bluuebunny/crossref_metadata_2025_split huggingface dataset:
A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma
Authors: Pal Sharmistha , Kaplan Jakub P. , Nguyen Huy , Stopka Sylwia A. , Savani Milan R. , Regan Michael S. , Nguyen Quang-De , Jones Kristen L. , Moreau Lisa A. , Peng Jingyu , Dipiazza Marina G. , Perciaccante Andrew J. , Zhu Xiaoting , Hunsel Bradley R. , Liu Kevin X. , Drissi Rachid , Filbin Mariella G. , McBrayer Samuel K. , Agar Nathalie Y.R. , Chowdhury Dipanjan , Haas-Kogan Daphne 
Published: December 2021

SUMMARYDiffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pathway for pyrimidine biosynthesis. A clinical stage inhibitor of DHODH (rate limiting enzyme in the de novo pathway) diminishes UMP pools, generates DNA damage, and induces apoptosis through suppression of replication forks--an “on target” effect, as shown by uridine rescue. MALDI mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.
Contrasting adaptation and optimization of stomatal traits across communities at continental-scale
Authors: Liu Congcong , Sack Lawren , Li Ying , He Nianpeng 
Published: December 2021

AbstractThe maximum stomatal conductance (g), a major anatomical constraint on plant productivity, is a function of the stomatal area fraction (f) and stomatal space-use efficiency (e). However,fandghave been considered as equivalents, witherarely considered, and their adaptation to the environment and their regulation of ecosystem productivity are unclear. Here, we analyzed the community-weighted mean, variance, skewness, and kurtosis of stomatal traits from tropical to cold-temperature forests. The variance ofgandfwas higher for arid sites, indicating greater functional niche differentiation, whereas that forewas lower, indicating convergence in efficiency. Besides, when other stomatal trait distributions remained unchanged, increasing kurtosis but decreasing skewness ofgwould improve ecosystem productivity, andfshowed the opposite patterns. These findings highlight how the relative importance and equivalence of inter-related traits can differ at community scale.
Broad neutralization of SARS-CoV-2 variants, including omicron, following breakthrough infection with delta in COVID-19 vaccinated individuals
Authors: Lechmere Thomas , Snell Luke B. , Graham Carl , Seow Jeffrey , Shalim Zayed A. , Charalampous Themoula , Alcolea-Medina Adela , Batra Rahul , Nebbia Gaia , Edgeworth Jonathan D. , Malim Michael H. , Doores Katie J. 
Published: December 2021

AbstractNumerous studies have shown that a prior SARS-CoV-2 infection can greatly enhance the antibody response to COVID-19 vaccination, with this so called “hybrid immunity” leading to greater neutralization breadth against SARS-CoV-2 variants of concern. However, little is known about how breakthrough infection (BTI) in COVID-19 vaccinated individuals will impact the magnitude and breadth of the neutralizing antibody response. Here, we compared neutralizing antibody responses between unvaccinated and COVID-19 double vaccinated individuals (including both AZD1222 and BNT162b2 vaccinees) who have been infected with the delta (B.1.617.2) variant. Rapid production of Spike-reactive IgG was observed in the vaccinated group providing evidence of effective vaccine priming. Overall, potent cross-neutralizing activity against current SARS-CoV-2 variants of concern was observed in the BTI group compared to the infection group, including neutralization of the omicron (B.1.1.529) variant. This study provides important insights into population immunity where transmission levels remain high and in the context of new or emerging variants of concern.
Comparison of Saliva and Mid-Turbinate Swabs for Detection of COVID-19
Authors: Lai Jianyu , German Jennifer , Hong Filbert , Tai S.-H. Sheldon , McPhaul Kathleen M. , Milton Donald K. ,   for the University of Maryland StopCOVID Research Group
Published: December 2021

