Miracle-dz/UniFAR-FTUs huggingface dataset:
Spectra of black-hole binaries in the low/hard state : From radio to X-rays

We propose a jet model for the low/hard state of Galactic black-hole X-ray sources that can explain the energy spectra from radio to X-rays. The model assumes that i) there is a magnetic field along the axis of the jet; ii) the electron density in the jet drops inversely proportional to distance; and iii) the electrons in the jet follow a power law distribution function. We have performed Monte Carlo simulations of Compton upscattering of soft photons from the accretion disk and have found power-law high-energy spectra with photon-number index in the range 1.5-2 and cutoff at a few hundred keV. The spectrum at long wavelengths (radio, infrared, optical) is modeled to come from synchrotron radiation of the energetic electrons in the jet. We find flat to inverted radio spectra that extend from the radio up to about the optical band. For magnetic field strengths of the order of $10^5{-}10^6$ G at the base of the jet, the calculated spectra agree well in slope and flux with the observations. Our model has the advantage over other existing models that it also explains many of the existing timing data such as the time lag spectra, the hardening of the power density spectra and the narrowing of the autocorrelation function with increasing photon energy.
A Noncanonical Basic Motif of Epstein-Barr Virus ZEBRA Protein Facilitates Recognition of Methylated DNA, High-Affinity DNA Binding, and Lytic Activation

The binding of ZEBRA to methylated and unmethylated viral DNA triggers activation of the EBV lytic cycle, leading to viral replication and, in some patients, cancer development. Our work thoroughly examines how ZEBRA uses a previously unrecognized basic motif to bind nonmethylated and methylated DNA targets, leading to viral lytic activation. Our findings show that two different positively charged motifs, including the canonical BZIP domain and a newly identified RRTRK motif, contribute to the mechanism of DNA recognition by a viral AP-1 protein. This work contributes to the assessment of ZEBRA as a potential therapeutic target for antiviral and oncolytic treatments. ABSTRACT The pathogenesis of Epstein-Barr virus (EBV) infection, including development of lymphomas and carcinomas, is dependent on the ability of the virus to transit from latency to the lytic phase. This conversion, and ultimately disease development, depends on the molecular switch protein, ZEBRA, a viral bZIP transcription factor that initiates transcription from promoters of viral lytic genes. By binding to the origin of viral replication, ZEBRA is also an essential replication protein. Here, we identified a novel DNA-binding motif of ZEBRA, N terminal to the canonical bZIP domain. This RRTRK motif is important for high-affinity binding to DNA and is essential for recognizing the methylation state of viral promoters. Mutations in this motif lead to deficiencies in DNA binding, recognition of DNA methylation, lytic cycle DNA replication, and viral late gene expression. This work advances our understanding of ZEBRA-dependent activation of the viral lytic cascade. IMPORTANCE The binding of ZEBRA to methylated and unmethylated viral DNA triggers activation of the EBV lytic cycle, leading to viral replication and, in some patients, cancer development. Our work thoroughly examines how ZEBRA uses a previously unrecognized basic motif to bind nonmethylated and methylated DNA targets, leading to viral lytic activation. Our findings show that two different positively charged motifs, including the canonical BZIP domain and a newly identified RRTRK motif, contribute to the mechanism of DNA recognition by a viral AP-1 protein. This work contributes to the assessment of ZEBRA as a potential therapeutic target for antiviral and oncolytic treatments.
Ion channels and regulation of insulin secretion in human β-cells

