bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human iPSC-derived brain endothelial microvessels in a multi-well format enable permeability screens of anti-inflammatory drugs
Authors: Fengler Sven , Kurkowsky Birgit , Kaushalya Sanjeev Kumar , Roth Wera , Fava Eugenio , Denner Philip 
Published: May 2021

AbstractOptimizing drug candidates for blood-brain barrier (BBB) penetration in humans remains one of the key challenges and many devastating brain diseases including neurodegenerative diseases still do not have adequate treatments. So far, it has been difficult to establish state-of-the-art human stem cell derivedin vitromodels that mimic physiological barrier properties including a 3D microvasculature in a format that is scalable enough to screen drugs for BBB penetration in early drug development phases. To address this challenge, we established human induced pluripotent stem cell (iPSC)-derived brain endothelial microvessels in a standardized and scalable multi-well plate format. iPSC-derived brain microvascular endothelial cells (BMECs) were supplemented with primary cell conditioned media and grew to intact microvessels in 10 days of culturing. Produced microvessels show a typical BBB phenotype including endothelial protein expression, tight-junctions and polarized localization of efflux transporter. Microvessels exhibited physiological relevant trans-endothelial electrical resistance (TEER), were leak-tight for 10 kDa dextran-Alexa 647 and strongly limited the permeability of sodium fluorescein (NaF). Permeability tests with reference compounds confirmed the suitability of our model as platform to identify potential BBB penetrating anti-inflammatory drugs. In summary, the here presented brain microvessel platform recapitulates physiological properties and allows rapid screening of BBB permeable anti-inflammatory compounds that has been suggested as promising substances to cure so far untreatable neurodegenerative diseases.
Gated recurrence enables simple and accurate sequence prediction in stochastic, changing, and structured environments
Authors: Foucault Cedric , Meyniel Florent 
Published: May 2021

AbstractFrom decision making to perception to language, predicting what is coming next is crucial. It is also challenging in stochastic, changing, and structured environments; yet the brain makes accurate predictions in many situations. What computational architecture could enable this feat? Bayesian inference makes optimal predictions but is prohibitively difficult to compute. Here, we show that a specific recurrent neural network architecture enables simple and accurate solutions in several environments. This architecture relies on three mechanisms: gating, lateral connections, and recurrent weight training. Like the optimal solution and the human brain, such networks develop internal representations of their changing environment (including estimates of the environment’s latent variables and the precision of these estimates), leverage multiple levels of latent structure, and adapt their effective learning rate to changes without changing their connection weights. Being ubiquitous in the brain, gated recurrence could therefore serve as a generic building block to predict in real-life environments.
Sex-specific multi-level 3D genome dynamics in the mouse brain
Authors: Rocks Devin , Shukla Mamta , Finnemann Silvia C. , Kalluchi Achyuth , Rowley M. Jordan , Kundakovic Marija 
Published: May 2021

AbstractThe female mammalian brain exhibits sex-hormone-driven plasticity during the reproductive period. Evidence implicates chromatin dynamics in gene regulation underlying this plasticity. However, whether ovarian hormones impact higher-order chromatin organization in post-mitotic neuronsin vivois unknown. Here, we mapped 3D genome of ventral hippocampal neurons across the estrous cycle and by sex in mice. In females, we found cycle-driven dynamism in 3D chromatin organization, including in estrogen-response-elements-enriched X-chromosome compartments, autosomal CTCF loops, and enhancer-promoter interactions. With rising estrogen levels, the female 3D genome becomes more similar to the male genome. Cyclical enhancer-promoter interactions are partially associated with gene expression and enriched for brain disorder-relevant genes. Our study reveals unique 3D genome dynamics in the female brain relevant to female-specific gene regulation, neuroplasticity, and disease risk.
Muscle fatigue revisited - Insights from optically pumped magnetometers
Authors: Sometti Davide , Semeia Lorenzo , Chen Hui , Dax Juergen , Kronlage Cornelius , Baek Sangyeob , Kirchgässner Milena , Romano Alyssa , Heilos Johanna , Staber Deborah , Oppold Julia , Righetti Giulia , Middelmann Thomas , Braun Christoph , Broser Philip , Marquetand Justus 
Published: May 2021

