bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multisensory integration of social signals by a pathway from the basal amygdala to the auditory cortex in maternal mice
Authors: Nowlan Alexandra C. , Choe Jane , Ansari Hoda J. , Kelahan Clancy , Shea Stephen D. 
Published: February 2022

SUMMARYSocial encounters are inherently multimodal events, yet how and where social cues of distinct sensory modalities merge and interact in the brain is poorly understood. When their pups wander away from the nest, mother mice use a combination of vocal and olfactory signals emitted by the pups to locate and retrieve them. Previous work revealed the emergence of multisensory interactions in the auditory cortex (AC) of both dams and virgins who co-habitate with pups (‘surrogates’). Here we identify a neural pathway that integrates information about odors with responses to sound. We found that a scattered population of glutamatergic neurons in the basal amygdala (BA) projects to the AC and responds to odors, including the smell of pups. These neurons exhibit increased activity when the female is searching for pups that terminates upon contact. Finally, we show that selective optogenetic activation of BA-AC neurons modulates responses to pup calls, and that this modulation switches from predominantly suppressive to predominantly excitatory after maternal experience. This supports an underappreciated role for the amygdala in directly shaping sensory representations in an experience-dependent manner. We propose that the BA-AC pathway integrates olfaction and audition to facilitate maternal care, and speculate that it may carry valence information to the AC.
The giant Mimivirus 1.2 Mb genome is elegantly organized into a 30 nm helical protein shield
Authors: Villalta Alejandro , Schmitt Alain , Estrozi Leandro F. , Quemin Emmanuelle R. J. , Alempic Jean-Marie , Lartigue Audrey , Pražák Vojtěch , Belmudes Lucid , Vasishtan Daven , Colmant Agathe M. G. , Honoré Flora A. , Couté Yohann , Grünewald Kay , Abergel Chantal 
Published: February 2022

AbstractMimivirus is the prototype of the Mimiviridae family of giant dsDNA viruses. Little is known about the organization of the 1.2 Mb genome inside the membrane-limited nucleoid filling the ∼0.5 µm icosahedral capsids. Cryo-electron microscopy, cryo-electron tomography and proteomics revealed that it is encased into a ∼30 nm diameter helical protein shell surprisingly composed of two GMC-type oxidoreductases, which also form the glycosylated fibrils decorating the capsid. The genome is arranged in 5- or 6-start left-handed super-helices, with each DNA-strand lining the central channel. This luminal channel of the nucleoprotein fiber is wide enough to accommodate oxidative stress proteins and RNA polymerase subunits identified by proteomics. Such elegant supramolecular organization would represent a remarkable evolutionary strategy for packaging and protecting the genome, in a state ready for immediate transcription upon unwinding in the host cytoplasm. The parsimonious use of the same protein in two unrelated substructures of the virion is unexpected for a giant virus with thousand genes at its disposal.One-Sentence SummaryMimivirus genome organization in the icosahedral virion.
Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance
Authors: Fröhlich Fabian , Gerosa Luca , Muhlich Jeremy , Sorger Peter K. 
Published: February 2022

