bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gut microbiome is associated with recurrence-free survival in patients with resected Stage IIIB-D or Stage IV melanoma treated with immune checkpoint inhibitors
Authors: Usyk Mykhaylo , Hayes Richard B. , Knight Rob , Gonzalez Antonio , Li Huilin , Osman Iman , Weber Jeffrey S. , Ahn Jiyoung 
Published: April 2024

SummaryThe gut microbiome (GMB) has been associated with outcomes of immune checkpoint blockade therapy in melanoma, but there is limited consensus on the specific taxa involved, particularly across different geographic regions. We analyzed pre-treatment stool samples from 674 melanoma patients participating in a phase-III trial of adjuvant nivolumab plus ipilimumab versus nivolumab, across three continents and five regions. Longitudinal analysis revealed that GMB was largely unchanged following treatment, offering promise for lasting GMB-based interventions. In region-specific and cross-region meta-analyses, we identified pre-treatment taxonomic markers associated with recurrence, includingEubacterium, Ruminococcus, Firmicutes, andClostridium. Recurrence prediction by these markers was best achieved across regions by matching participants on GMB compositional similarity between the intra-regional discovery and external validation sets. AUCs for prediction ranged from 0.83-0.94 (depending on the initial discovery region) for patients closely matched on GMB composition (e.g., JSD ≤0.11). This evidence indicates that taxonomic markers for prediction of recurrence are generalizable across regions, for individuals of similar GMB composition.HighlightsOverall gut microbiome (GMB) composition is largely unchanged during ICB treatment.GMB composition varies by geographic regionWe identified gut bacterial markers associated with recurrence in region-specific analyses.Region-identified markers are generalizable if GMB composition is taken into account by matching.
Chronic activation of astrocytic GqGPCR signaling has causal effects on visual LTP formation: implications for neurodegenerative diseases
Authors: Moukarzel Elsie , Antoine Sharmilee , Guinoiseau Sophie , Rubino Bruna , Stinnakre Jacques , Agulhon Cendra 
Published: April 2024

AbstractAstrocytes are the most abundant glial cells in the central nervous system and interact with other cell types, including neurons and microglia,viaGqprotein-coupled receptors (GqGPCRs) present on their surface. Astrocytic GqGPCR activation induces Ca2+release from internal stores, leading to intracellular Ca2+elevations. There is emerging evidence supporting that astrocytic GqGPCR Ca2+elevations are upregulated and dysregulated in neurodegenerative diseases and are thought to play an important role in the pathogenesis of such diseases. Furthermore, astrocytic GqGPCR Ca2+-dependent release of neuroactive or inflammatory molecules from astrocytes may occur in the early steps of the stress/inflammatory process in the diseased brain. In addition, low grade and chronic brain inflammation is involved in the etiology of neurodegenerative diseases.We hypothesized that chronic activation of astrocytic GqGPCR Ca2+signaling leads to an altered production of glutamate or pro-inflammatory factors from astrocytes, and consequent deficits in synaptic transmission, long-term potentiation (LTP), and memory formation. To test this hypothesis, we used an AAV-based chemogenetic tool to selectively activate astrocyte GqGPCR Ca2+signaling combined within vivoelectrophysiology, immunohistochemistry, and biochemistry.Using the mouse primary visual cortex (V1) as a model system, we found that chronically increased astrocytic GqGPCR Ca2+signaling leads to a decrease in LTP of visual-evoked potentials. Such LTP impairment was associated with microglial reactive phenotype - displaying a hyper-ramified and proliferative state - as well as a decrease in the number of interleukin 33 (IL-33)-expressing astrocytes. Our study is the first to have shown that chronic astrocytic GqGPCR activation is sufficient to alter visual LTP and induce astrocyte-to-microglia communication, possibly through and IL-33 pathway in the adult brain. Because GPCRs are important drug targets, our study could have relevant therapeutic implications in the treatment of some neurodegenerative diseases.
The dynamic fitness landscape of ageing haematopoiesis through clonal competition
Authors: Mon Père Nathaniel , Terenzi Francesco , Werner Benjamin 
Published: April 2024

