Miracle-dz/UniFAR-FTUs huggingface dataset:
Maybe Deep Neural Networks are the Best Choice for Modeling Source Code

Statistical language modeling techniques have successfully been applied to source code, yielding a variety of new software development tools, such as tools for code suggestion and improving readability. A major issue with these techniques is that code introduces new vocabulary at a far higher rate than natural language, as new identifier names proliferate. But traditional language models limit the vocabulary to a fixed set of common words. For code, this strong assumption has been shown to have a significant negative effect on predictive performance. But the open vocabulary version of the neural network language models for code have not been introduced in the literature. We present a new open-vocabulary neural language model for code that is not limited to a fixed vocabulary of identifier names. We employ a segmentation into subword units, subsequences of tokens chosen based on a compression criterion, following previous work in machine translation. Our network achieves best in class performance, outperforming even the state-of-the-art methods of Hellendoorn and Devanbu that are designed specifically to model code. Furthermore, we present a simple method for dynamically adapting the model to a new test project, resulting in increased performance. We showcase our methodology on code corpora in three different languages of over a billion tokens each, hundreds of times larger than in previous work. To our knowledge, this is the largest neural language model for code that has been reported.
Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

Significance Odor detection in mammals depends on the largest family of G protein-coupled receptors, the odorant receptors, which represent ∼2% of our protein-coding genes. The vast majority of odorant receptors are trapped within the cell when expressed in nonolfactory cells. The underlying causes of why odorant receptors cannot be functionally expressed in nonolfactory cells have remained enigmatic for over 20 years. Our study points to divergence from a consensus sequence as a key factor in a receptor’s inability to function in nonolfactory cells, which, in turn, helps explain odorant receptors’ exceptional functional diversity and rapid evolution. We also show the success of protein engineering strategies for promoting odorant receptor cell surface expression. Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing consensus odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations.
‘Next Generation Youth Well-being Study:’ understanding the health and social well-being trajectories of Australian Aboriginal adolescents aged 10–24 years: study protocol

Introduction Australian Aboriginal and/or Torres Strait Islander (hereafter referred to as ‘Aboriginal’) adolescents (10–24 years) experience multiple challenges to their health and well-being. However, limited evidence is available on factors influencing their health trajectories. Given the needs of this group, the young age profile of the Aboriginal population and the long-term implications of issues during adolescence, reliable longitudinal data are needed. Methods and analysis The ‘Next Generation: Youth Well-being Study’ is a mixed-methods cohort study aiming to recruit 2250 Aboriginal adolescents aged 10–24 years from rural, remote and urban communities in Central Australia, Western Australia and New South Wales. The study assesses overall health and well-being and consists of two phases. During phase 1, we qualitatively explored the meaning of health and well-being for adolescents and accessibility of health services. During phase 2, participants are being recruited into a longitudinal cohort. Recruitment is occurring mainly through community networks and connections. At baseline, participants complete a comprehensive survey and undertake an extensive age relevant clinical assessment. Survey and clinical data will be linked to various databases including those relating to health services; medication; immunisation; hospitalisations and emergency department presentations; death registrations; education; child protection and corrective services. Participants will receive follow-up surveys approximately 2 years after their baseline visit. The ‘Next Generation’ study will fill important evidence gaps by providing longitudinal data on the health and social well-being of Aboriginal adolescents supplemented with narratives from participants to provide context. Ethics and dissemination Ethics approvals have been sought and granted. Along with peer-reviewed publications and policy briefs, research findings will be disseminated via reports, booklets and other formats that will be most useful and informative to the participants and community organisations.
Multivalent nephrin–Nck interactions define a threshold for clustering and tyrosine-dependent nephrin endocytosis

ABSTRACT Assembly of signaling molecules into micrometer-sized clusters is driven by multivalent protein-protein interactions, such as those found within the nephrin–Nck (Nck1 or Nck2) complex. Phosphorylation on multiple tyrosine residues within the tail of the nephrin transmembrane receptor induces recruitment of the cytoplasmic adaptor protein Nck, which binds via its triple SH3 domains to various effectors, leading to actin assembly. The physiological consequences of nephrin clustering are not well understood. Here, we demonstrate that nephrin phosphorylation regulates the formation of membrane clusters in podocytes. We also reveal a connection between clustering and endocytosis, which appears to be driven by threshold levels of nephrin tyrosine phosphorylation and Nck SH3 domain signaling. Finally, we expose an in vivo correlation between transient changes in nephrin tyrosine phosphorylation, nephrin localization and integrity of the glomerular filtration barrier during podocyte injury. Altogether, our results suggest that nephrin phosphorylation determines the composition of effector proteins within clusters to dynamically regulate nephrin turnover and podocyte health. Summary: Nephrin tyrosine phosphorylation recruits the adaptor protein Nck to form membrane clusters, which are important for nephrin function. Tyrosine mutations result in abnormal cluster morphology and disrupted endocytosis.
Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver

A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5′ of the 18S and the 5′ of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.
Functional brain networks of patients with epilepsy exhibit pronounced multiscale periodicities, which correlate with seizure onset

Epileptic seizure detection and prediction by using noninvasive measurements such as scalp EEG signals or invasive, intracranial recordings, has been at the heart of epilepsy studies for at least three decades. To this end, the most common approach has been to consider short‐length recordings (several seconds to a few minutes) around a seizure, aiming to identify significant changes that occur before or during seizures. An inherent assumption in this approach is the presence of a relatively constant EEG activity in the interictal period, which is interrupted by seizure occurrence. Here, we examine this assumption by using long‐duration scalp EEG data (21–94 hr) in nine patients with epilepsy, based on which we construct functional brain networks. Our results reveal that these networks vary over time in a periodic fashion, exhibiting multiple peaks at periods ranging between 1 and 24 hr. The effects of seizure onset on the functional brain network properties were found to be considerably smaller in magnitude compared to the changes due to these inherent periodic cycles. Importantly, the properties of the identified network periodic components (instantaneous phase) were found to be strongly correlated to seizure onset, especially for the periodicities around 3 and 5 hr. These correlations were found to be largely absent between EEG signal periodicities and seizure onset, suggesting that higher specificity may be achieved by using network‐based metrics. In turn, this implies that more robust seizure detection and prediction can be achieved if longer term underlying functional brain network periodic variations are taken into account.
Current State of the Art on the Antioxidant Activity of Sage (Salvia spp.) and Its Bioactive Components

Abstract Common sage (Salvia spp., with the most common species Salvia officinalis) is an important medicinal and aromatic plant due to its bioactive components, secondary products of its metabolism. These components are mainly phenolics, terpenoids, polyphenols, and flavonoids. Many studies have identified their important role in fighting oxidative stress in cells and organisms, together with their anticancer, antimicrobial, and anti-inflammatory role. There are many methods measuring the antioxidant activity of sage phenolic components, usually based on radical scavenging of free radical species, such as 2,2-diphenyl-1-picrylydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), and determining the absorbance of the reduced product by a photometric assay. In addition, there are several in vitro and in vivo studies determining the protection of sage extracts in cells in culture or animals, respectively, after induction of oxidative stress. In this review, results from the currently available studies that unravel the significant role of sage bioactive compounds, as antioxidant compounds, and the variety of methods used have been critically analyzed and discussed.
Reviewers' Comments: Reviewer #1: Remarks to the Author: The manuscript entitled "DIETARY FATTY ACIDS FINE-TUNE PIEZO1 MECHANICAL RESPONSE" discusses the influence of fatty acids on the function of the mechanosensitive protein Piezo1

Reviewer #1: Remarks to the Author: The manuscript entitled "DIETARY FATTY ACIDS FINE-TUNE PIEZO1 MECHANICAL RESPONSE" discusses the influence of fatty acids on the function of the mechanosensitive protein Piezo1. The authors find that margaric acid increases the activation threshold for Piezo channels while cocosahexaenoic acid increases the inactivation kinetics keeping the receptor open for longer. the authors then nicely apply their findings and use these fatty acids to partially reverse symptoms related to Piezo gain of function and inactivation mutations which could be used in the future as treatment of red blood cell disorders.
Radiation metabolomics in the quest of cardiotoxicity biomarkers: the review