ABSTRACTBRAFV600E is prototypical of oncogenic mutations that can be targeted therapeutically and treatment of BRAF-mutant melanomas with RAF and MEK inhibitors results in rapid tumor regression. However, drug-induced rewiring causes BRAFV600E melanoma cells to rapidly acquire a drug-adapted state. In patients this is thought to promote acquisition or selection for resistance mutations and disease recurrence. In this paper we use an energy-based implementation of ordinary differential equations in combination with proteomic, transcriptomic and imaging data from melanoma cells, to model the precise mechanisms responsible for adaptive rewiring. We demonstrate the presence of two parallel MAPK (RAF-MEK-ERK kinase) reaction channels in BRAFV600E melanoma cells that are differentially sensitive to RAF and MEK inhibitors. This arises from differences in protein oligomerization and allosteric regulation induced by oncogenic mutations and drug binding. As a result, the RAS-regulated MAPK channel can be active under conditions in which the BRAFV600E-driven channel is fully inhibited. Causal tracing demonstrates that this provides a sufficient quantitative explanation for initial and acquired responses to multiple different RAF and MEK inhibitors individually and in combination.HighlightsA thermodynamic framework enables structure-based description of allosteric interactions in the EGFR and MAPK pathwaysCausal decomposition of efficacy of targeted drugs elucidates rewiring of MAPK channelsModel-based extrapolation from type I½ RAF inhibitors to type II RAF inhibitorsA unified mechanistic explanation for adaptive and genetic resistance across BRAF-cancers
LabGym: quantification of user-defined animal behaviors using learning-based holistic assessment
Authors: Hu Yujia , Ferrario Carrie R. , Maitland Alexander D. , Ionides Rita B. , Ghimire Anjesh , Watson Brendon , Iwasaki Kenichi , White Hope , Xi Yitao , Zhou Jie , Ye Bing 
Published: February 2022

ABSTRACTQuantifying animal behavior is important for many branches of biological research. Current computational tools for behavioral quantification typically rely on a few pre-defined, simplified features to identify a behavior. However, such an approach restricts the information used and the tool’s applicability to a limited range of behavior types or species. Here we report a new tool, LabGym, for quantifying animal behaviors without such limitations. Combining a novel approach for effective evaluation of animal motion with customizable convolutional recurrent networks for capturing spatiotemporal details, LabGym provides holistic behavioral assessment and accurately identify user-defined animal behaviors without restrictions on behavior types or animal species. It then provides quantitative measurements of each behavior, which quantify the behavior intensity and the body kinematics during the behavior. LabGym requires neither any intermediate step for processing features that causes information loss nor programming knowledge from users for post-hoc analysis. It tracks multiple animals simultaneously in various experimental settings for high-throughput and versatile analysis. It also provides users a way to generate visualizable behavioral datasets that are valuable resources for the research community. We demonstrate its efficacy in capturing subtle behavioral changes in animals ranging from soft-bodied invertebrates to mammals.
The probability of chromatin to be at the nuclear lamina has no systematic effect on its transcription level in fruit fly
Authors: Afanasyev Alexander Y. , Kim Yoonjin , Tolokh Igor S. , Sharakhov Igor V. , Onufriev Alexey V. 
Published: February 2022

AbstractMultiple studies have demonstrated a negative correlation between gene expression and the positioning of genes at the nuclear envelope (NE) lined by nuclear lamina. In this paper, we ask whether there is a causal, systematic relationship between the expression level of the groups of genes in topologically associating domains (TADs) of Drosophila nuclei and the probabilities of TADs to be found at the NE. To investigate the nature of this possible relationship, we combine a coarse-grained dynamic model of the entire Drosophila nucleus with genome-wide gene expression data; we analyze the TAD averaged transcription levels of genes against the probabilities of individual TADs to be near the NE in the control and lamins-depleted nuclei. Our findings demonstrate that, within the statistical error margin, the stochastic positioning ofDrosophila melanogasterTADs at the NE does not, by itself, systematically affects the mean level of gene expression in these TADs, while the expected negative correlation is confirmed. The correlation is weak and disappears completely for TADs not containing lamina-associated domains (LADs) or TADs containing LADs, considered separately. Verifiable hypotheses of the underlying mechanism for the presence of correlation without causality are discussed.
Single-Cell Multi-Omic Roadmap of Human Fetal Pancreatic Development
Authors: Sean de la O , Liu Zhe , Sun Han , Yu Shengyang K. , Wong Daniel M. , Chu Emily , Rao Sneha A. , Eng Nicolas , Peixoto Gabriel , Bouza Jacquelyn , Shen Yin , Knox Sarah M. , Tward Aaron D. , Gloyn Anna L. , Sneddon Julie B. 
Published: February 2022

