bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two ligand-binding sites on SARS-CoV-2 non-structural protein 1 revealed by fragment-based x-ray screening
Authors: Ma Shumeng , Damfo Shymaa , Lou Jiaqi , Pinotsis Nikos , Bowler Matthew W. , Haider Shozeb , Kozielski Frank 
Published: June 2022

AbstractThe regular reappearance of coronavirus (CoV) outbreaks over the past 20 years has caused significant health consequences and financial burdens worldwide. The most recent and still ongoing novel CoV pandemic, caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has brought a range of devastating consequences. Due to the exceptionally fast development of vaccines, the mortality rate of the virus has been curbed to a significant extent. However, the limitations of vaccination efficiency and applicability, coupled with the still high infection rate, emphasise the urgent need for discovering safe and effective antivirals against SARS-CoV-2 through suppressing its replication and or attenuating its virulence. Non-structural protein 1 (nsp1), a unique viral and conserved leader protein, is a crucial virulence factor for causing host mRNA degradation, suppressing interferon (IFN) expression and host antiviral signalling pathways. In view of the essential role of nsp1 in the CoV life cycle, it is regarded as an exploitable target for antiviral drug discovery. Here, we report a variety of fragment hits against SARS-CoV-2 nspl identified by fragment-based screening via X-ray crystallography. We also determined the structure of nsp1 at atomic resolution (0.95 Å). Binding affinities of hits against nsp1 were determined by orthogonal biophysical assays such as microscale thermophoresis and thermal sift assays. We identified two ligand-binding sites on nsp1, one deep and one shallow pocket, which are not conserved between the three medially relevant SARS, SARS-CoV-2 and MERS coronaviruses. Our study provides an excellent starting point for the development of more potent nsp1-targeting inhibitors and functional studies on SARS-CoV-2 nsp1.
SARS2Mutant: SARS-CoV-2 Amino-Acid Mutation Atlas Database
Authors: Rahimian Karim , Mahmanzar Mohammadamin , Mahdavi Bahar , Arefian Ehsan , Kuehu Donna Lee , Deng Youping 
Published: June 2022

AbstractThe coronavirus disease 19 (COVID-19) is a highly pathogenic viral infection of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in the global pandemic of 2020.A lack of therapeutic and preventive approaches including drugs and vaccines, has quickly posed significant threats to world health. A comprehensive understanding of the evolution and natural selection of SARS-CoV-2 against the host interaction and symptoms at the phenotype level could impact the candidate’s strategies for the fight against this virus.SARS-CoV-2 Mutation (SARS2Mutant, http://sars2mutant.com/) is a database thatprovides comprehensive analysis results based on tens of thousands of high-coverage and high-quality SARS-CoV-2 complete protein sequences. The structure of this database is designed to allow the users to search for the three different strategies among amino acid substitution mutations based on gene name, geographical zone or comparative analysis. Based on each strategy, five data types are available to the user: mutated sample frequencies, heat map of the mutated amino acid positions, timeline trend for mutation survivals and natural selections, and charts of changed amino acids and their frequencies. Due to the increase of virus protein sequence samples published daily showing the latest trends of current results, all sequences in the database are reanalyzed and updated monthly. The SARS-2Mutant database providescurrent analysis and updated data of mutation patterns and conserved regions, helpful in developing and designing targeted vaccines, primers and drug discoveries.
Alterations in the Nasopharyngeal Microbiome Associated with SARS-CoV-2 Infection Status and Disease Severity
Authors: Gauthier Nick P.G. , Locher Kerstin , MacDonald Clayton , Chorlton Samuel D. , Charles Marthe , Manges Amee R. 
Published: June 2022