AbstractClonal haematopoiesis (CH) – the ubiquitous expansion of variants in blood with age – is a prime example of ongoing somatic evolution in otherwise normal human tissues. The details of the underlying evolutionary processes and how they drive clonal dynamics and intra-tissue genetic heterogeneity remain to be understood. Here we show that clonal competition can explain the complex dynamics of CH with age. According to the model numerous clones of differing fitness continually appear and compete. This clonal competition implies an emerging fitness landscape of haematopoietic stem cells (HSCs) that changes over time in a highly stochastic manner within and between individuals. It naturally explains the presence of decreasing variant trajectories and declining average fitness in the elderly, the varying fitness of identical variants across individuals, and characteristic transitions of site frequency spectra with age. Comparisons of stochastic simulations of clonal competition-driven CH to time resolved clone trajectories in 385 individuals, and to changes of the HSC site frequency spectrum from newborns to octogenarians allow us to estimate the shape of the innate CH fitness distribution and the arrival rate of advantageous clones. We find a non-exponential fitness distribution with mean 0.07 to 0.09 and standard deviation 0.025 per year. We estimate an arrival rate of 2 to 20 advantageous clones per year, but the number of detectable clones above 1% frequency in the HSC population to remain between 3 to 20 by the age of 80.
Immunocompetent Cell Targeting by Food-Additive Titanium Dioxide
Authors: Wills John W. , Dabrowska Alicja , Robertson Jack , Miniter Michelle , Riedle Sebastian , Summers Huw D. , Hewitt Rachel E. , Fathima Adeeba , da Silva Alessandra Barreto , Bastos Carlos A. P. , Micklethwaite Stuart , Keita Åsa V. , Söderholm Johan D. , Roy Nicole C. , Otter Don , Jugdaohsingh Ravin , Mastroeni Pietro , Brown Andy P. , Rees Paul , Powell Jonathan J. 
Published: April 2024

ABSTRACTFood-grade titanium dioxide (fgTiO2) is a bio-persistent particle under intense regulatory scrutiny. Paradoxically, meaningfulin vivocellular accumulation has never been demonstrated: the only known cell reservoirs for fgTiO2are ‘graveyard’ intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify major new immunocompetent cell targets of fgTiO2in humans, most notably in the subepithelial dome region of intestinal Peyer’s patches. Using multimodal microscopy techniques with single-particle detection and per-cell / vesicle image analysis we achieved correlative dosimetry, quantitatively recapitulating human cellular exposures in the terminal ileum of mice fed a fgTiO2-containing diet. Epithelial microfold cells selectively funneled fgTiO2into LysoMac and LysoDC cells with ensuing accumulation. Notwithstanding, proximity extension analyses for 92 protein targets revealed no measureable perturbation of cell signalling pathways. When chased with oral ΔaroA-Salmonella, pro-inflammatory signalling was confirmed, but no augmentation by fgTiO2was revealed despite marked same-cell loading. Interestingly,Salmonellacaused the fgTiO2-recipient cells to migrate basolaterally in the patch and, sporadically, to the lamina propria, thereby fully recreating the intestinal tissue distribution of fgTiO2in humans. Immunocompetent cells that accumulate fgTiO2in vivoare now identified and we demonstrate a mouse model that finally enables human-relevant risk assessments of ingested, bio-persistent (nano)particles.
Tissue factor-dependent colitogenic CD4+ T cell thrombogenicity is regulated by activated protein C signalling
Authors: Leon Gemma , Klavina Paula A. , Rehill Aisling M. , Basavarajappa Shrikanth Chomanahalli , O’Donnell James S. , Hussey Seamus , Walsh Patrick T. , Preston Roger J.S. 
Published: April 2024

ABSTRACTInflammatory bowel disease (IBD) patients experience up to 6-fold increased risk of venous thromboembolism (VTE) compared to the general population, although the mechanistic basis for this increased risk remains poorly defined. We found that colitogenic CD4+T cells express tissue factor (TF) and promote rapid TF-dependent plasma thrombin generation in T cell-dependent calibrated automated thrombinography assays. Furthermore, we identified the presence of TF+CD4+CD3+T cells in the colons of both mice with colitis and paediatric IBD patients during active disease. TF is typically expressed in an ‘encrypted’ state and requires decryption for optimal procoagulant activity. Notably, flow cytometric analysis demonstrated that activated CD4+T cells express significantly increased acid sphingomyelinase and protein disulphide isomerase, critical mediators for TF decryption, on their cell membrane compared to naïve T cells. The protein C (PC) pathway is an important regulator of TF-mediated thrombin generation. Pertinently, pre-clinical studies suggest an important role for diminished PC pathway activity in IBD pathophysiology. To understand how this process might be regulated, we performed meta-transcriptomic and gene expression analysis of IBD patient gut biopsy tissue, identifying dysregulated expression of genes involved in the regulation of coagulation, including PC (PROC)and its receptor (EPCR;PROCR). Subsequent functional studies revealed that activated protein C (APC) signalling reduced colitogenic T cell generation and activity, potently impaired TF decryption and significantly reduced T cell-mediated thrombin generation and clot formation. These data identify TF-mediated colitogenic T cell thrombogenicity and demonstrate a new role for APC signalling in regulating T cell thrombo-inflammatory activity.
Rostral Pedunculopontine Nucleus Infusion of M4Positive Allosteric Modulator VU0467154 Augments L-DOPA Effects in Hemiparkinsonian Rats
Authors: Chambers Nicole E. , McLune Annique , Coyle Michael , Centner Ashley , Sergio Jordan , Delpriore Isabella , Lanza Kathryn , Lindsley Craig W. , Conn P. Jeffrey , Bishop Christopher 
Published: April 2024

