bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Nav1.6-mediated sodium currents underlie the homeostatic control of neuronal intrinsic excitability in the optic tectum of the developingXenopus laevistadpole
Authors: Thompson Adrian C. , Aizenman Carlos D. 
Published: October 2021

ABSTRACTFor individual neurons to function appropriately within a network that is undergoing synaptic reorganization and refinement due to developmental or experience-dependent changes in circuit activity, they must homeostatically adapt their intrinsic excitability to maintain a consistent output despite the changing levels of synaptic input. This homeostatic plasticity of excitability is particularly important for the development of sensory circuits, where subtle deficits in neuronal and circuit function cause developmental disorders including autism spectrum disorder and epilepsy. Despite the critical importance of this process for normal circuit development, the molecular mechanism by which this homeostatic control of intrinsic excitability is regulated is not fully understood. Here, we demonstrate thatXenopusoptic tectal neurons express distinct fast, persistent and resurgent Na+currents. Here, we demonstrate thatXenopusoptic tectal neurons express distinct fast, persistent and resurgent Na+currents. These are regulated with developmental changes in synaptic input, and homeostatically in response to changes in visual input. We show that expression of the voltage-gated Na+channel subtype Nav1.6 is regulated with changes in intrinsic excitability, that blocking Nav1.6 channels is sufficient to decrease intrinsic excitability. Furthermore, that upregulation of Nav1.6 expression is necessary for experience-dependent increases in Na+currents and intrinsic excitability. Finally, by examining behaviors that rely on visual and multisensory integration, we extend these findings to show that tight regulation of Na+channel gene expression during a critical period of tectal circuit development is required for the normal functional development of the tectal circuitry.
Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder
Authors: Xue Xiangning , Zong Wei , Glausier Jill R. , Kim Sam-Moon , Shelton Micah A. , Phan BaDoi N. , Srinivasan Chaitanya , Pfenning Andreas R. , Tseng George C. , Lewis David A. , Seney Marianne L. , Logan Ryan W. 
Published: October 2021

AbstractSevere and persistent disruptions to sleep and circadian rhythms are common features of people with opioid use disorder (OUD). Preclinical findings suggest altered molecular rhythms in the brain are involved in opioid reward and dependence. However, whether molecular rhythms are disrupted in brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. We previously used subjects’ times of death (TOD) as a marker of time of day to investigate transcriptional rhythm alterations in psychiatric disorders. Using TOD and RNA sequencing, we discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in opioid addiction, were largely distinct between OUD and unaffected comparison subjects. Further, fewer rhythmic transcripts were identified in DLPFC of OUD subjects compared to unaffected subjects, but nearly double the number of rhythmic transcripts were found in the NAc of OUD subjects. In OUD, rhythmic transcripts in the NAc peaked either in the evening or near sunrise, and were associated with dopamine, opioid, and GABAergic neurotransmission. Co-expression network analysis identified several OUD-specific modules in the NAc, enriched for transcripts involved in the modulation of dopamine and GABA synapses, including glutamatergic signaling and extracellular matrices. Integrative analyses with human GWAS revealed that rhythmic transcripts in DLPFC and NAc were enriched for genomic loci associated with sleep duration and insomnia. Overall, our results connect transcriptional rhythm changes in dopamine, opioid, and GABAergic synaptic signaling in human brain to sleep-related phenotypes and OUD.
Single-cell analysis of basal cell carcinoma reveals heat shock proteins promote tumor growth in response to WNT5A-mediated inflammatory signals
Authors: Guerrero-Juarez Christian F. , Lee Gun Ho , Liu Yingzi , Wang Shuxiong , Sha Yutong , Chow Rachel Y. , Nguyen Tuyen T.L. , Aasi Sumaira , Karikomi Matthew , Drummond Michael L. , Nie Qing , Sarin Kavita , Atwood Scott X. 
Published: October 2021

