bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlated host movements can reshape spatio-temporal disease dynamics: modeling the contributions of space use to transmission risk using movement data
Authors: Vargas Soto Juan S. , Kosiewska Justin , Muller Lisa I. , Grove Dan , Metts Dailee , Wilber Mark Q.
Published: April 2024

Despite decades of epidemiological theory making relatively simple assumptions about host movements, it is increasingly clear that non-random movements drastically affect disease transmission. To better predict transmission risk, theory needs to simultaneously account for how the environment affects host space use and how social dynamics affect correlation in space use. We develop new theory that decomposes the relative contributions of fine-scale space use and correlated movements to spatio-temporal transmission risk. Using analytical results, simulations, and empirical movement data, we show that even weak correlations can increase transmission risk by orders of magnitude compared to independent movement. Accounting for correlation is especially critical for pathogens with direct transmission or short environmental persistence. Our theory provides clear expectations for what has been observed empirically but largely ignored in disease models—movement correlation can reshape epidemiological landscapes, creating transmission hotspots whose magnitude and location are not necessarily predictable from spatial overlap alone.
A newOpn4crerecombinase mouse line to target intrinsically photosensitive retinal ganglion cells (ipRGCs)
Authors: Dyer Brannen , Yu Sue O. , Brown R. Lane , Lang Richard A. , D’Souza Shane P.
Published: April 2024

Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a crucial role in several physiological light responses. In this study we generate a newOpn4creknock-in allele (Opn4cre(DSO)), in which cre is placed immediately downstream of theOpn4start codon. This approach aims to faithfully reproduce endogenousOpn4expression and improve compatibility with widely used reporters. We evaluated the efficacy and sensitivity ofOpn4cre(DSO)for labeling in retina and brain, and provide an in-depth comparison with the extensively utilizedOpn4cre(Saha)line. Through this characterization,Opn4cre(DSO)demonstrated higher specificity in labeling ipRGCs, with minimal recombination escape. Leveraging a combination of electrophysiological, molecular, and morphological analyses, we confirmed its sensitivity in detecting all ipRGC types (M1-M6). Using this new tool, we describe the topographical distributions of ipRGC types across the retinal landscape, uncovering distinct ventronasal biases for M5 and M6 types, setting them apart from their M1-M4 counterparts. In the brain, we find vastly different labeling patterns between lines, withOpn4cre(DSO)only labeling ipRGC axonal projections to their targets. The combination of off-target effects ofOpn4cre(Saha)across the retina and brain, coupled with diminished efficiencies of bothCrelines when coupled to less sensitive reporters, underscores the need for careful consideration in experimental design and validation with anyOpn4credriver. Overall, theOpn4cre(DSO)mouse line represents an improved tool for studying ipRGC function and distribution, offering a means to selectively target these cells to study light-regulated behaviors and physiology.
Combining pupillometry and drift-diffusion models reveals auditory category learning dynamics
Authors: McHaney Jacie R. , Roark Casey L. , McGinley Matthew J. , Chandrasekaran Bharath
Published: April 2024

Pupillometry and drift-diffusion models (DDM) have emerged as powerful tools to offer insights into learning processes and decisional dynamics. Specifically, pupillary dilation can serve as a metric of arousal and cognitive processing, and DDMs examine processes underlying perceptual decision-making using behavioral accuracies and response times. Methodological constraints have complicated the combination of the two methods in the study of learning. DDMs require precise response times, yet pupillary responses are slow and are impacted by motor movements. Here, we developed a learning task that separately optimized measurement of behavioral response times and pupil dilation during learning. We modified a standard learning paradigm to include trials with and without timing delays between stimulus presentation and response. Delayed trials optimized measurement of the pupil, while immediate trials optimized behavioral response times. We tested whether decision-making processes estimated with DDMs could be recovered from delayed trials where pupil response measurement was optimized. Our results indicated that pupil responses on delayed trials showed distinct markers of learning that were not present on immediate trials. DDM parameters from delayed trials also showed expected trends for learning. Finally, we demonstrated that DDM parameters elicit differential pupillary responses. Together, these results indicate that learning dynamics and decisional processes can be decoded from pupillary responses.
DNA glycosylases Ogg1 and Mutyh mediate gene expression of PRC2 target genes important for neuronal processes underlying memory formation
Authors: Abentung Andreas , Sakshaug Teri , Dumaru Rabina , Liabakk Nina-Beate , Yang Mingyi , Wang Junbai , Bjørås Magnar , Scheffler Katja
Published: April 2024