AbstractMuscle fatigue is well characterized electromyographically, nevertheless only information about summed potential differences is detectable. In contrast, recently developed quantum sensors optically pumped magnetometers (OPMs) offer the advantage of recording both the electrical current propagation in the muscle as well as its geometry, by measuring the magnetic field generated by the muscular action potentials. Magnetomyographic investigation of muscle fatigue is still lacking and it is an open question whether fatigue is characterized similarly in magnetomyography (MMG) compared to electromyography (EMG). Herein, we investigated the muscle fatigue during a 3×1-min strong isometric contraction of the rectus femoris muscle of 12 healthy subjects using simultaneous EMG-MMG (4-channel surface EMG and 4 OPM along the rectus femoris muscle).Both EMG and MMG showed the characteristic frequency decrease in the signal magnitude during isometric contraction, which is typical for muscle fatigue. In addition, it was shown that the main part of this frequency decrease seems to occur in the circular component of the magnetic field around the muscle fibers and less longitudinally along the muscle fibers. Overall, these results show not only that magnetomyography is capable of reproducing the electromyographic standards in identifying muscular fatigue, but it also adds relevant information about the spatial characterization of the signal. Therefore, OPM-MMG offers new insights for the study of muscular activity and might serve as a new, supplementary neurophysiological method.
Orthology clusters from gene trees withPossvm
Authors: Grau-Bové Xavier , Sebé-Pedrós Arnau 
Published: May 2021

AbstractPossvm(PhylogeneticOrthologSorting withSpecies oVerlap andMCL) is a tool that automates the process of classifying clusters of orthologous genes from precomputed phylogenetic trees. It identifies orthology relationships between genes using the species overlap algorithm to infer taxonomic information from the gene tree topology, and then uses the Markov Clustering Algorithm (MCL) to identify orthology clusters and provide annotated gene family classifications. Our benchmarking shows that this approach, when provided with accurate phylogenies, is able to identify manually curated orthogroups with high precision and recall. Overall,Possvmautomates the routine process of gene tree inspection and annotation in a highly interpretable manner, and provides reusable outputs that can be used to obtain phylogeny-informed gene annotations and inform comparative genomics and gene family evolution analyses.
Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor Sema 3A
Authors: Creighton Blake A. , Ajit Deepa , Afriyie Simone , Bay Julia , Lorenzo Damaris 
Published: May 2021

AbstractVariants in the high confident autism spectrum disorder geneANK2target both ubiquitously expressed 220-kDa ankyrin-B and neurospecific 440-kDa ankyrin-B (AnkB440) isoforms. Previous work showed that knock-in mice expressing an ASD-linkedAnk2variant yielding a truncated AnkB440 product exhibit ectopic brain connectivity and behavioral abnormalities. Expression of this variant or loss of AnkB440 caused axonal hyperbranchingin vitro, which implicated AnkB440 microtubule bundling activity in suppressing collateral branch formation. Leveraging multiple mouse models, cellular assays, and live microscopy, we show that AnkB440 also modulates axon collateral branching stochastically by reducing the number of F-actin-rich branch initiation points. Additionally, we show that AnkB440 enables growth cone (GC) collapse in response to chemorepellent factor semaphorin 3A (Sema 3A) by stabilizing its receptor complex L1 cell adhesion molecule/neuropilin-1. ASD-linkedANK2variants failed to rescue Sema 3A-induced GC collapse. We propose that impaired response to repellent cues due to AnkB440 deficits leads to axonal guidance and branch pruning defects and may contribute to the pathogenicity ofANK2variants.
A conserved Guided Entry of Tail-anchored pathway is involved in the trafficking of tail-anchored membrane proteins inPlasmodium falciparum
Authors: Kumar Tarkeshwar , Maitra Satarupa , Rahman Abdur , Bhattacharjee Souvik 
Published: May 2021