ABSTRACTThe critical cellular transitions that govern human pancreas development are largely unknown. We performed large-scale single-cell RNA-sequencing (scRNA-Seq) to interrogate human fetal pancreas development from 8-20 weeks post conception. We identified 103 distinct cell types, including four novel endocrine progenitor subtypes displaying unique transcriptional features and differentiation potency. Integration with single-nucleus Assay for Transposase Accessible Chromatin Sequencing (snATAC-Seq) identified candidate regulators of human endocrine cell fate and revealed development-specific regulatory annotation at diabetes risk loci. Comparison of in vitro stem cell-derived and endogenous endocrine cells predicted aberrant genetic programs leading to the generation of off-target cells. Finally, knock-out studies revealed that the gene FEV regulates human endocrine differentiation. This work establishes a roadmap of human pancreatic development, highlights previously unappreciated cellular diversity and lineage dynamics, and provides a blueprint for understanding pancreatic disease and physiology, as well as generating human stem cell-derived islet cells in vitro for regenerative medicine purposes.
Atypical MAPK regulates translocation of GATA transcription factor in response to chemoattractant stimulation
Authors: Hadwiger Jeffrey A. , Cai Huaqing , Aranda Ramee G. , Fatima Saher 
Published: February 2022

SummaryThe Dictyostelium atypical MAPK Erk2 (a.k.a. ErkB) is required for chemotactic responses to external cAMP as individual amoeba aggregate and undergo a multicellular developmental program. External cAMP also stimulates the translocation of the GATA transcription factor, GtaC, a key regulator of developmental gene expression and a developmental timer of repeated cAMP stimulation of developing cells. In this study, atypical MAPK Erk2 was found to be essential for the translocation of GtaC in response to external cAMP as indicated by the cellular distribution of GFP-GtaC reporters. Erk2 was also demonstrated to mediate the translocation of GtaC in response to external folate, a signal that directs the foraging of amoeba for bacterial food sources. Erk1, the only other Dictyostelium MAPK, was not required for the GtaC translocation to either chemoattractant, indicating that GFP-GtaC is a kinase translocation reporter specific for atypical MAPKs. The translocation of GFP-GtaC in response to folate was absent in mutants lacking the folate receptor, Far1 (a.k.a. GrlL) or the coupled G protein, Gα4 subunit. Loss of GtaC function resulted in enhanced chemotactic movement to folate. Inspection of the GtaC primary sequence revealed four sites recognized as Erk2 preferred phosphorylation sites. The creation and analysis of GFP-GtaC mutants with alterations at these sites determined that these sites are required for translocation in response to folate. Consistent with the role of translocation for GtaC function certain combinations of these phosphorylation site alterations interfered with the ability of GFP-GtaC reporter to rescue aggregation of gtaC- cells. These findings provide the first evidence that atypical MAPKs can regulate transcription factors through specific phosphorylation sites in response to chemoattractants. The ability of different stimuli to regulate GtaC translocation through Erk2 indicates atypical MAPKs can regulate different cell fates in part through the translocation of transcription factors.
MafB, WDR77, and ß-catenin interact with each other and have similar genome association profiles
Authors: He Lizhi , Gao Mingshi , Pratt Henry , Weng Zhiping , Struhl Kevin 
Published: February 2022

ABSTRACTMafB (a bZIP transcription factor), ß-catenin (the ultimate target of the Wnt signal transduction pathway that acts as a transcriptional co-activator of LEF/TCF proteins), and WDR77 (a transcriptional co-activator of multiple hormone receptors) are important for breast cellular transformation. Unexpectedly, these proteins interact directly with each other, and they have similar genomic binding profiles. Furthermore, while some of these common target sites coincide with those bound by LEF/TCF, the majority are located just downstream of transcription initiation sites at a position near paused RNA polymerase (Pol II) and the +1 nucleosome. Occupancy levels of these factors at these promoter-proximal sites are strongly correlated with the level of paused Pol II and transcriptional activity.
Mechanism of Voltage Gating in the Voltage-Sensing Phosphatase Ci-VSP
Authors: Shen Rong , Meng Yilin , Roux Benoît , Perozo Eduardo 
Published: February 2022