ABSTRACTStandard treatment for Parkinson’s disease (PD) is dopamine replacement therapy with L-DOPA. However, chronic treatment often results in abnormal involuntary movements called L-DOPA-induced dyskinesia (LID). Prior evidence indicates that heightened striatal cholinergic tone may contribute to LID. Restoring cholinergic inhibition by targeting the inhibitory M4muscarinic acetylcholine (ACh) receptor (M4) reduces LID in preclinical models. Although intrinsic striatal sources of ACh have been considered for their role in LID, extrinsic sources of ACh such as the pedunculopontine nucleus (PPN) have not been well investigated for their role in LID. Therefore, the current study employed hemiparkinsonian Long-Evans rats with a PPN-targeted cannula ipsilateral to 6-OHDA lesion. Following chronic treatment with L-DOPA, we examined the effect of local unilateral PPN infusion of M4PAM VU0467154 on LID, motor performance, and c-fos expression within the PPN. It was expected that PPN infusion of VU0467154 would reduce LID, reduce L-DOPA’s motor benefit, and globally reduce c-fos expression in the PPN. Contrary to our expectations, PPN infusion of M4PAM did not significantly affect LID severity. Furthermore, the group receiving M4PAM showed slightly elevated motor improvement compared to L-DOPA, and decreased c-fos expression specifically in PPN cholinergic neurons. These results suggest that local PPN ACh dynamics differ from those of the striatum. Specifically, our results suggest that PPN cholinergic neurons may be a promising therapeutic target for augmenting L-DOPA-mediated motor benefit without increasing LID.
Dissociable memory modulation mechanisms facilitate fear amnesia at different timescales
Authors: Ni Yinmei , Wang Ye , Zhu Zijian , Hu Jingchu , Schiller Daniela , Li Jian 
Published: April 2024

AbstractMemory reactivation renders consolidated memory fragile and sets the stage for memory reconsolidation. However, whether memory retrieval facilitates update mechanisms other than memory reconsolidation remains unclear. We tested this hypothesis in three experiments with healthy human participants. First, we demonstrate that memory retrieval-extinction protocol prevents the return of fear expression shortly after extinction training and this short-term effect is memory reactivation dependent (Study 1,N= 57 adults). Furthermore, across different timescales, the memory retrieval-extinction paradigm triggers distinct types of fear amnesia in terms of cue-specificity and cognitive control dependence, suggesting that the short-term fear amnesia might be caused by different mechanisms from the cue-specific amnesia at a longer and separable timescale (Study 2,N= 79 adults). Finally, using continuous theta-burst stimulation (Study 3,N= 75 adults), we directly manipulated brain activity in the dorsolateral prefrontal cortex, and found that both memory reactivation and intact prefrontal cortex function were necessary for the short-term fear amnesia after the retrieval-extinction protocol. The differences in temporal scale, cue-specificity, and cognitive control ability dependence between the short- and long-term amnesia suggest that memory retrieval and extinction training trigger distinct underlying memory update mechanisms. These findings suggest the potential involvement of coordinated memory modulation processes upon memory retrieval and may inform clinical approaches for addressing persistent maladaptive memories.
CA1 Engram Cell Dynamics Before and After Learning
Authors: Monasterio Amy , Lienkaemper Caitlin , Coello Siria , Ocker Gabriel K. , Ramirez Steve , Scott Benjamin B. 
Published: April 2024