AbstractTail-anchored (TA) proteins are defined by the absence of N-terminus signal sequence and the presence of a single transmembrane domain (TMD) proximal to their extreme C-terminus. They play fundamental roles in cellular processes including vesicular trafficking, protein translocation and quality control. Accordingly, TA proteins are post-translationally integrated by the Guided Entry of TA (GET) pathway to the cellular membranes; with their N-terminus oriented towards the cytosol and C-terminus facing the organellar lumen. The TA repertoire and the GET machinery have been extensively characterized in the yeast and mammalian systems, however, they remain elusive in the human malaria parasitePlasmodium falciparum.In this study, we bioinformatically predicted a total of 63 TA proteins in theP. falciparumproteome and revealed the association of their subset with theP. falciparumhomolog of Get3 (PfGet3). In addition, our proximity labelling studies either definitively identified or shortlisted the other eligible GET constituents, and ourin vitroassociation studies validated associations between PfGet3 and the corresponding homologs of Get4 and Get2 inP. falciparum. Collectively, this study reveals the presence of proteins with hallmark TA signatures and the involvement of evolutionary conserved GET trafficking pathway for their targeted delivery within the parasite.SynopsisTail-anchored (TA) proteins, characterized by an absence of N-terminal signal sequence and the presence of a transmembrane domain near the C-terminus, are post-translationally inserted at organellar membranes by the conserved multi-component Guided Entry of TA (GET) pathway. Here, we identified the putative homologs of GET machinery in the human malaria parasitePlasmodium falciparumand revealed their association with a subset of bioinformatically predicted 63 putative TA proteins, thereby validating the functional existence of this trafficking pathway within the apicomplexan parasite.Graphical Abstract
DELAY OF GERMINATION 6, encoding theANAC060transcription factor, inhibits seed dormancy
Authors: Song Shuang , He Hanzi , Gühl Kerstin , van Bolderen-Veldkamp Marieke , Buijs Gonda , Willems Leo A.J. , Bentsink Leónie 
Published: May 2021

AbstractThe timing of seed germination is regulated by seed dormancy. There is ample natural variation for seed dormancy among as well as within plant species. In Arabidopsis severalDELAY OF GERMINATIONquantitative trait loci have been identified, of whichDOG1is best studied. Here we report the identification ofDOG6, a quantitative trait locus with a similar strong effect on seed dormancy asDOG1. DOG6affects the timing of germination both in laboratory as well as in field conditions. Complementation cloning revealed thatDOG6encodes the membrane bound transcription factorANAC060. The absence of the ANAC060 protein or its sequestration outside the nucleus results in increased seed dormancy levels. The different natural variants ofANAC060differ for the presence of the membrane binding domain, either due to the fact that this domain is absent in the genomic sequence or because the cDNA is alternatively spliced. Our data indicates that ANAC060 regulates seed dormancy by among others binding to and regulating the expression of protein phosphatases 2C class A proteins including PROTEIN PHOSPHATASE 2CA (PP2CA), ABI FIVE BINDING PROTEIN 3 (AFP3) and HIGHLY ABA-INDUCED PP2C GENE 3 (HAI3).Significance StatementANAC transcription factors are known to effect plant development as well as the response of plants to their environment. Here, we present the identification ofDELAY OF GERMINATION 6(DOG6), a seed dormancy quantitative trait locus that encodes theANAC060transcription factor. We have identified different natural alleles ofANAC060and show that these genetic variants determine the localization of the protein.ANAC060alleles that lack the membrane binding domain end up in the nucleus. Hence they affect transcription and as such attenuate seed dormancy.
Small-molecule modulators of TRMT2A decrease PolyQ aggregation and PolyQ-induced cell death
Authors: Margreiter Michael A , Witzenberger Monika , Wasser Yasmine , Davydova Elena , Janowski Robert , Sobisch Carina , Metz Jonas , Poma Benedetta , Palomino-Hernandez Oscar , Habib Pardes , Wagner Mirko , Carell Thomas , Shah N Jon , Schulz Jörg B , Niessing Dierk , Voigt Aaron , Rossetti Giulia 
Published: May 2021

