bluuebunny/crossref_metadata_2025_split huggingface dataset:
Constriction forces imposed by basement membranes regulate developmental cell migration
Authors: López Ester Molina , Kabanova Anna , Martín-Bermudo Maria D. 
Published: December 2022

SummaryThe basement membrane (BM) is a specialized extracellular matrix, which underlies or encase developing tissues. Mechanical properties of encasing BMs have been shown to profoundly influence the shaping of associated tissues. Here, we use the migration of the border cells (BCs) of theDrosophilaegg chamber to unravel a new role of encasing BMs in developmental cell migration. BCs move between a group of cells, the nurse cells (NCs), that are enclosed by a monolayer of follicle cells (FCs), enveloped in turn by a BM, the follicle BM. We show that increasing or reducing the stiffness of the follicle BM, by altering laminins or Coll IV levels, conversely affects BC migration speed and alters migration mode and dynamics. Follicle BM stiffness also controls pairwise NC and FC cortical tension. We propose that constriction forces imposed by the follicle BM influence NC and FC cortical tension, which, in turn, regulate BC migration. Encasing BMs emerge as key players in the regulation of collective cell migration during morphogenesis.
Regulation of excitatory presynaptic activity by Ambra1 protein determines neuronal networks in sex-dimorphic manner
Authors: Ju Anes , Altas Bekir , Rhee Hong Jun , Schwark Manuela , Hassouna Imam , Sigler Albrecht , Kawabe Hiroshi , Chowdhury Kamal , Ehrenreich Hannelore , Brose Nils , Rhee JeongSeop 
Published: December 2022

AbstractHeterozygous mutation ofAmbra1, known as a positive autophagy regulator, produces autismlike behavior in mice and autistic phenotypes in humans in a female-specific manner. However, the substantial roles of theAmbra1mutation in neurons are still unknown. We find thatAmbra1heterozygotes display a moderate decrease in excitatory synaptic releasein-vitroandex-vivoexclusively in females without autophagy activity, resulting in significant alterations in γ-oscillation power and seizure susceptibility by excitatory/inhibitory (E/I) imbalance. Specifically,Ambra1deficiency has no effect on neurogenesis and morphogenesis, but selectively decreases excitatory synaptic activity without changes in synapse number, quantal size, synaptic release probability, and synaptic plasticity. Therefore, the limited excitatory synaptopathy by Ambra1 expression levels ultimately determines E/I imbalance in global neural networks leading to the female-specific ASD.
A characterization of cardiac-induced noise in R2* maps of the brain
Authors: Raynaud Quentin , Di Domenicantonio Giulia , Yerly Jérôme , Dardano Thomas , van Heeswijk Ruud B. , Lutti Antoine 
Published: December 2022

AbstractPurposeCardiac pulsation increases the noise level in brain maps of the transverse relaxation rate R2*. Cardiac-induced noise is challenging to mitigate during the acquisition of R2* mapping data because its characteristics are unknown. In this work, we therefore aim to characterize cardiac-induced noise in brain maps of the MRI parameter R2*.MethodsWe designed a sampling strategy to acquire multi-echo 3D data in 12 intervals of the cardiac cycle, monitored with a fingertip pulse-oximeter. We measured the amplitude of cardiac-induced noise in this data and assessed the effect of cardiac pulsation on R2* maps computed across echoes. The area of k-space that contains most of the cardiac-induced noise in R2* maps was then identified. Based on these characteristics, we introduced a tentative sampling strategy that aims to mitigate cardiac-induced noise in R2* maps of the brain.ResultsIn inferior brain regions, cardiac pulsation accounts for R2* variations of up to 3s-1across the cardiac cycle, i.e. ∼35% of the overall variability. Cardiac-induced fluctuations occur throughout the cardiac cycle, with a reduced intensity during the first quarter of the cycle. 50-60% of the overall cardiac-induced noise is localized near the k-space centre (k < 0.074 mm-1). The tentative cardiac noise mitigation strategy reduced the variability of R2* maps across repetitions by 11% in the brainstem and 6% across the whole brain.ConclusionWe provide a characterisation of cardiac-induced noise in brain R2* maps that can be used as a basis for the design of mitigation strategies during data acquisition.
The arms race in noncoding regions of transposable element: the evolution of anti-silencing and RNAi
Authors: Sasaki Taku , Kato Kae , Hosaka Aoi , Fu Yu , Toyoda Atsushi , Fujiyama Asao , Tarutani Yoshiaki , Kakutani Tetsuji 
Published: December 2022