Base excision repair (BER) initiated by DNA glycosylases is known to preserve genomic integrity by removing damaged bases. Recently, several DNA glycosylases were identified as potential readers of epigenetic modifications and proteins involved in BER have been associated with active DNA demethylation. DNA glycosylases Ogg1 and Mutyh were shown to alter the hippocampal transcriptome associated with cognitive function and independent of global DNA damage accumulation. However, the mechanism of DNA glycosylases in regulating cognition and their role in epigenetic remodeling in the brain remains elusive. Here we report that the combined deficiency of Ogg1 and Mutyh impairs spatial but not associative long-term memory. We demonstrate that Ogg1 or Mutyh modulate DNA methylation at gene regulatory regions of polycomb repressive complex 2 (PRC2) target genes in the adult hippocampus. Moreover, we find that the distribution of the PRC2 complex and histone modifications associated with PRC2 activity changes in both hippocampal neurons and glia depend on Ogg1 and Mutyh. Epigenetic alterations correlated with cell-type specific gene expression changes which were associated with pathways important for neuronal function and cognition. Our results provide a novel role for Ogg1 and Mutyh beyond DNA repair in modulating the epigenome to control transcriptional responses in the brain important for memory formation.
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

The 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.

Highlights

Overall gut microbiome (GMB) composition is largely unchanged during ICB treatment.

GMB composition varies by geographic region

We 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

Astrocytes 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

Clonal 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

Food-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

Inflammatory 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

Standard 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

Memory 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

A 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.

Highlights

Tracked 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

1

Cloud 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

The 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

Algal-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..

Highlights

A 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

Timing, 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

The 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.
Calneuron 1 reveals the pivotal roles in schizophrenia via perturbing human forebrain development and causing hallucination-like behavior in mice
Authors: Li Hui-Juan , Yu Xiao , Liu Xi , Xu Jinhong , Chen Jinlong , Cheng Tianlin , Chung Sangmi , Shu Yousheng , Shao Zhicheng
Published: April 2024

Schizophrenia is a highly heritable neurodevelopmental disorder with unknown genetic pathogenic mechanisms. Here, we selected 11 schizophrenia risk genes and generated single-gene-knockout-precise-dorsal/ventral-forebrain-organoids (SKOPOS) via CRISPR-Cas9 system. 90 bulk and 249,430 single-cell RNA-sequencing of SKOPOS revealed that knockout of 11 risk genes lead to different levels of deficits in dorsal/ventral forebrain organoids. Among them, calneuron 1 (CALN1) acts as a pivotal pathogenic gene of schizophrenia via severe disruption of gene expression network, interaction with about 32% (34/106) known schizophrenia risk genes, delayed maturation and impaired spontaneous neural circuit in human developing forebrain. Furtherly, including the spontaneous abrupt burst spiking in cortical neurons and the defects of spatial memory, cognition and social ability,Caln1KO mice surprisingly displayed spontaneous startle behavior and head-twitch response correlated with hallucination-like behavior, which could be inhibited by antipsychotic drug SEP-363856. In summary,CALN1is identified as a pivotal pathogenic gene of schizophrenia in forebrain development.
Eigenmodes of the brain: revisiting connectomics and geometry
Authors: Sina Mansour L. , Behjat Hamid , De Ville Dimitri Van , Smith Robert E. , Yeo B.T. Thomas , Zalesky Andrew
Published: April 2024

