bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting binding affinity changes from long-distance mutations using MD simulations and Rosetta
Authors: Wells Nicholas G. M. , Smith Colin A. 
Published: May 2022

AbstractComputationally modeling how mutations affect protein-protein binding not only helps uncover the biophysics of protein interfaces, but also enables the redesign and optimization of protein interactions. Traditional high-throughput methods for estimating binding free energy changes are currently limited to mutations directly at the interface due to difficulties in accurately modeling how long-distance mutations propagate their effects through the protein structure. However, the modeling and design of such mutations is of substantial interest as it allows for greater control and flexibility in protein design applications. We have developed a method that combines high-throughput Rosetta-based side-chain optimization with conformational sampling using classical molecular dynamics simulations, finding significant improvements in our ability to accurately predict long-distance mutational perturbations to protein binding. Our approach uses an analytical framework grounded in alchemical free energy calculations while enabling exploration of a vastly larger sequence space. When comparing to experimental data, we find that our method can predict internal long-distance mutational perturbations with a level of accuracy similar to that of traditional methods in predicting the effects of mutations at the protein-protein interface. This work represents a new and generalizable approach to optimize protein free energy landscapes for desired biological functions.Author SummaryProtein-protein interactions are vital to almost all biological processes, and therefore the ability to accurately and efficiently predict how mutations alter protein binding has far-reaching applications in protein analysis and design. Current approaches to predict such mutational free energy changes are limited to mutations directly at the interaction interface. Much research has underlined the prevalence of allosteric protein regulation in biological processes, indicating the importance of understanding and predicting the effects of protein perturbations which act over long distances. In this work we develop a novel method based on molecular dynamics simulations, the Rosetta macromolecular modeling suite, and an analytical framework from alchemical free energy calculations which can predict the effects of long-distance mutations with levels of accuracy rivaling state of the art interface-specific methods. We hope that our method will serve as a novel framework for high throughput mutational analysis and therefore benefit future protein design efforts.
Utilising hippocampal neuronal calcium activity in mouse CA1 for a multimodal optical brain-computer interface
Authors: Sun Dechuan , Saatlou Forough Habibollahi , Yu Yang , Unnithan Ranjith Rajasekharan , French Chris 
Published: May 2022

AbstractThe hippocampus has been proposed to integrate information from multiple sensory modalities, supporting a comprehensive “cognitive map” for both spatial and non-spatial information. Previous studies have demonstrated decoding of hippocampal spatial information in real time by recording neuronal action potentials with electrodes. However, decoding of hippocampal non-spatial information robustly in real-time has not been previously shown. Here, we utilise the advantages of widefield optical calcium imaging to construct an optical brain-computer interface (BCI) driven by calcium activity of large neuronal ensembles (∼600 neurons) to decode spatial, visual and auditory information effectively in real time. We developed a high speed end-to-end analysis workflow with advanced machine learning techniques for decoding. This methodology achieves high decoding accuracy and provides a “cognitive translation” approach that may be applied to both research and clinical applications to allow direct neural communication with animals and patients with impairment of function.
Identification of novel senolytic compounds from natural food sources
Authors: Chaganti Tesko , Pendyala Brahmaiah 
Published: May 2022

