bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in microglia morphological profiles reflect divergent emotional temperaments: Insights from a selective breeding model
Authors: Maras Pamela M. , Blandino Peter , Hebda-Bauer Elaine K. , Watson Stanley J. , Akil Huda 
Published: May 2021

AbstractMicroglia are known to play critical roles in healthy brain development and function, as well as the neuropathology underlying a range of brain diseases. Despite the growing evidence for a role for microglia in affective regulation and mood disorders, relatively little is known regarding how variation in microglia status relates to individual differences in emotionality. Using a selective breeding model based on locomotor response to novelty, we have generated rat lines with unique temperamental phenotypes that reflect broad emotional traits: low responder rats (bLRs) are novelty-averse and model a passive coping style, whereas high responder rats (bHRs) are highly exploratory and model an active coping style. To identify a possible functional role of microglia in these phenotypes, we administered minocycline, an antibiotic with potent microglia inhibiting properties. We found changes in emotional and social behaviors in bLRs, with no discernable effects in bHRs. Using detailed anatomical analyses, we went on to explore the nature of baseline differences in hippocampal microglia populations associated with the divergent temperaments. Interestingly, we found that although bHRs and bLRs had comparable total numbers of hippocampal microglia, selective breeding was associated with a shift in the morphological features of these cells. Specifically, microglia from bLRs were characterized by a hyper-ramified morphology, with longer processes and more complicated branching patterns than microglia from bHRs. This morphology is thought to reflect an early stage of microglia activation and suggests that microglia from bLRs may be in a reactive state even when animals are not overtly stressed or challenged. Taken together, our results provide novel evidence linking variation in inborn temperament with differences in the baseline morphological status of microglia cells and highlight the importance of considering the role of microglia not only in acute responses to stress but also in shaping enduring characteristics of emotionality.
Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects
Authors: Rhinn Muriel , Zapata-Bodalo Irene , Klein Annabelle , Plassat Jean-Luc , Knauer-Meyer Tania , Keyes William M. 
Published: May 2021

AbstractTimely induction of cellular senescence is important during embryonic development and tissue repair, while aberrant activation contributes to many age-related diseases. However, whether abnormal induction of senescence in the embryo contributes to developmental defects remains unclear. To explore this, we investigated the clinically significant model of Valproic acid- (VPA) induced developmental defects. VPA is a widely prescribed drug to treat epilepsy, bipolar disorder and migraine. If taken during pregnancy however, exposure to the developing embryo can cause birth defects, cognitive impairment and Autism-Spectrum Disorder. How VPA causes these developmental defects remains unknown. We used embryonic mice and human organoids to model key features of drug exposure, including exencephaly, microcephaly and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find pronounced induction of cellular senescence in the neuroepithelial cells. Critically, through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but surprisingly, not exencephaly and spinal defects. Together, these findings uncover how misregulated senescence in neuroepithelial cells can contribute to developmental defects.
Dissecting Functional, Structural, and Molecular Requirements for Serotonin Release from Mouse Enterochromaffin Cells
Authors: Shaaban Ahmed , Maaß Frederike , Schwarze Valentin , Lund Mari L. , Beuermann Sabine , Chan Michelle , Harenberg Christiane , Bewick Gavin A. , Keating Damien J. , Benseler Fritz , Cooper Benjamin H. , Imig Cordelia 
Published: May 2021

AbstractSerotonergic enterochromaffin (EC) cells of the gut epithelium are secretory sensory cells that communicate with vagal neurons. EC cells exhibit many features of neurons in the brain, raising the hypothesis that synapse-like contacts may mediate fast and directed signalling. To dissect functional, structural, and molecular properties underlying serotonin release from genetically identified EC cells, we employed a multidisciplinary in vitro approach combining intestinal epithelial cell and organoid cultures, electrochemistry, correlated light- and electron microscopy, and gene expression and biochemical analyses. Despite the presence of key molecules of the synaptic neurotransmitter release machinery, we found that the majority of serotonin is released with slow kinetics from large dense-core rather than small synaptic-like vesicles. While we cannot exclude synapse-like transmission between EC cells and neurons in vivo, our data support the notion that the predominant mode of serotonin secretion is similar to that of other endocrine cell types.
Phenological segregation suggests speciation by time in the planktonic diatom Pseudo-nitzschia allochrona sp. nov.
Authors: Percopo Isabella , Ruggiero Maria Valeria , Sarno Diana , Longobardi Lorenzo , Rossi Rachele , Piredda Roberta , Zingone Adriana 
Published: May 2021

