bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methacrylic acid-based biomaterials promote peripheral innervation in the subcutaneous space of mice
Authors: Androschuk Alaura M. , Tam Theresa H. , Mahou Redouan , Lo Cheun , Salter Michael W. , Sefton Michael V. 
Published: April 2022

ABSTRACTPeripheral nerve innervation is essential for regulating tissue repair and regeneration. MAA-based biomaterials have been previously shown to promote angiogenesis. Here we show a new role for MAA-based biomaterials in promoting terminal axon nerve growth. Our results demonstrate that MAA-based biomaterials promote peripheral nerve growth in an Igf-1 and Shh dependent manner. The resulting nerves increased the sensitivity of treated mice paws to nociception. iDISCO clearing showed that MAA increased the presence of peripheral nerve structures in whole explants. MAA was also able to increase the expression of key neuronal markers and growth factors in a peripheral neuropathy model, the diabetic db/db mouse, suggesting that MAA-based biomaterials may be relevant to treatment of peripheral neuropathy. Moreover, in a peripheral neuropathy model, MAA was able to up-regulate the expression of growth factors for an extended duration suggesting MAA may prevent degeneration through an effect on factors that promote survival. As all tissues are innervated, MAA-based biomaterials could have broad applications in the promoting regeneration and preventing degeneration of peripheral nerves.HIGHLIGHTSMethacrylic acid-based biomaterials promote axon growth in-situ without exogenous growth factors or cellsMethacrylic acid-based biomaterial induced terminal axon growth displays nociception, an indicator of functional outgrowthMethacrylic acid-based biomaterials terminal axon growth is Igf-1 and Shh driven
CCR4 and CCR7 differentially regulate thymocyte localization with distinct outcomes for central tolerance
Authors: Li Yu , Tipan Pablo Guaman , Selden Hilary J. , Srinivasan Jayashree , Hale Laura P. , Ehrlich Lauren I.R. 
Published: April 2022

AbstractCentral tolerance ensures autoreactive T cells are eliminated or diverted to the regulatory T cell lineage, thus preventing autoimmunity. To undergo central tolerance, thymocytes must enter the medulla to test their TCRs for autoreactivity against the diverse self-antigens displayed by antigen presenting cells (APCs). While CCR7 is known to promote thymocyte medullary entry and negative selection, our previous studies implicate CCR4 in these processes, raising the question of whether CCR4 and CCR7 play distinct or redundant roles in central tolerance. Here, synchronized positive selection assays, 2-photon timelapse microscopy, and quantification of TCR-signaled apoptotic thymocytes, demonstrate that CCR4 and CCR7 promote medullary accumulation and central tolerance of distinct post-positive selection thymocyte subsets. CCR4 is upregulated within hours of positive selection signaling and promotes medullary entry and clonal deletion of immature post-positive selection thymocytes. In contrast, CCR7 is expressed several days later and is required for medullary localization and negative selection of mature thymocytes. In addition, CCR4 and CCR7 differentially enforce self-tolerance, with CCR4 enforcing tolerance to self-antigens presented by activated APCs, which express CCR4 ligands. Our findings show that CCR7 expression is not synonymous with medullary localization and support a revised model of central tolerance in which CCR4 and CCR7 promote early and late stages of negative selection, respectively, via interactions with distinct APC subsets.
Gut microbiome-linked metabolites in the pathobiology of depression and anxiety - a role for bile acids
Authors: MahmoudianDehkordi Siamak , Bhattacharyya Sudeepa , Brydges Christopher R , Jia Wei , Fiehn Oliver , Rush A John , Dunlop Boadie W , Kaddurah-Daouk Rima ,   the Mood Disorders Precision Medicine Consortium
Published: April 2022