AbstractBackgroundSaliva is an attractive sample for detecting SARS-CoV-2. However, contradictory reports exist concerning the sensitivity of saliva versus nasal swabs.MethodsWe followed close contacts of COVID-19 cases for up to 14 days from last exposure and collected self-reported symptoms, mid-turbinate swabs (MTS), and saliva every two or three days. Ct values, viral load, and frequency of viral detection by MTS and saliva were compared.Results58 contacts provided 200 saliva-MTS pairs; 14 contacts (13 with symptoms) had one or more positive samples. Saliva and MTS had similar rates of viral detection (p=0.78) and substantial agreement (κ=0.83). However, sensitivity varied significantly with time since symptom onset. Early on (days -3 to 2), saliva had 12 times (95%CI: 1.2, 130) greater likelihood of viral detection and 3.2 times (95% CI: 2.8, 3.8) higher RNA copy numbers compared to MTS. After day 2 post-symptoms, there was a non-significant trend toward greater sensitivity using MTS.ConclusionSaliva and MTS demonstrated high agreement making saliva a suitable alternative to MTS for COVID-19 detection. Saliva was more sensitive early in the infection when transmission is most likely to occur, suggesting that it may be a superior and cost-effective screening tool for COVID-19.
NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA
Authors: Nan Song , Yan Gao , Shanshan Lu , Shenglian Yang , Chao Yuan , Wenyu Sun 
Published: December 2021

AbstractMajor depressive disorder (MDD) is characterized by diverse debilitating symptoms that include loss of motivation and anhedonia. If multiple medications, psychotherapy, and electroconvulsive therapy fail in some patients with MDD, their condition is then termed treatment – resistant depression (TRD). MDD can be associated with abnormalities in the reward–system–dopaminergic mesolimbic pathway, in which the nucleus accumbens (NAc) and ventral tegmental area (VTA) play major roles. Deep brain stimulation (DBS) applied to the NAc alleviates the depressive symptoms of MDD. However, the mechanism underlying the effects of this DBS has remained elusive. In this study, using the chronic unpredictable mild stress (CUMS) mouse model, we investigated the behavioral and neurobiological effects of NAc – DBS on the multidimensional depression – like phenotypes induced by CUMS by integrating behavioral,in vivomicrodialysis coupled with high-performance liquid chromatography – electrochemical detector (HPLC – ECD), calcium imaging, pharmacological, and genetic manipulation methods in freely moving mice. We found that long–term and repeated, but not single, NAc–DBS induced robust antidepressant responses in CUMS mice. Moreover, even a single trial NAc–DBS led to the elevation of the γ–aminobutyric acid (GABA) neurotransmitter, accompanied by the increase in dopamine (DA) neuron activity in the VTA. Both the inhibition of the GABAAreceptor activity and knockdown of theGABAA–α1gene in VTA–GABA neurons blocked the antidepressant effect of NAc–DBS in CUMS mice. Our results showed that NAc– DBS could disinhibit VTA–DA neurons by regulating the level of GABA and the activity of VTA–GABA in the VTA and could finally correct the depression–like behaviors in the CUMS mouse model.
Protein structure dynamic prediction: a Machine Learning/Molecular Dynamic approach to investigate the protein conformational sampling
Authors: Audagnotto Martina , Czechtizky Werngard , De Maria Leonardo , Käck Helena , Papoian Garegin , Tornberg Lars , Tyrchan Christian , Ulander Johan 
Published: December 2021