AbstractTransposable elements (TEs) are among the most dynamic parts of genomes. Since TEs are potentially deleterious, eukaryotes silence them through epigenetic mechanisms such as DNA methylation and RNAi. We have previously reported that Arabidopsis TEs, calledVANDALs, counteract epigenetic silencing through a group of sequence-specific anti-silencing proteins, VANCs. VANC proteins bind to noncoding regions of specificVANDALcopies and induce a loss of silent chromatin marks. Sequence-specific anti-silencing allows these TEs to proliferate with minimum host damage. Here, we show that RNAi efficiently targets noncoding regions ofVANDALTEs to silence themde novo. Target motifs of VANC, in turn, evolved to escape RNAi. Escaping RNAi could be the primary event leading to the differentiation of sequence-specific anti-silencing systems. We propose that this selfish behaviour of TEs paradoxically could make them less harmful to the host.
Rewarding capacity of optogenetically activating a giant GABAergic central-brain interneuron in larvalDrosophila
Authors: Mancini Nino , Thoener Juliane , Tafani Esmeralda , Pauls Dennis , Mayseless Oded , Strauch Martin , Eichler Katharina , Champion Andrew , Kobler Oliver , Weber Denise , Sen Edanur , Weiglein Aliće , Hartenstein Volker , Thum Andreas S. , Rohwedder Astrid , Schleyer Michael , Gerber Bertram 
Published: December 2022

AbstractLarvae of the fruit flyDrosophila melanogasterare a powerful study case for understanding the neural circuits underlying behavior. Indeed, the numerical simplicity of the larval brain has permitted the reconstruction of its synaptic connectome, and genetic tools for manipulating single, identified neurons allow neural circuit function to be investigated with relative ease and precision. We focus on one of the most complex neurons in the brain of the larva (of either sex), the GABAergic anterior paired lateral neuron (APL). Using behavioral and connectomic analyses, optogenetics, Ca2+imaging and pharmacology, we study how APL affects associative olfactory memory. We first provide a detailed account of the structure, regional polarity, connectivity, and metamorphic development of APL, and further confirm that optogenetic activation of APL has an inhibiting effect on its main targets, the mushroom body Kenyon cells. All these findings are consistent with the previously identified function of APL in the sparsening of sensory representations. To our surprise, however, we found that optogenetically activating APL can also have a strong rewarding effect. Specifically, APL activation together with odor presentation establishes an odor-specific, appetitive, associative short-term memory, whereas naïve olfactory behavior remains unaffected. An acute, systemic inhibition of dopamine synthesis as well as an ablation of the dopaminergic pPAM neurons impair reward learning through APL activation. Our findings provide a study case of complex circuit function in a numerically simple brain, and suggest a previously unrecognized capacity of central-brain GABAergic neurons to engage in dopaminergic reinforcement.Significance statementThe single, identified giant anterior paired lateral (APL) neuron is one of the most complex neurons in the insect brain. It is GABAergic and contributes to the sparsening of neuronal activity in the mushroom body, the memory center of insects. We provide the most detailed account yet of the structure of APL in larvalDrosophilaas a neurogenetically accessible study case. We further reveal that, contrary to expectations, the experimental activation of APL can exert a rewarding effect, likely via dopaminergic reward pathways. The present study both provides an example of unexpected circuit complexity in a numerically simple brain, and reports an unexpected effect of activity in central-brain GABAergic circuits.
Chemoproteomics yields a selective molecular host for acetyl-CoA
Authors: Lieberman Whitney K. , Brown Zachary A. , Jing Yihang , Evans Nya D. , Jhulki Isita , Grose Carissa , Jones Jane E. , Meier Jordan L. 
Published: December 2022

