bluuebunny/crossref_metadata_2025_split huggingface dataset:
TCF7L2: a potential key regulator of antidepressant effects on hippocampal astrocytes in depression model mice
Authors: Koga Yusaku , Kajitani Naoto , Miyako Kotaro , Takizawa Hitoshi , Boku Shuken , Takebayashi Minoru 
Published: August 2023

AbstractAimClinical and preclinical studies suggest that hippocampal astrocyte dysfunction is involved in the pathophysiology of depression; however, the underlying molecular mechanisms remain unclear. Here, we attempted to identify the hippocampal astrocytic transcripts associated with antidepressant effects in a mouse model of depression.MethodsWe used a chronic corticosterone-induced mouse model of depression to assess the behavioral effects of amitriptyline, a tricyclic antidepressant. Hippocampal astrocytes were isolated using fluorescence-activated cell sorting, and RNA sequencing was performed to evaluate the transcriptional profiles associated with depressive effects and antidepressant responses.ResultsDepression model mice exhibited typical depression-like behaviors that improved after amitriptyline treatment; the depression group mice also had significantly reduced GFAP-positive astrocyte numbers in hippocampal subfields. Comprehensive transcriptome analysis of hippocampal astrocytes showed opposing responses to amitriptyline in depression group and control mice, suggesting the importance of using the depression model. Transcription factor 7 like 2 (TCF7L2) was the only upstream regulator gene altered in depression model mice and restored in amitriptyline-treated depression model mice. In fact, TCF7L2 expression was significantly decreased in the depression group. The level of TCF7L2 long non-coding RNA, which controls mRNA expression of the TCF7L2 gene, was also significantly decreased in this group and recovered after amitriptyline treatment. The Gene Ontology biological processes associated with astrocytic TCF7L2 included proliferation, differentiation, and cytokine production.ConclusionWe identified TCF7L2 as a gene associated with depression- and antidepressant-like behaviors in response to amitriptyline in hippocampal astrocytes. Our findings could provide valuable insights into the mechanism of astrocyte-mediated antidepressant effects.
Neuronal Connectivity as a Determinant of Cell Types and Subtypes
Authors: Liu Lijuan , Yun Zhixi , Manubens-Gil Linus , Chen Hanbo , Xiong Feng , Dong Hongwei , Zeng Hongkui , Hawrylycz Michael , Ascoli Giorgio A. , Peng Hanchuan 
Published: August 2023

AbstractClassifications of single neurons at brain-wide scale is a powerful way to characterize the structural and functional organization of a brain. We acquired and standardized a large morphology database of 20,158 mouse neurons, and generated a whole-brain scale potential connectivity map of single neurons based on their dendritic and axonal arbors. With such an anatomy-morphology-connectivity mapping, we defined neuron connectivity types and subtypes (both called “c-types” for simplicity) for neurons in 31 brain regions. We found that neuronal subtypes defined by connectivity in the same regions may share statistically higher correlation in their dendritic and axonal features than neurons having contrary connectivity patterns. Subtypes defined by connectivity show distinct separation with each other, which cannot be recapitulated by morphology features, population projections, transcriptomic, and electrophysiological data produced to date. Within this paradigm, we were able to characterize the diversity in secondary motor cortical neurons, and subtype connectivity patterns in thalamocortical pathways. Our finding underscores the importance of connectivity in characterizing the modularity of brain anatomy, as well as the cell types and their subtypes. These results highlight that c-types supplement conventionally recognized transcriptional cell types (t-types), electrophysiological cell types (e-types), and morphological cell types (m-types) as an important determinant of cell classes and their identities.
Agent-based modeling of nuclear chromosome ensemble identifies determinants of homolog pairing during meiosis
Authors: Chriss Ariana , Börner G. Valentin , Ryan Shawn D. 
Published: August 2023