In mammals an increase in glucose leads to block of ATP dependent potassium channels in pancreatic β cells leading to membrane depolarization. This leads to the repetitive firing of action potentials that increases calcium influx and triggers insulin granule exocytosis. Several important differences between species in this process suggest that a dedicated human-oriented approach is advantageous as extrapolating from rodent data may be misleading in several respects. We examined depolarization-induced spike activity in pancreatic human islet-attached β-cells employing whole-cell patch-clamp methods. We also reviewed the literature concerning regulation of insulin secretion by channel activity and constructed a data-based computer model of human β cell function. The model couples the Hodgkin-Huxley-type ionic equations to the equations describing intracellular Ca2+ homeostasis and insulin release. On the basis of this model we employed computational simulations to better understand the behavior of action potentials, calcium handling and insulin secretion in human β cells under a wide range of experimental conditions. This computational system approach provides a framework to analyze the mechanisms of human β cell insulin secretion.
Worse global intellectual and worse neuropsychological functioning in preterm‐born children at preschool age: a meta‐analysis

Preterm births (<32 weeks of gestational age) are associated with cognitive problems that are difficult to diagnose in infancy but potentially detectable at preschool age. This review aimed to evaluate the extent to which total intelligence quotient (IQ) and neuropsychological functions at ages three to five years differ between children born at <32 weeks gestational age or < 1500 g birth weight and children born at term. The secondary aim was to determine whether cognitive performance differs between extremely preterm (EPT)/extremely low birth weight (ELBW) children and very preterm (VPT) or very low birth weight (VLBW) children.
Compliance with osteoporosis medications.

BACKGROUND Long-term compliance with pharmacologic treatments for many asymptomatic conditions may be suboptimal, but little is known about compliance with medications used for osteoporosis. This study was undertaken to assess the level and determinants of compliance with drugs prescribed for osteoporosis. METHODS This retrospective cohort study used pharmacy claims data from US Medicare and filled prescriptions from a state pharmaceutical benefits program. We included persons 65 years or older who initiated use of a medication for osteoporosis (alendronate sodium, calcitonin, hormone therapy, raloxifene hydrochloride, or risedronate) from January 1, 1996, through December 31, 2002. The outcome of interest was suboptimal medication compliance, defined as equal to or less than 66% of days with medication during a 60-day period. RESULTS One year after initiating treatment for osteoporosis, 45.2% of the 40,002 patients were not continuing to fill prescriptions. Five years after initiation, 52.1% of patients were not continuing to fill prescriptions for an osteoporosis medication. Several characteristics independently predicted compliance: female sex, younger age, fewer comorbid conditions, using fewer nonosteoporosis medications, bone mineral density testing before and after initiating a medication, a fracture before and after initiating a medication, and nursing home residence during the 12 months before initiating a medication. However, models adjusted for the significant patient variables explained only 6% of the variation in compliance. CONCLUSIONS Most patients who initiate a medication for osteoporosis do not continue to take it as prescribed. Although several patient characteristics significantly correlated with compliance, adjusted models explained little of the variation.
Modulation of cancer cell signaling by long noncoding RNAs

Cellular signaling pathways play a very important role in almost all molecular processes in the cell, and are generally composed of a complex set of cascades in which enzymes and proteins play a key role. These signaling pathways include different types of cellular signaling classified based on their receptors and effector proteins such as enzyme‐linked receptors, cytokine receptors, and G‐protein‐coupled receptors each of which is subdivided into different classes. Signaling pathways are tightly controlled by different mechanisms mostly thorough inhibiting/activating their receptors or effector proteins. In the last two decades, our knowledge of molecular biology has changed dramatically and today we know that more than 85% of the human genome expresses noncoding RNAs most of which are crucial in the cellular and molecular mechanisms of cells. One of these noncoding RNAs are long noncoding RNAs (lncRNA) containing more than 200 nucleotides. LncRNAs participate in the progression of cancer growth through several mechanism including signaling pathways. In this review, we summarize some of the most important of lncRNAs and their effect on important signaling pathways.
Cryptanalysis of a Non-interactive Deniable Authentication Protocol Based on Factoring

