bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Optogenetic Stimulation of Glutamatergic, but not GABAergic, Vestibular Nuclei Neurons Induces Immediate and Reversible Postural Imbalance in Mice
Authors: Montardy Q. , Wei M. , Yi T. , Liu X. , Zhou Z. , Lai J. , Besnard S. , Tighilet B. , Chabbert C. , Wang L. 
Published: September 2020

AbstractGlutamatergic and GABAergic neurons represent the neural components of the medial vestibular nuclei. We assessed the functional role of glutamatergic and GABAergic neuronal pathways arising from the vestibular nuclei (VN) in the maintenance of gait and balance by optogenetically stimulating the VN in VGluT2-cre and GAD2-cre mice. We demonstrate that glutamatergic, but not GABAergic VN neuronal subpopulation is responsible for immediate and strong posturo-locomotor deficits, comparable to unilateral vestibular deafferentation models. During optogenetic stimulation, the support surface dramatically increased in VNVGluT2+mice, and rapidly fell back to baseline after stimulation, whilst it remained unchanged during similar stimulation of VNGAD2+mice. This effect persisted when vestibular compensation was removed. Posturo-locomotor alterations evoked in VNVGluT2+animals were still present immediately after stimulation, while they disappeared 1h later. Overall, these results indicate a fundamental role for VNVGluT2+neurons in balance and posturo-locomotor functions, but not for VNGAD2+neurons, in this specific context. This new optogenetic approach will be useful to characterize the role of the different VN neuronal populations involved in vestibular physiology and pathophysiology.HighlightsFor the first time, Vestibular nuclei were optogenetically stimulated in free-moving animals, to asses for glutamatergic and GABAergic neurons functions in posturo-locomotor behaviors.Brief optogenetic activation of VNVGluT2+, but not VNGAD2+, induced immediate and strong postural deficit.Stimulation of VNVGluT2+ neurons provoked an imbalance with continuous effect on locomotion for a short period of time after stimulation.These results are comparable to the classical vestibular deafferentation models during their peak of deficit, and set optogenetic stimulation as a new model to study vestibular deficits.
Cytotoxic CD4 Development Requires CD4 Effectors to Concurrently Recognize Local Antigen and Encounter Infection-Induced IL-15
Authors: Devarajan Priyadharshini , Vong Allen M. , Castonguay Catherine H. , Silverstein Noah J. , Kugler-Umana Olivia , Bautista Bianca L. , Kelly Karen A. , Luban Jeremy , Swain Susan L. 
Published: September 2020

ABSTRACTCytotoxic CD4 T cells (ThCTL) are tissue-resident effectors that enhance viral clearance by MHC-II-restricted cytotoxicity of infected cells. Using a model of influenza A virus (IAV) infection, we identify key factors that drive CD4 effectors to differentiate into lung-resident ThCTL. We find that, to become ThCTL, CD4 effectors must again recognize cognate antigen on antigen presenting cells (APC) within the lung. Different APC subsets can drive this transition, including dendritic cells, B cells, and to a lesser extent non-hematopoietic MHC-II+APC. CD28 co-stimulation is not required and can reduce ThCTL development. In contrast, T follicular helper cells (TFH) that are another specialized CD4 effector subset, require CD28 during this time. Optimal ThCTL generation also requires ongoing infection in the effector phase, that acts independently of antigen presentation. The mechanism involves production of Type I IFN, that induces IL-15 which acts to support further differentiation of CD4 effectors to ThCTL. The multiple spatial, temporal and cellular requirements for ThCTL generation from CD4 effectors described here would be expected to prevent cytotoxic CD4 responses in the lung after pathogen has already been cleared, while ensuring the development of potent lung-restricted ThCTL effectors when pathogen persists.
Inherently confinable split-drive systems inDrosophila
Authors: Terradas Gerard , Buchman Anna B. , Bennett Jared B. , Shriner Isaiah , Marshall John M. , Akbari Omar S. , Bier Ethan 
Published: September 2020