AbstractHow basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. Here we use singe-cell RNA sequencing to define the human BCC ecosystem and discriminate between normal and malignant epithelial cells. We identify spatial biomarkers of both tumors and their surrounding stroma that reinforce the heterogeneity of each tissue type. Combining pseudotime, RNA velocity, cellular entropy, and regulon analysis in stromal cells reveal a cancer-specific rewiring of fibroblasts where STAT1, TGF-β, and inflammatory signals induce a non-canonical WNT5A program that maintains the stromal inflammatory state. Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific inflammatory signaling pathways by producing heat shock proteins, which we validatedin situ. Finally, dose-dependent treatment with an HSP70 inhibitor suppressesin vitroBCC cell growth and Hedgehog signaling andin vivotumor growth in a BCC mouse model, validating HSP70’s essential role in tumor growth and reinforcing the critical nature of tumor microenvironment crosstalk in BCC progression.
Infection-induced miR-126 suppresses tsc1- and cxcl12a-dependent permissive macrophages during mycobacterial infection
Authors: Wright Kathryn , de Silva Kumudika , Plain Karren M. , Purdie Auriol C. , Britton Warwick J. , Oehlers Stefan H. 
Published: October 2021

AbstractRegulation of host microRNA (miRNA) expression is a contested node that controls the host immune response to mycobacterial infection. The host must overcome concerted subversive efforts of pathogenic mycobacteria to launch and maintain a protective immune response. Here we examine the role of miR-126 in the zebrafish model of Mycobacterium marinum infection and identify a protective role for this infection-induced miRNA through multiple effector pathways. Specifically, we analyse the impact of the miR-126 knockdown-induced tsc1a and cxcl12a/ccl2/ccr2 signalling axes during early host-M. marinum interactions. We find a strong detrimental effect of tsc1a upregulation that renders zebrafish embryos susceptible to higher bacterial burden and increased cell death despite dramatically higher recruitment of macrophages to the site of infection. We demonstrate that infection-induced miR-126 suppresses tsc1 and cxcl12a expression thus improving macrophage function early in infection, partially through activation of mTOR signalling and strongly through preventing the recruitment of Ccr2+ permissive macrophages, resulting in the recruitment of protective tnfa-expressing macrophages. Together our results demonstrate an important role for infection-induced miR-126 in shaping an effective immune response to M. marinum infection in zebrafish embryos.
VIP interneurons in mouse whisker S1 exhibit sensory and action-related signals during goal-directed behavior
Authors: Ramamurthy Deepa L. , Chen Andrew , Huang Patrick C. , Bharghavan Priyanka , Krishna Gayathri , Casale Kayla , Feldman Daniel E. 
Published: October 2021

SUMMARYVasoactive intestinal peptide-expressing (VIP) interneurons, which constitute 10-15% of the cortical inhibitory neuron population1,2, have emerged as an important cell type for regulating excitatory cell activity based on behavioral state. VIP cells in sensory cortex are potently engaged by neuromodulatory and motor inputs during active exploratory behaviors like locomotion and whisking, which in turn promote pyramidal cell firing via disinhibition3-5. Such state-dependent modulation of activity by VIP cells in sensory cortex has been studied widely in recent years. However, the function of VIP cells during goal-directed behavior is less well understood. It is not clear how task-related events like sensory stimuli, motor actions, or reward activate VIP cells in sensory cortex since there is often temporal overlap in the occurrence of these events. We developed a Go/NoGo whisker touch detection task which incorporates a post-stimulus delay period to separate sensory-driven activity from action- or reward-related activity during behavior. We used 2-photon calcium imaging to measure task-related signals of L2/3 VIP neurons in S1 of behaving mice. We report for the first time that VIP cells in mouse whisker S1 are activated by both whisker stimuli and goal-directed licking. Whisker- and lick-related signals were spatially organized in relation to anatomical columns in S1. Sensory responses of VIP cells were tuned to specific whiskers, whether or not they also displayed lick-related activity.
Gut Bacterial Dysbiosis and Instability is Associated with the Onset of Complications and Mortality in COVID-19
Authors: Schult David , Reitmeier Sandra , Koyumdzhieva Plamena , Lahmer Tobias , Middelhoff Moritz , Erber Johanna , Schneider Jochen , Kager Juliane , Frolova Marina , Horstmann Julia , Fricke Lisa , Steiger Katja , Jesinghaus Moritz , Janssen Klaus-Peter , Protzer Ulrike , Neuhaus Klaus , Schmid Roland M. , Haller Dirk , Quante Michael 
Published: October 2021