A deniable authentication protocol allows a sender to transfer an authenticated message to a receiver in such a way that the receiver cannot prove to a third party about the source of the message. In recent years, many deniable authentication protocols have been proposed. In 2005, Lu et al. proposed a secure and non-interactive deniable authentication protocol based on factoring. Although Lu et al. claimed that their protocol could provide complete security and properties of a deniable authentication protocol, we will point out that Lu et al. protocol is unable to achieve the second requirement of being the deniable authentication protocol.
Calcium-dependent Phospholipid Scramblase Activity of TMEM16 Protein Family Members*

Background: TMEM16A and 16B work as Cl− channel, whereas 16F works as phospholipid scramblase. The function of other TMEM16 members is unknown. Results: Using TMEM16F−/− cells, TMEM16C, 16D, 16F, 16G, and 16J were shown to be lipid scramblases. Conclusion: Some TMEM16 members are divided into two Cl− channels and five lipid scramblases. Significance: Learning the biochemical function of TMEM16 family members is essential to understand their physiological role. Asymmetrical distribution of phospholipids between the inner and outer plasma membrane leaflets is disrupted in various biological processes. We recently identified TMEM16F, an eight-transmembrane protein, as a Ca2+-dependent phospholipid scramblase that exposes phosphatidylserine (PS) to the cell surface. In this study, we established a mouse lymphocyte cell line with a floxed allele in the TMEM16F gene. When TMEM16F was deleted, these cells failed to expose PS in response to Ca2+ ionophore, but PS exposure was elicited by Fas ligand treatment. We expressed other TMEM16 proteins in the TMEM16F−/− cells and found that not only TMEM16F, but also 16C, 16D, 16G, and 16J work as lipid scramblases with different preference to lipid substrates. On the other hand, a patch clamp analysis in 293T cells indicated that TMEM16A and 16B, but not other family members, acted as Ca2+-dependent Cl− channels. These results indicated that among 10 TMEM16 family members, 7 members could be divided into two subfamilies, Ca2+-dependent Cl− channels (16A and 16B) and Ca2+-dependent lipid scramblases (16C, 16D, 16F, 16G, and 16J).
Are software engineers' responses to incomplete requirements related to project characteristics?

Software requirements quality affects software product quality. For high-quality software products, software requirements must be complete. When faced with incomplete requirements, software engineers attempt to fill the requirements' gaps differently, either by getting feedback from the user or by making assumptions. Assumptions may be explicit or implicit. Explicit assumptions are preferable to implicit assumptions as explicit assumptions can be validated. We conduct an empirical study to determine whether the number of explicit assumptions made by software engineers is related to a project's characteristics. Using data from two CMMI Level 3 companies and 16 projects, we investigated the responses of 92 software engineers to the same incomplete software requirement. Our findings show possible relationships between projects' characteristics and the number of explicit assumptions.
Homozygous variants in the gene SCAPER cause syndromic intellectual disability

The S‐Phase Cyclin A Associated Protein In The ER (SCAPER) gene is a ubiquitously expressed gene with unknown function in the brain. Recently, biallelic SCAPER variants were described in four patients from three families with retinitis pigmentosa (RP) and intellectual disability (ID). Here, we expand the spectrum of pathogenic variants in SCAPER and report on 10 further patients from four families with ID, RP, and additional dysmorphic features carrying homozygous variants in SCAPER. The variants found comprise frameshift, nonsense, and missense variants as well as an intragenic homozygous deletion, which spans SCAPER exons 15 and 16 and introduces a frameshift and a premature stop codon. Analyses of SCAPER expression in human and mouse brain revealed an upregulation of SCAPER expression during cortical development and a higher expression of SCAPER in neurons compared to neural progenitors. In the adult brain SCAPER is expressed in several regions including the cerebral cortex where it shows a layer‐specific expression with an expression peak in lower layer glutamatergic neurons. Our study supports the role of SCAPER variants in the pathogenesis of ID and RP, expands the variant spectrum and highlights the need for functional studies concerning the role of SCAPER during brain development and function.
Genetic Polymorphisms in Dopamine- and Serotonin-Related Genes and Treatment Responses to Risperidone and Perospirone

We investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients.
Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy.