Abstract Purpose: Ionizing radiation is a risk factor to the whole organism, including the heart. Cardiac damage is considered to be a late effect of radiation exposure. While the acute cardiotoxicity of high doses is well characterized, the knowledge about nature and magnitude of the cardiac risk following lower doses exposure is incomplete. It has been shown that the cardiotoxic effects of radiation are source-, dose- and time-dependent. This paper provides an overview on these dependencies with regard to the molecular responses at the cellular and tissue levels. Main focus is put on the Nuclear Magnetic Resonance (NMR)-based and Mass Spectrometry (MS)-based metabolomic approaches in search of toxicity markers of relatively small doses of radiation. Conclusions: Available literature indicates that radiation exposure affects metabolites associated with: energy production, degradation of proteins and cell membranes, expression of proteins and stress response. Such effects are common for both animal and human studies. However, the specific metabolic response depends on several factors, including the examined organ. Radiation metabolomics can be used to explain the mechanisms of development of radiation-induced heart disease and to find an organ-specific biomarker of radiation exposure. The main aim of this review was to collect the information on the human cardiotoxicity biomarkers. In addition it also summarizes results of the studies on the metabolic responses to ionizing radiation for other organs, as well as the comparative data concerning animal studies.
Influence of nutrients involved in one-carbon metabolism on DNA methylation in adults-a systematic review and meta-analysis.

CONTEXT Aberrant DNA methylation is linked to various diseases. The supply of methyl groups for methylation reactions is mediated by S-adenosylmethionine, which depends on the availability of folate and related B vitamins. OBJECTIVES To investigate the influence of key nutrients involved in 1-carbon metabolism on DNA methylation in adults. DATA SOURCES Systematic literature searches were conducted in the Cochrane Library, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature Plus, Scopus, and Web of Science databases. Studies that met the inclusion criteria and were published in English were included. DATA EXTRACTION The first author, study design, sample size, population characteristics, type and duration of intervention, tissue type or cells analyzed, molecular techniques, and DNA methylation outcomes. DATA SYNTHESIS A meta-analysis of randomized, controlled trials (RCTs) was conducted to investigate the effect of 1-carbon metabolism nutrients on global DNA methylation. Functional analysis and visualization were performed using BioVenn software. RESULTS From a total of 2620 papers screened by title, 53 studies met the inclusion criteria. Qualitative analysis indicated significant associations between 1-carbon metabolism nutrients and DNA methylation. In meta-analysis of RCTs stratified by method of laboratory analysis, supplementation with folic acid alone or in combination with vitamin B12 significantly increased global DNA methylation in studies using liquid chromatography-mass spectrometry, which had markedly lower heterogeneity (n = 3; Z = 3.31; P = 0.0009; I2 = 0%) in comparison to other methods. Functional analysis highlighted a subset of 12 differentially methylated regions that were significantly related to folate and vitamin B12 biomarkers. CONCLUSION This study supports significant associations between 1-carbon metabolism nutrients and DNA methylation. However, standardization of DNA methylation techniques is recommended to reduce heterogeneity and facilitate comparison across studies. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number: CRD42018091898.
Serum Irisin Predicts Posthepatectomy Complications in Patients with Hepatocellular Carcinoma

Background Hepatectomy remains one of the most effective treatments for patients with hepatocellular carcinoma (HCC); however, it can lead to serious complications. Irisin, a key regulator of energy metabolism, is secreted into the circulation by shedding of the extracellular portion of the fibronectin type III domain-containing 5 (FNDC5). We have shown that irisin administration alleviates liver ischemia-reperfusion injury in mice. However, the role of preoperative irisin levels in HCC patients who underwent hepatectomy remained unknown. The purpose of this study was to determine how irisin expression changes in HCC and to explore the relationship between preoperative serum irisin levels and complications after hepatectomy. Methods FNDC5/irisin expression data in HCC were extracted from The Cancer Genome Atlas (TCGA) dataset. A total of 219 participants, including 102 healthy controls and 117 HCC patients, were recruited in this study. All HCC patients underwent hepatectomy at the First Affiliated Hospital of the Xi'an Jiaotong University. Preoperative serum irisin levels were measured by ELISA. Postoperative complications were assessed using the comprehensive complication index (CCI) score. The Pearson rank correlation coefficient was computed to assess the correlation between preoperative serum irisin levels and postoperative CCI scores. Results In TCGA dataset, FNDC5/irisin expression was downregulated in HCC tissues (P < 0.001). Similarly, serum irisin levels were decreased in HCC patients (P < 0.001). Low preoperative serum irisin levels were significantly correlated with high CCI scores after hepatectomy. Conclusions Irisin may be a novel serum biomarker in the diagnosis of HCC and a predictor of complications after hepatectomy.
Renal Excretion of Contrast on CT Myelography: A Specific Marker of CSF Leak