AbstractPolyglutamine (polyQ) diseases are characterized by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats encoding for an uninterrupted prolonged polyQ tract. We previously identified TRMT2A as a strong modifier of polyQ-induced toxicity in an unbiased large-scale screen in Drosophila melanogaster. This work aimed at identifying and validating pharmacological TRMT2A inhibitors as treatment opportunities for polyQ diseases in humans. Computer-aided drug discovery was implemented to identify human TRMT2A inhibitors. Additionally, the crystal structure of one protein domain, the RNA recognition motif (RRM), was determined, and Biacore experiments with the RRM were performed. The identified molecules were validated for their potency to reduce polyQ aggregation and polyQ-induced cell death in human HEK293T cells and patient derived fibroblasts. Our work provides a first step towards pharmacological inhibition of this enzyme and indicates TRMT2A as a viable drug target for polyQ diseases.
In amygdala we trust: different contributions of the basolateral and central amygdala in learning whom to trust
Authors: Sladky Ronald , Riva Federica , Rosenberger Lisa , van Honk Jack , Lamm Claus 
Published: May 2021

ABSTRACTHuman societies are built on cooperation and mutual trust, but not everybody is trustworthy. Research on rodents suggests an essential role of the basolateral amygdala (BLA) in learning from social experiences (Hernandez-Lallement J et al., 2016), which was also confirmed in human subjects with selective bilateral BLA damage as they failed to adapt their trust behavior towards trustworthy vs. untrustworthy interaction partners (Rosenberger LA et al., 2019). However, neuroimaging in neurotypical populations did not consistently report involvement of the amygdala in trust behavior. This might be explained by the difficulty of differentiating between amygdala’s structurally and functionally different subnuclei, i.e., the BLA and central amygdala (CeA), which have even antagonistic features particularly in trust behavior (van Honk J et al., 2013). Here, we used fMRI of the amygdala subnuclei of neurotypical adults (n=31f/31m) engaging in the repeated trust game. Our data show that both the BLA and the CeA play a role and indeed differentially: While the BLA was most active when obtaining feedback on whether invested trust had been reciprocated or not, the CeA was most active when subjects were preparing their next trust decision. In the latter phase, improved learning was associated with higher activation differences in response to untrustworthy vs. trustworthy trustees, in both BLA and CeA. Our data not only translate to rodent models and support our earlier findings in BLA-damaged subjects, but also show the specific contributions of other brain structures in the amygdala-centered network in learning whom to trust, and better not to trust.SIGNIFICANCE STATEMENTIn this fMRI study, the central amygdala was found active during trust behavior planning, while the basolateral amygdala was active during outcome evaluation. When planning trust behavior, central and basolateral amygdala activation differences between the players was related to whether participants learned to differentiate the players’ trustworthiness. Nucleus accumbens tracked whether trust was reciprocated but was not related to learning. This suggests learning whom to trust is not related to reward processing in the nucleus accumbens but rather to engagement of the basolateral amygdala. This study overcomes major empirical gaps between animal models and human neuroimaging and shows how different amygdala subnuclei and connected areas orchestrate learning to form different subjective trustworthiness beliefs about others and guide trust choice behavior.
The PPLD has advantages over conventional regression methods in application to moderately sized genome-wide association studies
Authors: Vieland Veronica J. , Seok Sang-Cheol 
Published: May 2021

SummaryIn earlier work, we have developed and evaluated an alternative approach to the analysis of GWAS data, based on a statistic called the PPLD. More recently, motivated by a GWAS for genetic modifiers of the X-linked Mendelian disorder Duchenne Muscular Dystrophy (DMD), we adapted the PPLD for application to time-to-event (TE) phenotypes. Because DMD itself is relatively rare, this is a setting in which the very large sample sizes generally assembled for GWAS are simply not attainable. For this reason, statistical methods specially adapted for use in small data sets are required. Here we explore the behavior of the TE-PPLD via simulations, comparing the TE-PPLD with Cox Proportional Hazards analysis in the context of small to moderate sample sizes. Our results will help to inform our approach to the DMD study going forward, and they illustrate several respects in which the TE-PPLD, and by extension the original PPLD, offer advantages over regression-based approaches to GWAS in this context.
The ALOG family membersOsG1L1andOsG1L2regulate inflorescence branching in rice
Authors: Franchini Emanuela , Beretta Veronica M. , Din Israr Ud , Lacchini Elia , Van den Broeck Lisa , Sozzani Rosangela , Orozco-Arroyo Gregorio , Adam Hélène , Jouannic Stefan , Gregis Veronica , Kater Martin M. 
Published: May 2021