AbstractMore than 23% of today’s population suffers from age-associated diseases such as arthritis, cancer, heart disease, and more. The ongoing economic impact of these diseases has been in the billions of dollars worldwide with no clear solution to date. This study addresses the underlying cause of these diseases by identifying the compounds that potentially eliminate senescent cells. Existing senolytic drugs are not abundantly found in nature, reducing accessibility. Hence, over 70,000 natural compounds available in the Canadian Food Database were used to screen penitential senolytic compounds that block PI3Kγ, reactivating apoptotic processes in senescent cells. Molecular docking results revealed 23 natural compounds that blocks the PI3Kγ. Out of 23 compounds, Cianidanol, Ellagic acid, Eriodictyol, Kaempferol and Cyanidin were found abundantly in food sources range from 85 to 735 mg/100 g. These compounds are up to 46 times more abundant in foods than proven senolytic drug Fisetin. Further, molecular dynamics results showed ligand stability for 4 nanoseconds with PI3Kγ. The five compounds are proven to eliminate cancerous cells, have the potential to prevent age-related diseases, and could even slow down natural aging.
An atlas of epithelial cell states and plasticity in lung adenocarcinoma
Authors: Han Guangchun , Sinjab Ansam , Treekitkarnmongkol Warapen , Lu Wei , Serrano Alejandra G. , Hernandez Sharia D. , Rahal Zahraa , Cao Xuanye , Dai Enyu , Gomez-Bolanos Lorena I. , Parra Edwin R. , Negrao Marcelo Vailati , Cascone Tina , Sepesi Boris , Moghaddam Seyed Javad , Chen Jichao , Dubinett Steven M. , Scheet Paul , Fujimoto Junya , Solis Luisa M. , Wistuba Ignacio I. , Stevenson Christopher S. , Spira Avrum E. , Wang Linghua , Kadara Humam 
Published: May 2022

AbstractUnderstanding cellular processes underlying early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here, we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal alveolar and airway lineages as well as cancer cell populations. Diversity among cancer cells was strongly linked to LUAD patient-specific oncogenic drivers. KRAS-mutant cancer cells were unique in their transcriptional features, strikingly reduced differentiation, low levels of DNA copy number changes, and increased variability amongst the cells themselves. The local niche of LUADs, relative to that of normal lungs, was enriched with intermediary cells in lung alveolar differentiation with potential to transition to KRAS-mutant cancer cells. A subset of alveolar intermediate cells with elevated KRT8 expression (KRT8+ alveolar cells; KACs) showed increased plasticity, and their gene expression profiles were enriched in lung precancer and LUAD and signified poor survival. Murine KACs were evident in lungs of tobacco carcinogen-exposed mice that develop KRAS-mutant LUADs but not in the saline-treated control group. While murine KACs emerged prior to tumor onset, they persisted for months after carcinogen cessation, acquired driver Kras mutations and, like their human counterparts, were poorly differentiated and harbored KRAS-specific transcriptional programs. This study provides new insights into early LUAD development and identifies potential targets for treatment.
Detailed investigation on the role of lipid metabolizing enzymes in the pathogenesis of retinopathy of prematurity among preterm infants
Authors: Kumar Saurabh , Patnaik Satish , Joshi Manjunath B , Jalali Subhadra , Agarwal Komal , Kekunnaya Ramesh , Chakrabarti Subhabrata , Kaur Inderjeet 
Published: May 2022

AbstractPurposeExtremely preterm infants are at risk of developing retinopathy of prematurity (ROP), characterized by an initial insufficient vascular network development in the retina (due to hyperoxia) that progress to neovascularization and neuroinflammation (hypoxic phase) ultimately leading to partial or total vision loss. Lipid metabolism has been shown to be a significant pathway that is involved in the regulation of angiogenesis, inflammation, and apoptosis in oxygen induced retinopathy mouse model, however, it is not explored in human ROP patients. The present study aimed to explore the association of lipid metabolizing, angiogenic and apoptotic genes with altered lipid metabolites in the ROP patients with different severity.MethodsThe blood, vitreous humor (VH), and fibrovascular membrane (FVM) samples were collected from premature infants diagnosed with ROP and controls. Gene expression of lipid metabolizing enzymes, angiogenesis, and apoptotic genes were performed using semi-quantitative PCR in blood. Lipid metabolites were identified and quantified by LC-MS in VH and were correlated with gene expression. The expression of key lipid metabolizing enzymes in severe stages of ROP was assessed by measuring their expression in FVM by immunohistochemistry.ResultsGenes coding for the lipid metabolizing enzymes such as CYP1B1, CYP2C8, COX2, and ALOX15 were upregulated while EPHX2 responsible for the conversion of epoxide fatty acids into diol fatty acids was significantly downregulated in ROP cases. The increase in the metabolic intermediates generated from the lipid metabolism pathway further confirmed the role of these enzymes in ROP. except for EPHX2 which did not show any change in its activity. The glial cells in the FVM of ROP infants too showed a lack of EPHX2 expression. A significantly higher expression of genes involved in angiogenesis (VEGF165/189, NOTCH1, and APH1B) and apoptosis (CASP3/8) correlated with altered activity of lipid metabolizing enzymes (based on metabolites levels) among ROP cases.ConclusionsLipid metabolism may play a significant role in ROP development and progression. EPHX2 activity is a key step in the metabolic pathway of arachidonic acid that mediates and regulates inflammation and vascular pathology in preterm infants.
Identification of Fusarium Head Blight resistance in Triticum timopheevii accessions and characterisation of wheat-T. timopheevii introgression lines for enhanced resistance
Authors: Steed Andrew , King Julie , Grewal Surbhi , Yang Cai-yun , Clarke Martha , King Ian , Nicholson Paul 
Published: May 2022

