bluuebunny/crossref_metadata_2025_split huggingface dataset:
Explainable AI enables clinical trial patient selection to retrospectively improve treatment effects in schizophrenia
Authors: Mellem Monika S. , Kollada Matt , Tiller Jane , Lauritzen Thomas 
Published: January 2021

AbstractBackgroundHeterogeneity among patients’ responses to treatment is prevalent in psychiatric disorders. Personalized medicine approaches – which involve parsing patients into subgroups better indicated for a particular treatment – could therefore improve patient outcomes and serve as a powerful tool in patient selection within clinical trials. Machine learning approaches can identify patient subgroups but are often not “explainable” due to the use of complex algorithms that do not mirror clinicians’ natural decision-making processes.MethodsHere we combine two analytical approaches – Personalized Advantage Index and Bayesian Rule Lists – to identify paliperidone-indicated schizophrenia patients in a way that emphasizes model explainability. We apply these approaches retrospectively to randomized, placebo-controlled clinical trial data to identify a paliperidone-indicated subgroup of schizophrenia patients who demonstrate a larger treatment effect (outcome on treatment superior than on placebo) than that of the full randomized sample as assessed with Cohen’s d. For this study, the outcome corresponded to a reduction in the Positive and Negative Syndrome Scale (PANSS) total score which measures positive (e.g., hallucinations, delusions), negative (e.g., blunted affect, emotional withdrawal), and general psychopathological (e.g., disturbance of volition, uncooperativeness) symptoms in schizophrenia.ResultsUsing our combined explainable AI approach to identify a subgroup more responsive to paliperidone than placebo, the treatment effect increased significantly over that of the full sample (p<0.0001 for a one-sample t-test comparing the full sample Cohen’s d=0.82 and a generated distribution of subgroup Cohen’s d’s with mean d=1.22, std d=0.09). In addition, our modeling approach produces simple logical statements (if-then-else), termed a “rule list”, to ease interpretability for clinicians. A majority of the rule lists generated from cross-validation found two general psychopathology symptoms, disturbance of volition and uncooperativeness, to predict membership in the paliperidone-indicated subgroup.ConclusionsThese results help to technically validate our explainable AI approach to patient selection for a clinical trial by identifying a subgroup with an improved treatment effect. With these data, the explainable rule lists also suggest that paliperidone may provide an improved therapeutic benefit for the treatment of schizophrenia patients with either of the symptoms of high disturbance of volition or high uncooperativeness.Trial Registrationclincialtrials.gov identifier: NCT 00083668; registered May 28, 2004
T-cell Receptor Diversity Estimates for Repertoires (TCRDivER) uses sequence similarity to find signatures of immune response
Authors: Vujović Milena , Marcatili Paolo , Chain Benny , Kaplinsky Joseph , Andresen Thomas Lars 
Published: January 2021

AbstractWe propose TCRDivER, a global approach to T-cell repertoire comparison using diversity profiles sensitive to both clone size and sequence similarity. As immunotherapies improve, the long standing biological interest in connecting outcome with T cell receptor (TCR) repertoire status has become more urgent. Here we show that new insights can be extracted from high throughput repertoire sequencing data. Most current efforts focus on identification of immunisation-specific sequence motifs or on monitoring changes in frequency of individual clones. Applying TCRDivER to murine spleen samples shows it characterises an additional dimension of repertoire variation, beyond conventional diversity estimates, allowing distinction between immunised and non-immunised samples. We further apply TCRDivER to repertoires from human blood. In both cases we show characteristic relationships between repertoire features. These reveal biologically interpretable relationships between sequence similarity and clonal expansions. We thereby demonstrate a new tool for investigation in clinical and research applications.
Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery
Authors: Quante Markus , Iske Jasper , Heinbokel Timm , Desai Bhavna N. , Biefer Hector Rodriguez Cetina , Nian Yeqi , Krenzien Felix , Uehara Hirofumi , Maenosono Ryoichi , Azuma Haruhito , Pratschke Johann , Falk Christine , Lo Tammy , Sheu Eric , Tavakkoli Ali , Perkins David , Alegre Maria-Luisa , Banks Alexander S. , Elkhal Abdallah , Tullius Stefan G. 
Published: January 2021

AbstractObesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities.We performed sleeve-gastrectomies (SGx) in a pre-clinical mouse model of diet-induced obesity (DIO), delineating the effects on long-term remission from obesity. SGx resulted in sustained weight loss and improved glucose tolerance. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of taurodeoxycholic acid (TDCA) and L-valine in DIO mice. Notably, TDCA and L-Valine levels were restored after SGx in both human and mice to levels comparable with lean controls.Strikingly, combined systemic treatment with TDCA and valine induced a profound weight loss in DIO mice analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone.In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.
A modified fluctuation assay reveals a natural mutator phenotype that drives mutation spectrum variation withinSaccharomyces cerevisiae
Authors: Jiang Pengyao , Ollodart Anja R. , Sudhesh Vidha , Herr Alan J. , Dunham Maitreya J. , Harris Kelley 
Published: January 2021

AbstractAlthough studies ofSaccharomyces cerevisiaehave provided many insights into mutagenesis and DNA repair, most of this work has focused on a few laboratory strains. Much less is known about the phenotypic effects of natural variation withinS. cerevisiae’s DNA repair pathways. Here, we use natural polymorphisms to detect historical mutation spectrum differences among several wild and domesticatedS. cerevisiaestrains. To determine whether these differences are likely caused by genetic mutation rate modifiers, we use a modified fluctuation assay with aCAN1reporter to measurede novomutation rates and spectra in 16 of the analyzed strains. We measure a 10-fold range of mutation rates and identify two strains with distinctive mutation spectra. These strains, known as AEQ and AAR, come from the panel’s “Mosaic beer” clade and share an enrichment for C>A mutations that is also observed in rare variation segregating throughout the genomes of several Mosaic beer and Mixed origin strains. Both AEQ and AAR are haploid derivatives of the diploid natural isolate CBS 1782, whose rare polymorphisms are enriched for C>A as well, suggesting that the underlying mutator allele is likely active in nature. We use a plasmid complementation test to show that AAR and AEQ share a mutator allele in the DNA repair geneOGG1, which excises 8-oxoguanine lesions that can cause C>A mutations if left unrepaired.
Immunological and cardio-vascular pathologies associated with SARS-CoV-2 infection in golden syrian hamster
Authors: Rizvi Zaigham Abbas , Dalal Rajdeep , Sadhu Srikant , Kumar Yashwant , Shrivastava Tripti , Gupta Sonu Kumar , Agarwal Suruchi , Tripathy Manas Ranjan , Yadav Amit Kumar , Medigeshi Guruprasad R. , Pandey Amit Kumar , Samal Sweety , Asthana Shailendra , Awasthi Amit 
Published: January 2021

SummarySevere acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in golden Syrian hamster (GSH) causes lung pathology and resembles human coronavirus disease (Covid-19). However, extra-pulmonary pathologies of SARS-CoV-2 infection that result in long Covid remains undefined in GSH. Here, usingin silicomodelling we show that hamster angiotensin-converting enzyme-2 (ACE-2) and neuropilin-1 (NRP-1) interaction with SARS-CoV-2 is similar to human. Intranasal SARS-CoV-2 infection in GSH resulted in early onset of lung pathologies marked by aggressive inflammatory response. Remarkably, late phase of SARS-CoV2 infection in GSH showed cardiovascular complications (CVC) characterized by ventricular hypertrophy, ventricular wall thickening, interstitial coronary fibrosis and altered lipidomics with elevated cholesterol, low-density lipoprotein and long chain fatty acid triglycerides. Moreover, serum metabolomics profile of infected GSH correlated with Covid19 patients. Together, we propose GSH as a suitable animal model to study immediate and long Covid19 pathologies that could be extended to therapeutics against Covid19 related CVC.
Symptomatic fever management in children: A systematic review of national and international guidelines
Authors: Green Cari , Kraft Hanno , Guyatt Gordon , Martin David 
Published: January 2021

