bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective deletion of interleukin-1 alpha in microglia does not modify acute outcome but regulates neurorepair processes after experimental ischemic stroke
Authors: Lemarchand Eloïse , Grayston Alba , Wong Raymond , Rogers Miyako , Ouvrier Blake , Llewellyn Benjamin , Webb Freddie , Lénárt Nikolett , Denes Adam , Brough David , Allan Stuart M , Bix Gregory J , Pinteaux Emmanuel
Published: February 2024

Inflammation is a key contributor to stroke pathogenesis and exacerbates brain damage leading to poor outcome. Interleukin-1 (IL-1) is an important regulator of post-stroke inflammation, and blocking its actions is beneficial in pre-clinical stroke models and safe in the clinical setting. However, the distinct roles of the two major IL-1 receptor type 1 agonists, IL-1α and IL-1β, and the specific role of IL-1α in ischemic stroke remain largely unknown. Here we show that IL-1α and IL-1β have different spatio-temporal expression profiles in the brain after experimental stroke, with early microglial IL-1α expression (4 h) and delayed IL-1β expression in infiltrated neutrophils and a small microglial subset (24-72 h). We examined for the first time the specific role of microglial-derived IL-1α in experimental permanent and transient ischemic stroke through microglial-specific tamoxifen-inducible Cre-loxP-mediated recombination. Microglial IL-1α deletion did not influence acute brain damage, cerebral blood flow, IL-1β expression, neutrophil infiltration, microglial nor endothelial activation after ischemic stroke. However, microglial IL-1α knock out (KO) mice showed reduced peri-infarct vessel density and reactive astrogliosis at 14 days post-stroke, alongside long-term impaired functional recovery. Our study identifies for the first time a critical role for microglial IL-1α on neurorepair and functional recovery after stroke, highlighting the importance of targeting specific IL-1 mechanisms in brain injury to develop more effective therapies.
Oleic acid triggers CD4+T cells to be metabolically rewired and poised to differentiate into proinflammatory T cell subsets upon activation
Authors: Reilly Nathalie A. , Sonnet Friederike , Dekkers Koen F. , Kwekkeboom Joanneke C. , Sinke Lucy , Hilt Stan , Suleiman Hayat M. , Hoeksema Marten A. , Mei Hailiang , van Zwet Erik W. , Everts Bart , Ioan-Facsinay Andreea , Jukema J. Wouter , Heijmans Bastiaan T.
Published: February 2024

T cells are the most common immune cells in atherosclerotic plaques and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, results in a preferential differentiation into pro-inflammatory subsets upon activation by upregulating core metabolic pathways. RNA-sequencing of non-activated CD4+T cells revealed that oleic acid upregulates genes encoding enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis linked this rewiring to the differentiation of pro-inflammatory subsets. Indeed, spectral flow cytometry showed that pre-exposure to oleic acid results in a skew toward IL-9, IL-17A, IL-5 and IL-13 producing T cells upon activation. Importantly, inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, fatty acids may affect inflammatory diseases by influencing T cell metabolism.
Revisiting the high-dimensional geometry of population responses in visual cortex
Authors: Pospisil Dean A. , Pillow Jonathan W.
Published: February 2024

Recent advances in large-scale recording technology have spurred exciting new inquiries into the high-dimensional geometry of the neural code. However, characterizing this geometry from noisy neural responses, particularly in datasets with more neurons than trials, poses major statistical challenges. We address this problem by developing new tools for the accurate estimation of high-dimensional signal geometry. We apply these tools to investigate the geometry of representations in mouse primary visual cortex. Previous work has argued that these representations exhibit a power law, in which then’th principal component falls off as 1/n. Here we show that response geometry in V1 is better described by a broken power law, in which two different exponents govern the falloff of early and late modes of population activity. Our analysis reveals that later modes decay more rapidly than previously suggested, resulting in a substantially larger fraction of signal variance contained in the early modes of population activity. We examined the signal representations of the early population modes and found them to have higher fidelity than even the most reliable neurons. Intriguingly there are many population modes not captured by classic models of primary visual cortex indicating there is highly redundant yet poorly characterized tuning across neurons. Furthermore, inhibitory neurons tend to co-activate in response to stimuli that drive the early modes consistent with a role in sharpening population level tuning. Overall, our novel and broadly applicable approach overturns prior results and reveals striking structure in a population sensory representation.