AbstractA diverse panel of wheat wild relative species was screened for resistance to Fusarium head blight (FHB) by spray inoculation. The great majority of species and accessions were susceptible or highly susceptible to FHB. Accessions of Triticum timopheevii (P95-99.1-1), Agropyron desertorum (9439957) and Elymus vaillantianus (531552) were highly resistant to FHB while additional accessions of T. timopheevii were found to be susceptible to FHB. A combination of spray and point inoculation assessments over two consecutive seasons indicated that the resistance in accession P95-99.1-1 was due to enhanced resistance to initial infection of the fungus (type 1 resistance), and not to reduction in spread (type 2 resistance).A panel of wheat-T. timopheevii (accession P95-99.1-1) introgression lines was screened for FHB resistance over two consecutive seasons using spray inoculation. Most introgression lines were similar in susceptibility to FHB as the wheat recipient (Paragon) but substitution of the terminal portion of chromosome 3BS of wheat with a similar-sized portion of 3G of T. timopheevii significantly enhanced FHB resistance in the wheat background.
Flexible perceptual encoding by discrete gamma events
Authors: Perrenoud Quentin , de O. Fonseca Antonio H. , Airhart Austin , Bonanno James , Mao Rong , Cardin Jessica A. 
Published: May 2022

AbstractSpatiotemporal patterns of activity in the neocortex are linked to cognitive processes underlying behavior. However, identifying discrete underlying events within highly dynamic cortical network fluctuations remains a critical challenge. Here, we demonstrate a novel analytical method to track network events underlying state-dependent β- (15-30Hz) and γ- (30-80Hz) range activity in mouse primary visual cortex (V1). We find that γ events are selectively associated with enhanced visual encoding by V1 neurons and γ event rate increases prior to visually-cued behavior, accurately predicting single trial visual detection. This relationship between γ events and behavior is sensory modality-specific and rapidly modulated by changes in task objectives. These findings illuminate a distinct role for transient patterns of cortical activity, indicating that γ supports flexible encoding according to behavioral context.
A toxin-mediated policing system in Bacillus improves population fitness via penalizing non-cooperating phenotypic cheaters
Authors: Huang Rong , Shao Jiahui , Xu Zhihui , Chen Yuqi , Liu Yunpeng , Wang Dandan , Feng Haichao , Xun Weibing , Shen Qirong , Zhang Nan , Zhang Ruifu 
Published: May 2022