Eigenmodes can be derived from various structural brain properties, including cortical surface geometry1and interareal axonal connections comprising an organism’s connectome2. Pang and colleagues map geometric and connectome eigenmodes to spatial patterns of human brain activity, assessing whether brain connectivity or geometry provide greater explanatory power of brain function3. The authors find that geometric eigenmodes are superior predictors of cortical activity compared to connectome eigenmodes. They conclude that this supports the predictions of neural field theory (NFT)4, in that “brain activity is best represented in terms of eigenmodes derived directly from the shape of the cortex, thus emphasizing a fundamental role of geometry in constraining dynamics”. The experimental comparisons favoring geometric eigenmodes over connectome eigenmodes, in conjunction with specific statements regarding the relative efficacy of geometry in representing brain activity, have been widely interpreted to mean that geometry imposes stronger constraints on cortical dynamics than connectivity5–9. Here, we reconsider the comparative experimental evidence focusing on the impact of connectome mapping methodology. Utilizing established methods to mitigate connectome construction limitations, we map new connectomes for the same dataset, finding that eigenmodes derived from these connectomes reach comparable accuracy in explaining brain activity to that of geometric eigenmodes. We conclude that the evidence presented to support the comparative proposition that “eigenmodes derived from brain geometry represent a more fundamental anatomical constraint on dynamics than the connectome” may require reconsideration in light of our findings. Pang and colleagues present compelling evidence for the important role of geometric constraints on brain function, but their findings should not be interpreted to mean that geometry has superior explanatory power over the connectome.
Electrophysiological Brain Network Estimation with Simultaneous Scalp EEG and Intracranial EEG: Inference Algorithm and Applications
Authors: Yang Shihao , Liu Feng
Published: April 2024

Activity in the human brain is composed of complex firing patterns and interactions among neurons and neuronal circuits. The neuroimaging field underwent a paradigm shift over the past decades from mapping tasked evoked brain regions of activations towards identifying and characterizing the dynamic brain networks of coordinating brain regions. Electrophysiological signals are the direct manifestation of brain activities, thus characterizing the whole brain electrophysiological networks (WBEN) can serve as a fundamental tool for neuroscience studies and clinical applications. The electrophysiological network inferred from electroencephalogram (EEG) source imaging suffers from low accuracy limited by the Restricted Isometry Property (RIP), while the invasive EEG-derived electrophysiological networks can only characterize partial brain regions where invasive electrodes reside. In this work, we introduce the first framework for the integration of scalp EEG and intracranial EEG (iEEG) for WBEN estimation with a principled estimation framework based on state-space models, where an Expectation-Maximization (EM) algorithm is designed to infer the state variables and brain connectivity simultaneously. We validated the proposed method on synthetic data, and the results revealed improved performance compared to traditional two-step methods using scalp EEG only, which demonstrates the importance of the inclusion of iEEG signal for WBEN estimation. For real data with simultaneous EEG and iEEG, we applied the developed framework to understand the information flows of the encoding and maintenance phases during the working memory task. The information flows between the subcortical and cortical regions are delineated, which highlights more significant information flows from cortical to subcortical regions compared to maintenance phases. The results are consistent with previous research findings, however with the view of the whole brain scope, which underscores the unique utility of the proposed framework.
Quantifying spontaneous infant movements using state-space models
Authors: Passmore Elyse , Kwong Amanda K.L. , Olsen Joy E , Eeles Abbey , Cheong Jeanie L.Y , Spittle Alicia J , Ball Gareth
Published: April 2024

Over the first few months after birth, the typical emergence of spontaneous, fidgety general movements is associated with later developmental outcomes. In contrast, the absence of fidgety movements is a core feature of several neurodevelopmental and cognitive disorders. Currently, manual assessment of early infant movement patterns is time consuming and labour intensive, limiting its wider use. Recent advances in computer vision and deep learning have led to the emergence of pose estimation techniques, computational methods designed to locate and track body points from video without specialised equipment or markers, for movement tracking. In this study, we use automated markerless tracking of infant body parts to build statistical models of early movements. Using autoregressive, state-space models we demonstrate that infant movement can be modelled as a sequence of motor states, each characterised by specific body part movements, with expression that varies with age and differs in infants at high-risk of poor neurodevelopmental outcome.
Endothelial c-Src mediates neovascular tuft formation in Oxygen-Induced Retinopathy
Authors: Frampton Emmanuelle , Som Priyanka , Hill Brittany , Yu Alexander , Noordstra Ivar , Gordon Emma , Schimmel Lilian
Published: April 2024