ABSTRACTBackgroundThe gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut-bacterial enzymes, thus requiring both human and gut microbiome enzymatic processes in their metabolism. BAs participate in a range of important host functions such as lipid transport and metabolism, cellular signaling and regulation of energy homeostasis. BAs have recently been implicated in the pathophysiology of Alzheimer’s and several other neuropsychiatric diseases, but the biochemical underpinnings of these gut microbiome-linked metabolites in the pathophysiology of depression and anxiety remains largely unknown.MethodUsing targeted metabolomics, we profiled primary and secondary BAs in the baseline serum samples of 208 untreated outpatients with MDD. We assessed the relationship of BA concentrations and the severity of depressive and anxiety symptoms as defined by the 17-item Hamilton Depression Rating Scale (HRSD17) and the 14-item Hamilton Anxiety Rating Scale (HRSA-Total), respectively. We also evaluated whether the baseline metabolic profile of BA informs about treatment outcomes.ResultsThe concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log2 fold difference (LFD)= -0.48; p=0.021) and highly anxious (LFD= -0.43; p=0.021) participants compared to participants with less severe symptoms. The gut bacteria-derived secondary BAs produced from CDCA such as lithocholic acid (LCA) and several of its metabolites, and their ratios to primary BAs, were significantly higher in the more anxious participants (LFD’s range=[0.23,1.36]; p’s range=[6.85E-6,1.86E-2]). The interaction analysis of HRSD17 and HRSA-Total suggested that the BA concentration differences were more strongly correlated to the symptoms of anxiety than depression. Significant differences in baseline CDCA (LFD= -0.87, p=0.0009), isoLCA (LFD= -1.08, p=0.016) and several BA ratios (LFD’s range [0.46, 1.66], p’s range [0.0003, 0.049]) differentiated treatment failures from remitters.ConclusionIn patients with MDD, BA profiles representing changes in gut microbiome compositions are associated with higher levels of anxiety and increased probability of first-line treatment failure. If confirmed, these findings suggest the possibility of developing gut microbiome-directed therapies for MDD characterized by gut dysbiosis.
Perivascular SPP1 Mediates Microglial Engulfment of Synapses in Alzheimer’s Disease Models
Authors: De Schepper Sebastiaan , Ge Judy Z , Crowley Gerard , Ferreira Laís SS , Garceau Dylan , Toomey Christina E , Sokolova Dimitra , Childs Thomas , Lashley Tammaryn , Burden Jemima J , Jung Steffen , Sasner Michael , Frigerio Carlo Sala , Hong Soyon 
Published: April 2022

SummaryMicroglia are phagocytes of the brain parenchyma, where they interact with neurons to engulf synapses in a context-dependent manner. Genetic studies in Alzheimer’s disease (AD) highlight dysfunctional phagocytic signaling in myeloid cells as disease-associated pathway. In AD models, there is a region-specific reactivation of microglia-synapse phagocytosis involving complement; however, what drives microglia-synapse engulfment remains unknown. Here, we show that SPP1 (Osteopontin), a glycoprotein associated with inflammation, is regionally upregulated and modulates microglial synaptic engulfment in AD mouse models. Ultrastructural examination revealed SPP1 expression predominantly by perivascular macrophages, a subtype of border-associated macrophages, in the hippocampus of mice and patient tissues. Cell-cell interaction networks of single-cell transcriptomics data suggested that perivascular SPP1 drives microglial functional states in the hippocampal microenvironment of AD mice. Absence of Spp1 expression resulted in failure of microglia to mediate synaptic phagocytosis. This study suggests a critical role for perivascular SPP1 in neuroimmune crosstalk in AD-relevant context.
DomeVR: A setup for experimental control of an immersive dome virtual environment created with Unreal Engine 4
Authors: Shapcott Katharine A. , Weigand Marvin , Glukhova Iuliia , Havenith Martha N. , Schölvinck Marieke L. 
Published: April 2022

1AbstractImmersive virtual reality (VR) environments are a powerful tool to explore cognitive processes ranging from memory and navigation to visual processing and decision making - and to do so in a naturalistic yet controlled setting. As such, they have been employed across different species, and by a diverse range of research groups. Unfortunately, designing and implementing behavioural tasks in such environments often proves complicated. To tackle this challenge, we created DomeVR, an immersive VR environment built using Unreal Engine 4 (UE4). UE4 is a powerful game engine with photo-realistic graphics containing a visual scripting language designed for use by non-programmers. As a result, virtual environments are easily created using drag-and-drop elements. DomeVR aims to make these features accessible to neuroscience experiments. This includes a logging and synchronization system to solve timing uncertainties inherent in UE4; an interactive GUI for scientists to observe subjects during experiments and adjust task parameters on the fly, and a dome projection system for full task immersion in non-human subjects. These key features are modular and can easily be added individually into other UE4 projects. Finally, we present proof-of-principle data highlighting the functionality of DomeVR in three different species: human, macaque and mouse.
Loss of HOXA10 causes endometrial hyperplasia progressing to endometrial cancer
Authors: Mishra Anuradha , Ganguli Nirmalya , Majumdar Subeer S. , Modi Deepak 
Published: April 2022