AbstractMicrobial cooperation is vulnerable to exploitation by social cheaters. Although the strategies for controlling genotypic cheaters have been well investigated, the mechanism and significance of preventing phenotypic cheating remain largely unknown. Here, we revealed the molecular mechanism and ecological significance of a policing system for punishing phenotypic cheaters in the community of a plant beneficial strain Bacillus velezensis SQR9. Coordinated activation of extracellular matrix (ECM) production and autotoxin bacillunoic acids (BAs) biosynthesis/self-immunity, punished public goods-nonproducing cheaters in strain SQR9’s community. Spo0A was identified to be the co-regulator for triggering both ECM production and BAs synthesis/immunity, which activates acetyl-CoA carboxylase (ACC) to produce malonyl-CoA, an essential precursor for BAs biosynthesis, thereby stimulating BAs production and self-immunity. Elimination of phenotypic cheaters by this policing system, significantly enhanced population fitness under different stress conditions and in plant rhizosphere. This study provides insights into our understanding of maintenance and evolution of microbial cooperation.
Composition can buffer protein dynamics within liquid-like condensates
Authors: Jelenic Stela , Bindics Janos , Czermak Philipp , Pillai Balashankar R , Ruer Martine , Hoege Carsten , Holehouse Alex S , Saha Shambaditya 
Published: May 2022

SummaryMost non-membrane-bound compartments in cells that form via phase separation have complex composition. While phase separation of individual proteins that form these compartments is well-documented, the mechanisms that modulate dynamics of individual proteins in multicomponent systems remain unclear. Here, we used in vitro reconstitution and in vivo experiments to investigate how the dynamics of a scaffold protein PGL-3 is regulated within the liquid-like ‘P granule’ compartment inC. elegans. Using mutational and biophysical perturbations, we generated PGL-3 constructs that form condensates in vitro with widely varying dynamics. Using these PGL-3 constructs, we show that introducing other P granule components buffers against change of dynamics within liquid-like condensates. This dynamics-buffering effect is mediated by weak interactions among two or more components. Such dynamics-buffering may contribute to robust functional output of cellular liquid-like compartments.
The ATLAS™ screening assay reveals distinct CD4+ and CD8+ SARS-CoV-2 antigen response profiles which have implications to Omicron cellular immunity
Authors: Foti James J. , Lema Kevin , Strickland Justin , Tjon Emily , Li Adrienne , Rivera Amalia , Cabral Crystal , Cormier Laura , Dowal Louisa , Rao Sudhir , Vemulapalli Vijetha , Flechtner Jessica B. 
Published: May 2022

AbstractThe emergence of SARS-CoV-2 variants are a persistent threat to the efficacy of currently developed prophylactic vaccines and therapeutic antibodies. These variants accumulate mutations in the spike protein which encodes the epitopes necessary for neutralizing antibody binding. Moreover, emerging evidence suggest that robust antibody responses are insufficient to prevent severe disease and long-lasting viral immunity requires T cells. Thus, understanding how the T cell antigen landscape evolves in the context of these emerging variants remains crucial. T cells responses are durable and recognize a wider breadth of epitopes reducing the possibility of immune escape through mutation. Here, we deploy the ATLAS™ assay which identifies CD4+ and CD8+ T cell antigens by utilizing the endogenous HLA class-I and class-II peptide processing pathways. Profiling of T cells from exposed and unexposed donors revealed rich and complex patterns which highlighted the breadth of antigenic potential encoded in SARS-CoV-2. ATLAS revealed several common or frequent antigenic regions as well as an abundance of responses in the unexposed cohort potentially the result of pre-exposure to related coronaviruses. ORF10 was a common CD4+ response in the unexposed cohort while spike was identified as a common and frequent target in both cohorts. Moreover, the spike response profiles allowed us to accurately predict the impact of Omicron spike mutations. This analysis could thus be applied to study the impact of future emerging VOCs.
Innovation strategies in sports management: COVID-19 and the Latin American tennis federations
Authors: Crespo Celda Miguel , Botella-Carrubi Dolores , Jabaloyes Jose , Simón-Moya Virginia 
Published: May 2022