AbstractObjectivesThe COVID-19 pandemic and ensuing public health emergency has emphasized the need to study SARS-CoV-2 pathogenesis. The human microbiome has been shown to regulate the host immune system and may influence host susceptibility to viral infection, as well as disease severity. Several studies have assessed whether compositional alterations in the nasopharyngeal microbiota are associated with SARS-CoV-2 infection. However, the results of these studies were varied, and many did not account for disease severity. This study aims to examine whether compositional differences in the nasopharyngeal microbiota are associated with SARS-CoV-2 infection status and disease severity.MethodsWe performed Nanopore full-length 16S rRNA sequencing on 194 nasopharyngeal swab specimens from hospitalized and community-dwelling SARS-CoV-2-infected and uninfected individuals. Sequence data analysis was performed using the BugSeq 16S analysis pipeline.ResultsWe found significant beta (PERMANOVA p < 0.05), but not alpha (Kruskal-Wallis p > 0.05) diversity differences in the nasopharyngeal microbiota among our study groups. We identified several differentially abundant taxa associated with SARS-CoV-2 infection status and disease severity using ALDEx2. Finally, we observed a trend towards higher abundance of Enterobacteriaceae in specimens from hospitalized SARS-CoV-2-infected patients.ConclusionsThis study identified several alterations in the nasopharyngeal microbiome associated with SARS-CoV-2 infection status and disease severity. Understanding the role of the microbiome in infection susceptibility and severity may open new avenues of research for disease prevention and treatment.
The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: a systematic review and meta-analysis
Authors: Almulla Abbas F. , Thipakorn Yanin , Vasupanrajit Asara , Abo Algon Ali Abbas , Tunvirachaisakul Chavit , Hashim Aljanabi Ashwan Abdulzahra , Oxenkrug Gregory , Al-Hakeim Hussein K. , Maes Michael 
Published: June 2022

AbstractBackgroundThere is now evidence that affective disorders including major depressive disorder (MDD) and bipolar disorder (BD) are mediated by immune-inflammatory and nitro-oxidative pathways. Activation of these pathways may be associated with activation of the tryptophan catabolite (TRYCAT) pathway leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs).AimsTo systematically review and meta-analyze TRP, its competing amino-acids (CAAs) and TRYCAT data in MDD and BD.MethodsThis review searched PubMed, Google Scholar and SciFinder and included 121 full-text articles and 15470 individuals, including 8024 MDD/BD patients and 7446 healthy controls.ResultsTRP levels (either free and total) and the TRP/CAAs ratio were significantly decreased (p<0.0001) in MDD/BD as compared with controls with a moderate effect size (standardized mean difference for TRP: SMD=-0.513, 95% confidence interval, CI: -0.611; -0.414; and TRP/CAAs: SMD=-0.558, CI: -0.758; -0.358). Kynurenine (KYN) levels were significantly decreased in patients as compared with controls with a small effect size (p<0.0001, SMD= -0.213, 95%CI: -0.295; -0.131). These differences were significant in plasma (p<0.0001, SMD=-0.304, 95%CI: -0.415, -0.194) but not in serum (p=0.054) or the central nervous system (CNS, p=0.771). The KYN/TRP ratio, frequently used as an index of indoleamine-dioxygenase (IDO) activity, and neurotoxicity indices based on downstream TRYCATs were unaltered or even lowered in MDD/BD.ConclusionsOur findings revealed that MDD/BD are accompanied by TRP depletion without IDO and TRYCAT pathway activation. Lowered TRP availability is probably the consequence of lowered serum albumin during the inflammatory response in affective disorders.
Computational Prediction of Synthetic Circuit Function Across Growth Conditions
Authors: Cummins Breschine , Moseley Robert C. , Deckard Anastasia , Weston Mark , Zheng George , Bryce Daniel , Nowak Joshua , Gameiro Marcio , Gedeon Tomas , Mischaikow Konstantin , Beal Jacob , Johnson Tessa , Vaughn Matthew , Gaffney Niall I. , Gopaulakrishnan Shweta , Urrutia Joshua , Goldman Robert P. , Bartley Bryan , Nguyen Tramy T. , Roehner Nicholas , Mitchell Tom , Vrana Justin D. , Clowers Katie J. , Maheshri Narendra , Becker Diveena , Mikhalev Ekaterina , Biggers Vanessa , Higa Trissha R. , Mosqueda Lorraine A. , Haase Steven B. 
Published: June 2022

