bluuebunny/crossref_metadata_2025_split huggingface dataset:
RatInABox: A toolkit for modelling locomotion and neuronal activity in continuous environments
Authors: George Tom M , Rastogi Mehul , de Cothi William , Clopath Claudia , Stachenfeld Kimberly , Barry Caswell 
Published: August 2022

ABSTRACTGenerating synthetic locomotory and neural data is a useful yet cumbersome step commonly required to study theoretical models of the brain’s role in spatial navigation. This process can be time consuming and, without a common framework, makes it difficult to reproduce or compare studies which each generate test data in different ways. In response we present RatInABox, an open-source Python toolkit designed to model realistic rodent locomotion and generate synthetic neural data from spatially modulated cell types. This software provides users with (i) the ability to construct one-or two-dimensional environments with configurable barriers and visual cues, (ii) a physically realistic random motion model fitted to experimental data, (iii) rapid online calculation of neural data for many of the known self-location or velocity selective cell types in the hippocampal formation (including place cells, grid cells, boundary vector cells, head direction cells) and (iv) a framework for constructing custom cell types, multi-layer network models and data-or policy-controlled motion trajectories. The motion and neural models spatially and temporally continuous as well as topographically sensitive to boundary conditions and walls. We demonstrate that out-of-the-box parameter settings replicate many aspects of rodent foraging behaviour such as velocity statistics and the tendency of rodents to over-explore walls. Numerous tutorial scripts are provided, including examples where RatInABox is used for decoding position from neural data or to solve a navigational reinforcement learning task. We hope this tool significantly streamline computational research into the brain’s role in navigation.
Hepatitis D virus infection of stem cell-derived hepatocytes triggers an IFN- and NFκB-based innate immune response unable to clear infection
Authors: Lange Frauke , Garn Jonathan , Anagho Holda , von Hahn Thomas , Pietschmann Thomas , Carpentier Arnaud 
Published: August 2022

ABSTRACTHuman pluripotent stem cell-derived hepatocyte-like cells (HLCs) are a valuable model to investigate host-pathogen interactions of hepatitis viruses in a mature and authentic environment. Here, we investigated the susceptibility of HLCs to the Hepatitis D Virus (HDV), a virus that in co-infection with HBV is responsible for the most severe form of viral hepatitis. Cells undergoing hepatic differentiation became susceptible to HDV infection after acquiring expression of the Na+-taurocholate cotransporting polypeptide (NTCP), the receptor mediating HBV and HDV entry. Inoculation of mature HLCs with HDV lead to increasing amounts of intracellular HDV RNA and accumulation of the HDV antigen in the cells. The infection was abrogated when using known entry inhibitors targeting NTCP or by disrupting genome replication using the nucleoside analogue Ribavirin. Upon infection, the HLCs mounted an innate immune response based on induction of the interferons IFNB and L, but not IFNA, and were associated with an upregulation of interferon-stimulated genes. The intensity of this immune response positively correlated with the level of viral replication and was dependant on both the JAK/STAT and NFκB pathway activation. Importantly, neither this innate immune response nor an exogenous treatment of IFNα2b inhibited HDV replication. However, pre-treatment of the HLCs with IFNα2b reduced viral infection, suggesting that ISGs may limit early stages of infection.This novel HDV in vitro infection model represents a valuable tool for studying HDV replication and investigating candidate antiviral drugs in cells displaying mature hepatic functions.Lay summaryHDV can infect stem cell-derived hepatocytes through an NTCP-mediated entry process. Infection triggers an IFN and NFκB dependent innate immune response. However, viral replication seems unaffected by this innate response or by exogenous IFN treatment.Graphical abstract
A TCF4/BRD4-dependent regulatory network confers cross-resistance to targeted and immune checkpoint therapy in melanoma
Authors: Pozniak Joanna , Pedri Dennis , Landeloos Ewout , Herck Yannick Van , Antoranz Asier , Karras Panagiotis , Nowosad Ada , Makhzami Samira , Bervoets Greet , Dewaele Michael , Vanwynsberghe Lukas , Cinque Sonia , Kint Sam , Vandereyken Katy , Voet Thierry , Vernaillen Frank , Annaert Wim , Lambrechts Diether , Boecxstaens Veerle , van den Oord Joost , Bosisio Francesca , Leucci Eleonora , Rambow Florian , Bechter Oliver , Marine Jean-Christophe 
Published: August 2022

