bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards Convergence in Folding Simulations of RNA Tetraloops: Comparison of Enhanced Sampling Techniques and Effects of Force Field Corrections
Authors: Mlýnský Vojtěch , Janeček Michal , Kührová Petra , Fröhlking Thorben , Otyepka Michal , Bussi Giovanni , Banáš Pavel , Šponer Jiří 
Published: December 2021

ABSTRACTAtomistic molecular dynamics (MD) simulations represent established technique for investigation of RNA structural dynamics. Despite continuous development, contemporary RNA simulations still suffer from suboptimal accuracy of empirical potentials (force fields,ffs) and sampling limitations. Development of efficient enhanced sampling techniques is important for two reasons. First, they allow to overcome the sampling limitations and, second, they can be used to quantifyffimbalances provided they reach a sufficient convergence. Here, we study two RNA tetraloops (TLs), namely the GAGA and UUCG motifs. We perform extensive folding simulations and calculate folding free energies (ΔGfold) with the aim to compare different enhanced sampling techniques and to test several modifications of the nonbonded terms extending the AMBER OL3 RNAff. We demonstrate that replica exchange solute tempering (REST2) simulations with 12-16 replicas do not show any sign of convergence even when extended to time scale of 120 μs per replica. However, combination of REST2 with well-tempered metadynamics (ST-MetaD) achieves good convergence on a time-scale of 5-10 μs per replica, improving the sampling efficiency by at least two orders of magnitude. Effects offfmodifications on ΔGfoldenergies were initially explored by the reweighting approach and then validated by new simulations. We tested several manually-prepared variants of gHBfix potential which improve stability of the native state of both TLs by up to ~2 kcal/mol. This is sufficient to conveniently stabilize the folded GAGA TL while the UUCG TL still remains under-stabilized. Appropriate adjustment of van der Waals parameters for C-H…O5’ base-phosphate interaction are also shown to be capable of further stabilizing the native states of both TLs by ~0.6 kcal/mol.
Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance
Authors: Zephyr Jacqueto , Rao Desaboini Nageswara , Vo Sang V. , Henes Mina , Kosovrasti Klajdi , Matthew Ashley N. , Hedger Adam K. , Timm Jennifer , Chan Elise T. , Ali Akbar , Yilmaz Nese Kurt , Schiffer Celia A. 
Published: December 2021

ABSTRACTThird generation Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs), glecaprevir and voxilaprevir, are highly effective across genotypes and against many resistant variants. Unlike earlier PIs, these compounds have fluorine substitutions on the P2-P4 macrocycle and P1 moieties. Fluorination has long been used in medicinal chemistry as a strategy to improve physicochemical properties and potency. However, the molecular basis by which fluorination improves potency and resistance profile of HCV NS3/4A PIs is not well understood. To systematically analyze the contribution of fluorine substitutions to inhibitor potency and resistance profile, we used a multi-disciplinary approach involving inhibitor design and synthesis, enzyme inhibition assays, co-crystallography, and structural analysis. A panel of inhibitors in matched pairs were designed with and without P4 cap fluorination, tested against WT protease and the D168A resistant variant, and a total of 22 high-resolution co-crystal structures were determined. While fluorination did not significantly improve potency against the WT protease, PIs with fluorinated P4 caps retained much better potency against the D168A protease variant. Detailed analysis of the co-crystal structures revealed that PIs with fluorinated P4 caps can sample alternate binding conformations that enable adapting to structural changes induced by the D168A substitution. Our results elucidate molecular mechanisms of fluorine-specific inhibitor interactions that can be leveraged in avoiding drug resistance.
Topoisomerases I and II facilitate condensin DC translocation to organize and repress X chromosomes in C. elegans
Authors: Morao Ana Karina , Kim Jun , Obaji Daniel , Sun Siyu , Ercan Sevinc 
Published: December 2021