SummaryA fundamental question in neuroscience is how memory formation shapes brain activity at the level of populations of neurons. Recent studies of hippocampal ‘engram’ cells, identified by immediate-early genes (IEGs) induced by learning, propose that these populations act as a neuronal substrate for memory storage. The current framework for engram formation proposes that cells join ensembles based on increased intrinsic excitability, and that after initial learning, they co-activate to support memory retrieval. However, direct evidence of how engram population dynamics evolve across learning is limited. Here we combined activity-dependent genetic tagging and two-photon calcium imaging to characterize CA1 engram population activity before and after learning. We observed that spontaneous activity two days before learning predicted genetic tagging, consistent with a model in which spontaneous fluctuations bias cells into forming engram assemblies. Surprisingly, we were unable to detect increased spontaneous activity rates or pairwise correlations amongst tagged CA1 neurons after learning. These results were consistent with computational network models that incorporate strong and specific inhibitory connections, supporting the idea that excitatory/inhibitory balance in CA1 may play a key role in engram dynamics. Together these results highlight a potential role for slow time scale excitability fluctuations in driving engram formation and suggest that excitatory-inhibitory balance may regulate engram cell co-activation.HighlightsTracked calcium activity and Fos tagging in CA1 across time and learning.Spontaneous activity days before learning predicts TetTagging.No observed changes in TetTagged cell correlations in spontaneous activity after learning.Modeling suggests E/I balance regulates engram dynamics
Ultra-secure storage and analysis of genetic data for the advancement of precision medicine
Authors: Blindenbach Jacob , Kang Jiayi , Hong Seungwan , Karam Caline , Lehner Thomas , Gürsoy Gamze 
Published: April 2024

1AbstractCloud computing provides the opportunity to store the ever-growing genotype-phenotype data sets needed to achieve the full potential of precision medicine. However, due to the sensitive nature of this data and the patchwork of data privacy laws across states and countries, additional security protections are proving necessary to ensure data privacy and security. Here we present SQUiD, asecurequeryabledatabase for storing and analyzing genotype-phenotype data. With SQUiD, genotype-phenotype data can be stored in a low-security, low-cost public cloud in the encrypted form, which researchers can securely query without the public cloud ever being able to decrypt the data. We demonstrate the usability of SQUiD by replicating various commonly used calculations such as polygenic risk scores, cohort creation for GWAS, MAF filtering, and patient similarity analysis both on synthetic and UK Biobank data. Our work represents a new and scalable platform enabling the realization of precision medicine without security and privacy concerns.
Cure or Curse? Simulation Indicates that Microbes Proliferate under Disinfection Measures in the Space Station
Authors: Li Shuaishuai , Liu Xiaolei , Chen Letian , Liu Hong , Hu Dawei 
Published: April 2024

AbstractThe long-term stay on the space station requirement poses a knotty issue about the stable hardware and reliable guarantee of astronauts’ health. Despite regular cleaning with wipes, microbes still proliferate in the space station. This study distilled three key factors—low-dose ionizing radiation, dilution and quaternary ammonium compound from the scenario. Species abundance and differential metabolites were applied to test their sole/combined influences on the three-simple-species microbial community succession. Mechanisms were built in mathematical models to generate the structural and behavior similarity. Results showed that LDIR, dilution and QAC, solely or jointly, could contribute to microbial proliferation. The synergy of disturbances might convert them from harmful factors to rewarding ones (e.g. the transformation of QAC into nutrients under LDIR), leading to this “Ecological Surprise”. These results shed light on mechanisms driving microbial community succession in the space station and highlight the need for tailored biocontrol strategies in the specific environment.
Insight into the Impact of Air Flow Rate on Algal-Bacterial Granules: Reactor Performance, Hydrodynamics by Computational Fluid Dynamics (CFD) and Microbial Community Analysis
Authors: Zhang Tengge , El-Sayed Waleed M. M. , Zhang Jie , He Leiyu , Bruns Mary Ann , Wang Meng 
Published: April 2024