AbstractA challenge in the design and construction of synthetic genetic circuits is that they will operate within biological systems that have noisy and changing parameter regimes that are largely unmeasurable. The outcome is that these circuits do not operate within design specifications or have a narrow operational envelope in which they can function. This behavior is often observed as a lack of reproducibility in function from day to day or lab to lab. Moreover, this narrow range of operating conditions does not promote reproducible circuit function in deployments where environmental conditions for the chassis are changing, as environmental changes can affect the parameter space in which the circuit is operating. Here we describe a computational method for assessing the robustness of circuit function across broad parameter regions. Previously designed circuits are assessed by this computational method and then circuit performance is measured across multiple growth conditions in budding yeast. The computational predictions are correlated with experimental findings, suggesting that the approach has predictive value for assessing the robustness of a circuit design.
Large-scale structural rearrangements unleash indiscriminate nuclease activity of CRISPR-Cas12a2
Authors: Bravo Jack P. K. , Hallmark Thom , Naegle Bronson , Beisel Chase L. , Jackson Ryan N. , Taylor David W. 
Published: June 2022

AbstractCas12a2 is a CRISPR-associated nuclease that performs RNA-guided degradation of non-specific single-stranded (ss)RNA, ssDNA and double-stranded (ds)DNA upon recognition of a complementary RNA target, culminating in abortive infection (Dmytrenko 2022). Here, we report structures of Cas12a2 in binary, ternary, and quaternary complexes to reveal a complete activation pathway. Our structures reveal that Cas12a2 is autoinhibited until binding a cognate RNA target, which exposes the RuvC active site within a large, positively charged cleft. Double-stranded DNA substrates are captured through duplex distortion and local melting, stabilized by pairs of ‘aromatic clamp’ residues that are crucial for dsDNA degradation and invivoimmune system function. Our work provides a structural basis for this unprecedented mechanism of abortive infection to achieve population-level immunity, which can be leveraged to create rational mutants that degrade a spectrum of collateral substrates.
Glucocorticoid-sensitive period of corticotroph development – implications in early life stress
Authors: Peles Guy , Swaminathan Amrutha , Levkowitz Gil 
Published: June 2022

AbstractCorticotrophs are intermediaries in the hypothalamic-pituitary-adrenal (HPA) axis, which plays a crucial role in vertebrates’ stress response. The HPA axis displays an intricate mode of negative feedback regulation, whereby the peripheral effector, cortisol inhibits the secretion of its upstream regulator, adrenocorticotropic hormone (ACTH) from proopiomelanocortin (POMC)-expressing cells in the pituitary. While the feedback regulation of the HPA axis is well characterized in the adult organism, the effect of feedback regulation on the development of corticotrophs is poorly understood. Here, we study the effect of glucocorticoids on the development of POMC-expressing cells in the zebrafish pituitary. The development of POMC cells displayed striking robustness in terms of their steady increase in numbers between 2-6 days post fertilization. Inhibition of endogenous glucocorticoid synthesis resulted in an increase in POMC cell number due to reduced developmental feedback inhibition of cortisol on POMC cells. Conversely, addition of exogenous dexamethasone at a critical developmental window led to a decrease in POMC cell number, mimicking greater feedback control. Finally, developmental dysregulation of ACTH levels resulted in impaired anxiety-like and stress-coping behaviours. Hence, we identified a sensitive developmental window for the effect of glucocorticoids on corticotrophs and demonstrate the downstream effect on stress-responsive behaviour.
Shoc2 controls ERK1/2-driven neural crest development by balancing components of the extracellular matrix
Authors: Norcross Rebecca G. , Abdelmoti Lina , Rouchka Eric C. , Andreeva Kalina , Tussey Olivia , Landestoy Daileen , Galperin Emilia 
Published: June 2022