SummaryCondensin complexes are evolutionarily conserved molecular motors that translocate along DNA and form loops. While condensin-mediated DNA looping is thought to direct the chain-passing activity of topoisomerase II to separate sister chromatids, it is not known if topological constraints in turn regulate loop formation in vivo. Here we applied auxin inducible degradation of topoisomerases I and II to determine how DNA topology affects the translocation of an X chromosome specific condensin that represses transcription for dosage compensation in C. elegans (condensin DC). We found that both topoisomerases colocalize with condensin DC and control its movement at different genomic scales. TOP-2 depletion hindered condensin DC translocation over long distances, resulting in accumulation around its X-specific recruitment sites and shorter Hi-C interactions. In contrast, TOP-1 depletion did not affect long-range spreading but resulted in accumulation of condensin DC within expressed gene bodies. Both TOP-1 and TOP-2 depletions resulted in X chromosome transcriptional upregulation indicating that condensin DC translocation at both scales is required for its function in gene repression. Together the distinct effects of TOP-1 and TOP-2 on condensin DC distribution revealed two distinct modes of condensin DC association with chromatin: long-range translocation that requires decatenation/unknotting of DNA and short-range translocation across genes that requires resolution of transcription-induced supercoiling.
The evolution of ovary-biased gene expression in Hawaiian Drosophila
Authors: Church Samuel H. , Munro Catriona , Dunn Casey W. , Extavour Cassandra G. 
Published: December 2021

1AbstractWith detailed data on gene expression accessible from an increasingly broad array of species, we can test the extent to which our developmental genetic knowledge from model organisms predicts expression patterns and variation across species. But to know when differences in gene expression across species are significant, we first need to know how much evolutionary variation in gene expression we expect to observe. Here we provide an answer by analyzing RNAseq data across twelve species of Hawaiian Drosophilidae flies, focusing on gene expression differences between the ovary and other tissues. We show that over evolutionary time, there exists a cohort of ovary specific genes that is stable and that largely corresponds to described expression patterns from laboratory model Drosophila species. Our results also provide a demonstration of the prediction that, as phylogenetic distance increases, variation between species overwhelms variation between tissue types. Using ancestral state reconstruction of expression, we describe the distribution of evolutionary changes in tissue-biased expression, and use this to identify gains and losses of ovary-biased expression across these twelve species. We then use this distribution to calculate the evolutionary correlation in expression changes between genes, and demonstrate that genes with known interactions in D. melanogaster are significantly more correlated in their evolution than genes with no or unknown interactions. Finally, we use this correlation matrix to infer new networks of genes that share evolutionary trajectories, and we present these results as a dataset of new testable hypotheses about genetic roles and interactions in the function and evolution of the Drosophila ovary.
MK2 Expression Promotes Non-Small Cell Lung Cancer Cell Death and Predicts Survival
Authors: Del Rosario Othello , Suresh Karthik , Kallem Medha , Singh Gayatri , Shah Anika , Xin Yun , Philip Nicolas M. , Jiang Haiyang , D’Alessio Franco , Srivastava Meera , Bera Alakesh , Shimoda Larissa A. , Merchant Michael , Rane Madhavi J. , Machamer Carolyn E. , Mock Jason , Hagan Robert , Kolb Todd M. , Damarla Mahendra 
Published: December 2021

ABSTRACTNon-small cell lung cancers demonstrate intrinsic resistance to cell death even in response to chemotherapy. Previous work suggested that defective nuclear translocation of active caspase 3 may play a role in resistance to cell death. Separately, our group has identified that mitogen activated protein kinase activated protein kinase 2 (MK2) is required for nuclear translocation of active caspase 3 in the execution of apoptosis. This study demonstrates a relatively low expression of MK2 in non-small cell lung carcinoma cell lines compared to small cell carcinoma cell lines. Further, overexpression of MK2 in non-small cell lung carcinoma cell lines results in increased caspase 3 activity and caspase 3 mediated cell death. Higher MK2 transcript levels were observed in patients with earlier-stage non-small cell lung cancer. Higher expression of MK2 is associated with better survival in patients with early stage non-small cell lung cancer across two independent clinical datasets. Using data sets spanning multiple cancer types, we observed improved survival with higher MK2 expression was unique to lung adenocarcinoma. Mechanistically, MK2 promotes nuclear translocation of caspase 3 leading to PARP1 cleavage and execution of cell death. While MK2 can directly phosphorylate caspase 3, neither phosphorylation status of caspase 3 nor the kinase activity of MK2 impacts caspase 3 activation, nuclear translocation and execution of cell death. Rather, a non-kinase function of MK2, specifically trafficking via its nuclear localization sequence, is required for caspase 3 mediated cell death. In summary this study highlights the importance of a non-enzymatic function of MK2 in the execution of apoptosis, which may be leveraged in the adjunctive treatment of NSCLC or other conditions where regulation of apoptosis is crucial.
Oligodendrocytes are a lifelong source of nuclear and ribosomal material for neurons in the mouse brain
Authors: Mayrhofer Florian , Hanson Angela M. , Falcone Carmen , Xiang Yang K. , Navedo Manuel F. , Deng Wenbin , Chechneva Olga 
Published: December 2021