Significance Statement

The nervous system encodes the visual environment across millions of neurons. Such high-dimensional signals are difficult to estimate—and consequently—to characterize. We address this challenge with a novel statistical method that revises past conceptions of the complexity of encoding in primary visual cortex. We discover population encoding is dominated by approximately ten features while additional features account for much less of the representation than previously thought. Many dominant features are not explained by classic models indicating highly redundant encoding of poorly characterized nonlinear image features. Interestingly, inhibitory neurons respond in unison to dominant features consistent with a role in sharpening population representation. Overall, we discover striking properties of population visual representation with novel, broadly applicable, statistical tools.
Random sampling of ligand arrangements on a one-dimensional lattice
Authors: Mohanta Dibyajyoti , Dvirnas Albertas , Ambjörnsson Tobias
Published: February 2024

We introduce a transfer-matrix-based sequential sampling scheme for generating random samples of ligand arrangements on one-dimensional templates. The number of ligand types is arbitrary, the binding constants can have positional dependence, and cooperativity parameters are included. From the random arrangements, any (linear or non-linear) observable can be calculated using sample averaging. We provide a publically available software with a computational time that scales linearly with the lattice size. As an example application, we study the competitive binding of three ligand types (the sequence-specific binder netropsin, YOYO-1 and ethidium bromide) to a DNA molecule.
PeakPerformance - a tool for Bayesian inference-based fitting of LC-MS/MS peaks
Authors: Nießer Jochen , Osthege Michael , von Lieres Eric , Wiechert Wolfgang , Noack Stephan
Published: February 2024

A major bottleneck of chromatography-based analytics has been the elusive fully automated identification and integration of peak data without the need of extensive human supervision. The presented Python packagePeakPerformanceapplies Bayesian inference to chromatographic peak fitting, and provides an automated approach featuring model selection and uncertainty quantification. Currently, its application is focused on data from targeted liquid chromatography tandem mass spectrometry (LC-MS/MS), but its design allows for an expansion to other chromatographic techniques.PeakPerformanceis implemented in Python and the source code is available on GitHub. It is unit-tested on Linux and Windows and accompanied by general introductory documentation, as well as example notebooks.

Practical application

The presentedPeakPerformancetool performs automated chromatographic peak data fitting using Bayesian methodology. Accordingly, it innovates by delivering built-in uncertainty quantification for each peak, thus taking the measurement noise into account. Using a convergence statistic and based on the determined peak uncertainties, the differentiation of signals into peak and noise was improved and false positives or negatives were largely eliminated. The provided documentation and the implemented convenience functions are meant to lower the barrier of entry for users with little programming experience. Lastly, the modular design of the software enables modification and expansion to data from different chromatographic methods.
Oxygen carrying nanoemulsions and respiratory hyperoxia eliminate tumor hypoxia-induced suppression and improve cancer immunotherapy
Authors: Halpin-Veszeleiova Katarina , Mallouh Michael , Apro Ashley , Romero Nuria , Bahr Camille , Shin Maureen , Ward Kelly , Rosenberg Laura , Sitkovsky Michail V. , Spiess Bruce , Hatfield Stephen M.
Published: February 2024

Hypoxia-HIF-1α-driven immunosuppressive transcription and cAMP-elevating signaling through A2A-adenosine receptors (A2AR) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patient’s refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a novel and feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). It is shown that oxygenation agent therapy i) eliminates tumor hypoxia, ii) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby iii) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to re-programming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immune-suppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy.

Oxygen delivering nanoemulsions and respiratory hyperoxia address limitations of blood vessel-mediated tumor oxygenation and promote anti-tumor immune responses to enhance immunotherapy.
Hist2Cell: Deciphering Fine-grained Cellular Architectures from Histology Images
Authors: Zhao Weiqin , Liang Zhuo , Huang Xianjie , Huang Yuanhua , Yu Lequan
Published: February 2024