AbstractAlgal-bacterial granules have been drawing attention in wastewater treatment due to their rapid settling ability and efficient nutrient removal performance. This study evaluated the impact of air flow rates on nitrogen removal and the formation of algal-bacterial granules in domestic wastewater treatment. The highest nitrogen removal efficiency was achieved by operating with two separate feedings and the addition of an external carbon source. The higher air flow rate resulted in a higher nitrification rate and produced smaller and more compact granules on average. However, increasing the air flow rate did not necessarily increase extracellular polymeric substances (EPS) production. Computational Fluid Dynamics (CFD) simulations revealed that mechanical mixing was the primary source of shear force. Increasing the air flow rate from 0.2 LPM to 0.5 LPM only yielded a 12% increment in the volume-averaged strain rate. Further analysis of microbial communities showed that changes in bioreactor operation, especially sodium acetate addition and aerations, shifted the microbial community composition. The sodium acetate addition led to the increase of microbial diversity and the relative abundance of denitrifiers such asThauera, while the aeration caused the increasing relative abundances of nitrogen-related genera (such asNitrospira) and the decreasing relative abundances of cyanobacteria andChlorellain the long-term operation of the photobioreactors. Moreover, the decrease in total abundance of grazers and pathogens along with the operation, includingChytridiomycetes, Sessilida, and Operculariidae, might result from the shear force and the decrease of prokaryotic species, such asChlorellaspp..HighlightsA higher air flow rate resulted in a higher nitrification rate.Shear stress, microbial composition, and carbon source affected EPS production.Increasing the air flow rate from 0.2 to 0.5 LPM led to only 12% of the increment of shear stress.Microbial community differed with aeration rate and carbon source.Graphical Abstract
CoralBleachRisk-Global projections of coral bleaching risk in the 21stcentury
Authors: Mellin Camille , Brown Stuart C , Heron Scott F , Fordham Damien A 
Published: April 2024

AbstractTiming, duration, and severity of marine heatwaves are changing rapidly in response to anthropogenic climate change, thereby increasing the frequency of coral bleaching events. Mass coral bleaching events occur because of cumulative heat stress, which is commonly quantified through Degree Heating Weeks (DHW). Here we introduceCoralBleachRisk, a daily-resolution global dataset that characterises sea surface temperatures, heat stress anomalies, and the timing, duration, and magnitude of severe coral bleaching conditions from the recent past (1985) to the future (2100) under three contrasting Shared Socioeconomic Pathways. Our projections are downscaled to a 0.5° resolution (~50km), bias-corrected and validated using remotely sensed data of sea surface temperatures and a global dataset of historical coral bleaching events. An accompanying online software tool allows non-specialist users to access aggregated metrics of coral bleaching risk and generate time series projections of coral vulnerability for Earth’s coral reefs. More broadly, our dataset enables regional to global comparisons of future trends in severe coral bleaching risk and the identification of potential climate refugia for corals.
A 3D atlas of sexually dimorphic lumbosacral motor neurons that control and integrate pelvic visceral and somatic functions in rats
Authors: Fuller-Jackson John-Paul , Yang Ziying , Wiedmann Nicole M , Watson Alan , Jenkins Nathaniel EC , Keast Janet R , Osborne Peregrine B 
Published: April 2024

AbstractThe lumbosacral spinal motor system comprises somatic motor neurons (SMNs) that target striated muscle and visceral motor neurons (VMNs; autonomic preganglionic neurons) that target peripheral ganglia. The brain coordinates these pathways to mediate functions such as continence, voiding and sexual function by ensuring appropriate changes of organ state with striated muscle activity (e.g., sphincter opening, relevant postural changes). These spinal circuits are important therapeutic targets for bioelectronic medicine yet are poorly defined in comparison with limb SMNs. We aimed to define the structural features and relationships between SMNs and VMNs relevant to pelvic function in male and female rats, by building 3D maps of lumbosacral spinal cord. We achieved this by applying large-volume immunostaining (choline acetyltransferase), with tissue clearing and advanced whole mount microscopy (light sheet and ribbon scanning confocal microscopy). We identified VMNs specific to pelvic organ function by microinjecting cholera toxin (beta-subunit) into the major pelvic ganglia (MPG). These VMNS are primarily located in segments L1-L2 (dorsal commissural nucleus) and L6-S1 (intermediolateral nucleus). Unexpectedly, small groups of SMNs in the urethral rhabdosphincter, cremaster and levator ani motor pools also projected through the MPG. Motor neuron counts and analysis of dendritic fields detected sexual dimorphism in both SMNs and VMNs. Their colocation of dendritic bundles suggested a mechanism of coordinating activity. This study has provided the first multiscale 3D atlas of rat lumbosacral cord. This will be shared as a resource on an open science platform (sparc.science) to allow further exploration and modeling of network features and cellular morphology.