AbstractEndometrial cancer is the fourth most common malignancy in women and the precursor lesion is endometrial hyperplasia. HOXA10 is a transcription factor that plays key roles in endometrial functions such as the endowment of receptivity, embryo implantation, and trophoblast invasion. Herein, using testicular transgenesis, we developed transgenic mice that expressed an shRNA against HOXA10 and observed that in these animals there was nearly 70% reduction in the expression of HOXA10. We termed these animals as HOXA10 hypomorphs and observed that downregulation of HOXA10 led to the development of endometrial hyperplasia and most animals developed well-differentiated endometrial adenocarcinoma with age. There was an increased proliferation of the uterine glands and stromal cells in the hypomorphs along with a gain of OVGP1 expression and increased levels of ERα and ERβ. In parallel, there was increased expression of Wnt4 and β-Catenin, SOX9 and YAP1. We propose that chronic reduction in HOXA10 expression disrupts multiple pathways in the uterus that aids in the development of endometrial hyperplasia which progresses to endometrial cancer with age.
Nrf2 prevents diabetic cardiomyopathy via antioxidation and normalization of glucose and lipid metabolism in the heart
Authors: Yang Ge , Zhang Qihe , Dong Chao , Hou Guowen , Li Jinjie , Meng Lingbin , Jiang Xin , Xin Ying 
Published: April 2022

AbstractObjectiveMetabolic disorders and oxidative stress are the main causes of diabetic cardiomyopathy. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a powerful antioxidant effect and prevents the progression of diabetic cardiomyopathy. However, the mechanism of its cardiac protection and direct action on cardiomyocytes are not well understood.MethodsIn this study, cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) were used to directly observe whether cardiomyocyte-specific overexpression of Nrf2 can prevent diabetic cardiomyopathy and correct glucose and lipid metabolism disorders in the heart.ResultsCompared to wild-type (WT) mice, Nrf2-TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin (STZ)-induced type 1 diabetes mouse model. This was primarily manifested as improved echocardiography results as well as reduced myocardial fibrosis, cardiac inflammation, and oxidative stress.ConclusionThese results showed that Nrf2 can directly act on cardiomyocytes to play a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by targeting the metabolic pathways of Akt/GSK-3 β/HK-II and AMPK/Sirt1/PGC-1α.
Unique genomic sequences in a novelMycobacterium aviumsubsp.hominissuislineage enable fine scale transmission route tracing during pig movement
Authors: Komatsu Tetsuya , Ohya Kenji , Ota Atsushi , Nishiuchi Yukiko , Yano Hirokazu , Matsuo Kayoko , Odoi Justice Opare , Suganuma Shota , Sawai Kotaro , Hasebe Akemi , Asai Tetsuo , Yanai Tokuma , Fukushi Hideto , Wada Takayuki , Yoshida Shiomi , Ito Toshihiro , Arikawa Kentaro , Kawai Mikihiko , Ato Manabu , Baughn Anthony D. , Iwamoto Tomotada , Maruyama Fumito 
Published: April 2022