AbstractProteins exist in several different conformations. These structural changes are often associated with fluctuations at the residue level. Recent findings show that co-evolutionary analysis coupled with machine- learning techniques improves the precision by providing quantitative distance predictions between pairs of residues. The predicted statistical distance distribution from Multi Sequence Analysis (MSA) reveals the presence of different local maxima suggesting the flexibility of key residue pairs. Here we investigate the ability of the residue-residue distance prediction to provide insights into the protein conformational ensemble. We combine deep learning approaches with mechanistic modeling to a set of proteins that experimentally showed conformational changes. The predicted protein models were filtered based on energy scores, RMSD clustering, and the centroids selected as the lowest energy structure per cluster. The models were compared to the experimental-Molecular Dynamics (MD) relaxed structure by analyzing the backbone residue torsional distribution and the sidechain orientations. Our pipeline not only allows us to retrieve the global experimental folding but also the experimental structural dynamics. We show the potential correlation between the experimental structure dynamics and the predicted model ensemble demonstrating the susceptibility of the current state-of-the-art methods in protein folding and dynamics prediction and pointing out the areas of improvement.
Paracrine role for endothelial IGF-1 receptor in white adipocyte beiging
Authors: Haywood Natalie J , Bridge Katherine I , Luk Cheukyau , Warmke Nele , Simmons Katie J , Drozd Michael , Moran Amy , Straw Sam , Scragg Jason L , Smith Jessica , Limumpornpetch Sunti , Ozber Claire H , Wilkinson Chloe G , Skromna Anna , Makava Natallia , Walker Andrew , Watt Nicole T , Mughal Romana , Griffin Kathryn J , Viswambharan Hema , Yuldasheva Nadira Y , Beech David J , Sukumar Piruthivi , Vidal-Puig Antonio , Witte Klaus K , Wheatcroft Stephen B , Cubbon Richard M , Roberts Lee D , Kearney Mark T 
Published: December 2021

SummaryThere are at least two distinct types of thermogenic adipocyte in mammals: a pre-existing form established during development, termed classical brown adipocytes and an inducible form, ‘beige’ adipocytes1–3. Various environmental cues can stimulate a process frequently referred to as ‘beiging’ of white adipose tissue (WAT), leading to enhanced thermogenesis and obesity resistance 4, 5. Whilst beiging of WAT as a therapeutic goal for obesity and obesity-related complications has attracted much attention6–9; therapeutics stimulating beiging without deleterious side-effects remain elusive10. The endothelium lines all blood vessels and is therefore in close proximity to all cells. Many studies support the possibility that the endothelium acts as a paracrine organ11–14. We explored the potential role of endothelial insulin-like growth factor-1 receptor (IGF-1R) as a paracrine modulator of WAT phenotype. Here we show that a reduction in endothelial IGF-1R expression in the presence of nutrient excess leads to white adipocyte beiging, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell autonomous paracrine mechanism. We demonstrate that this is mediated by endothelial release of malonic acid, which we show, using prodrug analogues, has potentially therapeutically-relevant properties in the treatment of metabolic disease.
A Comparison of Macaque Hair Hormone Concentration Following Enhanced Cognitive Experiences or Standard Nonhuman Primate Environmental Enrichment
Authors: Meidam Brooke J. , Meredith Emilia K. , Kapoor Amita , Bennett Allyson J. , Pierre Peter J. 
Published: December 2021

ABSTRACTExperience with enriched environments positively impacts the health and wellbeing of nonhuman animals ranging from rodents to primates. Little is known, however, about the specific effects of enhanced cognitive enrichment (ECE) on nonhuman primates. The study reported here used archival samples to provide preliminary analysis of ECE on hormones associated with stress and wellbeing, as well as evaluation of persistent effects of infant social rearing. Hair samples from 24 adult male rhesus macaques were analyzed via LC-MS/MS technique for the main stress response hormones: cortisol, cortisone, and dehydroepiandrosterone. The ECE and care-as-usual (CAU) groups did not significantly differ in any of the mean analyte values. Cortisol and dehydroepiandrosterone were strongly and positively correlated in the ECE group. By contrast, for the CAU group the two analytes were weakly correlated. Within the ECE group, cortisol and dehydroepiandrosterone were significantly and positively correlated in the mother-reared group, but not in the nursery-reared group. Overall, these results provide preliminary evidence that experience with ECE could help to maintain a balanced cortisol:dehydroepiandrosterone ratio, possibly indicative of a healthy stress response. Further examination of this ratio in hair is needed to support this hypothesis. These observations may also suggest that nursery rearing could have persistent effects, including dysregulation of the hypothalamic-pituitary-adrenal axis, apparent in the unbalanced cortisol:dehydroepiandrosterone ratio. Together these findings are consistent with the growing literature that supports the use of ECE to promote nonhuman primate wellbeing and healthy development.
Cooperative engagement and subsequent selective displacement of SR proteins define the pre-mRNA 3D structural scaffold for early spliceosome assembly
Authors: Saha Kaushik , Ghosh Gourisankar 
Published: December 2021