AbstractNuclear and ribosomal components define cell identity and function by regulating chromatin dynamics, gene expression, and protein turnover. Here we report that in the mouse central nervous system (CNS) under normal conditions, neurons accumulate nuclear and ribosomal material of oligodendrocyte (OL) origin. We show that neuronal accumulation of OL-derived nuclear and ribosomal material is brain area-specific, and in the cortex and hippocampal dentate gyrus gradually propagates during postnatal brain maturation. We further demonstrate that OL-to-neuron material transfer persists throughout adulthood and responds to neuroinflammation. We found that satellite OL of the gray matter form internuclear contacts with receiving neurons in the mouse brain. Similar close internuclear associations between satellite OL and neurons are present in the adult human cortex. Our findings provide the first evidence of wide-spread dynamic and selective OL-to-neuron nuclear and ribosomal material transfer in the mouse CNS and indicate that satellite OL serve as powerful mediators of neuronal function. Equivalent processes may occur in the human CNS and cause neurological disorders when dysregulated.One Sentence SummaryNeurons receive OL-derived nuclear and ribosomal material
A Resident State Allows Influenza Polymerase to Smoothly Switch between Transcription and Replication Cycles
Authors: Li Huanhuan , Wu Yixi , Li Minke , Guo Lu , Wang Quan , Lai Zhaohua , Zhang Jihua , Zhang Xing , Zhu Lixin , Lan Ping , Rao Zihe , Liu Yingfang , Liang Huanhuan 
Published: December 2021

SUMMARYInfluenza polymerase (FluPol) transcripts viral mRNA and switches to replicate viral genome after transcription. However, it remains unknown how FluPol switches between transcription and replication cycles, especially when considering that the structural basis of these two functions is fundamentally different. Here, we proposed a mechanism that FluPol achieves the functional switching between these two cycles through an unreported intermediate conformation, termed as resident state. We obtained a resident state structure of H5N1 FluPol at 3.7 Å using cryo-EM, which is characterized by a blocked Cap-binding domain and a contracted core region, distinct from the structures of either transcription or replication states. Structural analysis results suggest that the resident state structure is feasible to smoothly transit into structures of both transcription and replication states. Furthermore, we show that formation of the resident state is required for both transcription and replication activities of FluPol. Together, the transcription and replication cycles of FluPol are connected via a resident state.
Prediction of drug targets for specific diseases leveraging gene perturbation data: A machine learning approach
Authors: Zhao Kai , Shi Yujia , So Hon-Cheong 
Published: December 2021