AbstractMycobacterium aviumsubsp.hominissuis(MAH) is one of the most prevalent mycobacteria causing non-tuberculous mycobacterial disease in humans and animals. Of note, MAH is a major cause of mycobacterial granulomatous mesenteric lymphadenitis outbreaks in pig populations. To determine the precise source of infection of MAH in a pig farm and to clarify the epidemiological relationship among pig, human and environmental MAH lineages, we collected 50 MAH isolates from pigs reared in Japan and determined draft genome sequences of 30 isolates. A variable number of tandem repeat analysis revealed that most pig MAH isolates in Japan were closely related to North American, European and Russian human isolates but not to those from East Asian human and their residential environments. Historical recombination analysis revealed that most pig isolates could be classified into SC2/4 and SC3, which contain MAH isolated from pig, European human and environmental isolates. Half of the isolates in SC2/4 had many recombination events with MAH lineages isolated from humans in East Asia. To our surprise, four isolates belonged to a new lineage (SC5) in the global MAH population. Members of SC5 had few footprints of inter-lineage recombination in the genome, and carried 80 unique genes, most of which were located on lineage specific-genomic islands. Using unique genetic features, we were able to trace the putative transmission route via their host pigs. Together, we clarify the possibility of species-specificity of MAH in addition to local adaptation. Our results highlight two transmission routes of MAH, one exposure on pig farms from the environment and the other via pig movement. Moreover, our study also warns that the evolution of MAH in pigs is influenced by MAH from patients and their residential environments, even if the MAH are genetically distinct.HighlightsVariable number of tandem repeat analysis ofMycobacterium aviumsubsp.hominissuis(MAH) isolated from pigs (n=50) were conducted.Draft genome sequences of MAH (n=30) and genome analysis were conducted.Pig MAHs were genetically far from East Asian human isolates and close to those of Western countries.Novel MAH lineage which were transmitted farms by pig movement was found.Human MAH isolates influenced the evolution of pig isolates.
Point mutations in the catalytic domain disrupt cellulose synthase (CESA6) vesicle trafficking and protein dynamics
Authors: Huang Lei , Zhang Weiwei , Li Xiaohui , Staiger Christopher J. , Zhang Chunhua 
Published: April 2022

AbstractCellulose, as the main component of the plant cell wall, is synthesized by a multimeric protein complex named the cellulose synthase (CESA) complex or CSC. In plant cells, CSCs are transported through the endomembrane system to the PM, but how catalytic activity or conserved motifs around the catalytic core domain influence vesicle trafficking or protein dynamics is not well understood. Here, we used a functional YFP-tagged AtCESA6 and site- directed mutagenesis to create 18 single amino acid replacement mutants in key motifs of the catalytic domain including DDG, DXD, TED and QXXRW, to comprehensively analyze how catalytic activity affects plant growth, cellulose biosynthesis, complex formation, as well as CSC dynamics and trafficking. Plant growth and cellulose content were reduced by nearly all mutations. Moreover, mutations in most conserved motifs reduced the speed of CSC movement in the PM as well as delivery of CSCs to the PM. Interestingly, the abundance of YFP-CESA6 in the Golgi apparatus was increased or reduced by mutations in DDG and QXXRW motifs, respectively. Post-Golgi trafficking of CSCs was also differentially perturbed by these mutations and, based on these phenotypes, the 18 mutations could be divided into two major groups. Group I comprises mutations causing significantly increased fluorescence intensity of YFP-CESA6 in Golgi with either an increase or no change in the abundance of cortical small CESA-containing compartments (SmaCCs). In contrast, Group II represents mutations with significantly decreased fluorescence intensity of YFP-CESA6 in Golgi and/or reduced SmaCC density. In addition, two Group II mutations in the QXXRW motif reduced CSC assembly in the Golgi. We propose that Group I mutations cause CSC trafficking defects whereas Group II mutations, especially in the QXXRW motif, affect normal CSC rosette formation in the ER or Golgi and hence interfere with subsequent CSC trafficking. Collectively, our results demonstrate that the catalytic domain of CESA6 is essential not only for cellulose biosynthesis, but also CESA complex formation, protein folding and dynamics, vesicle trafficking, or all of the above.One sentence summaryA comprehensive mutational analysis of the catalytic domain of Arabidopsis CESA6 reveals distinct roles for conserved motifs in CSC vesicle trafficking, protein complex formation, or protein dynamics
Molecular dissection of condensin II-mediated chromosome assembly using in vitro assays
Authors: Yoshida Makoto M. , Kinoshita Kazuhisa , Aizawa Yuuki , Tane Shoji , Yamashita Daisuke , Shintomi Keishi , Hirano Tatsuya 
Published: April 2022