AbstractPrimary resistance drastically limits the clinical success of immune checkpoint blockade (ICB) in melanoma. Resistance to ICB may also develop when tumours relapse after targeted therapy. To identify cancer cell-intrinsic mechanisms driving resistance to ICB, we generated single-cell RNA-sequencing (scRNA-seq) data from a prospective longitudinal cohort of patients on ICB therapy, including an early time point obtained after only one cycle of treatment. Comparing these data with murine scRNA-seq datasets, we established a comprehensive view of the cellular architecture of the treatment-naïve melanoma ecosystem, and defined 6 evolutionarily conserved melanoma transcriptional metaprograms (Melanocytic or MEL, Mesenchymal-like or MES, Neural Crest-like, Antigen Presentation, Stress (hypoxia response) and Stress (p53 response)). Spatial multi-omics revealed a non-random geographic distribution of cell states that is, at least partly, driven by the tumour microenvironment. The single-cell data allowed unambiguous discrimination between melanoma MES cells and cancer-associated fibroblasts bothin silicoandin situ, a long-standing challenge in the field. Importantly, two of the melanoma transcriptional metaprograms were associated with divergent clinical responses to ICB. While the Antigen Presentation cell population was more abundant in tumours from patients who exhibited a clinical response to ICB, MES cells were significantly enriched in early on-treatment biopsies from non-responders, and their presence significantly predicted lack of response. Critically, we identified TCF4 (E2-2) as a master regulator of the MES program and suppressor of both MEL and Antigen Presentation programs. TargetingTCF4expression in MES cells either genetically or pharmacologically using a bromodomain inhibitor increased immunogenicity and sensitivity to targeted therapy. This study describes an increasingly complex melanoma transcriptional landscape and its rapid evolution under ICB. It also identifies a putative biomarker of early response to ICB and an epigenetic therapeutic strategy that increases both immunogenicity of ICB-refractory melanoma and their sensitivity to targeted therapy.
Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma
Authors: Gaglia Giorgio , Burger Megan L. , Ritch Cecily C. , Rammos Danae , Dai Yang , Crossland Grace E. , Tavana Sara Z. , Warchol Simon , Jaeger Alex M. , Naranjo Santiago , Coy Shannon , Nirmal Ajit J. , Krueger Robert , Lin Jia-Ren , Pfister Hanspeter , Sorger Peter K , Jacks Tyler , Santagata Sandro 
Published: August 2022

ABSTRACTLymphocytes play a key role in immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. Here, we used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of tumor-bearing lung tissues from a Kras/p53 (KP) mouse model and human resections. Networks of directly interacting lymphocytes (‘lymphonets’) emerge as a distinctive feature of the anti-cancer immune response. Lymphonets nucleate from small T-cell clusters and incorporate B cells with increasing size. CXCR3-mediated trafficking modulates lymphonet size and number, but neoantigen expression directs intratumoral localization. Lymphonets preferentially harbor TCF1+/PD1+ progenitor CD8 T cells involved in responses to immune checkpoint blockade (ICB). Upon treatment of mice with ICB therapy or a neoantigen-targeted vaccine, lymphonets retain progenitor and gain cytotoxic CD8 T-cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8 T-cell anti-tumor responses.
FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation
Authors: Chen Dailu , Wosztyl Aleksandra , Mullapudi Vishruth , Bali Sofia , Vaquer-Alicea Jaime , Melhem Shamiram , Seelaar Harro , van Swieten John C. , Diamond Marc I. , Joachimiak Lukasz A. 
Published: August 2022