AbstractObjectiveThere is a growing debate about the involvement of the gut microbiome in COVID-19, although it is not conclusively understood whether the microbiome has an impact on COVID-19, or vice versa, especially as analysis of amplicon data in hospitalized patients requires sophisticated cohort recruitment and integration of clinical parameters. Here, we analyzed fecal and saliva samples from SARS-CoV-2 infected and post COVID-19 patients and controls considering multiple influencing factors during hospitalization.Design16S rRNA gene sequencing was performed on fecal and saliva samples from 108 COVID-19 and 22 post COVID-19 patients, 20 pneumonia controls and 26 asymptomatic controls. Patients were recruited over the first and second corona wave in Germany and detailed clinical parameters were considered. Serial samples per individual allowed intra-individual analysis.ResultsWe found the gut and oral microbiota to be altered depending on number and type of COVID-19-associated complications and disease severity. The occurrence of individual complications was correlated with low-risk (e.g., Faecalibacterium prausznitzii) and high-risk bacteria (e.g., Parabacteroides). We demonstrated that a stable gut bacterial composition was associated with a favorable disease progression. Based on gut microbial profiles, we identified a model to estimate mortality in COVID-19.ConclusionGut microbiota are associated with the occurrence of complications in COVID-19 and may thereby influencing disease severity. A stable gut microbial composition may contribute to a favorable disease progression and using bacterial signatures to estimate mortality could contribute to diagnostic approaches. Importantly, we highlight challenges in the analysis of microbial data in the context of hospitalization.
A mechanobiological model for tumor spheroids evolution: application to glioblastoma
Authors: Carrasco-Mantis Ana , Castro-Abril Héctor , Randelovic Teodora , Ochoa Ignacio , Doblaré Manuel , Sanz-Herrera José A. 
Published: October 2021

AbstractSpheroids are in vitro spherical structures of cell aggregates, eventually cultured within a hydrogel matrix, that are used, among other applications, as a technological platform to investigate tumor formation and evolution. Several interesting features can be replicated using this methodology, such as cell communication mechanisms, the effect of gradients of nutrients, or the creation of realistic 3D biological structures. In this paper, we propose a continuum mechanobiological model which accounts for the most relevant phenomena that take place in tumor spheroids evolution under in vitro suspension, namely, nutrients diffusion in the spheroid, kinetics of cellular growth and death, and mechanical interactions among the cells. The model is qualitatively validated, after calibration of the model parameters, versus in vitro experiments of spheroids of different glioblastoma cell lines. This preliminary validation allowed us to conclude that glioblastoma tumor spheroids evolution is mainly driven by mechanical interactions of the cell aggregate and the dynamical evolution of the cell population. In particular, it is concluded that our model is able to explain quite different setups, such as spheroids growth (up to six times the initial configuration for U-87 MG cell line) or shrinking (almost half of the initial configuration for U-251 MG cell line); as the result of the mechanical interplay of cells driven by cellular evolution. Indeed, the main contribution of this work is to link the spheroid evolution with the mechanical activity of cells, coupled with nutrient consumption and the subsequent cell dynamics. All this information can be used to further investigate mechanistic effects in the evolution of tumors and their role in cancer disease.Author summarySpheroids structures of cell aggregates are an available experimental platform to analyze the evolution and drug response of solid tumors. In particular, the dynamics of different glioblastoma cell lines have been studied in this work using spheroids. Interestingly, very different behaviors were observed, from a half of the initial configuration shrinking for U-251 MG cell line to six times the initial configuration growth for U-87 MG cell line. These results were replicated by means of a coupled mathematical model which accounts for nutrients diffusion in the spheroid, kinetics of cellular growth and death, and mechanical interactions among the cells. Tumor growth or shrinkage can be explained from a continuum mechanics view driven by cell activity and nutrients availability. This modeling put the focus on mechanistic effects and is aligned with novel experimental techniques to quantify the mechanical microenvironment in tumors. These techniques may be combined with the approach presented in this work to further investigate the role of mechanics in cancer disease.
Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
Authors: Dietzen Noah M. , Arcario Mark J. , Chen Lawrence J. , Petroff John T. , Krishnan Kathiresan , Brannigan Grace , Covey Douglas F. , Cheng Wayland W. L. 
Published: October 2021

ABSTRACTPolyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs) but the mechanism of inhibition is not well understood. The PUFA, docosahexaenoic acid (DHA), inhibits agonist responses of the pLGIC, ELIC, more effectively than palmitic acid, similar to the effects observed in the GABAA receptor and nicotinic acetylcholine receptor. Using photo-affinity labeling and coarse-grained molecular dynamics simulations, we identified two fatty acid binding sites in the outer transmembrane domain (TMD) of ELIC. Fatty acid binding to the photolabeled sites is selective for DHA over palmitic acid, and specific for an agonist-bound state. Hexadecyl-methanethiosulfonate modification of one of the two fatty acid binding sites in the outer TMD recapitulates the inhibitory effect of PUFAs in ELIC. The results demonstrate that DHA selectively binds to multiple sites in the outer TMD of ELIC, but that state-dependent binding to a single intrasubunit site mediates DHA inhibition of ELIC.
High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance
Authors: Cortés-López Mariela , Schulz Laura , Enculescu Mihaela , Paret Claudia , Spiekermann Bea , Busch Anke , Orekhova Anna , Kielisch Fridolin , Quesnel-Vallières Mathieu , Torres-Diz Manuel , Faber Jörg , Barash Yoseph , Thomas-Tikhonenko Andrei , Zarnack Kathi , Legewie Stefan , König Julian 
Published: October 2021

AbstractDuring CART-19 immunotherapy for B-cell acute lymphoblastic leukaemia (B-ALL), many patients relapse due to loss of the cognate CD19 epitope. Since epitope loss can be caused by aberrant CD19 exon 2 processing, we herein investigate the regulatory code that controls CD19 splicing. We combine high-throughput mutagenesis with mathematical modelling to quantitatively disentangle the effects of all mutations in the region comprising CD19 exons 1-3. Thereupon, we identify ~200 single point mutations that alter CD19 splicing and thus could predispose B-ALL patients to CART-19 resistance. Furthermore, we report almost 100 previously unknown splice isoforms that emerge from cryptic splice sites and likely encode non-functional CD19 proteins. We further identify cis-regulatory elements and trans-acting RNA-binding proteins that control CD19 splicing (e.g., PTBP1 and SF3B4) and validate that loss of these factors leads to enhanced CD19 mis-splicing. Our dataset represents a comprehensive resource for potential prognostic factors predicting success of CART-19 therapy.HighlightsMutations in relapsed CART-19 patients lead to CD19 mis-splicingHigh-throughput mutagenesis uncovers ~200 single point mutations with a potential role in CART-19 therapy resistanceMany mutations generate non-functional CD19 proteins by activating cryptic splice sitesRNA-binding proteins such as PTBP1 are key to the expression of properly spliced, CART-19 immunotherapy-sensitive isoforms
Investigation of vitamin B12 concentrations and tissue distributions in larval and adult Pacific oysters and related bivalves
Authors: Vogeler Susanne , Wikfors Gary H. , Li Xiaoxu , Sauvage Justine , Joyce Alyssa 
Published: October 2021