AbstractChemoproteomic profiling is a powerful approach to define the selectivity of small molecules and endogenous metabolites with the human proteome. In addition to mechanistic studies, proteome specificity profiling also has the potential to identify new scaffolds for biomolecular sensing. Here we report a chemoproteomics-inspired strategy for selective sensing of acetyl-CoA. First, we use chemoproteomic capture experiments to validate the N-terminal acetyltransferase NAA50 as a protein capable of differentiating acetyl-CoA and CoA. A Nanoluc-NAA50 fusion protein retains this specificity and can be used to generate a bioluminescence resonance energy transfer (BRET) signal in the presence of a CoA-linked fluorophore. This enables the development of a ligand displacement assay in which CoA metabolites are detected via their ability to bind the Nanoluc-NAA50 protein ‘host’ and compete binding of the CoA-linked fluorophore ‘guest.’ We demonstrate that the specificity of ligand displacement reflects the molecular recognition of the NAA50 host, while the window of dynamic sensing can be controlled by tuning the binding affinity of the CoA-linked fluorophore guest. Finally, we show the method’s specificity for acetyl-CoA can be harnessed for gain-of-signal optical detection of enzyme activity. Overall, our studies demonstrate the potential of harnessing insights from chemoproteomics for molecular sensing and provide a foundation for future applications in target engagement and selective metabolite detection.
Automated segmentation of fetal intracranial volume in 3D ultrasound using deep learning: identifying sex differences in prenatal brain development
Authors: de Zwarte Sonja MC , Teeuw Jalmar , He Jiaojiao , Bekker Mireille N , van Sloun Ruud JG , Hulshoff Pol Hilleke E 
Published: December 2022

AbstractThe human brain undergoes major developmental changes during pregnancy. Three-dimensional (3D) ultrasound images allow for the opportunity to investigate typical prenatal brain development on a large scale. Here, we developed a convolutional neural network (CNN) model for automated segmentation of fetal intracranial volume (ICV) from 3D ultrasound, and we applied the trained model in a large independent sample (N = 9795 ultrasounds; N=1763 participants) from the YOUth Baby and Child cohort measured at 20- and 30-week of gestational age to investigate sex differences in fetal ICV and ICV growth. 168 3D ultrasound images with ICV annotations were included to develop a 3D CNN model for automated fetal ICV segmentation. A data augmentation strategy provided physical variation and additional data to train the network. K-fold cross-validation and Bayesian optimization were used for network selection and the ensemble-based system combined multiple networks to form the final ensemble network. The final ensemble network produced consistent and high-quality segmentations of ICV. Our trained model successfully predicted ICV and ICV growth in a large independent longitudinal data set. Boys had significantly larger ICV at 20- (B=2.83;p=1.4e-13) and 30-weeks of pregnancy (B=12.01;p=2.0e-28), and more pronounced ICV growth than girls (t=-4.395;p=1.3e-5). Our approach provides us with the opportunity to investigate fetal brain development on a much larger scale and to answer fundamental questions related to prenatal brain development.
Purging due to self-fertilization does not prevent accumulation of expansion load
Authors: Zeitler Leo , Parisod Christian , Gilbert Kimberly J. 
Published: December 2022