AbstractAmyloid deposition of the microtubule-associated protein tau is a unifying theme in a multitude of neurodegenerative diseases. Disease-associated missense mutations in tau are associated with frontotemporal dementia (FTD) and enhance tau aggregation propensity. However, the molecular mechanism of how mutations in tau promote tau assembly into amyloids remains obscure. There is a need to understand how tau folds into pathogenic conformations to cause disease. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation. We use recombinant protein and synthetic peptide systems, computational modeling, cross-linking mass spectrometry, and cell models to investigate the mechanism of spontaneous aggregation of the S320F FTD-tau mutant. We discover that the S320F mutation drives the stabilization of a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif. We identify a suppressor mutation that reverses the S320F aggregation phenotype through the reduction of S320F-based hydrophobic clustering in vitro and in cells. Finally, we use structure-based computational design to engineer rapidly aggregating tau sequences by optimizing nonpolar clusters in proximity to the S320 site revealing a new principle that governs the regulation of tau aggregation. We uncover a mechanism for regulating aggregation that balances transient nonpolar contacts within local protective structures or in longer-range interactions that sequester amyloid motifs. The introduction of a pathogenic mutation redistributes these transient interactions to drive spontaneous aggregation. We anticipate deeper knowledge of this process will permit control of tau aggregation into discrete structural polymorphs to aid design of reagents that can detect disease-specific tau conformations.
Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis
Authors: Lara-Astiaso D , Goñi-Salaverri A , Mendieta-Esteban J , Narayan N , Del Valle C , Gross T , Giotopoulos G , Navarro-Alonso M , Zazpe J , Marchese F , Torrea N , Calvo IA , Lopez C , Alignani D , Lopez A , Saez B , Taylor-King J. P , Prosper F , Fortelny N , Huntly B. J. P 
Published: August 2022

AbstractInteractions between transcription factors (TF) and chromatin factors (CF) regulate gene expression programmes to determine cellular fate. However, unlike for TF, the exact role of CF in this process is poorly understood. Using haematopoiesis as a model system and utilising novel functional CRISPR screens ex vivo and in vivo, coupled with Perturb-Seq, CF binding and genome-wide chromatin accessibility in primary murine cells, we assess the role of 550 chromatin factors in lineage choice in normal haematopoiesis and the maintenance of acute myeloid leukaemia (AML). These studies demonstrate marked specificity for a large number of CFs in lineage determination, highlighting functional diversity within specific families of chromatin regulators, including MLL-H3K4-methyltransferases and different BAF-complexes, that regulate disparate lineage decisions across haematopoiesis. Conversely, we demonstrate that unrelated Repressive complexes function similarly to restrain excessive myeloid differentiation and protect lineage diversity. We identify interactions between CF and TF that, at least in part, explain the regulatory function of CF and link Brd9-loss to a premalignant state. Utilising similar experiments in a relevant murine AML model, we demonstrate opposing effects for CF in normal haematopoiesis and AML, where MLL-H3K4-methyltransferases, c-BAF-remodelers and Repressive complexes prevent differentiation and maintain leukaemic fitness. We show that this alteration relates to differential utilisation of TF by CF complexes between normal and malignant haematopoiesis, highlighting corrupted TF-CF interactions as potential novel avenues for therapeutic intervention in AML. Together, this study provides novel insights on the functional diversity of chromatin factors in governing cell-fate.
A Dual Role for LAR-RPTP in Regulating Long-distance Transport and Synaptic Retention of AMPARs, Essential for Long Term Associative Memory
Authors: Pierce D.M. , Lenninger Z. , Doser R.L. , Knight K.M. , Stetak A. , Hoerndli F.J. 
Published: August 2022

SUMMARYThe AMPA subtype of ionotropic glutamate receptors (AMPARs) plays an essential role in excitatory synaptic transmission, learning, and memory. The majority of AMPARs are made in the cell body and are transported by molecular motors to synapses. Maintaining the proper number of synaptic receptors requires coordinated regulation of receptor production, export from the soma and delivery at synapses. This major logistical process is essential for circuit function and behavior. Although recent studies have shown that long-distance synaptic transport is regulated by neuronal activity, little is known about the mechanisms that coordinate somatic export or synaptic delivery and removal. Here we show that loss of the PTP-3A isoform of the receptor tyrosine phosphatase PTP-3 (the C. elegans homologue of vertebrate LAR-RPTP) leads to a ∼60% decrease in AMPAR transport; this affects synaptic delivery of AMPARs and synaptic functions necessary for long-term associative olfactory memory in C. elegans. Interestingly, while complete loss of PTP-3A leads to defects in transport and local synaptic trafficking of AMPARs, loss of only PTP-3 phosphatase function affects local synaptic recycling and retention of AMPARs. Finally, we show that the N-terminus of PTP-3A regulates transport, whereas the C-terminal regulates synaptic retention of AMPARs. Altogether, our results suggest a model in which the two domains of PTP-3/LAR-RPTPs have specific, complementary roles in coordinating somatic export and local retention of AMPARs essential for long-term associative memory.
Measurement error associated with gait cycle selection in treadmill running at various speeds
Authors: Fox Aaron S. , Bonacci Jason , Warmenhoven John , Keast Meghan F. 
Published: August 2022