The authors performed a retrospective review of postmyelographic CT scans from 49 consecutive patients seen between January 2009 and August 2018 with imaging and/or clinical findings related to intracranial hypotension. Each scan was evaluated by both a neuroradiology fellow and a board-certified neuroradiologist for the presence of contrast in the renal excretory system. A similar assessment was also performed on 90 consecutive control subjects who underwent CT myelography for alternative indications. Among the 49 patients with suspected CSF leak, 21 (43%) had an overt CSF leak on postmyelographic CT (group 1) and 28 (57%) did not (group 2). Overall, renal contrast was identified in 7/49 patients (14.3%): 5 (24%) patients in group 1, and 2 (7%) patients in group 2. Renal contrast was not seen in any of the 90 controls on postmyelographic CT. Renal contrast was exclusively seen in patients with a clinically or radiographically suspected CSF leak. Identification of this finding should prompt a second look for subtle myelographic contrast extravasation or an underlying CSF-venous fistula. BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the sensitivity and specificity of renal/ureteric opacification on postmyelographic CT as a sign of CSF leak. MATERIALS AND METHODS: We performed a retrospective review of postmyelographic CT scans from 49 consecutive patients seen between January 2008 and August 2018 with imaging and/or clinical findings related to intracranial hypotension. Each scan was evaluated by both a neuroradiology fellow and a board-certified neuroradiologist for the presence of contrast in the renal excretory system. A similar assessment was also performed on 90 consecutive control subjects who underwent CT myelography for alternative indications. RESULTS: Among the 49 patients with suspected CSF leak, 21 (43%) had an overt CSF leak on postmyelographic CT (group 1) and 28 (57%) did not (group 2). Overall, renal contrast was identified in 7/49 patients (14.3%): 5 (24%) patients in group 1, and 2 (7%) patients in group 2. Renal contrast was not seen in any of the 90 controls on postmyelographic CT. CONCLUSIONS: Renal contrast was exclusively seen in patients with a clinically or radiographically suspected CSF leak. Given its 100% specificity, identification of this finding should prompt a second look for subtle myelographic contrast extravasation or an underlying CSF-venous fistula. Our results suggest that this sign may be considered an additional diagnostic criterion for CSF leak in the absence of an identifiable leak.
Neurourology and Urodynamics

Department of Obstetrics and Gynecology, Complejo Asistencial Universitario de Leon (CAULE), Leon, Spain Department of Obstetrics and Gynecology, Valme University Hospital, Seville, Spain Department of Obstetrics and Gynecology, University of Seville, Seville, Spain Department of Obstetrics and Gynecology, Complejo Asistencial Universitario de Gran Canarias, Gran Canarias, Spain Biostatistics Unit, Department of Preventive Medicine and Public Health, University of Seville, Seville, Spain
Functional and effective reorganization of the aging brain during unimanual and bimanual hand movements

Motor performance decline observed during aging is linked to changes in brain structure and function, however, the precise neural reorganization associated with these changes remains largely unknown. We investigated the neurophysiological correlates of this reorganization by quantifying functional and effective brain network connectivity in elderly individuals (n = 11; mean age = 67.5 years), compared to young adults (n = 12; mean age = 23.7 years), while they performed visually‐guided unimanual and bimanual handgrips inside the magnetoencephalography (MEG) scanner. Through a combination of principal component analysis and Granger causality, we observed age‐related increases in functional and effective connectivity in whole‐brain, task‐related motor networks. Specifically, elderly individuals demonstrated (i) greater information flow from contralateral parietal and ipsilateral secondary motor regions to the left primary motor cortex during the unimanual task and (ii) decreased interhemispheric temporo‐frontal communication during the bimanual task. Maintenance of motor performance and task accuracy in elderly was achieved by hyperactivation of the task‐specific motor networks, reflecting a possible mechanism by which the aging brain recruits additional resources to counteract known myelo‐ and cytoarchitectural changes. Furthermore, resting‐state sessions acquired before and after each motor task revealed that both older and younger adults maintain the capacity to adapt to task demands via network‐wide increases in functional connectivity. Collectively, our study consolidates functional connectivity and directionality of information flow in systems‐level cortical networks during aging and furthers our understanding of neuronal flexibility in motor processes.