AbstractIdentification of the correct targets is a key element for successful drug development. However, there are limited approaches for predicting drug targets for specific diseases using omics data, and few have leveraged expression profiles from gene perturbations.We present a novel computational target discovery approach based on machine learning(ML) models. ML models are first trained on drug-induced expression profiles, with outcomes defined as whether the drug treats the studied disease. The goal is to “learn” expression patterns associated with treatment. The fitted ML models were then applied to expression profiles from gene perturbations(over-expression[OE]/knockdown[KD]). We prioritized targets based on predicted probabilities from the ML model, which reflects treatment potential.The methodology was applied to predict targets for hypertension, diabetes mellitus(DM), rheumatoid arthritis(RA) and schizophrenia(SCZ). We validated our approach by evaluating whether the identified targets may ‘re-discover’ known drug targets from an external database(OpenTargets). We indeed found evidence of significant enrichment across all diseases under study. Further literature search revealed that many candidates were supported by previous studies. For example, we predicted PSMB8 inhibition to be associated with treatment of RA, which was supported by a study showing PSMB8 inhibitors(PR-957) ameliorated experimental RA in mice.In conclusion, we propose a new ML approach to integrate expression profiles from drugs and gene perturbations and validated the framework. Our approach is flexible and may provide an independent source of information when prioritizing targets.
A key design parameter proposal for aerodynamically efficient subsonic blended wing body
Authors: Durmus Seyhun 
Published: December 2021

Purpose
Blended wing body (BWB) is a very advantageous design in terms of low fuel consumption, low emission and low noise levels. Because of these advantages, the BWB is a candidate to become the commercial passenger aircraft of the future by providing a paradigm shift in conventional designs. This paper aims to propose a key design parameter for wing sizing of subsonic BWB and a performance parameter for calculating the lift/drag ratio values of BWBs.

Design/methodology/approach
The parameter proposed in the study is based on the square/cube law, that is, the idea that the wetted area is proportional to the power of 2/3 of the weight. Data on the weight, wing area, wingspan, lift-to-drag (L/D) ratio for 19 BWB used in the analyzes were compiled from the published literature and a theoretical methodology was developed to estimate the maximum lift to drag ratio of BWBs. The accuracy of the proposed key design parameter was questioned by comparing the estimated L/Dmax values with the actual values.

Findings
In the current study, it is claimed that the wingspan/(take-off gross weight)(1/3) parameter provides an L/D efficiency coefficient regardless of aircraft size. The proposed key design parameter is useful both for small-scale BWB, that is unmanned aerial vehicles BWB and for large-scale BWB designs. Therefore, the b/Wg(1/3) parameter offers a dimensionless L/D efficiency coefficient for BWB designs of different scales. The wetted aspect ratio explains how low aspect ratio (AR)-BWB designs can compete with high AR-tube-and-wing designs. The key parameter is also useful for getting an idea of good or bad BWB with design and performance data published in the literature. As a result, reducing the blending area and designing a smaller central body are typical features of aerodynamically efficient BWB.

Originality/value
As the role of the square/cube law in the conceptual aircraft design stage has not been sufficiently studied in the literature, the application of this law to BWBs, a new generation of designs, makes the study original. Estimation of the wetted area ratio using only wingspan and gross weight data is an alternative and practical method for assessing the aerodynamic performance of the BWB. According to the model proposed in the current study, reducing the take-off gross weight of the BWBs using lighter building materials and designing with a larger wingspan (b) are the main recommendations for an aerodynamically efficient BWB.
Motivation for users' knowledge-sharing behavior in virtual brand communities: a psychological ownership perspective
Authors: Jiang Ying , Liao Junyun , Chen Jiawen , Hu Yanghong , Du Peng 
Published: December 2021

PurposeUsers' knowledge sharing provides valuable resources for brand community participants and is, therefore, critical for the viability of virtual brand communities. Drawing from both self-determination theory (SDT) and psychological ownership theory, the paper aims to investigate the impact of fulfillment of three basic psychological needs on brand users' knowledge-sharing behavior and examines psychological ownership as a mediator.Design/methodology/approachSurvey data consisting of 316 valid responses were collected from users of Huawei Pollen Club Community. Confirmatory factor analysis (CFA) confirmed the reliability and validity of measures, and hierarchical linear regression and bootstrapping were used to test all hypotheses.FindingsFulfillment of the need for autonomy, relatedness and competence in a virtual brand community boosts users' psychological ownership and has a positive influence on their knowledge-sharing behavior. Furthermore, psychological ownership partially mediates the relationships between the fulfillment of psychological needs and knowledge-sharing behavior. In addition, the authors found that when users participate in more offline brand activities, the positive impact of the fulfillment of the need for relatedness on psychological ownership is strengthened, while the positive impact of the fulfillment of the need for autonomy on psychological ownership is weakened.Originality/valueThe paper contributes to the existing literature by exploring the relationships between fulfilling users' three basic psychological needs and their knowledge-sharing behavior through the mediating role of psychological ownership. The authors also provide insight into how offline brand activities interact with the fulfillment of psychological needs in virtual brand communities.
Understanding regional variation in the use of local food in public catering
Authors: Kujala Susanna , Hakala Outi , Viitaharju Leena 
Published: December 2021