AbstractThe conformational changes in voltage-sensing domain (VSD) are driven by the transmembrane electric field acting on charges and countercharges. Yet, the overall energetics and detailed mechanism of this process are not fully understood. Here, we determined free energy and displacement charge landscapes, as well as major conformations corresponding to a complete functional gating cycle in the isolated voltage-sensing domain of the phosphatase Ci-VSP (Ci-VSD) comprising four transmembrane helices (segments S1-S4). Molecular dynamics simulations highlight the extent of S4 movements. In addition to the crystallographically determined activated ‘Up’ and resting ‘Down’ states, the simulations predict two novel Ci-VSD conformations: a deeper resting state (‘Down-minus’) and an extended activated (‘Up-plus’) state. These additional conformations were experimentally probed via systematic cysteine mutagenesis with metal-ion bridges and the engineering of proton conducting mutants at hyperpolarizing voltages. These results show that voltage activation involves sequentially populating these four states in a stepwise way, translating one arginine across the membrane electric field per step, transferring ~3 e0 charges.
Highlighting the factors governing transglycosylation in the GH5_5 endo-1,4-β-glucanase RBcel1
Authors: Collet Laetitia , Vander Wauven Corinne , Oudjama Yamina , Galleni Moreno , Dutoit Raphaël 
Published: February 2022

Transglycosylating glycoside hydrolases (GHs) offer great potential for the enzymatic synthesis of oligosaccharides. Although knowledge is progressing, there is no unique strategy to improve the transglycosylation yield. Obtaining efficient enzymatic tools for glycan synthesis with GHs remains dependent on an improved understanding of the molecular factors governing the balance between hydrolysis and transglycosylation. This enzymatic and structural study of RBcel1, a transglycosylase from the GH5_5 subfamily isolated from an uncultured bacterium, aims to unravel such factors. The size of the acceptor and donor sugars was found to be critical since transglycosylation is efficient with oligosaccharides at least the size of cellotetraose as the donor and cellotriose as the acceptor. The reaction pH is important in driving the balance between hydrolysis and transglycosylation: hydrolysis is favored at pH values below 8, while transglycosylation becomes the major reaction at basic pH. Solving the structures of two RBcel1 variants, RBcel1_E135Q and RBcel1_Y201F, in complex with ligands has brought to light some of the molecular factors behind transglycosylation. The structure of RBcel1_E135Q in complex with cellotriose allowed a +3 subsite to be defined, in accordance with the requirement for cellotriose as a transglycosylation acceptor. The structure of RBcel1_Y201F has been obtained with several transglycosylation intermediates, providing crystallographic evidence of transglycosylation. The catalytic cleft is filled with (i) donors ranging from cellotriose to cellohexaose in the negative subsites and (ii) cellobiose and cellotriose in the positive subsites. Such a structure is particularly relevant since it is the first structure of a GH5 enzyme in complex with transglycosylation products that has been obtained with neither of the catalytic glutamate residues modified.
Nexus between construction sector and economic indicators for Turkey and European Union evidenced by panel data analysis
Authors: Qabaja Mohammad , Tenekeci Goktug 
Published: February 2022