AbstractIntroductionA comprehensive assessment of the recommendations made by clinical practice guidelines (CPGs) on symptomatic fever management in children has not been carried out.MethodsSearches were conducted on Pubmed, google scholar, pediatric society websites and guideline databases to locate CPGs from each country. Rather than assessing overall guideline quality, the level of evidence for each recommendation was evaluated according to criteria of the Oxford Centre for Evidence-Based Medicine (OCEBM). A GRADE assessment was undertaken to assess the body of evidence related to a single question: the threshold for initiating antipyresis.Results74 guidelines were retrieved. Recommendations for antipyretic threshold, type and dose; ambient temperature; dress/covering; activity; fluids; nutrition; proctoclysis; external applications; complementary/herbal recommendations; media; and age-related treatment differences all varied widely. OCEBM evidence levels for most recommendations were low (Level 3-4) or indeterminable. The GRADE assessment revealed a very low level of evidence for a threshold for antipyresis.ConclusionThere is no recommendation on which all guidelines agree, and many are inconsistent with the evidence – this is true even for recent guidelines. The threshold question is of fundamental importance and has not yet been answered. Guidelines for the most frequent intervention (antipyresis) remain problematic.
Scientific Article Dietary electrolyte balance on serum hematological and biochemical parameters of broilers under heat stress
Authors: Silva e Silva Danilo Rodrigo , de Sousa Moura Francinete Alves , de Sousa Lima Vânia Batista , Miranda Lopes Patrícia , de Fatima Saraiva Cardoso Janaina , do Prado Alan Costa , Machado Luciana Pereira , Átila de Sousa Richard , Biagiotti Daniel , Barros Dourado Leilane Rocha 
Published: January 2021

AbstractThe aim of this study was to evaluate the effect of different dietary electrolyte balance (DEB) levels over the hematological parameters and the biochemical profile of broilers under stress caused by cyclic heat. We used 1050 male broilers from Ross lineage, for two experimental phases: phase 1 (broilers from 1 until 21 days old) and phase 2 (broilers from 22 until 42 days old). The broilers were distributed under a completely randomized design, built for five treatments (110; 175; 240; 305; 370 mEq of DEB/kg of ration) and seven repetitions. For the hematological analyses were used two broilers in each repetition, one to blood count evaluation (Hemogram) and another one to the biochemistry evaluation, collected in the end of each experimental phase. During the phase of 1 - 21 days old, the variable hemoglobin number (Heme), mean corpuscular volume (MCV) and Serum Chloride (Cl) presented a linear effect (p<0,05) DEB levels. There was no effects (p>0,05) over the corpuscular volume (CV), total plasma protein (TPP), leukocytes number (Leu), heterophiles (Het), lymphocytes (Lyn), eosinophils (Eos), basophils (Bas), monocytes (Mon), calcium (Ca), phosphor (P), uric acid (UA) e urea (U). During the phase two of 22 – 42 days old there was effect (p<0,05) quadratic to the variables Leu and Het and linear to the variable P and significative difference (p<0,05) between the variable means UA at the levels of DEB tested.There was no effect (p>0,05) over the variable CV, Heme, MCV, TPP, Lyn, Eos, Bas, Mon, Cl, Ca and U on the DEB levels tested. The supplementation of the DEB levels 110, 175 e 240, 305 and 370 to the phase from 1 until 21 days old presented great results in the hematological evaluation and biochemical, because it provided possibly a longer useful life to the Hem without promoting a metabolic imbalance. In the phase from 22 until 42 days old the level of 268 to 280 mEq of DEB/kg of ration presented a better answer from the broilers immune systemic.
Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma
Authors: Williams Gareth H , Thatcher Robert , Hardisty Keeda-Marie , Loddo Marco 
Published: January 2021