AbstractSpecies range expansions are a common demographic history presenting populations with multiple evolutionary challenges. It is not yet fully understood if self-fertilization, which is often observed at species range edges, may create an evolutionary advantage against these challenges. Selfing provides reproductive reassurance to counter Allee effects and selfing may purge accumulated mutational burden due to founder events (expansion load) by further increasing homozygosity. We study how selfing impacts the accumulation of genetic load during range expansion via purging and/or speed of colonization. Using simulations, we disentangle inbreeding effects due to demography versus due to selfing and find that selfers expand faster, but still accumulate load, regardless of mating system. The severity of variants contributing to this load, however, differs across mating system: higher selfing rates purge large-effect recessive variants leaving a burden of smaller-effect alleles. We compare these predictions to the mixedmating plantArabis alpina, using whole-genome sequences from refugial outcrossing populations versus expanded selfing populations. Empirical results indicate accumulation of expansion load along with evidence of purging in selfing populations, concordant with our simulations, and suggesting that while purging is a benefit of selfing evolving during range expansions, it is not sufficient to prevent load accumulation due to range expansion.Author SummaryThe geographic space that species occupy, i.e. the species range, is known to fluctuate over time due to changing environmental conditions. Since the most recent glaciation, many species have recolonized available habitat as the ice sheets melted, expanding their range. When populations at species range margins expand into newly available space, they suffer from an accumulation of deleterious alleles due to repeated founder effects. We study whether self-fertilization, which is considered an evolutionary deadend, can be favored under these expanding edge conditions. Selfing has two important effects: allowing for faster expansion due to reproductive assurance and purging recessive deleterious alleles by exposing them to selection as homozygotes. We use simulations to identify the impact of selfing on expanded populations and then compare these results to an empirical dataset to assess whether our predictions are met. We use the mixed-mating plant alpine rock-cress (Arabis alpina) since it has both expanded since the last glaciation and undergone a mating shift to selfing. We find that selfing does not prevent the accumulation of deleterious load, however purging does still act to remove the most severe variants, indicating that selfing provides this benefit during range expansions.
Similar neural pathways link psychological stress and brain health in health and multiple sclerosis
Authors: Schulz Marc-Andre , Hetzer Stefan , Eitel Fabian , Asseyer Susanna , Meyer-Arndt Lil , Schmitz-Hübsch Tanja , Bellmann-Strobl Judith , Cole James H. , Gold Stefan M. , Paul Friedemann , Ritter Kerstin , Weygandt Martin 
Published: December 2022

SummaryClinical and neuroscientific studies suggest a link between psychological stress and reduced brain health - in healthy humans and patients with neurological disorders. However, it is unclear which neural pathways mediate between stress and brain health and whether these pathways are similar in health and disease. Here, we applied an Arterial-Spin-Labeling MRI stress task in 42 healthy persons and 56 with multiple sclerosis. We tested whether brain-predicted age differences (“brain-PAD”), a highly sensitive structural brain health biomarker derived from machine learning, mirror functional connectivity between stress-responsive regions. We found that regional neural stress responsivity did not differ between groups. Although elevated brain-PAD indicated worse brain health in patients, anterior insula-occipital functional connectivity correlated with brain-PAD in both groups. Grey matter variations contributed similarly to brain-PAD in both groups. These findings suggest a generic connection between stress and brain health whose impact is amplified in multiple sclerosis by disease-specific vulnerability factors.
Small Molecule Properties Define Partitioning into Biomolecular Condensates
Authors: Thody Sabareesan Ambadi , Clements Hanna D. , Baniasadi Hamid , Lyon Andrew S. , Sigman Matthew S. , Rosen Michael K. 
Published: December 2022

AbstractBiomolecular condensates regulate cellular function by compartmentalizing molecules without a surrounding membrane1,2. Condensate functions are believed to arise from the specific exclusion or enrichment of molecules3-5. Thus, understanding the principles governing condensate composition is critical to characterizing condensate function. The molecular bases of macromolecular composition have been studied in detail for several condensates6-9, but partitioning of small molecules into condensates remains poorly understood. Using mass spectrometry with validation by fluorescence microscopy, we quantified partitioning of ∼1700 metabolites and FDA-approved drugs into four condensates composed of different DNA and/or protein scaffolds. We found that partitioning spanned from ∼100-fold exclusion to ∼10,000-fold enrichment. Strong correlations between the different condensates suggest an underlying physical similarity despite disparate macromolecular components. Strongly partitioning molecules generally did not bind condensate-forming proteins with high affinity under conditions where condensates do not form, suggesting only a minor role for stereospecific interactions in partitioning. We developed a machine learning model that accurately predicts partitioning using only physicochemical properties of the compounds. The strongest predictors of partitioning were features related to aqueous solubility and hydrophobicity. Small molecule partitioning was similar for condensates in aqueous buffer and in concentrated cell extracts, suggesting analogous behaviors in vivo. Together, the data and model suggest that small molecule partitioning is not generally based on high-affinity, stereospecific interactions with scaffolds, but rather on physical properties of the compounds, and their compatibility with an emergent hydrophobic environment within the condensate. Our results will aid design of chemical compounds that target biomolecular condensates and reveal unexpected physical and functional similarities of distinct condensates.
Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3
Authors: Gao Yiwei , Xu Shuai , Cui Xiaoli , Xu Hao , Qiu Yunlong , Wei Yiqing , Dong Yanli , Zhu Boling , Peng Chao , Liu Shiqi , Zhang Xuejun Cai , Sun Jianyuan , Huang Zhuo , Zhao Yan 
Published: December 2022