AbstractDuring meiosis, pairing of homologous chromosomes (homologs) ensures the formation of haploid gametes from diploid precursor cells, a prerequisite for sexual reproduction. Pairing during meiotic prophase I facilitates crossover recombination and homolog segregation during the ensuing reductional cell division. Mechanisms that ensure stable homolog alignment in the presence of an excess of non-homologous chromosomes have remained elusive, but rapid chromosome movements during prophase I appear to play a role in the process. Apart from homolog attraction, provided by early intermediates of homologous recombination, dissociation of non-homologous associations also appears to contribute to homolog pairing, as suggested by the detection of stable non-homologous chromosome associations in pairing-defective mutants. Here, we have developed an agent-based model for homolog pairing derived from the dynamics of a naturally occurring chromosome ensemble. The model simulates unidirectional chromosome movements, as well as collision dynamics determined by attractive and repulsive forces arising from close-range physical interactions. In addition to homolog attraction, chromosome number and size as well as movement velocity and repulsive forces are identified as key factors in the kinetics and efficiency of homologous pairing. Dissociation of interactions between non-homologous chromosomes may contribute to pairing by crowding homologs into a limited nuclear area thus creating preconditions for close-range homolog attraction. Predictions from the model are readily compared to experimental data from budding yeast, parameters can be adjusted to other cellular systems and predictions from the model can be tested via experimental manipulation of the relevant chromosomal features.Author summaryPairing of homologous chromosomes (homologs) is a key feature of multiple cellular processes including gene expression control, chromosome break repair, and chromosome segregation. Homolog pairing during meiosis is shared among all sexually reproducing eukaryotes. Mechanistic determinants of homology-specific chromosome alignment are presently unknown. We have developed an agent-based model where contributions of the entire chromosome set to the pairing process is taken into account, comprising both homologous and non-homologous chromosomal encounters. Incorporating natural chromosome lengths, the model accurately recapitulates efficiency and kinetics of homolog pairing observed for wild-type and mutant meiosis in budding yeast, and can be adapted to nuclear dimensions and chromosome sets of other organisms.
BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas
Authors: Huchedé Paul , Meyer Swann , Berthelot Clément , Hamadou Maud , Bertrand-Chapel Adrien , Rakotomalala Andria , Manceau Line , Tomine Julia , Lespinasse Nicolas , Lewandowski Paul , Cordier-Bussat Martine , Broutier Laura , Dutour Aurélie , Rochet Isabelle , Blay Jean-Yves , Degletagne Cyril , Attignon Valéry , Montero-Carcaboso Angel , Le Grand Marion , Pasquier Eddy , Vasiljevic Alexandre , Gilardi-Hebenstreit Pascale , Meignan Samuel , Leblond Pierre , Ribes Vanessa , Cosset Erika , Castets Marie 
Published: August 2023

AbstractPediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded byACVR1.However, the potential impact of the BMP pathway in tumors non-mutated forACVR1is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels betweenACVR1wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.
The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria
Authors: Koch Christian , Räschle Markus , Prescianotto-Baschong Cristina , Spang Anne , Herrmann Johannes M. 
Published: August 2023

AbstractMost mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER encounter structure (ERMES) and Tom70 are part of two parallel and partially redundant ER-to-mitochondria transfer routes. When ER-to-mitochondria transfer is prevented, many mitochondrial precursor proteins associate with ER membranes, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.
Structure-based development of new cyclic compounds targeting PSD-95 PDZ3 domain
Authors: Naik Mandar T. , Naik Nandita , Hu Tony , Wang Szu-Huan , Marshall John 
Published: August 2023

AbstractAberrant BDNF signaling has been proposed to contribute to the pathophysiology of depression and other neurological disorders such as Angelman syndrome. We have previously shown that targeting the TrkB / PSD-95 nexus by peptidomimetic inhibitors is a promising approach for therapeutic intervention. Here we used structure-based knowledge to develop a new peptidomimetic compound series that fuses SynGAP-derived peptides to our prototype compound CN2097. These compounds target the PSD-95 PDZ3 domain and adjoining αC helix to achieve bivalent binding that results in up to 7-fold stronger affinity compared to CN2097. These compounds were designed to improve CN2097 specificity for the PDZ3 domain and limited SAR studies have been performed to improve their resistance to proteolysis.
Neurons in the human entorhinal cortex map abstract emotion space
Authors: Qasim Salman E. , Reinacher Peter C. , Brandt Armin , Schulze-Bonhage Andreas , Kunz Lukas 
Published: August 2023