AbstractThe standard treatment for glioblastoma involves a combination of surgery, radiation and chemotherapy but have limited impact on survival. The exponential increase in targeted agents directed at pivotal oncogenic pathways now provide new therapeutic opportunities for this tumour type. However, lack of comprehensive precision oncology testing at diagnosis means such therapeutic opportunities are potentially overlooked.To investigate the role of semiconductor sequencing for detection of predictive biomarkers in routine glioblastoma samples we have undertaken analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 764 of the leading anti-cancer targeted agents/combinations and immunotherapies via analysis of actionable genomic variants distributed across 505 genes. Analysis was performed across a cohort of 55 glioblastoma patients.Analysis of trending data has revealed a complex and rich actionable mutational landscape in which 166 actionable mutations were detected across 36 genes linked to 17 off label targeted therapy protocols and 111 clinical trials. The majority of patients harboured three or more actionable mutations affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signalling pathways, DNA-damage repair pathways and cell cycle checkpoints. Linkage with immunotherapy and PARP inhibitors was identified in 44% of glioblastoma patients as a consequence of alterations in DNA-damage repair genes.Taken together our data indicates that precision oncology testing utilising semiconductor sequencing can be used to identify a broad therapeutic armamentarium of targeted therapies and immunotherapies that can be potentially employed for the improved clinical management of glioblastoma patients.
MultipleTesting.com: a tool for life science researchers for multiple hypothesis testing correction
Authors: Menyhárt Otília , Weltz Boglárka , Győrffy Balázs 
Published: January 2021

ABSTRACTScientists from nearly all disciplines face the problem of simultaneously evaluating many hypotheses. Conducting multiple comparisons increases the likelihood that a non-negligible proportion of associations will be false positives, clouding real discoveries.Drawing valid conclusions require taking into account the number of performed statistical tests and adjusting the statistical confidence measures. Several strategies exist to overcome the problem of multiple hypothesis testing. We aim to summarize critical statistical concepts and widely used correction approaches while also draw attention to frequently misinterpreted notions of statistical inference.We provide a step-by-step description of each multiple-testing correction method with clear examples and present an easy-to-follow guide for selecting the most suitable correction technique.To facilitate multiple-testing corrections, we developed a fully automated solution not requiring programming skills or the use of a command line. Our registration free online tool is available atwww.multipletesting.comand compiles the five most frequently used adjustment tools, including the Bonferroni, the Holm (step-down), the Hochberg (step-up) corrections, allows to calculate False Discovery Rates (FDR) and q-values.The current summary provides a much needed practical synthesis of basic statistical concepts regarding multiple hypothesis testing in a comprehensible language with well-illustrated examples. The web tool will fill the gap for life science researchers by providing a user-friendly substitute for command-line alternatives.
Experimental and mathematical insights on the interactions between poliovirus and a defective interfering genome
Authors: Shirogane Yuta , Rousseau Elsa , Voznica Jakub , Xiao Yinghong , Su Weiheng , Catching Adam , Whitfield Zachary J. , Rouzine Igor M. , Bianco Simone , Andino Raul 
Published: January 2021

1AbstractDuring replication, RNA viruses accumulate genome alterations, such as mutations and deletions. The interactions between individual variants can determine the fitness of the virus population and, thus, the outcome of infection. To investigate the effects of defective interfering genomes (DI) on wild-type (WT) poliovirus replication, we developed an ordinary differential equation model. We experimentally determined virus and DI replication during co-infection, and use these data to infer model parameters. Our model predicts, and our experimental measurements confirm, that DI replication and encapsidation are the most important determinants for the outcome of the competition. WT replication inversely correlates with DI replication. Our model predicts that genome replication and effective DI genome encapsidation are critical to effectively inhibit WT production, but an equilibrium can be established which enables WT to replicate, albeit to reduce levels.
The genome of a daddy-long-legs (Opiliones) illuminates the evolution of arachnid appendages and chelicerate genome architecture
Authors: Gainett Guilherme , González Vanessa L. , Ballesteros Jesús A. , Setton Emily V. W. , Baker Caitlin M. , Gargiulo Leonardo Barolo , Santibáñez-López Carlos E. , Coddington Jonathan A. , Sharma Prashant P. 
Published: January 2021