AbstractIn vertebrates, condensin I and condensin II cooperate to assemble rod-shaped chromosomes during mitosis. Despite recent progress in our understanding of the mechanism of action of condensin I, how condensin II might work has remained largely unexplored. By introducing recombinant condensin II complexes into Xenopus egg extracts, we dissect the roles of its individual subunits in chromosome assembly. We show that two HEAT subunits, CAP-D3 and CAP-G2, play positive and negative roles, respectively, in condensin II-mediated chromosome assembly. The SMC ATPase and the basic amino acid clusters of the kleisin subunit are essential for this process. Deletion of the C-terminal tail of CAP-D3 increases the ability of condensin II to assemble chromosomes and further exposes a hidden function of CAP-G2 in the lateral compaction of chromosomes. Taken together, our results uncover a multilayered regulatory mechanism unique to condensin II, and provide profound implications in the evolution of condensin II.
Single-cell transcriptomics reveal hyperacute cytokine and immune checkpoint axis in patients with poor neurological outcomes after cardiac arrest
Authors: Tamura Tomoyoshi , Cheng Changde , Chen Wenan , Merriam Louis T. , Pinilla-Vera Mayra , Varon Jack , Hou Peter C. , Lawler Patrick R. , Oldham William M. , Seethala Raghu R. , Tesfaigzi Yohannes , Weissman Alexandra J. , Baron Rebecca M. , Ichinose Fumito , Berg Katherine M. , Bohula Erin A. , Morrow David A. , Chen Xiang , Kim Edy Y. ,   Immunology of Cardiac Arrest Network (I-CAN)
Published: April 2022

SummaryNeurological injury is a major driver of mortality among patients hospitalized after cardiac arrest (CA). The early systemic inflammatory response after CA is associated with neurological injury and mortality but remains poorly defined. We determine the innate immune network induced by clinical CA at single-cell resolution. Immune cell states diverge as early as 6h post-CA between patients with good or poor neurological outcomes at hospital discharge. Nectin-2+monocyte and Tim-3+natural killer (NK) cell subpopulations associate with poor outcomes, and interactome analysis highlights their crosstalk via cytokines and immune checkpoints. Ex vivo studies on peripheral blood cells from CA patients demonstrate that immune checkpoints are a compensatory mechanism against inflammation after CA. IFNγ/IL-10 induce Nectin-2 on monocytes; in a negative feedback loop, Nectin-2 suppresses IFNγ production by NK cells. The initial hours after CA may represent a window for therapeutic intervention in the resolution of inflammation via immune checkpoints.
Intracellular acidification is a hallmark of thymineless death in E. coli
Authors: Ketcham Alexandra , Freddolino Peter L. , Tavazoie Saeed 
Published: April 2022

AbstractThymidine starvation causes rapid cell death. This enigmatic process known as thymineless death (TLD) is the underlying killing mechanism of diverse antimicrobial and antineoplastic drugs. Despite decades of investigation, we still lack a mechanistic understanding of the causal sequence of events that culminate in TLD. Here, we used a diverse set of unbiased approaches to systematically determine the genetic and regulatory underpinnings of TLD in Escherichia coli. In addition to discovering novel genes in previously implicated pathways, our studies revealed a critical and previously unknown role for intracellular acidification in TLD. We observed that a decrease in cytoplasmic pH is a robust early event in TLD across diverse genetic backgrounds. Furthermore, we show that acidification is a causal event in the death process, as chemical and genetic perturbations that increase intracellular pH substantially reduce killing. We also observe a decrease in intracellular pH in response to exposure to the antibiotic gentamicin, suggesting that intracellular acidification may be a common mechanistic step in the bactericidal effects of other antibiotics.
Dichotomic Regulation of Striatal Plasticity by Dynorphin
Authors: Yang Renzhi , Tuan Rupa R. Lalchandani , Hwang Fuu-Jiun , Bloodgood Daniel W. , Kong Dong , Ding Jun B. 
Published: April 2022

SUMMARYModulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action selection, and reward. Synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) are dichotomically regulated by two distinct networks of GPCR signaling cascades. While it is well-known that dopamine D2 and adenosine A2a receptors bidirectionally regulate iSPN plasticity, it remains unclear how D1 signaling modulation of synaptic plasticity is counteracted by a dSPN-specific Gi signaling. Here, we show that striatal dynorphin selectively suppresses long-term potentiation (LTP) through Kappa Opioid Receptor (KOR) in dSPNs. Both KOR antagonism and conditional deletion of dynorphin in dSPNs enhance LTP counterbalancing with different levels of D1 receptor activation. Behaviorally, mice lacking dynorphin specifically in dSPNs show normal motor behavior and reward-based learning, but enhanced flexibility during reversal learning. These findings support a model in which D1R and KOR signaling bidirectionally modulate synaptic plasticity in striatal direct pathways and behavior.