PurposeThe purpose of this paper is to discuss some of the most relevant innovation strategies used by the Latin American national tennis federations as a response to the COVID-19 pandemic.Design/methodology/approachThe methodology consists of a survey. The survey consisted of three sections apart from the consent one: a general descriptive part, one with 30 questions to assess attitudes and perceptions and a final section which included open questions. After the data were collected, the SPSS software was used to test the distribution of the sample.FindingsResults show that executives' perception toward their need for involvement in the decision-making process varies.Research limitations/implicationsThe first limitation relates to the sample size of executives who completed the questionnaire. The second limitation refers to the details provided in the open section of the questionnaire. Specifically, the space allocated for the answers and the degree of detail required could have been optimized by providing further instructions on the importance of facilitating information related to the implementation of the programs.Practical implicationsThe results demonstrate that, although traditional management, organizational and administrative behaviors are still present in the tennis ecosystem, a more innovative mentality should embed these organizations. It is then relevant that sport and tennis organizations commit to the implementation of innovative strategies for the optimization of the administration of their ecosystems.Originality/valueThe paper adds more understanding to the brand of sports management. Furthermore, the fact of developing the study in a COVID-19 context sheds light on the issues faced by sports in a pandemic like this one.
The interplay between employee development factors and succession planning in predicting employee performance: evidence from retail banks
Authors: Mehreen Aqsa , Ali Zulqurnain 
Published: May 2022

Purpose
The purpose of this study is to examine how employee development factors directly influence succession planning and indirectly improve employee performance using the tenets of human capital theory. Moreover, whether succession planning enhances employee performance or not?

Design/methodology/approach
Using the time-lag method, this study collected data from bank employees and tested the proposed model and hypotheses in Mplus.

Findings
The results from 239 participants highlight that succession planning improves bank employee performance. Employee orientation and training and development are positively linked to succession planning and employee performance. Succession planning mediates the association between employee development factors and employee performance.

Practical implications
The research assists bank management to promote a learning culture for developing their human resources to realize their organizational goals. The findings exhibit that succession planning generates a pool of skilled and talented employees, which creates a competitive edge for banks having skilled employees and reduces recruitment costs. Banks to save human recruitment costs. Moreover, bank managers can solve the issue of sudden vacant positions and provide excellent customer service.

Originality/value
Retaining talented individuals has remained a challenging task for organizations in the current business environment. The research contributes to theoretically and empirically exploring the association between employee development factors (training and development and employee orientation) and employee performance via succession planning to retain talented employees in the organization.
Natural climate reconstruction in the Norwegian stave churches through time series processing with variational autoencoders
Authors: Manara Noemi , Rosset Lorenzo , Zambelli Francesco , Zanola Andrea , Califano America 
Published: May 2022

PurposeIn the field of heritage science, especially applied to buildings and artefacts made by organic hygroscopic materials, analyzing the microclimate has always been of extreme importance. In particular, in many cases, the knowledge of the outdoor/indoor microclimate may support the decision process in conservation and preservation matters of historic buildings. This knowledge is often gained by implementing long and time-consuming monitoring campaigns that allow collecting atmospheric and climatic data.Design/methodology/approachSometimes the collected time series may be corrupted, incomplete and/or subjected to the sensors' errors because of the remoteness of the historic building location, the natural aging of the sensor or the lack of a continuous check of the data downloading process. For this reason, in this work, an innovative approach about reconstructing the indoor microclimate into heritage buildings, just knowing the outdoor one, is proposed. This methodology is based on using machine learning tools known as variational auto encoders (VAEs), that are able to reconstruct time series and/or to fill data gaps.FindingsThe proposed approach is implemented using data collected in Ringebu Stave Church, a Norwegian medieval wooden heritage building. Reconstructing a realistic time series, for the vast majority of the year period, of the natural internal climate of the Church has been successfully implemented.Originality/valueThe novelty of this work is discussed in the framework of the existing literature. The work explores the potentials of machine learning tools compared to traditional ones, providing a method that is able to reliably fill missing data in time series.