Introduction

Vascular retinopathy, characterised by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathological feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. In this study, we investigate the role of c-Src in neovascular tuft formation. Although c-Src has been acknowledged as a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathological retinal angiogenesis remains to be fully understood.

Methods

We utilised the Oxygen-Induced Retinopathy (OIR) model to induce the formation of neovascular tufts in both Cre-mediated vascular specific c-Src knockout mice and their wildtype littermates. Subsequently, we conducted high-resolution imaging and analysis of isolated retinas, to elucidate the precise role of c-Src in the formation of vascular tufts.

Results

c-Src depletion demonstrated a significant reduction in the formation of neovascular tufts within the OIR model, underscoring the pivotal role of c-Src in pathological retinal angiogenesis. Notably, this decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation or cell adhesion and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology.

Conclusion

These findings underscore the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.
InstructPLM: Aligning Protein Language Models to Follow Protein Structure Instructions
Authors: Qiu Jiezhong , Xu Junde , Hu Jie , Cao Hanqun , Hou Liya , Gao Zijun , Zhou Xinyi , Li Anni , Li Xiujuan , Cui Bin , Yang Fei , Peng Shuang , Sun Ning , Wang Fangyu , Pan Aimin , Tang Jie , Ye Jieping , Lin Junyang , Tang Jin , Huang Xingxu , Heng Pheng Ann , Chen Guangyong
Published: April 2024

Large language models are renowned for their efficacy in capturing intricate patterns, including co-evolutionary relationships, and underlying protein languages. However, current methodologies often fall short in illustrating the emergence of genomic insertions, duplications, and insertion/deletions (indels), which account for approximately 14% of human pathogenic mutations. Given that structure dictates function, mutated proteins with similar structures are more likely to persist throughout biological evolution. Motivated by this, we leverage crossmodality alignment and instruct fine-tuning techniques inspired by large language models to align a generative protein language model with protein structure instructions. Specifically, we present a method for generating variable-length and diverse proteins to explore and simulate the complex evolution of life, thereby expanding the repertoire of options for protein engineering. Our proposed protein LM-based approach, InstructPLM, demonstrates significant performance enhancements both in silico and in vitro. On native protein backbones, it achieves a perplexity of 2.68 and a sequence recovery rate of 57.51, surpassing Protein-MPNN by 39.2% and 25.1%, respectively. Furthermore, we validate the efficacy of our model by redesigning PETase and L-MDH. For PETase, all fifteen designed variable-length PETase exhibit depolymerization activity, with eleven surpassing the activity levels of the wild type. Regarding L-MDH, an enzyme lacking an experimentally determined structure, InstructPLM is able to design functional enzymes with an AF2-predicted structure. Code and model weights of InstructPLM are publicly available*.
A Libra in the Brain: Neural Correlates of Error Awareness Predict Moral Wrongness and Guilt Proneness
Authors: Chen Chenyi , Kao Scott S.-C. , Fan Yang-Teng , Chen Yu-Chun , Cheng Yawei
Published: April 2024