AbstractThe emergence of new species is poorly understood in marine plankton, where the lack of physical barriers and homogeneous environmental conditions limit spatial and ecological segregation. Here we combine molecular and ecological information from a long term time series and propose Pseudo-nitzschia allochrona, a new cryptic diatom, as a possible case of speciation by temporal segregation. The new species differs in several genetic markers (18S, LSU and ITS rDNA fragments and rbcL) and is reproductively isolated from its closest relative, which is morphologically identical. Data from a long term plankton time series show Pseudo-nitzschia allochrona invariably occurring in summer-autumn in the Gulf of Naples, where its sister species are instead found in winter-spring. Temperature and nutrients are the main factors associated with the occurrence of P. allochrona, which could have evolved in sympatry by switching its phenology and occupying a new ecological niche. This case of possible speciation by time shows the relevance of combining ecological time series with molecular information to shed light on the eco-evolutionary dynamics of marine microorganisms.
A robust approach to estimate relative phytoplankton cell abundance from metagenomes
Authors: Karlusich Juan José Pierella , Pelletier Eric , Zinger Lucie , Lombard Fabien , Zingone Adriana , Colin Sébastien , Gasol Josep M. , Dorrell Richard G. , Scalco Eleonora , Acinas Silvia G. , Wincker Patrick , de Vargas Colomban , Bowler Chris 
Published: May 2021

AbstractPhytoplankton account for >45% of global primary production, and have an enormous impact on aquatic food webs and on the entire Earth System. Their members are found among prokaryotes (cyanobacteria) and multiple eukaryotic lineages containing chloroplasts. Phytoplankton communities are generally studied by PCR amplification of bacterial (16S), nuclear (18S) or chloroplastic (16S) rRNA marker genes from DNA extracted from environmental samples. However, our appreciation of phytoplankton abundance or biomass is limited by PCR-amplification biases, rRNA gene copy number variations across taxa, and the fact that rRNA genes do not provide insights into metabolic traits such as photosynthesis. In addition, rRNA marker genes fail to capture both cyanobacteria and photosynthetic eukaryotes simultaneously. Here, we targeted the photosynthetic genepsbOfrom metagenomes to circumvent these limitations: the method is PCR-free, and the gene is universally and exclusively present in photosynthetic prokaryotes and eukaryotes, mainly in one copy per genome. We applied and validated this new strategy with theTaraOceans datasets, and showed improved correlations with flow cytometry and microscopy than when based on rRNA genes. Furthermore, we revealed unexpected features of the ecology of these organisms, such as the high abundance of picocyanobacterial aggregates and symbionts in the ocean, and the decrease in relative abundance of phototrophs towards the larger size classes of marine dinoflagellates. To facilitate the incorporation ofpsbOin molecular-based surveys, we compiled a curated database of >18,000 unique sequences. Overall,psbOappears to be a promising new gene marker for molecular-based evaluations of entire phytoplankton communities.
A suitable murine model for studying respiratory coronavirus infection and therapeutic countermeasures in BSL-2 laboratories
Authors: dos Santos Pereira Andrade Ana Cláudia , Campolina-Silva Gabriel Henrique , Queiroz-Junior Celso Martins , de Oliveira Leonardo Camilo , de Souza Barbosa Lacerda Larisse , Pimenta Jordane Clarisse , de Souza Filipe Resende Oliveira , de Meira Chaves Ian , Passos Ingredy Beatriz , Teixeira Danielle Cunha , Bittencourt-Silva Paloma Graziele , Costa Valadão Priscila Aparecida , Rossi-Oliveira Leonardo , Antunes Maisa Mota , Almeida Figueiredo André Felipe , Wnuk Natália Teixeira , Temerozo Jairo R. , Ferreira André Costa , Cramer Allysson , Oliveira Cleida Aparecida , Durães-Carvalho Ricardo , Arns Clarice Weis , Guimarães Pedro Pires Goulart , Costa Guilherme Mattos Jardim , de Menezes Gustavo Batista , Guatimosim Cristina , da Silva Glauber Santos Ferreira , Souza Thiago Moreno L. , Barrioni Breno Rocha , de Magalhães Pereira Marivalda , de Sousa Lirlândia Pires , Teixeira Mauro Martins , Costa Vivian Vasconcelos 
Published: May 2021