AbstractWhen animals move through space, neurons in their entorhinal cortex activate periodically at multiple locations to form a map of the spatial environment. These grid cells may also map non-physical, conceptual spaces to support various other complex behaviors. Here, using intracranial recordings in neurosurgical patients performing an emotional memory task, we find that neurons in the human medial temporal lobe activate in a grid-like pattern across a two-dimensional feature space characterized by emotional valence and arousal. These neurons were different from cells tuned solely to valence or arousal, were preferentially located in the entorhinal cortex, and exhibited theta-phase locking. Our observation of grid-like neuronal activity during emotional processing in humans supports the idea that the neural structure of cognitive maps generalizes beyond spatial navigation.
The juxtamembrane linker of synaptotagmin 1 regulates Ca2+binding via liquid-liquid phase separation
Authors: Mehta Nikunj , Mondal Sayantan , Watson Emma T. , Cui Qiang , Chapman Edwin R. 
Published: August 2023

AbstractSynaptotagmin (syt) 1, a Ca2+sensor for synaptic vesicle exocytosis, functionsin vivoas a multimer. Syt1 senses Ca2+via tandem C2-domains that are connected to a single transmembrane domain via a juxtamembrane linker. Here, we show that this linker segment harbors a lysine-rich, intrinsically disordered region that is necessary and sufficient to mediate liquid-liquid phase separation (LLPS). Interestingly, condensate formation negatively regulates the Ca2+-sensitivity of syt1. Moreover, Ca2+and anionic phospholipids facilitate the observed phase separation, and increases in [Ca2+]i promote the fusion of syt1 droplets in living cells. Together, these observations suggest a condensate-mediated feedback loop that serves to fine-tune the ability of syt1 to trigger release, via alterations in Ca2+binding activity and potentially through the impact of LLPS on membrane curvature during fusion reactions. In summary, the juxtamembrane linker of syt1 emerges as a regulator of syt1 function by driving self-association via LLPS.
N-glycosylation as a eukaryotic protective mechanism against protein aggregation
Authors: Duran-Romaña Ramon , Houben Bert , Vleeschouwer Matthias De , Louros Nikolaos , Wilson Matthew P , Matthijs Gert , Schymkowitz Joost , Rousseau Frederic 
Published: August 2023

ABSTRACTThe tendency for proteins to form aggregates is an inherent part of every proteome and arises from the self-assembly of short protein segments called aggregation-prone regions (APRs). While post-translational modifications (PTMs) have been implicated in modulating protein aggregation, their direct role in APRs remains poorly understood. In this study, we used a combination of proteome-wide computational analyses and biochemical techniques to investigate the potential involvement of PTMs in aggregation regulation. Our findings reveal that while most PTM types are disfavored near APRs, N-glycosylation is enriched and evolutionarily selected, especially in proteins prone to misfolding. Experimentally, we show that N-glycosylation inhibits the aggregation of peptidesin vitrothrough steric hindrance. Moreover, mining existing proteomics data, we find that the loss of N-glycans at the flanks of APRs leads to specific protein aggregation in Neuro2a cells. Our results point towards a novel intrinsic role for N-glycosylation, directly preventing protein aggregation in eukaryotes.
Redox regulation of autophagy in Arabidopsis: differential effects of reactive oxygen species
Authors: Robert Germán , Enet Alejandro , Saavedra Laura , Lascano Ramiro 
Published: August 2023