AbstractChelicerates exhibit dynamic evolution of genome architecture, with multiple whole genome duplication events affecting groups like spiders, scorpions, and horseshoe crabs. Yet, genomes remain unavailable for several chelicerate orders, such as Opiliones (harvestmen), which has hindered comparative genomics and developmental genetics across arachnids. We assembled a draft genome of the daddy-long-legsPhalangium opilio,which revealed no signal of whole genome duplication. To test the hypothesis that single-copy Hox genes of the harvestman exhibit broader functions than subfunctionalized spider paralogs, we performed RNA interference againstDeformedinP. opilio.Knockdown ofDeformedincurred homeotic transformation of the two anterior pairs of walking legs into pedipalpal identity; by comparison, knockdown of the spatially restricted paralogDeformed-Ain the spider affects only the first walking leg. To investigate the genetic basis for leg elongation and tarsomere patterning, we identified and interrogated the function of anEpidermal growth factor receptor (Egfr)homolog. Knockdown ofEgfrincurred shortened appendages and the loss of distal leg structures. The overlapping phenotypic spectra ofEgfrknockdown experiments in the harvestman and multiple insect models are striking because tarsomeres have evolved independently in these groups. Our results suggest a conserved role forEgfrin patterning distal leg structures across arthropods, as well as cooption of EGFR signaling in tarsomere patterning in both insects and arachnids. The establishment of genomic resources forP. opilio,together with functional investigations of appendage fate specification and distal patterning mechanisms, are key steps in understanding how daddy-long-legs make their long legs.
Maternal behavior and the neonatal HPA axis in the Wistar Audiogenic Rat (WAR) strain: early life implications for a genetic animal model in epilepsy
Authors: Godoy Lívea Dornela , Garcia-Cairasco Norberto 
Published: January 2021

AbstractEpileptogenesis is a multistage process and seizure susceptibility can be influenced by stress early in life.Wistar Audiogenic Rat(WAR) strain is an interesting model to study the association between stress and epilepsy, since it is naturally susceptible to seizures and present changes in the hypothalamus-pituitary-adrenal (HPA) axis activity. All these features are related to the pathogenic mechanisms usually associated to psychiatric comorbidities present in epilepsy. Therefore, the current study aimed to evaluate the neonate HPA axis function and maternal care under control and stress conditions in the WAR strain. Maternal behavior and neonate HPA axis were evaluated in Wistar and WAR strains under rest and after the presence of stressors. We observed that WAR pups present higher plasmatic corticosterone concentration as compared to Wistar pups. Although WAR dams do not show significant altered maternal behavior at rest, there is a higher latency to recover the litter in the pup retrieval test, while some did not recover all the litter. WAR dams presented similar behaviors to Wistar dams to a female intruder and maternal care with the pups in the maternal defense test. Taken together, these findings indicate that the WAR strain could show HPA axis disruption early in life and dams present altered maternal behavior under stressful events. Those alterations make the WAR strain an interesting model to evaluate vulnerability to epilepsy and its associated neuropsychiatric comorbidities.
SplitStaphylococcus aureusprime editor for AAV delivery
Authors: Aird Eric J. , Zdechlik Alina C. , Ruis Brian L. , Rogers Colette B. , Lemmex Andrew L. , Nelson Andrew T. , Hendrickson Eric A. , Schmidt Daniel , Gordon Wendy R. 
Published: January 2021

AbstractPrime editing brings immense promise to correct a large number of human pathogenic mutations and enact diverse edit types without introducing widespread undesired editing events. Delivery of prime editors in vivo would enable such edits to be introduced in a clinical setting. The coding sequence for prime editor, however, is too large to fit within the size-constrained adeno-associated virus (AAV) genome. Herein, we describe a splitStaphylococcus aureusprime editor capable of being delivered by dual AAVs. We characterize the editing ability of plasmid-based versions of anS. aureusprime editor in vitro at a variety of loci with diverse edit types. We investigate various split prime editor architectures and alternative dimerization domains. Finally, we demonstrate the capacity of prime editor to be co-delivered by dual AAVs in vitro. While editing rates are lower than desired, this approach presents an important step to translate prime editing for in vivo delivery.