Error awareness is a fundamental mechanism in humans. Through traditional psychological tasks, certain neural activities that represent errors in objective manners have been identified. However, there is limited knowledge on how humans subjectively determine right from wrong in moral contexts. In this study, participants (N=39) mentally simulated themselves as the agents of moral and immoral behaviors, while viewing a series of actions with EEG recording and MRI scanning, respectively. A significant difference in error-related negativity (ERN) was observed among morally wrong scenarios, accompanied by higher wrongfulness ratings. Additionally, individual differences in guilt-proneness could predict the subjects’ ERN amplitude. The ERN amplitude was correlated with the BOLD activity in the anterior mid-cingulate cortex and anterior insula to immoral scenarios, reflecting error awareness toward moral wrongfulness. The late potential component displayed greater negativity to immoral scenarios and was correlated with BOLD activities in the amygdala, ventromedial prefrontal cortex, and temporoparietal junction, indicating cognitive and affective evaluation in moral judgment. In line with the moral dynamic framework, our results demonstrated individual variability in moral judgments, as indicated by dispersed and overlapping cognitive neural networks. This suggests that subjective evaluations of wrongfulness are underpinned by neural mechanisms, associated with those involved in objective error awareness.
Connectomes, simultaneous EEG-fMRI resting-state data and brain simulation results from 50 healthy subjects
Authors: Meier Jil , Triebkorn Paul , Schirner Michael , Ritter Petra
Published: April 2024

We present raw and processed multimodal empirical data as well as simulation results from a study with The Virtual Brain (TVB).

Simultaneous electroencephalography (EEG) - functional magnetic resonance imaging (fMRI) resting-state data, diffusion-weighted MRI, and structural MRI were acquired for 50 healthy adult subjects (18 - 80 years of age) at the Charité University Medicine, Berlin, Germany.

We constructed personalized models from this multimodal data with TVB by optimizing parameters on an individual basis that predict multiple empirical features in fMRI and EEG, e.g. dynamic functional connectivity and bimodality in the alpha band power.

We annotated this large comprehensive empirical and simulated data set according to the openMINDS meta data schema and structured it following Brain Imaging Data Structure (BIDS) standards for EEG and MRI as well as the BIDS Extension Proposal for computational modeling data.

This dataset provides ready-to-use data for future research at various levels of processing including the thereof inferred brain simulation results for a large data set of healthy subjects with a wide age range.
Advancing Tolerogenic Immunotherapy: A Multi-Epitope Vaccine Design Targeting the CYP2D6 Autoantigen in Autoimmune Hepatitis Through Immuno-Informatics
Authors: Kolla Harish Babu , Kumar Anuj , Nanjunadappa Roopa Hebbandi , Hillyard Briley , Dutt Mansi , Chauhan Deepak , Marshal Jean , Kelvin David , Umeshappa Channakeshava Sokke
Published: April 2024

Juvenile autoimmune hepatitis (JAIH) is a rare autoimmune disorder affecting children, characterized by the immune system’s misguided attack on liver cells, primarily targeting the CYP2D6 autoantigen. This repeated attack leads to hepatic inflammation, fibrosis, and eventual liver failure. Current therapeutic strategies predominantly rely on immunosuppressive agents or whole B cell depletion antibodies, which render patients susceptible to infections and cancers. Hence, there is an urgent need for antigen-specific therapies to mitigate the severity of autoimmune hepatitis. Tolerogenic antigens represent a promising avenue in immunotherapy, capable of dampening autoimmunity. Here, we present a novel computationally designed multi-epitope tolerogenic vaccine tailored to target CYP2D6, aimed at inducing tolerogenic dendritic cells (DCs) and halting autoimmune progression in JAIH patients. To validate our approach, we have developed a similar vaccine for testing in mouse models of JAIH. The selected tolerogenic epitopes exhibit antigenicity without allergenicity or toxicity, and specifically induce IL-10 production (restricted to CD4+ T cell epitopes). In our vaccine design, tolerogenic poly-epitopes are linked with Toll-like receptor (TLR)-4-agonist, the 50S ribosomal unit, and IL-10, effectively programming DCs towards a tolerogenic state. Molecular docking and dynamic simulations have confirmed strong binding affinities and stable complexes between the vaccine structures, TLR4 and IL-10 receptor alpha (IL-10RA), indicating their potential forin vivoDC interaction and programming. Consequently, this innovative vaccine approach demands further exploration through wet lab experiments to assess its tolerogenicity, safety, and efficacy, thereby laying the groundwork for potential application in clinical settings.