ABSTRACTThe extracellular signal-regulated kinase (ERK1/2) pathway is essential in embryonic development. The scaffold protein Shoc2 is a critical modulator of ERK1/2 signals, and mutations in the shoc2 gene lead to the human developmental disease known as Noonan-like syndrome with loose anagen hair (NSLH). The loss of Shoc2 and the shoc2 NSLH-causing mutations affect the tissues of neural crest (NC) origin. In this study, we utilized the zebrafish model to dissect the role of Shoc2-ERK1/2 signals in the development of NC. These studies established that the loss of Shoc2 significantly altered the expression of transcription factors regulating the specification and differentiation of NC cells. Using comparative transcriptome analysis of NC-derived cells from shoc2 CRISPR/Cas9 mutant larvae, we found that Shoc2-mediated signals regulate gene programs at several levels, including expression of genes coding for the proteins of extracellular matrix (ECM) and ECM regulators. Together, our results demonstrate that Shoc2 is an essential regulator of NC development. This study also indicates that disbalance in the turnover of the ECM may lead to the abnormalities found in NSLH patients.
Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter
Authors: Singh Isha , Seth Anubha , Billesbølle Christian B. , Braz Joao , Rodriguiz Ramona M. , Roy Kasturi , Bekele Bethlehem , Craik Veronica , Huang Xi-Ping , Boytsov Danila , Lak Parnian , O’Donnell Henry , Sandtner Walter , Roth Bryan L. , Basbaum Allan I. , Wetsel William C. , Manglik Aashish , Shoichet Brian K. , Rudnick Gary 
Published: June 2022

SUMMARYThe serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has an unusual anti-depressant profile and stabilizes the inward-open conformation. Unfortunately, ibogaine is promiscuous and cardiotoxic, limiting understanding of inward-open state ligands. We computationally docked over 200 million small molecules against the ibogaine stabilized inward-open state of SERT. Thirty-six top-ranking compounds were synthesized and thirteen inhibited with potencies ranging from 29 to 5000 nM. Structure-based optimization led to two novel inhibitors with Ki values down to 3 nM. The new molecules stabilized an outward-closed state of the transporter and had little activity against off-targets. A cryo-EM structure of one of these bound to SERT confirmed the predicted geometry. In mouse behavioral assays, both had anxiolytic and anti-depressant activity, with potencies up to 200 better than fluoxetine.
Regulation of nuclear actin levels and MRTF/SRF target gene expression during PC6.3 cell differentiation
Authors: Kyheröinen Salla , Hyrskyluoto Alise , Sokolova Maria , Vartiainen Maria K. 
Published: June 2022

AbstractActin has important functions in both cytoplasm and nucleus of the cell, with active nuclear transport mechanisms maintaining the cellular actin balance. Nuclear actin levels are subject to regulation during many cellular processes from cell differentiation to cancer. Here we show that nuclear actin levels increase upon differentiation of PC6.3 cells towards neuron-like cells. Photobleaching experiments demonstrate that this increase is due to decreased nuclear export of actin during cell differentiation. Increased nuclear actin levels lead to decreased nuclear localization of MRTF-A, a well-established transcription cofactor of SRF. In line with MRTF-A localization, transcriptomics analysis reveals that MRTF/SRF target gene expression is first transiently activated, but then substantially downregulated during PC6.3 cell differentiation. This study therefore describes a novel cellular context, where regulation of nuclear actin is utilized to tune MRTF/SRF target gene expression during cell differentiation.
Knowledge recombination, environmental turbulence and firms' innovation quality: the evidence from Chinese pharmaceutical industry
Authors: Luo Zhen , Callaert Julie , Zeng Deming , Looy Bart Van 
Published: June 2022