AbstractA common approach in biomechanical analysis of running technique is to average data from several gait cycles to compute a ‘representative mean.’ However, the impact of the quantity and selection of gait cycles on biomechanical measures is not well understood. We examined the effects of gait cycle selection on kinematic data by: (i) comparing representative means calculated from varying numbers of gait cycles to ‘global’ means from the entire capture period; and (ii) comparing representative means from varying numbers of gait cycles sampled from different parts of the capture period. We used a public dataset (n = 28) of lower limb kinematics captured during a 30-second period of treadmill running at three speeds (2.5m · s-1, 3.5m · s-1 and 4.5m · s-1). ‘Ground truth’ values were determined by averaging data across all collected strides and compared to representative means calculated from random samples (1,000 samples) of n (range = 5—30) consecutive gait cycles. We also compared representative means calculated from n (range = 5—15) consecutive gait cycles randomly sampled (1,000 samples) from within the same data capture period. The mean, variance and range of the absolute error of the representative mean compared to the ‘ground truth’ mean progressively reduced across all speeds as the number of gait cycles used increased. Similar magnitudes of ‘error’ were observed between the 2.5m · s-1 and 3.5m · s-1 speeds at comparable gait cycle numbers — where the maximum errors were < 1.5 degrees even with a small number of gait cycles (i.e. 5-10). At the 4.5m · s-1 speed, maximum errors typically exceeded 2-4 degrees when a lower number of gait cycles were used. Subsequently, a higher number of gait cycles (i.e. 25-30) was required to achieve low errors (i.e. 1-2 degrees) at the 4.5m · s-1 speed. The mean, variance and range of absolute error of representative means calculated from different parts of the capture period was consistent irrespective of the number of gait cycles used. The error between representative means was low (i.e. <1.5 degrees) and consistent across the different number of gait cycles at the 2.5m · s-1 and 3.5m · s-1 speeds, and consistent but larger (i.e. up to 2-4 degrees) at the 4.5m · s-1 speed. Our findings suggest that selecting as many gait cycles as possible from a treadmill running bout will minimise potential ‘error.’ Analysing a small sample (i.e. 5-10 cycles) will typically result in minimal ‘error’ (i.e. < 2 degrees), particularly at lower speeds (i.e. 2.5m · s-1 and 3.5m · s-1). Researchers and clinicians should consider the balance between practicalities of collecting and analysing a smaller number of gait cycles against the potential ‘error’ when determining their methodological approach. Irrespective of the number of gait cycles used, we recommend that the potential ‘error’ introduced by the choice of gait cycle number be considered when interpreting the magnitude of effects in treadmill-based running studies.
A microglia-CD4+ T cell partnership generates protective anti-tumor immunity to glioblastoma
Authors: Chen Dan , Varanasi Siva Karthik , Hara Toshiro , Traina Kacie , McDonald Bryan , Farsakoglu Yagmur , Clanton Josh , Xu Shihao , Mann Thomas H. , Du Victor , Chung H. Kay , Xu Ziyan , Tripple Victoria , Casillas Eduardo , Ma Shixin , O’Connor Carolyn , Yang Qiyuan , Zheng Ye , Hunter Tony , Lemke Greg , Kaech Susan M. 
Published: August 2022