PurposeThe main aim of this study is to identify the factors that can affect regional differences in the procurement of local food in public catering. Understanding how some regions procure more local food products than others could help promote the use of local food in public catering. Regions with a lower share of local food can learn from regions that have a higher local food share.Design/methodology/approachThe studied phenomenon is complex; therefore, we used several approaches to identify the share of local food procurement and the reasons behind the regional differences. The study gathered survey data and used fuzzy-set qualitative comparative analysis (fsQCA), a computable general equilibrium model and several data sources.FindingsThe share of local food within the total food procurement varies markedly between regions. The highest local food shares can be linked to a combination of three factors: sufficient and suitable supply, adequate organisational conditions and a political atmosphere that encourages the use of local food. In addition to limited political incentives, poor supply or inadequate organisational conditions effectively characterise why some regions use very few local food products. Hence, a move towards using more local food in public catering requires political decision makers, food producers and procurement personnel to demonstrate a common will and take cohesive action.Originality/valueBy examining regional variation, the results of this study offer a new perspective on the use of local food in public catering.
Food safety knowledge and behaviour among food handlers in catering establishments: a case study
Authors: Jevšnik Mojca , Raspor Peter 
Published: December 2021

PurposeThe main objective of this study is to find out how food handlers in catering establishments perceive ensuring food safety and which problems they meet along the way.Design/methodology/approachUsing a qualitative approach, ten food handlers in Slovenian catering facilities were included in the case study. A semi-structured approach was applied to provide a deeper insight into food safety barriers perceived by respondents. Participants first read short fictitious newspaper news about a foodborne disease at a tourist farm, which served as a starting point.FindingsThe results demonstrate barriers which most often originate in a lack of knowledge (e.g. improper food safety training, incorrect food safety knowledge testing, knowledge and maintaining of CCPs), shortage of food hygiene skills (e.g. handwashing, food defrosting) and weak work satisfaction (e.g. insufficient payment, poor interpersonal relationships and weak motivation). Food safety knowledge and consequently training methods were found to be the biggest barrier for the efficiency of the HACCP system in practice.Research limitations/implicationsDue to the small sample, the results cannot be generalised to the entire population of food handlers in Slovenia.Practical implicationsThe results indicate weaknesses in food safety knowledge among professional food handlers.Originality/valueThe study provides a deeper insight into implicit opinions of ten food handlers in catering facilities regarding barriers in providing food safety, their knowledge and behaviour in their work with food.
Comparative analysis of two-level and three-level multilevel inverter for electric vehicle application using BLDC motor drive
Authors: Ammaiyappan Bharathi Sankar , Ramalingam Seyezhai 
Published: December 2021

Purpose
The conventional two-level inverter suffers from harmonics, higher direct current (DC) link voltage requirement, higher dv/dt and heating of the rotor. This study aims to overcome by using a multilevel inverter for brushless DC (BLDC) drive.

Design/methodology/approach
This paper presents a comparative analysis of the conventional two-level and three-level multilevel inverter for electric vehicle (EV) application using BLDC drive.

Findings
A three-level Active Neutral Point Clamped Multilevel inverter (ANPCMLI) is proposed in this paper which provides DC link voltage control. Simulation studies of the multilevel inverter and BLDC motor is carried out in MATLAB.

Originality/value
The ANPCMLI fed BLDC simulation results shows that there is the significant reduction in the BLDC motor torque ripple, switching stress and harmonic distortion in the BLDC motor fed ANPCMLI compared to the conventional two-level inverter. A prototype of ANPCMLI fed BLDC drive along with field programmable gate array (FPGA) control is built and MATLAB simulation results are verified experimentally.