ABSTRACTAutophagy plays a key role in the responses to different stress condition in plants. Reactive oxygen species (ROS) are common modulators of stress responses, having both toxic and signaling functions. In this context, the relationship between ROS and autophagy regulation remains unclear, and in some aspects, contradictory. In this study, we employed pharmacological and genetic approaches to investigate the effects of different ROS on the cytoplastic redox state and autophagic flux inArabidopsis thaliana. Ours results demonstrated that oxidative treatments with H2O2and MV, which drastically increased the oxidized state of the cytoplasm, reduced the autophagic flux. Conversely, singlet oxygen, which did not have significant effects on the cytoplasmic redox state, increased the autophagic flux. Additionally, our findings indicated that after H2O2and high light treatments and during the recovery period, the cytoplasm returned to its reduced state, while autophagy was markedly induced. In summary, our study unveils the differential effects of ROS on the autophagic flux, establishing a correlation with the redox state of the cytoplasm. Moreover, it emphasizes the dynamic nature of autophagy in response to oxidative stress and the subsequent recovery period.HIGHLIGHTSThis research shows the differential effects of reactive oxygen species on autophagic modulation, highlighting their impact on the cytoplasmic redox state. The relationship between ROS and autophagy regulation remains unclear, and in some aspect’s contradictory. Here, we present a comprehensive investigation characterizing the effects of different ROS, such as hydrogen peroxide and singlet oxygen, on the modulation of autophagy in Arabidopsis. In brief, our findings reveal differential impacts on cytoplasmic redox states and autophagic flux, providing insight into the dynamic nature of autophagy, especially in stress and post-stress conditions.To the best of our knowledge, our work is the first to evaluate autophagic flux both during and after oxidative stress in plants. Our results indicate that this differentiation is crucial when analyzing the effects of oxidative stress on autophagy.
Core bacteria associated with hyphosphere ofFusarium oxysporumf. sp.niveumover spatial and temporal differences
Authors: Thomas Vanessa E. , Antony-Babu Sanjay 
Published: August 2023

BackgroundBacteria and fungi co-inhabit the soil microbiome in dynamic interactions. In the rhizosphere, fungi and bacteria have been studied to synergistically colonize soil as beneficial or as antagonists to form a pathobiome. These variations of soil bacterial community from pathogen and nonpathogen form of FOSC have been researched, however the bacterial community within the hyphosphere has yet to be studied thoroughly for direct pathogen interkingdom interactions. This study used 16S rRNA gene sequencing and a to decipher the bacteriome diversity associated with the hyphosphere of three isolates ofFusarium oxysporumf. sp.niveumrace 2 (FON2) with temporal and spatial differences.ResultsOur results show a core microbiome that is shared among the three isolates regardless of the differences of spatial and temporal differences. The core hyphosphere community visualized as a ternary plot was made up 15 OTUs which were associated with all three FON2. Although a few operational taxonomic units (OTUs) were significantly correlated with a particular isolate of FON2, reported in the LDA (p<0.05), these OTUs were still present as part of the core in all isolates. Co-occurrence analysis and correlation plot identified a negative correlation among most of the microbiota which may indicate a positive correlation to the FON2 that is not tested.ConclusionsThe study indicates a core microbiota associated with FON2 regardless of the isolate’s temporal and spatial differences. Through our results we provide insights into the microbe-microbe dynamic of the pathogen’s success and its ability to recruit a core pathobiome. Our research promotes the concept of pathogens not being lone invaders but recruits from the established host microbiome to form a pathobiome.
The amoeboid migration of monocytes in confining channels requires the local remodeling of the cortical actin cytoskeleton by cofilin-1
Authors: Ullo Maria F. , D’Amico Anna E. , Lavenus Sandrine B. , Logue Jeremy S. 
Published: August 2023