ABSTRACTWe recently reported that serine-arginine-rich (SR) protein-mediated pre-mRNA structural remodeling generates a pre-mRNA 3D structural scaffold that is stably recognized by the early spliceosomal components. However, the intermediate steps between the free pre-mRNA and the assembled early spliceosome are not yet characterized. By probing the early spliceosomal complexesin vitroand RNA-protein interactionsin vivo, we show that the SR proteins bind the pre-mRNAs cooperatively generating a substrate that recruits U1 snRNP and U2AF65 in a splice signal-independent manner. Excess U1 snRNP selectively displaces some of the SR protein molecules from the pre-mRNA generating the substrate for splice signal-specific, sequential recognition by U1 snRNP, U2AF65, and U2AF35. Our work thus identifies a novel function of U1 snRNP in mammalian splicing substrate definition, explains the need for excess U1 snRNP compared to other U snRNPsin vivo, demonstrates how excess SR proteins could inhibit splicing, and provides a conceptual basis to examine if this mechanism of splicing substrate definition is employed by other splicing regulatory proteins.
Temporary layoffs, short-time work and COVID-19: the case of a dual labour market
Authors: Osuna Victoria , García Pérez José Ignacio 
Published: December 2021

Purpose
This paper aims to study the type of short-time work (STW) schemes implemented in Spain to preserve jobs and workers’ incomes during the COVID-19 crisis and the corresponding labour market outcomes.

Design/methodology/approach
A dynamic macroeconomic model of job creation and destruction of the search and matching type in a dual labour market.

Findings
The model shows that the availability of STW schemes does not necessarily prevent a large increase in unemployment and job destruction. The quantitative effects depend on the degree of subsidization of payroll taxes and on the design of the policy. A scenario with a moderate degree of subsidization and where the subsidy is independent of the reduction in hours worked is the least harmful for both welfare and fiscal deficit. The cost of such a strategy is a higher unemployment rate. Concerning heterogeneous effects, the unemployed are the ones who experience the strongest distributional changes.

Originality/value
The effectiveness of STW schemes in dual labour markets using a search and matching model in the context of the COVID-19 crisis has not been analysed elsewhere. The literature has emphasized the importance of dynamics, labour market institutions and workers’ heterogeneity to understand workforce adjustment decisions in the face of temporary shocks to de- mand especially when firms’ human capital is relevant. These elements are present in the model. In addition, this paper computes welfare and distributional effects and the cost of these policies.
A cross-cultural analysis of the motivation factors and profitability of online wine tastings during Covid-19 pandemic
Authors: Szolnoki Gergely , Lueke Moritz Nikolaus , Tafel Maximilian , Blass Marvin , Ridoff Niklas , Nilsson Calle 
Published: December 2021

PurposeThe pioneers of online wine tastings have set a new standard and introduced an innovative tool that combines various goals: contacting existing and recruiting new customers, entertaining participants and boosting sales. Within the framework of the study, the authors addressed questions such as the reasons for offering online wine tasting, profitability and the basic characteristics and future perspectives of this new interactive online tool.Design/methodology/approachA mixed-methods research was conducted using a sequential exploratory design to analyse online wine tastings during Covid-19 pandemic. First, 40 in-depth interviews in Germany were conducted and, based on these results, a global online survey was undertaken with 1,423 wineries from more than 40 countries.FindingsThe survey results clearly show the effect of Covid-19 on the growing tendency to employ online wine tastings. This tool is about more than just providing entertainment for wine lovers in that it also has a tangible business aspect.Practical implicationsBased on these results, the authors assume that online wine tastings will continue to be offered after the Covid-19 crisis.Originality/valueThis paper offers a situation analysis of the first 10 months of the Covid-19 pandemic in the field of online wine tastings worldwide. The authors conducted a quantitative online survey that built on a qualitative pre-study. Given the fact that no academic paper has been published on the topic, this paper provides first insights on a global scale.
Antioxidant potential, anti-nutritional factors, volatile compounds and phenolic composition of microwave heat-treated plum (Prunus domestica. L.) kernels: an analytical approach
Authors: Sheikh Mohd Aaqib , Saini Charanjiv Singh , Sharma Harish Kumar 
Published: December 2021