PurposeShifting focus from innovation quantity to innovation quality becomes a priority in innovation study, business and policy. This paper aims to figure out whether and how knowledge recombination (recombinant exploration/recombinant exploitation) affects firms' innovation quality (technological value/economic value) and how these relationships are moderated by environmental turbulence (technological turbulence/market turbulence) in the context of open innovation.Design/methodology/approachA panel data set is built on 373 Chinese pharmaceutical firms' patents and new product data from 1997 to 2020. And a negative binomial regression model is applied to test the hypotheses.FindingsThe analyses indicate that (1) recombinant exploration favors technological value but hinders economic value, while (2) recombinant exploitation benefits both. Regarding environmental turbulence's moderating effects, (3) technological turbulence has opposite moderating effects on the impacts of recombinant exploration versus exploitation on technological value, whereas (4) market turbulence benefits the impacts of both on economic value.Practical implicationsThis research provides the answer to practitioners' question that “How to improve innovation quality?” That is “Think from a recombination logic, clarify your internal value preference and the external turbulence.”Originality/valueFrom an emerging perspective of innovation, this research expands the innovation quality research to a recombination logic. A multi-dimensional research framework is developed to clarify the complex relationships between knowledge recombination and innovation quality. Finally, two moderators, technological versus market turbulence, formulate more targeted implications for firms' innovation management in open innovation.
Impact of lean principles on operational performance in high uncertainty
Authors: Thoumy Mira , Jobin Marie-Helene , Baroud Juliette , El Nakhel Khalil Claude 
Published: June 2022

PurposeThe purpose of this research is to study the impact of perceived adoption of Lean principles on operational performance in Lebanese pharmaceutical industries.Design/methodology/approachA quantitative method was implemented using a questionnaire that targeted 253 respondents working in eight good manufacturing practices (GMP) certified Lebanese pharmaceutical companies. Reliability analysis was performed using SPSS, and the research hypotheses were tested using regression analysis.FindingsThe results demonstrated that Lean principles positively and directly affected operational performance. It also positively affected operational performance factors of quality, cost and time. However, the analysis of each of Lean principles impact on operational performance cost was analyzed perfection, value, and value stream mapping (VSM) significantly increased operational performance. In addition, pull only positively augmented the cost reduction, whereas flow did not show any effects on any of operational performance’s factors.Practical implicationsIn addition to enhancing operational performance, the positive effect of the perceived adoption of Lean principles on performance is also explained by managers’ efforts in studying the flow of actions in their processes to reduce wastes. To face uncertainty, training and building a workforce that is able to implement Lean principles, equipping this workforce with needed artifacts, and promoting a high-performance culture are crucial for the successful implementation of Lean principles.Originality/valueLean approach has become a major pathway of improvement especially in pharmaceutical companies. Few studies analyzed the impact of each of the Lean principles on the operational performance in companies that operate in era of uncertainty. Furthermore, the perceived adoption of Lean principles is under investigated in the Middle East in general and in Lebanon in particular.
Investigating the effect of service feedback and physician popularity on physician demand in the virtual healthcare environment
Authors: Shah Adnan Muhammad , Muhammad Wazir , Lee KangYoon 
Published: June 2022

PurposeThis study examines how service feedback and physician popularity affect physician demand in the context of virtual healthcare environment. Based on the signaling theory, the critical factor of environment uncertainty (i.e. disease risk) and its impact on physician demand is also investigated. Further, the research on the endogeneity of online reviews in healthcare is also examined in the current study.Design/methodology/approachA secondary data econometric analysis using 3-wave data sets of 823 physicians obtained from two PRWs (Healthgrades and Vitals) was conducted. The analysis was run using the difference-in-difference method to consider physician and website-specific effects.FindingsThe study's findings indicate that physician popularity has a stronger positive effect on physician demand compared with service feedback. Improving popularity leads to a relative increase in the number of appointments, which in turn enhance physician demand. Further, the impact of physician popularity on physician demand is positively mitigated by the disease risk.Originality/valueThe authors' research contributes to a better understanding of the signaling transmission mechanism in the online healthcare environment. Further, the findings provide practical implications for key stakeholders into how an efficient feedback and popularity mechanism can be built to enhance physician service outcomes in order to maximize the financial efficiency of physicians.