AbstractSeveral animal models are being used to explore important features of COVID-19, nevertheless none of them recapitulates all aspects of the disease in humans. The continuous refinement and development of other options ofin vivomodels are opportune, especially ones that are carried out at BSL-2 (Biosafety Level 2) laboratories. In this study, we investigated the suitability of the intranasal infection with the murine betacoronavirus MHV-3 to recapitulate multiple aspects of the pathogenesis of COVID-19 in C57BL/6J mice. We demonstrate that MHV-3 replicated in lungs 1 day after inoculation and triggered respiratory inflammation and dysfunction. This MHV-model of infection was further applied to highlight the critical role of TNF in cytokine-mediated coronavirus pathogenesis. Blocking TNF signaling by pharmacological and genetic strategies greatly increased the survival time and reduces lung injury of MHV-3-infected mice.In vitrostudies showed that TNF blockage decreased SARS-CoV-2 replication in human epithelial lung cells and resulted in the lower release of IL-6 and IL-8 cytokines beyond TNF itself. Taken together, our results demonstrate that this model of MHV infection in mice is a useful BSL-2 screening platform for evaluating pathogenesis for human coronaviruses infections, such as COVID-19.
Using a recently approved tumor mutational burden biomarker to stratify patients for immunotherapy may introduce a sex bias
Authors: Sinha Neelam , Sinha Sanju , Cheng Kuoyuan , Madan Sanna , Erez Ayelet , Ryan Bríd M. , Schäffer Alejandro A. , Aldape Kenneth , Ruppin Eytan 
Published: May 2021

AbstractThe U.S. Food and Drug Administration (FDA) recently approved the treatment with pembrolizumab, an immune checkpoint inhibitor (ICI) targeting PD1 (anti-PD1), for patients with advanced solid tumors with a high tumor mutational burden (TMB) (defined as TMB ≥10 mutations/Mb). However, following recent studies suggest that TMB levels and response to ICI treatment may differ between male and female melanoma patients, we investigated whether using this high-TMB threshold for selecting patients for anti-PD1 treatment may induce a sex-dependent bias. We analyzed a large ICI cohort of 1,286 patients across nine cancer types treated with anti-PD1/PDL1. We find that using this threshold would indeed result in an unwarranted sex bias in melanoma, successfully stratifying female but not male patients. While this threshold is currently not a regulatory prerequisite for ICI treatment in melanoma, it is important to raise awareness to this bias. Notably, no sex-dependent significant differences were observed in the response of melanoma patients to anti-CTLA4 therapies, different chemotherapies or combination therapies. Beyond melanoma, the high-TMB threshold additionally introduces a sex bias of considerable magnitude in glioblastoma and in patients with cancers of unknown origin, however, these results are not statistically significant. A power analysis shows that these biases may become significant with larger sample size, warranting further careful testing in larger cohorts.
Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures
Authors: Dhanwani Rekha , Lima-Junior João Rodrigues , Sethi Ashu , Pham John , Williams Gregory , Frazier April , Xu Yaqian , Amara Amy W. , Standaert David G. , Goldman Jennifer G. , Litvan Irene , Alcalay Roy N. , Peters Bjoern , Sulzer David , Arlehamn Cecilia S. Lindestam , Sette Alessandro 
Published: May 2021

