding sites drives gene expression in a Kr‐like location in the centre of the embryo. Our results show that this fragment represents a target for the redundant activator/repressor system provided by the anterior morphogens bcd and hb.
Secondary Contact and Admixture between Independently Invading Populations of the Western Corn Rootworm, Diabrotica virgifera virgifera in Europe

The western corn rootworm, Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae), is one of the most destructive pests of corn in North America and is currently invading Europe. The two major invasive outbreaks of rootworm in Europe have occurred, in North-West Italy and in Central and South-Eastern Europe. These two outbreaks originated from independent introductions from North America. Secondary contact probably occurred in North Italy between these two outbreaks, in 2008. We used 13 microsatellite markers to conduct a population genetics study, to demonstrate that this geographic contact resulted in a zone of admixture in the Italian region of Veneto. We show that i) genetic variation is greater in the contact zone than in the parental outbreaks; ii) several signs of admixture were detected in some Venetian samples, in a Bayesian analysis of the population structure and in an approximate Bayesian computation analysis of historical scenarios and, finally, iii) allelic frequency clines were observed at microsatellite loci. The contact between the invasive outbreaks in North-West Italy and Central and South-Eastern Europe resulted in a zone of admixture, with particular characteristics. The evolutionary implications of the existence of a zone of admixture in Northern Italy and their possible impact on the invasion success of the western corn rootworm are discussed.
Interferon-free treatment for hepatitis C virus infection induces normalization of extrahepatic type I interferon signaling

Background/Aims Hepatitis C virus (HCV) replicates in the peripheral blood mononuclear cells (PBMCs), leading to the production of type I interferons (IFNs). It is well known that the gene expression profile of PBMC is similar to that of the liver. The present study explored the dynamic gene expression profile of PBMCs collected from HCV-infected patients undergoing direct-acting antiviral (DAA) therapy. Methods A prospective cohort comprising 27 patients under DAA therapy was formed. Expression level of IFN-β and its downstream interferon-stimulated genes (ISGs) was measured in PBMCs before and after DAA treatment. Furthermore, immunoblotting was performed to identify the signaling molecules involved in the expression of ISGs. Results The pretreatment expression level of interferon-induced protein 44 (IFI44) and C-X-C motif chemokine ligand 10 (CXCL10) correlated with the pretreatment expression level of IFN-β. After DAA treatment, a significant decrease in the expression levels of IFN-β, IFI44, and CXCL10 was observed in the PBMCs. Furthermore, the pretreatment expression level of IFN-β and ISGs correlated with the level of signal transducer and activator of transcription 1 (STAT1) phosphorylation, and DAA treatment abrogated STAT1 phosphorylation. Conclusions Pretreatment activation of IFN-β response is rapidly normalized after DAA treatment. The present study suggests that the decreased type I IFN response by the clearance of HCV might contribute to DAA-induced alleviation of extrahepatic manifestation of chronic HCV infection.
The Interaction between Nidovirales and Autophagy Components

Autophagy is a conserved intracellular catabolic pathway that allows cells to maintain homeostasis through the degradation of deleterious components via specialized double-membrane vesicles called autophagosomes. During the past decades, it has been revealed that numerous pathogens, including viruses, usurp autophagy in order to promote their propagation. Nidovirales are an order of enveloped viruses with large single-stranded positive RNA genomes. Four virus families (Arterividae, Coronaviridae, Mesoniviridae, and Roniviridae) are part of this order, which comprises several human and animal pathogens of medical and veterinary importance. In host cells, Nidovirales induce membrane rearrangements including autophagosome formation. The relevance and putative mechanism of autophagy usurpation, however, remain largely elusive. Here, we review the current knowledge about the possible interplay between Nidovirales and autophagy.
Possible Role of Horizontal Gene Transfer in the Colonization of Sea Ice by Algae

Diatoms and other algae not only survive, but thrive in sea ice. Among sea ice diatoms, all species examined so far produce ice-binding proteins (IBPs), whereas no such proteins are found in non-ice-associated diatoms, which strongly suggests that IBPs are essential for survival in ice. The restricted occurrence also raises the question of how the IBP genes were acquired. Proteins with similar sequences and ice-binding activities are produced by ice-associated bacteria, and so it has previously been speculated that the genes were acquired by horizontal transfer (HGT) from bacteria. Here we report several new IBP sequences from three types of ice algae, which together with previously determined sequences reveal a phylogeny that is completely incongruent with algal phylogeny, and that can be most easily explained by HGT. HGT is also supported by the finding that the closest matches to the algal IBP genes are all bacterial genes and that the algal IBP genes lack introns. We also describe a highly freeze-tolerant bacterium from the bottom layer of Antarctic sea ice that produces an IBP with 47% amino acid identity to a diatom IBP from the same layer, demonstrating at least an opportunity for gene transfer. Together, these results suggest that the success of diatoms and other algae in sea ice can be at least partly attributed to their acquisition of prokaryotic IBP genes.
Maltreatment and Affective and Behavioral Problems in Emerging Adults With and Without Oppositional Defiant Disorder Symptoms: Mediation by Parent–Child Relationship Quality