ABSTRACTThe architecture of the rice inflorescence is an important determinant of seed yield. The length of the inflorescence and the number of branches are among the key factors determining the amount of spikelets, and thus seeds, that will develop. Especially the timing of the identity transition from indeterminate branch meristem to determinate spikelet meristem regulates the complexity of the inflorescence. In this context, theALOGgeneTAWAWA1(TAW1) has been shown to delay the transition to determinate spikelet development in rice. Recently, by combining precise laser microdissection of inflorescence meristems with RNA-seq we observed that twoALOGgenes,Oryza sativa OsG1-like 1(OsG1L1) andOsG1L2, have an expression profile similar toTAW1. Here we report thatosg1l1andosg1l2loss-of-function CRISPR mutants have similar phenotypes as thetaw1mutant, suggesting that these genes might act on related pathways during inflorescence development. Transcriptome analysis of theosg1l2mutant suggested interactions ofOsG1L2with other known inflorescence architecture regulators and the datasets were also used for the construction of a gene regulatory network (GRN) proposing interactions between genes potentially involved in controlling inflorescence development in rice.The spatio-temporal expression profiling and phenotypical analysis of CRISPR loss-of-function mutants of the homeodomain-leucine zipper transcription factor geneOsHOX14suggest that the proposed GRN indeed serves as a valuable resource for the identification of new players involved in rice inflorescence development.One-sentence summaryOsG1L1andOsG1L2control panicle architecture through delaying the transition from indeterminate branch- to determinate spikelet-meristem identity.
A review of innovative bond instruments for sustainable development in Asia
Authors: Prakash Nisha , Sethi Madhvi 
Published: May 2021

Purpose
Advancing the economies in Asia toward meeting sustainable development goals (SDGs) needs an unprecedented investment in people, processes and the planet. The participation of the private sector is necessary to bridge the financing gap to attain this objective. Engaging the private sector can contribute significantly to attaining the 2030 agenda for SD. However, the financial markets in Asian economies are yet to realize this potential. In this context, this paper aims to discuss the state of finance for SD in Asia and identifies innovative financial instruments for attracting private investments for SDs in these economies.

Design/methodology/approach
This study relies on published articles, reports and policy documents on financing mechanisms for SD. The literature review covered journal data sources, reports from global institutions such as the UN, World Bank, International Monetary Fund and think-tanks operating in the field of climate change policies. Though the topic was specific to financial market instruments, a broader search was conducted to understand the different sources of sustainable finance available, particularly in Asia.

Findings
The investments that are required for meeting the SDGs remain underfunded. Though interest in sustainability is growing in the Asian economies, the financial markets are yet to transition to tap the growing interest in sustainable investing among global investors. This paper concludes that to raise capital from private investors the Asian economies should ensure information availability, reduce distortions and unblock regulatory obstacles. It would also need designing policies and introducing blended financing instruments combining private and public funds.

Research limitations/implications
Though the study has grouped Asian economies, the financing strategy for SDGs should be developed at the country-level considering the domestic financial markets, local developmental stage, fiscal capacity and nationally determined contributions. Further research can focus on developing country-specific strategies for using innovative financial instruments.

Originality/value
Mobilizing funds for implementing the 2030 Agenda for SD is a major challenge for Asian economies. The paper is addressed to national policymakers in Asian economies for developing strategies to raise capital for SD through private participation. It provides opportunities for revisiting national approaches to sustainable finance in these economies.