PurposeThe research aims to study the regression, cointegration and causality between the construction sector (CS) and the Gross Domestic Product (GDP), considering other variables in the study such as interest rate, taxation, industry sector, investment and Foreign Direct Investment (FDI), which are analyzed through unique panel models. The study was conducted in Turkey and the ten other countries of the European Union (EU) from 1988 to 2019.Design/methodology/approachRegression, cointegration and causality methods were used to investigate the different types of relationships between variables in the models. Data were obtained from official databases and the study contains four main stages, which are explained in detail in the methodology section.FindingsThe study used the analysis methods of regression, cointegration and causality tests and found that the CS and GDP have long-run estimates and the relationship between the two for different countries is negative in a two-way direction. Results are detailed in the analysis section.Research limitations/implicationsNo data were available for the variables before 1988 for most countries, which led to a limited number of observations and issues in statistical analysis methods.Originality/valuePreviously, only input and output tables were used in the analysis. The impact of interest rate, taxation, investment and FDI has not been analyzed. Key variables are very relevant for Turkey, which suffers from chronical inflation and taxation regimes. These show variability with the EU countries for comparative analysis and have not been explored to date, remaining as a major gap for the construction industry. No attempts were made to use regression, cointegration and causality methods with variables. These analysis methods enable an understanding of the differences in variance (heteroscedasticity) and the presence of cross-sectional dependence (CSD), both critical for the reliability of the comparison of data sets and analysis.
Creating a link between healthy homes and architectural elements: a qualitative study of modern residential buildings
Authors: Mohd Latif Hafizah , Essah Emmanuel A. , Donyavi Sohrab 
Published: February 2022

PurposeThe aim of the research presented in this paper is to provide information on the common problems of healthy homes in the context of architectural design deficiencies. Especially because determining the status of a healthy house is particularly challenging if the design is poor.Design/methodology/approachQualitative methods, i.e. interviews, site visits and graphic elicitation diagramming were used in two different stages of data collection. They were then analysed using thematic analysis.FindingsThe findings show that the architectural elements can have positive or negative effects on the health and safe environments. The quantity of doors and the use of transparent glass have largely contributed to the thermal transmission and increased indoor temperatures. The roof aluminium sheets and absence of vents inhibited indoor heat loss. This has led to discomfort and overuse of air-conditioning units, particularly during the COVID-19 pandemic where most households stayed/worked from home. The inappropriate height of the ceiling and roof made it challenging for maintenance purpose, reducing safety levels, which could result in physical injuries.Originality/valueThe concept of healthy homes is not new. Studies have been conducted in Western countries and in the field of healthcare. However, there is lack of study in built environment particularly in developing countries and inadequate inter-disciplinary and empirical research to connect the healthcare field. The pervasive and recurring design deficiencies in the construction industry remain a source of unhealthy homes, which must be addressed. Future investigations are necessary to expand the conclusions that can be drawn from this paper for health equity within the society and nation.
Transformational leadership and employees' helping and innovative behaviors: contextual influences of organizational justice
Authors: Lim Jae Young , Moon Kuk-Kyoung 
Published: February 2022

PurposeThis article explores whether transformational leadership (TFL) influences individuals' extra-role behaviors, specifically helping and innovative behaviors. More importantly, it focuses on whether TFL's influence on employees' helping and innovative behaviors is contingent upon two subdimensions of organizational justice (OJ): distributive justice (DJ) and procedural justice (PJ).Design/methodology/approachThe authors relied on the 2017 Korean Public Employee Viewpoint Survey conducted by the Korea Institute of Public Administration (KIPA), which is based on stratified, two-stage cluster sampling. Because the dependent variables for the empirical models were summed averages, the authors used OLS as a statistical method. The regression was performed using Stata 14.FindingsThe results revealed that TFL was positively associated with both helping and innovative behaviors. When moderated by DJ, TFL has a positive impact only on helping behavior. However, when moderated by PJ, TFL has a positive influence on both behaviors.Research limitations/implicationsTFL was measured using four items. While the measure reflects four dimensions of TFL, its construct validity may be subject to criticism. Relying on a one-year cross-sectional dataset means that this study's findings might not be fully generalizable to all public sector environments across different cultures.Practical implicationsThis article's findings on how TFL is contextualized under different OJ contexts will help advance understanding of how it works in contemporary public organizations.Originality/valueDespite the importance of OJ as a vital heuristic that reshapes employees' perceptions of their organizations, few studies have focused on how it can moderate the relationship between TFL and employees' extra-role behaviors. By investigating such moderating effects, this study advances the scholarly understanding of boundary conditions that affect TFL and its effectiveness in organizational settings. It utilizes a South Korean survey, which brings an international perspective to this understanding.