AbstractVitamin B12 (B12) is an essential micronutrient for all animals, but is not present in plants and is produced de novo only by bacteria or archaea. Accordingly, humans must derive required B12 from eating animal products or vitamin supplements, as deficiencies can lead to severe health issues including neuropathy. An often overlooked source in the human diet of B12 is shellfish, in particular bivalves, which have significantly higher levels of B12 than other animal sources, including all vertebrate meats. Origins and key metabolic processes involving B12 in bivalves remain largely unknown, despite the exceptionally high levels. In this study, we examined in several Australian bivalve species, hypotheses concerning B12 utilisation and uptake through diet or microorganism symbiosis. Vitamin B12 is not distributed evenly across different tissues types of the Pacific oyster, the commercial scallop and Goolwa cockle (pipi), with higher accumulation in the oyster adductor muscle and gill, and mantle and syphons of the Goolwa cockle. Oyster larvae before first feeding already contained high amount of B12; however, a significant decrease in B12 concentration post metamorphosis indicates a higher utilisation of B12 during this life event. We demonstrated that microalgal feed can be supplemented with B12, resulting in an enriched feed, but this did not result in an increase in larval B12 concentrations when oyster larvae were fed with this diet relative to controls, thus supporting the theory that a B12 producing microbiome within bivalves was the potential source of B12 rather than feed. However, B12 concentrations in the digestive tract of adult oysters were low compared to other tissue types, which might challenge this theory, at least in adults. Our findings provide insight into B12 uptake and function in bivalve species, which will aid the promotion of bivalves as suitable B12 source for humans as well as provide crucial information to the aquaculture industry in relation to optimisation of vitamin supplementation in bivalve hatchery production.
Epigenetic Control of Temperature-Dependent Female Reproductive Life History Trade-Offs in Seed Beetles, Callosobruchus maculatus
Authors: McCaw Beth A , Leonard Aoife M , Stevenson Tyler J , Lancaster Lesley T 
Published: October 2021

ABSTRACTMany species are threatened by climate change and must rapidly respond to survive changing environments. Epigenetic modifications, such as DNA methylation, can facilitate plastic responses by regulating gene expression in response to environmental cues. Understanding epigenetic responses is therefore essential for predicting species’ ability to rapidly adapt in the context of global environmental change. Here, we investigated the functional significance of DNA methylation on temperature-dependent life history in seed beetles, Callosobruchus maculatus. We assessed changes in DNA methyltransferase (Dnmt1 and Dnmt2) expression levels under ambient conditions and thermal stress, and reproductive performance following artificially-induced epimutation via 3-aminobenzamide (3AB) and Zebularine (Zeb), at a range of ambient and warmer temperatures over two generations. We found that Dnmt1 and Dnmt2 were greatly expressed in females, throughout the body, and exhibited temperature-dependence; in contrast, Dnmt expression was minimal in males. Epimutation led to shifts in female reproductive life history trade-off allocation, and differentially altered thermal optima of fecundity and offspring viability. This study revealed the optimal allocation strategy among these fitness components is temperature-dependent, and trade-offs become increasingly difficult to resolve epigenetically under more extreme warming. Results suggest that epigenetic mechanisms are strongly implicated in, and perhaps limiting of, invertebrate life history responses to temperature change. Further investigation will reveal targeted DNA methylation patterns and specific loci associated with temperature-dependent life history trade-offs in seed beetles and other invertebrates.
Determining criteria interaction and criteria priorities in the freight village location selection process: the experts' perspective in Turkey
Authors: Pekkaya Mehmet , Keleş Nuh 
Published: October 2021

PurposeConsidering the contribution of freight villages (FVs) to the economy and sector, transportation cost advantage, environmental externalities, labor costs, employment, etc. criteria evaluation is important in selecting FV location. Environmental sustainability and social dimensions are becoming important criteria for companies in logistics. The purpose of the study is to determine/model the criteria interaction and also determine the criteria priorities in the FV location selection process. Meanwhile, the study aims to evaluate these criteria and present information to researchers and decision makers.Design/methodology/approachSix main criteria and 29 sub-criteria are selected from related literature. Decision making trial and evaluation laboratory (DEMATEL) method is used for determining/modeling the criteria interaction and sketching interaction diagram, and the Analytical Hierarchy Process (AHP) method is used for determining the criteria priorities. One/two-way pairwise compared main/sub-criteria views are obtained from 48 experts for calculations.Findings“Trade potential”, “transportation networks” and “economic factors” have the highest priorities, respectively, out of six main criteria, and they have the most powerful interactions that put these criteria to the center of decision process. Sub-criteria of “foreign trade potential”, “proximity to the port”, “market opportunities” and “proximity to the railway” out of 29 have a total 36.42% priority, more than one-third of the importance.Originality/valueCriteria are evaluated in FV location selection for FV sustainability using criteria interaction diagrams, affecting/being affected by the level of each criterion and their priorities. This study shows a hybrid derivation from DEMATEL-AHP usage methods together. High-volumed and qualified/experienced expert group judgments in Turkey are evaluated.