The current study examined the indirect effect of maternal and paternal emotional and physical maltreatment on affective and behavioral symptoms of oppositional defiant disorder (ODD) through parent–child relationship quality; gender and overall ODD symptoms were examined as moderators. Participants included 2,362 emerging adults who completed questionnaires about parental emotional and physical maltreatment, parent–child relationship quality, and affective and behavioral ODD symptoms. These characteristics were compared across parent and child gender (i.e., maternal and paternal effects as well as male and female differences) as well as participants reporting high and low ODD symptoms. In the low ODD group, indirect effects of emotional maltreatment occurred in all parent–child dyads except the mother–son dyad, whereas in the high ODD group, indirect effects occurred only in the father–son dyad. Indirect effects of physical maltreatment occurred only in the father–son dyad in the low ODD group, and only in the mother–daughter dyad on behavioral ODD symptoms in the high ODD group. The results suggest that specific parent–child gender dyads respond differently, warranting further investigation of gender effects. Moreover, emerging adults in the low ODD symptoms group demonstrated a positive association between parental maltreatment and ODD symptoms and a negative association between parent–child relationship quality and ODD symptoms, whereas those high in the high ODD symptoms group did not demonstrate these associations. That is, emerging adults reporting high ODD symptoms demonstrated no relationship between their ODD symptoms and harsh parenting, suggesting an ineffective coercive process.
Bioequivalence and Pharmacokinetic Study of Two Different Omeprazole Capsule Formulations in Healthy Bangladeshi Volunteers

Abstract Omeprazole (CAS 73590-58-6) effectively suppresses the gastric acid secretion in the parietal cells of the stomach and is a widely prescribed proton pump inhibitor in Bangladesh. The increasing number of omeprazole containing products available in the market raises questions of therapeutic equivalence and/or generic substitution which are yet to be conducted with Bangladeshi population. The aim of the study is to assess the bioequivalence and pharmacokinetic properties of two oral formulations of 20 mg omeprazole capsule, the reference product and Omep-20 as test product using serum data. The randomized, two-way crossover study was conducted on 24 healthy male subjects in compliance with the Declaration of Helsinki and ICH guidelines. Subjects were assigned to receive test and reference as a single dose of 20 mg capsule under fasting condition, following a washout period of one week. After oral administration, blood samples were collected at various time intervals and analyzed for omeprazole concentrations using a validated HPLC method. The pharmacokinetic parameters were determined by non-compartmental method. From serum data, the obtained values for test and reference products were 648.07 ± 216.27 and 632.69 ± 257.01 ng/ml for Cmax; 2 012.24 ± 634.48 and 1907.86 ± 761.91 ng · h/ml for AUC0–24; 2105.21 ± 623.79 and 1 979.18 ± 748.12 ng · h/ml for AUC0–∞ respectively. No statistically significant differences were observed between two formulations by analyzing different pharmacokinetic parameters in terms of period, sequence or formulation. From the paired t-test, no significant differences between two formulation were observed (p > 0.05). The 90% confidence intervals of Cmax, AUC0–24 and AUC0–24 were found to be 91.59% to 122.60%, 101.86% to 116.78% and 102.77% to 116.68% respectively which are within the FDA accepted limits for bioequivalence (80%–125%). Finally it can be concluded that both products are bioequivalent in terms of rate and extent of drug absorption and therefore interchangeable.
NELL1, whose high expression correlates with negative outcomes, has different methylation patterns in alveolar and embryonal rhabdomyosarcoma

Rhabdomyosarcoma (RMS), which represents the most frequent soft tissue sarcoma in pediatric populations, is classified into two major subtypes: embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS subtype, which shows greater aggressiveness and proneness to metastasis with respect to ERMS, are characterized, in about 75% of cases, by specific chromosomal translocations that involve PAX and FOXO1 genes. Many findings have demonstrated that PAX/FOXO1-positive ARMS have a worse prognosis than PAX/FOXO1-negative ones and that distinct molecular features characterize RMS with different gene fusion statuses. DNA methylation, which presently represents a challenging research area, is involved in the modulation of gene expression. We performed a genome-wide DNA methylation analysis using reduced-representation bisulfite sequencing (RRBS) in RMS samples and we found that fusion-positive alveolar and embryonal subgroups have different DNA methylation signatures and that ARMS fusion-positive subtypes are characterized by overall hypomethylation levels. While NELL1 was found to be hypomethylated and transcriptionally enhanced in RMS alveolar subtypes, high NELL1 expression levels, which proved to be correlated with negative RMS prognostic factors such as fusion status and histology (P < 0.0001), were found to discriminate between RMS patients with different outcomes (P < 0.05). In conclusion, our results demonstrated that different DNA methylation patterns distinguish between different RMS subgroups and they suggest that epigenetic signatures could be useful for risk stratification of patients.