AbstractHigh-voltage-activated R-type CaV2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human CaV2.3 in complex with the α2δ1 and β1 subunits. The VSDIIis stabilized in the resting state. Electrophysiological experiments elucidate that the conformational change of VSDIIin response to variation in membrane potential is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6II, which is exclusively conserved in the CaV2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5IIhelix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of CaV2 channels.
A superoxide reductase contributes toClostridioides difficileresistance to oxygen
Authors: Kochanowsky Rebecca , Carothers Katelyn , Roxas Bryan Angelo P. , Anwar Farhan , Viswanathan V.K. , Vedantam Gayatri 
Published: December 2022

AbstractClostridioides difficilecauses a serious diarrheal disease and is a common healthcare-associated bacterial pathogen. Although it has a major impact on human health, mechanistic details ofC. difficileintestinal colonization remain undefined.C. difficileis highly sensitive to oxygen and requires anaerobic conditions forin vitrogrowth. However, the mammalian gut is not entirely devoid of oxygen, andC. difficiletolerates moderate oxidative stressin vivo. TheC. difficilegenome encodes several antioxidant proteins, including a predicted superoxide reductase (SOR) that is upregulated upon exposure to antimicrobial peptides. The goal of this study was to establish SOR enzymatic activity and assess its role in protectingC. difficileagainst oxygen exposure. Insertional inactivation ofsorrenderedC. difficilemore sensitive to superoxide indicating that SOR contributes to antioxidant defense. HeterologousC. difficile sorexpression inEscherichia coliconferred protection against superoxide-dependent growth inhibition, and the corresponding cell lysates showed superoxide scavenging activity. Finally, aC. difficileSOR mutant exhibited global proteome changes under oxygen stress when compared to its parent strain. Collectively, our data establish the enzymatic activity ofC. difficileSOR, confirm its role in protection against oxidative stress, and demonstrate its broader impacts on the vegetative cell proteome.ImportanceClotridioides difficileis an important pathogen strongly associated with healthcare settings and capable of causing severe diarrheal disease. While considered a strict anaerobein vitro, C. difficilehas been shown to tolerate low levels of oxygen in its mammalian host. Among other well-characterized antioxidant proteins, theC. difficilegenome includes a predicted superoxide reductase (SOR), an understudied component of antioxidant defense in pathogens. The significance of the research reported herein is the characterization of the enzymatic activity of the putative SOR protein, including confirmation of its role in protection ofC. difficileagainst oxidative stress. This furthers our understanding ofC. difficilepathogenesis and presents a potential new avenue for targeted therapies.
The common oral parasitic protozoanEntamoeba gingivalisforms cysts in response to antibiotic treatment
Authors: Becker Christin , Adam Aysegül , Dommisch Henrik , Stach Thomas , Schaefer Arne S. 
Published: December 2022

AbstractThe eukaryotic protozoanEntamoeba gingivalis(E.g.) is strongly associated with inflamed periodontal pockets. Unlike other obligate anaerobicEntamoebaspecies, it is considered to not have a life cycle of actively dividing trophozoites and dormant cysts. Accordingly, it has been regarded as non-infectious. To investigate ifE.gis capable of encystation in response to adverse environmental conditions, we cultivated clinical isolates ofE.g. collected from inflamed periodontal pockets in antibiotics for 8 days. The cytomorphological and ultrastructure forms of the amoeba were investigated by transmission and scanning electron microscopy to reveal cyst formation. We observed exocysts and the encapsulated trophozoids separated by an intra-cystic space, a dense poorly vesiculated cytoplasma and polygonal surface areas of cysts. The cysts walls were composed of chitin. Cysts were conspicuously smaller compared to trophozoids and lacked pseudo- and filipodia. We did not observe multi-nucleated trophozoids after antibiotic induces encystation. Cyst formation inE.gmay explain why established treatment approaches often do not stop periodontal tissue destruction during periodontitis and periimplantitis.