OBJECTIVE To assess the effect of oral cannabidiol (CBD) administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with idiopathic epilepsy. DESIGN Randomized blinded controlled clinical trial. ANIMALS 26 client-owned dogs with intractable idiopathic epilepsy. PROCEDURES Dogs were randomly assigned to a CBD (n = 12) or placebo (14) group. The CBD group received CBD-infused oil (2.5 mg/kg [1.1 mg/lb], PO) twice daily for 12 weeks in addition to existing antiepileptic treatments, and the placebo group received noninfused oil under the same conditions. Seizure activity, adverse effects, and plasma CBD concentrations were compared between groups. RESULTS 2 dogs in the CBD group developed ataxia and were withdrawn from the study. After other exclusions, 9 dogs in the CBD group and 7 in the placebo group were included in the analysis. Dogs in the CBD group had a significant (median change, 33%) reduction in seizure frequency, compared with the placebo group. However, the proportion of dogs considered responders to treatment (≥ 50% decrease in seizure activity) was similar between groups. Plasma CBD concentrations were correlated with reduction in seizure frequency. Dogs in the CBD group had a significant increase in serum alkaline phosphatase activity. No adverse behavioral effects were reported by owners. CONCLUSIONS AND CLINICAL RELEVANCE Although a significant reduction in seizure frequency was achieved for dogs in the CBD group, the proportion of responders was similar between groups. Given the correlation between plasma CBD concentration and seizure frequency, additional research is warranted to determine whether a higher dosage of CBD would be effective in reducing seizure activity by ≥ 50%.
UBA6 and Its Bispecific Pathways for Ubiquitin and FAT10

Questions have been raised since the discovery of UBA6 and its significant coexistence with UBE1 in the ubiquitin–proteasome system (UPS). The facts that UBA6 has the dedicated E2 enzyme USE1 and the E1–E2 cascade can activate and transfer both ubiquitin and ubiquitin-like protein FAT10 have attracted a great deal of attention to the regulational mechanisms of the UBA6–USE1 cascade and to how FAT10 and ubiquitin differentiate with each other. This review recapitulates the latest advances in UBA6 and its bispecific UBA6–USE1 pathways for both ubiquitin and FAT10. The intricate networks of UBA6 and its interplays with ubiquitin and FAT10 are briefly reviewed, as are their individual and collective functions in diverse physiological conditions.
Plasma Klotho concentrations predict functional outcome at three months after acute ischemic stroke patients

Abstract Background: The Klotho protects the cardiovascular system by protecting against cell apoptosis, inhibiting the production of reactive oxygen species, and modulating inflammation. We aimed to investigate relationship of plasma Klotho concentrations with functional outcome at 3 months after acute cerebral infarction. Methods: We prospectively enrolled 262 first-ever acute cerebral infarction patients from whom a blood sample was acquired within 24 h of admission. An enzyme-linked immunosorbent assay was used for evaluating plasma Klotho concentration. Functional outcome on admission and three months was evaluated. Results: Of the 262 patients, 152 (58.0%) were men. The mean age of these patients was 64.7 years. The mean ± standard deviation of plasma Klotho concentrations was 312.7 ± 153.3 pg/mL. As opposed to patients with good outcome, plasma Klotho levels were lower in the poor outcome group (207.8 ± 96.2 vs. 342.5 ± 153.5 pg/mL, p = .001). In multivariate analysis, increased plasma Klotho concentrations were independently associated with good functional outcome (Odds ratio: 2.42, 95% confidence interval: 1.45–4.04, p < .001). Conclusions: Increased plasma Klotho concentrations were associated with good functional outcome in patients with acute ischemic stroke. We attribute these associations to the pleiotropic effects of Klotho in stroke and vascular diseases. Key message Increased plasma Klotho concentrations were associated with good functional outcome in patients with acute ischemic stroke.
Reviewing the characteristics of BRCA and PALB2-related cancers in the precision medicine era