AbstractCRISPR-based gene drive systems, which copy themselves based on gene conversion mediated by the homology directed repair (HDR) pathway, have potential to revolutionize vector control. However, mutant alleles generated by the competing non-homologous end-joining (NHEJ) pathway that are rendered resistant to Cas9 cleavage can interrupt the spread of genedrive elements. We hypothesized that drives targeting genes essential for viability or reproduction also carrying recoded sequences to restore endogenous gene functionality should benefit from dominantly-acting maternal clearance of NHEJ alleles, combined with recessive Mendelian processes. Here, we test split gene-drive (sGD) systems inDrosophila melanogasterthat were inserted into essential genes required for viability (rab5, rab11, prosalpha2) or fertility (spo11). In single generation crosses, sGDs copy with variable efficiencies and display sex-biased transmission. In multi-generational cage trials, sGD follow distinct drive trajectories reflecting their differential tendencies to induce target chromosome damage or lethal/sterile mosaic phenotypes, leading to inherently confineable drive outcomes.
Role of Epigenetics in Unicellular to Multicellular Transition inDictyostelium
Authors: Wang Simon Yuan , Pollina Elizabeth Ann , Wang I-Hao , Bushnell Henry L. , Takashima Ken , Fritsche Colette , Sabin George , Greer Paul Lieberman , Greer Eric Lieberman 
Published: September 2020

AbstractThe evolution of multicellularity is a critical event that remains incompletely understood. We use the social amoeba,Dictyostelium discoideum,one of the rare organisms that exists in both unicellular and multicellular stages, to examine the role of epigenetics in regulating multicellularity. While transitioning to multicellular states, patterns of H3K4 methylation and H3K27 acetylation significantly change. By combining transcriptomics, epigenomics, chromatin accessibility, and syntenic analyses with other unicellular and multicellular organisms, we identify 52 conserved genes, which are specifically accessible and expressed during multicellular states. We validated that four of these genes, including the H3K27 deacetylasehdaD,are necessary and that an SMC-like gene,smcl1,is sufficient for multicellularity. These results highlight the importance of epigenetics in reorganizing chromatin architecture to facilitate the evolution of multicellularity.One Sentence SummaryEpigenetic regulation of multicellularity
Transcriptome analysis of a protein-truncating mutation insortilin-related receptor 1associated with early-onset familial Alzheimer’s disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains
Authors: Barthelson Karissa , Pederson Stephen , Newman Morgan , Lardelli Michael 
Published: September 2020

AbstractThe early cellular stresses which eventually lead to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic late-onset AD (LOAD). SORL1 has been shown to play a role in the trafficking of the amyloid β A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid β (Aβ) peptide. However, the other functions of SORL1 are less well understood. Here, we employed a reverse genetics approach to characterise the effect of an EOfAD mutation inSORL1using zebrafish as a model organism. We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue ofSORL1, and performed RNA-sequencing on mRNA isolated from a family of fish either heterozygous for the EOfAD-like mutation or their wild type siblings and identified subtle effects on the expression of genes which likely indicate changes in mitochondrial and ribosomal function. These changes appear to be independent of changes to expression of APP-related proteins in zebrafish, and mitochondrial content.
Retromer Combinatorials for Gene-Therapy Across a Spectrum of Neurological Diseases
Authors: Qureshi Yasir H. , Patel Vivek M. , Kannan Suvarnambiga , Waksal Samuel D , Petsko Gregory A. , Small Scott A. 
Published: September 2020

ABSTRACTEndosomal trafficking is a biological pathway implicated in Alzheimer’s and Parkinson’s disease, and a growing number of other neurological disorders. For this category of diseases, the endosome’s trafficking complex retromer has emerged as a validated therapeutic target. Retromer’s core is a heterotrimeric complex composed of the scaffold protein VPS35 to which VPS26 and VPS29 bind. Unless it is deficient, increasing expression of VPS35 by viral vectors has a limited effect on other trimeric members and on retromer’s overall function. Here we set out to address these constraints and, based on prior insight, hypothesized that co-expressing VPS35 and VPS26 would synergistically interact and elevate retromer’s trimeric expression and function. Neurons, however, are distinct in expressing two VPS26 paralogs, VPS26a and VPS26b, and so to test the hypothesis we generated three novel AAV9 vectors harboring the VPS35, or VPS26a, or VPS26b transgene. First, we optimized their expression in neuroblastoma cell lines, then, in a comprehensive series of neuronal culture experiments, we expressed VPS35, VPS26a, and VPS26b individually and in all possible combinations. Confirming our hypothesis, expressing individual proteins failed to affect the trimer, while VPS35 and VPS26 combinatorials synergized the trimer’s expression. In addition, we illustrate functional synergy by showing that only VPS35 and VPS26 combinatorials significantly increase levels of Sorl1, a key retromer-receptor deficient in Alzheimer’s disease. Collectively, and together with other recent observations, these results suggest a precision-medicine logic when applying retromer gene therapy to a host of neurological disorders, depending on each disorder’s specific retromer-related molecular and anatomical phenotype.
mTOR driven gene transcription is required for cholesterol production in neurons of the developing cerebral cortex
Authors: Schüle Martin , Butto Tamer , Dewi Sri , Schlichtholz Laura , Strand Susanne , Gerber Susanne , Endres Kristina , Schweiger Susann , Winter Jennifer 
Published: September 2020

AbstractDysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood.Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signalingin vitroin primary neurons andin vivoin the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1 and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.
Shugoshin promotes efficient activation of spindle assembly checkpoint and timely spindle disassembly
Authors: Sane Aakanksha , Sridhar Shreyas , Sanyal Kaustuv , Ghosh Santanu K 
Published: September 2020

AbstractShugoshin proteins are evolutionary conserved across eukaryotes with some species-specific cellular functions ensuring the fidelity of chromosome segregation. Shugoshin being present at various subcellular locales, acts as an adaptor to mediate various protein-protein interactions in a spatio-temporal manner. Here, we characterize shugoshin (Sgo1) in the human fungal pathogen,Candida albicans. Interestingly, we discover a novelin vivolocalization of Sgo1 along the length of the mitotic spindle. Further, Sgo1 performs a hitherto unknown function of facilitating timely disassembly of spindle in this organism. We observe that Sgo1 retains its centromeric localization and performs its conserved functions that include regulating the centromeric condensin localization, chromosome passenger complex (CPC) maintenance and sister chromatid biorientation. We identify novel roles of Sgo1 as a spindle assembly checkpoint (SAC) component with functions in maintaining the SAC proteins, Mad2 and Bub1, at the kinetochores, in response to faulty kinetochore-microtubule attachments. These findings provide an excellent evidence of the functional rewiring of shugoshin in maintaining genomic stability.
Similarity of brain activity patterns during learning and subsequent resting state predicts memory consolidation
Authors: Zavecz Z. , Janacsek K. , Simor P. , Cohen M.X. , Nemeth D. 
Published: September 2020

AbstractLong-term memory depends on memory consolidation that seems to rely on learning-induced changes in the brain activity. Here, we introduced a novel approach analyzing continuous EEG data to study learning-induced changes as well as trait-like characteristics in brain activity underlying consolidation. Thirty-one healthy young adults performed a learning task and their performance was retested after a short (~1h) delay, that enabled us to investigate the consolidation of serial-order and probability information simultaneously. EEG was recorded during a pre- and post-learning rest period and during learning. To investigate the brain activity associated with consolidation performance, we quantified similarities in EEG functional connectivity of learning and pre-learning rest (baseline similarity) as well as learning and post-learning rest (post-learning similarity). While comparable patterns of these two could indicate trait-like similarities, changes in similarity from baseline to post-learning could indicate learning-induced changes, possibly spontaneous reactivation. Individuals with higher learning-induced changes in alpha frequency connectivity (8.5–9.5 Hz) showed better consolidation of serial-order information. This effect was stronger for more distant channels, highlighting the role of long-range centro-parietal networks underlying the consolidation of serial-order information. The consolidation of probability information was associated with learning-induced changes in delta frequency connectivity (2.5–3 Hz) and seemed to be dependent on more local, short-range connections. Beyond these associations with learning-induced changes, we also found substantial overlap between the baseline and post-learning similarity and their associations with consolidation performance, indicating that stable (trait-like) differences in functional connectivity networks may also be crucial for memory consolidation.Significance statementWe studied memory consolidation in humans by characterizing how similarity in neural oscillatory patterns during learning and rest periods supports consolidation. Previous studies on similarity focused on learning-induced changes (including reactivation) and neglected the stable individual characteristics that are present over resting periods and learning. Moreover, learning-induced changes are predominantly studied invasively in rodents or with neuroimaging or event-related electrophysiology techniques in humans. Here, we introduced a novel approach that enabled us 1) to reveal both learning-induced changes and trait-like individual differences in brain activity and 2) to study learning-induced changes in humans by analyzing continuous EEG. We investigated the consolidation of two types of information and revealed distinct learning-induced changes and trait-like characteristics underlying the different memory processes.
Development of modular school design as a permanent solution for post-disaster reconstruction in Indonesia
Authors: Yatmo Yandi Andri , Atmodiwirjo Paramita , Saginatari Diandra Pandu , Harahap Mochammad Mirza Yusuf 
Published: September 2020

Purpose
This paper describes the development and implementation of a modular school building design prototype to support “build back better” after the disaster. The purpose of this paper is to bridge the gap between the two standard practices of post-disaster reconstruction: the quickly temporary construction and the permanent solution with longer time to complete.

Design/methodology/approach
The modular school design prototype was developed based on three design criteria established to achieve a relatively quick construction with good quality as a post-disaster permanent solution. The prototype was implemented in Kerandangan Village, Lombok and evaluated to review its compliance with the design criteria.