PurposeThe study was aimed to explore the potential impact of microwave heating (450 W for 2, 4, 6 and 8 min) on antioxidant activity, anti-nutritional factors, volatile and phenolic compounds of the plum kernels.Design/methodology/approachPlum kernels are rich in proteins, lipids and bioactive compounds that are mostly underused and undervalued.FindingsThe results showed that microwave heating at 450 W for 6 min significantly (p < 0.05) increased the antioxidant activity, total phenolic and flavonoid content, while the longer treatment time (450 W for 8 min) adversely affected the phenolic compounds. Most importantly, the anti-nutritional factors like amygdalin, hydrocyanic acid, phytic acid and tannin content were reduced up to 87.1, 84.7, 20.9 and 46.2%, respectively at 450 W for 6 min treatment conditions, which was confirmed from the larger shifts observed in FT-IR spectra near 1,157 cm−1. Microwave heating at 450 W for 6 min also proved beneficial in improving the bioavailability of volatile and phenolic compounds including chlorogenic acid, gallic acid, syringic acid, (+)-catechin, caffeic acid, ß-carotene, trans-ferulic acid, rutin trihydrate, 3,4-dihydroxybenzoic acid, tannic acid and quercetin by liberating them from the plant matrix.Originality/valueThe results thus indicate that controlled microwave heating could be an effective approach for the reduction of anti-nutritional factors besides leading to an overall improvement in antioxidant potential and volatile and phenolic compounds. This novel technological approach can proliferate the use of plum kernels in different diversified food formulations.
Building information modelling (BIM) and the return on investment: a systematic analysis
Authors: Sompolgrunk Apeesada , Banihashemi Saeed , Mohandes Saeed Reza 
Published: December 2021

Purpose
The purpose of this study is to identify and analyse the key measurable returning factors, value drivers and strategic benefits associated with building information modelling (BIM) return on investment (ROI). The findings of this study provide researchers and practitioners with up-to-date information in formulating appropriate strategies to quantify the monetary value of BIM. The suggested research agenda provided would also advance what is presently a limited body of knowledge relating to the evaluation of BIM ROI.

Design/methodology/approach
To fill the identified gap, this study develops a comprehensive systematic review of mainstream studies on factors affecting BIM ROI published from 2000 to 2020. A total of 23 academic records from different sources such as journals, conference proceedings, dissertation and PhD theses were identified and thoroughly reviewed.

Findings
The reported BIM ROI ranged greatly from −83.3% to 39,900%. A total of 5 returning factors, namely, schedule reduction and compliance, productivity improvement, request for information reduction, rework reduction and change orders reduction were identified as the most commonly reported factors that influence BIM ROI. Four quantification techniques including general assumptions-based theoretical model, perceived BIM ROI based on survey, factors affecting BIM ROI with no reported ROI and quantified BIM ROI based on a case study were observed and pointed out in the review, together with their limitations. Finally, three major gaps were raised as the lack of consideration on the likelihood of BIM assisting in a construction project, intangible returning factors influencing BIM-based projects and industry standards in benchmarking BIM ROI.

Practical implications
The outcomes of this study would assist practitioners by providing the current evaluation techniques that address the limitations with BIM investment and present issues relating to the economic evaluation of BIM in the construction industry. It is also expected that presenting a deeper and wider perspective of the research work performed until now will direct a more focussed approach on productivity improvement efforts in the construction industry.

Originality/value
This study identifies and analyses the key measurable returning factors, value drivers and strategic benefits associated with BIM ROI on an industry scale rather than a particular organisation or a project scale.