AbstractWithin the bloodstream, monocytes must traverse the microvasculature to prevent leukostasis, which is the entrapment of monocytes within the confines of the microvasculature. Using the model cell line, THP-1, and VCAM-1 coated channels to simulate the microvasculature surface, we demonstrate that monocytes predominantly adopt an amoeboid phenotype, which is characterized by the formation of blebs. As opposed to cortical actin flow in leader blebs, cell movement is correlated with myosin contraction at the cell rear. It was previously documented that cofilin-1 promotes cortical actin turnover at leader bleb necks in melanoma cells. In monocytes, our data suggest that cofilin-1 promotes the local upregulation of myosin contractility through actin cytoskeleton remodeling. In support of this concept, cofilin-1 is found to localize to a single cell edge. Moreover, the widespread upregulation of myosin contractility was found to inhibit migration. Thus, monocytes within the microvasculature may avoid entrapment by adopting an amoeboid mode of migration.Summary StatementIn confining channels, monocytes largely adopt an amoeboid migrating phenotype, which is found to depend on the upregulation of myosin contractility at the cell rear and cortical actin remodeling by cofilin-1.
The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells
Authors: Gonzales Gerone A. , Huang Song , Rajwani Jahanara , Wilkinson Liam , Nguyen Jenny A. , Wood Cassandra M. , Dinh Irene , Moore Melanie , Cedeño Eymi , Sikdar Saif , McKenna Neil , Ebacher Vincent , Rosin Nicole L. , Carneiro Matheus B. , Surewaard Bas , Peters Nathan C. , Biernaskie Jeff , Mahoney Douglas J. , Yates Robin M. , Canton Johnathan 
Published: August 2023

AbstractType I conventional dendritic cells (cDC1s) are essential for the generation of protective cytotoxic T lymphocyte (CTL) responses against many types of viruses and tumours. They do so by internalizing antigens from virally infected or tumour cells and presenting them to CD8+T cells in a process known as cross-presentation (XP). Despite the obvious biological importance of XP, the molecular mechanism(s) driving this process remain unclear. Here, we show that a cDC-specific pore-forming protein called apolipoprotein 7C (APOL7C) is upregulated in response to innate immune stimuli and is recruited to phagosomes. Strikingly, the association of APOL7C with phagosomes leads to phagosomal rupture, which in turn allows for the escape of engulfed protein antigens to the cytosol where they can be processed via the endogenous major histocompatibility complex (MHC) class I antigen processing pathway. We show that APOL7C recruitment to phagosomes is voltage-dependent and occurs in response to NADPH oxidase-induced depolarization of the phagosomal membrane. Our data indicate the presence of dedicated pore-forming apolipoproteins that mediate the delivery of phagocytosed proteins to the cytosol of activated cDC1s to facilitate MHC class I presentation of exogenous antigen and to regulate adaptive immunity.
Creativity, innovation and employment growth in sub-Saharan Africa
Authors: Medase Stephen Kehinde , Savin Ivan 
Published: August 2023

PurposeAlthough employees' creativity is vital for firm innovation and overall performance, little is done to examine the potential association between creativity and employment. This paper investigates the contribution of employees' creativity, process and product innovations to firm-level employment growth.Design/methodology/approachThe authors use data from World Bank Enterprise Survey and Innovation Follow-up Survey on 9503 firms covering the period 2012–2015 in 11 countries from sub-Saharan Africa and Heckman's two-stage estimation model.FindingsThis study's results indicate a positive role of creativity on firm-level employment growth. In addition, the authors find evidence for a complementary effect arising from the combination of creativity with managerial experience, staff level of education and their associated skills, in contrast, combining creativity with internal or external R&D results in a substitution effect. Interestingly, these synergy effects are pronounced for SMEs but absent for large firms.Practical implicationsPolicy makers in developing economies of sub-Saharan Africa should stimulate company management to use free time offered to employees to be creative in the workplace as one of their key strategies to stimulate employment growth. This strategy is expected to be particularly fruitful among SMEs having some managerial experience and skilled stuff.Originality/valueIn contribution to innovative work practices and workforce creativity, the authors demonstrate that providing employees with free time could be an alternative way to enhance the focal firms' performance.