SummaryParkinson’s disease (PD) is a multi-stage neurodegenerative disorder with largely unknown etiology. Recent findings have identified PD-associated autoimmune features including roles for T cells. To further characterize the role of T cells in PD, we performed RNA sequencing on PBMC and peripheral CD4 and CD8 memory T cell subsets derived from PD patients and age-matched healthy controls. When the groups were stratified by their T cell responsiveness to alpha-synuclein (α-syn) as a proxy for ongoing inflammatory autoimmune response, the study revealed a broad differential gene expression profile in memory T cell subsets and a specific PD associated gene signature. We identified a significant enrichment of transcriptomic signatures previously associated with PD, including for oxidative stress, phosphorylation, autophagy of mitochondria, cholesterol metabolism and inflammation, and the chemokine signaling proteins CX3CR1, CCR5 and CCR1. In addition, we identified genes in these peripheral cells that have previously been shown to be involved in PD pathogenesis and expressed in neurons, such as LRRK2, LAMP3, and aquaporin. Together, these findings suggest that features of circulating T cells with α-syn-specific responses in PD patients provide insights into the interactive processes that occur during PD pathogenesis and suggest potential intervention targets.
Multi-Omics Analysis of Fibroblasts from the Invasive Tumor Edge Reveals that Tumor-Stroma Crosstalk Induces O-glycosylation of the CDK4-pRB Axis
Authors: Bouchard Gina , Marques Fernando Jose Garcia , Karacosta Loukia Georgiou , Zhang Weiruo , Bermudez Abel , Riley Nicholas McIlvain , Mehl Lindsey Catherine , Benson Jalen Anthony , Shrager Joseph B , Bertozzi Carolyn Ruth , Pitteri Sharon , Giaccia Amato J , Plevritis Sylvia Katina 
Published: May 2021

AbstractThe invasive leading edge represents a potential gateway for tumor invasion. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in the activation of key biological pathways depending on their location in the tumor (edge vs core). Here, we highlight phenotypic differences between Tumor-Adjacent-Fibroblasts (TAFs) from the invasive edge and Cancer-Associated Fibroblasts (CAFs) from the tumor core, established from human lung adenocarcinomas. We use an innovative multi-omics approach that includes genomics, proteomics and, O-glycoproteomics to characterize crosstalk between TAFs and cancer cells. Our analysis shows that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the CDK4-pRB axis in the stroma, and indirectly modulates pro-invasive features of cancer cells. In summary, aside from improving the efficacy of CDK4 inhibitors anti-cancer agents, the O-glycoproteome poses a new consideration for important biological processes involved in tumor-stroma crosstalk.
Boundary cells in the representation of episodes in the human hippocampus
Authors: Yoo Hye Bin , Umbach Gray , Lega Bradley C. 
Published: May 2021

AbstractThe representation of episodes is a fundamental requirement for forming episodic memories, but the specific electrophysiological mechanisms supporting episode construction in the human hippocampus remain unknown. Experiments in rodent models indicate that a population of neurons sensitive to edges of an environment, termed border or boundary neurons in spatial navigation, fulfills a role analogous to episode demarcation. We hypothesized that such boundary neurons could be identified in the human mesial temporal lobe, with firing rates sensitive specifically to the beginning and end of mnemonically-relevant episodes in the free recall task. Using a generalized linear model to control for factors such as encoding success and item onset times along with other variables, we found 44 Boundary neurons out of a total 736 single neurons recorded across 27 subjects. We distinguish boundary neurons from a separate population of ramping neurons, which are time-sensitive neurons whose activity provides complementary but distinct information during episodic representation. We also describe evidence that the firing of boundary neurons within the preferred windows (at the beginning and end of episodes) is organized by hippocampal theta oscillations, using spike-field coherence metrics.
Aldosterone and Dexamethasone Activate African Lungfish Mineralocorticoid Receptor: Increased Activation After Removal of the Amino-Terminal Domain
Authors: Katsu Yoshinao , Oana Shin , Lin Xiaozhi , Hyodo Susumu , Baker Michael E. 
Published: May 2021

ABSTRACTAldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding, hinge and steroid-binding domains, had a stronger response to corticosteroids and progesterone than full-length lungfish MR, indicating that the N-terminal domain represses steroid activation of lungfish MR, unlike human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR.
Somatic mutations of activated signaling genes, transcription factors, or tumor suppressors are a precondition for leukemic transformation from myelodysplastic syndromes: a sequencing analysis of 64 paired samples
Authors: Li Xiao , Chang Chun-Kang , Xu Feng , Wu Lin-Yun , Guo Juan , Song Lu-Xi , Tao Yin , He Qi , Zhang Zheng , Wu Dong , Zhou Li-Yu , Xiao Chao , Su Ji-Ying 
Published: May 2021

AbstractThe transformation biology of secondary AML from MDS is still not fully understood. Here, we performed a large cohort of paired sequences including target, whole-exome and single cell sequencing to search AML transformation-related mutations (TRM). The results showed that fifty-five out of the 64 (85.9%) patients presented presumptive TRM involving activated signaling, transcription factors, or tumor suppressors. Most of TRM (63.6%, 35 cases) emerged at the leukemia transformation point. All five of the remaining nine patients analyzed by paired whole exome sequencing showed TRM which are not included in the reference targets. Single-cell sequencing indicated that the activated cell signaling route was related to TRM which take place prior to phenotypic development. Of note, defined TRM was limited to a small set of genes (less than ten, in the order: NRAS/KRAS, CEBPA, TP53, FLT3, RUNX1, CBL, PTPN11 and WT1, accounted for 91.0% of the mutations). In conclusion, somatic mutations involving in activated signaling, transcription factors, or tumor suppressors appeared to be a precondition for AML transformation from myelodysplastic syndromes. The TRM may be considered as new therapy targets.
A connectomic study of a petascale fragment of human cerebral cortex
Authors: Shapson-Coe Alexander , Januszewski Michał , Berger Daniel R. , Pope Art , Wu Yuelong , Blakely Tim , Schalek Richard L. , Li Peter H. , Wang Shuohong , Maitin-Shepard Jeremy , Karlupia Neha , Dorkenwald Sven , Sjostedt Evelina , Leavitt Laramie , Lee Dongil , Bailey Luke , Fitzmaurice Angerica , Kar Rohin , Field Benjamin , Wu Hank , Wagner-Carena Julian , Aley David , Lau Joanna , Lin Zudi , Wei Donglai , Pfister Hanspeter , Peleg Adi , Jain Viren , Lichtman Jeff W. 
Published: May 2021

AbstractWe acquired a rapidly preserved human surgical sample from the temporal lobe of the cerebral cortex. We stained a 1 mm3 volume with heavy metals, embedded it in resin, cut more than 5000 slices at ∼30 nm and imaged these sections using a high-speed multibeam scanning electron microscope. We used computational methods to render the three-dimensional structure containing 57,216 cells, hundreds of millions of neurites and 133.7 million synaptic connections. The 1.4 petabyte electron microscopy volume, the segmented cells, cell parts, blood vessels, myelin, inhibitory and excitatory synapses, and 104 manually proofread cells are available to peruse online. Many interesting and unusual features were evident in this dataset. Glia outnumbered neurons 2:1 and oligodendrocytes were the most common cell type in the volume. Excitatory spiny neurons comprised 69% of the neuronal population, and excitatory synapses also were in the majority (76%). The synaptic drive onto spiny neurons was biased more strongly toward excitation (70%) than was the case for inhibitory interneurons (48%). Despite incompleteness of the automated segmentation caused by split and merge errors, we could automatically generate (and then validate) connections between most of the excitatory and inhibitory neuron types both within and between layers. In studying these neurons we found that deep layer excitatory cell types can be classified into new subsets, based on structural and connectivity differences, and that chandelier interneurons not only innervate excitatory neuron initial segments as previously described, but also each other’s initial segments. Furthermore, among the thousands of weak connections established on each neuron, there exist rarer highly powerful axonal inputs that establish multi-synaptic contacts (up to ∼20 synapses) with target neurons. Our analysis indicates that these strong inputs are specific, and allow small numbers of axons to have an outsized role in the activity of some of their postsynaptic partners.