SummaryThe limited efficacy of immunotherapies against glioblastoma illustrates the urgent need to better understand the interactions between the central nervous system and the immune system. Here, we showed that a protective response to αCTLA-4 therapy depended on a mutualistic relationship between microglia and CD4+ T cells. Suppression of gliomas by CD4+ T cells did not require tumor-intrinsic MHC-II expression, but rather was dependent on the selective expression of MHC-II and antigen presentation by local microglia that in turn, sustained CD4+ T cell tumoricidal effector functions. CD4+ T cell secretion of IFNγ made the glioma cells vulnerable to enhanced tumor surveillance and phagocytosis by microglia via the AXL/MER tyrosine kinase receptors that were necessary for tumor suppression. This work illustrates a novel partnership between CD4+ T cells and microglia that unleashes the tumoricidal properties of microglia that can be harnessed to improve immunotherapies for glioblastoma.
Dendritic cell-Natural Killer cell Crosstalk Modulates T cell activation in Response to Influenza A Viral Infection
Authors: Harvey Abigail G. , Graves Athens M. , Uppalapati Chandana K. , Matthews Saoirse M. , Rosenberg Stephanie , Fagerlie Madison H. , Guinan Jack , Lopez Brina , Kronstad Lisa M. 
Published: August 2022

AbstractInfluenza viruses lead to substantial morbidity and mortality including ~3-5 million cases of severe illness and ~290,000-650,000 deaths annually. One of the major hurdles regarding influenza vaccine efficacy is generating a durable, robust cellular immune response. Appropriate stimulation of the innate immune system is key to generating cellular immunity. Crosstalk between innate dendritic cells (DC) and natural killer (NK) cells plays a key role in activating virus-specific T cells, yet the mechanisms used by influenza A viruses (IAV) to govern this process remain incompletely understood. Here, we used anex vivoautologous human primary immune cell culture system to evaluate the impact of genetically distinct IAV strains on DC-NK cell crosstalk and subsequent T cell activation. We report that the addition of NK cells to cultures containing both DCs and naïve T cells led to an increase in the frequency of CD69+and CD25+T cells and elevated levels of IFN-γ, TNF, and IL-10. However, upon IAV infection of DCs, the addition of NK cells to cultures no longer increased the frequency of CD25+T cells nor elevated IFN-γ, TNF, and IL-10 cytokine levels. Investigation of the impact of IAV infection on DC-NK crosstalk revealed that exposure of DCs to influenza virus in co-culture led to an increased frequency of HLA-DR+and a decreased frequency of CD83+and CD86+cells–molecules involved in stimulating T cell activation. An expansion of an HLA-DR+NK cell subset was observed following culture with influenza-infected DCs in a contact-dependent and cytokine independent-manner. Overall, our results indicate a role for DC-NK cell crosstalk in T cell priming in the context of influenza infection, informing the immunological mechanisms that could be manipulated for the next generation influenza vaccine or immunotherapeutic.
Somatic and terminal CB1 receptors are differentially coupled to voltage-gated sodium channels in neocortical neurons
Authors: Steiger Luke , Tsintsadze Timur , Mattheisen Glynis B. , Smith Stephen M. 
Published: August 2022

SummaryEndogenous cannabinoid signaling is vital for important brain functions and can be modified pharmacologically to treat pain, epilepsy, and posttraumatic stress disorder. Endocannabinoid mediated changes to excitability are predominantly attributed to 2-arachidonoylglycerol at synapses. Here we identify a pathway in the neocortex by which anandamide, the other major endocannabinoid, powerfully inhibits sodium conductances in the soma resulting in a loss of neuronal excitability. This pathway is mediated by the cannabinoid receptor, and its activation results in a decrease of recurrent action potential generation. The synthetic cannabinoid, WIN 55,212-2, also inhibits VGSC currents indicating this pathway is positioned to mediate the actions of exogenous cannabinoids.HighlightsAnandamide (AEA), a major endocannabinoid, indirectly inhibits VGSC currents in neocortical neurons.This prevalent signaling pathway involves AEA activation of CB1 and other G-protein-coupled receptors localized to the intracellular compartment of neurons.CB1 activation by AEA reduces VGSC availability at the soma but not at the axonal compartment suggesting tighter functional coupling between VGSCs and CB1 at the cell body.Cannabinoid action on somatic CB1 inhibits VGSCs with high efficacy, providing a parallel pathway outside of nerve terminals, by which these ligands reduce neuronal excitability in the neocortex.