Findings
Three design strategies were proposed to respond to the main design criteria: the use of modular units and components, the material durability and availability, and the “plug-and-play” configuration system. Through these strategies, the prototype demonstrated the ability to perform as a permanent solution to be implemented in a short time. The prototype evaluation suggests some possible improvement to ensure a more efficient process and further replicability.

Originality/value
The development of the modular design bridges the gap between temporary and permanent approach for post-disaster school reconstruction. The highlighted criteria and the proposed design strategies contribute to the “build back better” attempt by providing better learning experiences for children through a replicable modular design that could be flexibly adapted to various local contexts.
Public leadership and the wicked problem continuum
Authors: Wexler Mark N. , Oberlander Judy 
Published: September 2020

PurposeThis paper examines the relevance of the wicked problem continuum, particularly the emergence of super wicked challenges for public leadership researchers. Contemporary theorizing on public leadership adequately deals with tame challenges, struggles with wicked problems and remains in the dark with regards to the implications of super wicked problemsDesign/methodology/approachThe wicked problem continuum provides a typology or set of dilemmas running from tame to wicked through to super wicked problems. These different problem types are treated as if they were on a three-zone continuum in which the difficulty of solving or substantially reducing the problem varies from relatively low to very high.FindingsWe delineate the three-problem contexts in the wicked problem continuum and discuss the ideal type of organization thriving in each zone. We then posit two opposing wicked problem interpretations-taming and wilding- for those interested in public leadership. Taming calls for prudent, results-oriented leaders employing tried and tested practices. Wilding demands leaders who test the status quo by seeking alternatives.Social implicationsOn the global leadership agenda, wilding problems—those calling attention to the super wicked zone—are escalating. Despite this, public leaders' training lacks a framework for making sense of these urgent and publicly contentious super wicked problems.Originality/valuePublic policy researchers are beginning to direct attention to super wicked problems such as climate change, and pandemics. This work introduces the wicked problem continuum and demonstrates its pertinence for researchers of public leadership.
Leading in the shadows: understanding administrative leadership in the context of COVID-19 pandemic management in Bangladesh
Authors: Alam M Aslam 
Published: September 2020

PurposeThis article aims to examine the COVID-19 pandemic management system in Bangladesh and the role played by various bureaucratic leaders both at national and local levels. Particularly, attention is paid to the interface between the health sector and administrative leaders. The role played by front-line public servants and their superiors are also examined. Also, an attempt is made to encapsulate lessons learned from the crisis and the ways to prepare for the next one.Design/methodology/approachThis study is based on secondary data and observation by the author as well as insights from the author's 36 years of experience in the Bangladesh bureaucracy. Administrative leadership is conceptualized as bureaucrats appointed to administrative positions and discharging administrative duties both at the national and local levels.FindingsA disfunctionality in the COVID-19 management system is observed, which is a direct consequence of the administrative leaders' preference for leading from behind. Some structural constraints in the system are also uncovered.Originality/valueIt draws on observations, experiences and insights from the author's long association with the Bangladesh administrative system. Its intended users are researchers and practitioners of public leadership.
Cash holdings: Do they boost or hurt firms’ performance? Evidence from listed non-financial firms in Saudi Arabia
Authors: Alnori Faisal 
Published: September 2020

Purpose
The purpose of this paper is to study the relationship between corporate cash holdings and financial performance, both linearly and non-linearly, for listed non-financial firms in Saudi Arabia.

Design/methodology/approach
The data include all listed firms in Saudi Arabia’s primary stock market, excluding banks and insurance companies, over 2005–2016. The source for all data is the Osiris database. In evaluating the association between cash holdings and financial performance, static (i.e. pooled ordinary least squares) and dynamic (i.e. system generalized method of moments) specifications were implemented. Further, to confirm the non-linear linkage between cash reserves and financial performance, a U test was used.

Findings
The findings show that cash holdings play a significant role in firms’ performance; specifically, this relationship is non-linear, exhibiting an inverse U shape, driven by levels of cash reserves. This non-linear relationship verifies the tenets of the trade-off theory of optimum cash level based on the benefits and costs of holding cash.

Research limitations/implications
It is recommended that future studies investigate corporate liquidity and performance among Shariah-compliant firms and their conventional counterparts.

Practical implications
The findings of this study provide useful insights for managers and policymakers on efficient levels of corporate liquidity management.

Social implications
This paper provides further insights for investors on the role of corporate cash holding levels in firm performance.

Originality/value
To the best of the author’s knowledge, this paper is among the first to explore a non-linear relationship between cash holdings and firms’ performance using accounting measures.