Abstract Germline mutations in BRCA1 and BRCA2 (BRCA) genes confer high risk of developing cancer, especially breast and ovarian tumors. Since the cloning of these tumor suppressor genes over two decades ago, a significant amount of research has been done. Most recently, monoallelic loss-of-function mutations in PALB2 have also been shown to increase the risk of breast cancer. The identification of BRCA1, BRCA2 and PALB2 as proteins involved in DNA double-strand break repair by homologous recombination and of the impact of complete loss of BRCA1 or BRCA2 within tumors have allowed the development of novel therapeutic approaches for patients with germline or somatic mutations in said genes. Despite the advances, especially in the clinical use of PARP inhibitors, key gaps remain. Now, new roles for BRCA1 and BRCA2 are emerging and old concepts, such as the classical two-hit hypothesis for tumor suppression, have been questioned, at least for some BRCA functions. Here aspects regarding cancer predisposition, cellular functions, histological and genomic findings in BRCA and PALB2-related tumors will be presented, in addition to an up-to-date review of the evolution and challenges in the development and clinical use of PARP inhibitors.
Ubiquitin‐dependent internalization and down‐regulation of plasma membrane proteins

The modification of cytosolic proteins with polyubiquitin chains targets them for recognition and degradation by the multisubunit proteolytic particle, the 26S proteasome. Membrane proteins are also substrates for ubiquitination. Integral membrane proteins of the endoplasmic reticulum are ubiquitinated and destroyed by the proteasome (reviewed in refs 1, 2). However, it has been shown recently that the ubiquitination of Saccharomyces cerevisiae plasma membrane proteins signals their degradation by the proteolytic system in the lysosome‐like vacuole. Ubiquitination of several different classes of cell surface proteins serves as a signal for their entry into the endocytic pathway; this leads to their transport to the vacuole, where they are permanently inactivated by degradation. In yeast, ubiquitin has been implicated as an internalization signal for most, if not all, endogenous plasma membrane proteins that are known to be endocytosed. Ubiquitin‐dependent internalization has been best characterized for two proteins: the mating pheromone α‐factor receptor and the uracil permease. Some mammalian cell surface receptors are also ubiquitinated at the plasma membrane. Ubiquitination machinery is required for ligand‐induced endocytosis of the growth hormone receptor, suggesting that ubiquitin‐dependent endocytosis and sorting is also an important regulatory process in mammalian cells. Mammalian receptors may also be down‐regulated through the degradation of their cytosolic domains by a proteasome‐dependent pathway. —Hicke, L. Ubiquitin‐dependent internalization and down‐regulation of plasma membrane proteins. FASEB J. 11, 1215–1226 (1997)
Openness and Innovation Performance: Are Small Firms Different?

We explore whether and how the benefits of openness in innovation are different for small plants (less than 50 employees) compared to medium and large plants. Using panel data from Irish manufacturing we find that the contribution of the “breadth” of openness (i.e., the variety of plants' innovation linkages) on innovation performance is stronger for small plants than for larger plants. Both small and larger plants face diminishing returns as the breadth of openness increases, but small plants experience negative returns at lower level of the breadth of openness than larger plants. Our results suggest that small plants can gain significantly from using wider set of innovation linkages, but for such plants appropriate partner choice is a particularly important issue. Small plants also gain significantly more than larger ones from investing in the linkages within the supply chain.
The Research in Improving the Quality of DW Data: The Job-Scheduling and Checking Based Program in Upgrading DW Performance

ETL is an important segment to build an accurate data warehouse. The improvements of the quality in the data warehouse help to guarantee the reliability and help the enterprise to summarize and use the data for a long period of time. There are many methods to improve the quality of data. The paper mainly focused on the ETL dispatcher and the way of checking to improve data quality of data warehouse. And the experiment on EMC projects had proved that it could improve data quality of DW effectively.