Histology images, with low cost, are unleashing great power of predicting cellular phenotypes in tissue, thanks to the emerging spatial transcriptomics serving as annotations. Recent efforts aimed to predict individual gene expression, suffering from low accuracy and high variability, while no methods are tailored to predict fine-grained transcriptional cell types -the most critical phenotype. Here, we present Hist2Cell, a Vision Graph-Transformer framework, to accurately resolve fine-grained transcriptional cell types (up to 40 cell types) directly from histology images and further create cellular maps of diverse tissues at a customizable resolution. Specifically, trained on human lung and breast cancer spatial transcriptome datasets, Hist2Cell accurately predicts the abundance of each cell type across space in new patient samples with Pearson Correlation Coefficient of biological informative cell types over 0.80, and effectively capturing their colocalization directly from histology images. Moreover, without re-training, it robustly generalizes to large-scale histology cancer cohorts from TCGA, highlighting recurrent cell co-localization and supporting precise survival prediction by revealing distinct tissue micro-environments and insightful cell type-patient mortality relationship. Therefore, Hist2Cell enables cost-efficient histology analysis for large-scale studies of spatial biology and precise cancer prognosis in real-world clinical diagnostics.
Multiplexed dynamic control of temperature to probe and observe mammalian cells
Authors: Benman William , Iyengar Pavan , Mumford Thomas , Huang Zikang , Bugaj Lukasz J.
Published: February 2024

Temperature is aa critical parameter for biological function, yet there is a lack of approaches to modulate the temperature of biological specimens in a dynamic and high-throughput manner. We present the thermoPlate, a device for programmable control of temperature in each well of a 96-well plate, in a manner compatible with mammalian cell culture and live cell imaging. The thermoPlate maintains precise feedback control of temperature patterns independently in each well, with minutes-scale heating and cooling through ΔT ∼15-20°C. A computational model that predicts thermal diffusion guides optimal design of heating protocols. The thermoPlate allowed systematic characterization of both synthetic and natural thermo-responsive systems. We first used the thermoPlate in conjunction with live-cell microscopy to characterize the rapid temperature-dependent phase separation of a synthetic elastin-like polypeptide (ELP53). We then measured stress granule (SG) formation in response to heat stress, observing differences in SG dynamics with each increasing degree of stress. We observed adaptive formation of SGs, whereby SGs formed but then dissolved in response to persistent heat stress (> 42°C). SG adaptation revealed a biochemical memory of stress that depended on both the time and temperature of heat shock. Stress memories continued to form even after the removal of heat and persisted for 6-9 hours before dissipating. The capabilities and open-source nature of the thermoPlate will empower the study and engineering of a wide range of thermoresponsive phenomena.
Polygenic risk for depression and resting state functional connectivity of subgenual anterior cingulate cortex in young adults
Authors: Chen Yu , Li Huey-Ting , Luo Xingguang , Li Guangfei , Ide Jaime S. , Li Chiang-Shan R.
Published: February 2024

Genetic variants may confer risks for depression by modulating brain structure and function. Prior evidence has underscored a key role of the subgenual anterior cingulate cortex (sgACC) in depression. Here, we built on the literature and examined how the resting state functional connectivity (rsFC) of the sgACC was associated with polygenic risks for depression. We followed published routines and computed seed-based whole-brain sgACC rsFC and polygenic risk scores (PRS) of 717 young adults curated from the Human Connectome Project. We performed whole-brain regression against PRS and severity of depression symptoms in a single model for all subjects and for men and women alone, controlling for age, sex (for all), race, severity of alcohol use, and household income, and evaluated the results at a corrected threshold. We found lower sgACC rsFC with the default mode network and frontal regions in association with PRS and lower sgACC-cerebellar rsFC in association with depression severity. We also noted sex differences in the connectivity correlates of PRS and depression severity. In an additional set of analyses, we observed a significant correlation between PRS and somatic complaints score and altered sgACC-somatosensory cortical connectivity in link with the severity of somatic complaints. Our findings collectively highlighted the pivotal role of distinct sgACC-based networks in the genetic predisposition to depression and the clinical manifestation of depression. Distinguishing the risk from severity markers of depression may have implications in developing early and effective treatments for individuals at risk for depression.
Intrinsic Disorder and Salt-dependent Conformational Changes of the N-terminal Region of TFIP11 Splicing Factor
Authors: Juniku Blinera , Mignon Julien , Carême Rachel , Genco Alexia , Obeid Anna Maria , Mottet Denis , Monari Antonio , Michaux Catherine
Published: February 2024

Tuftelin Interacting Protein 11 (TFIP11) was recently identified as a critical human spliceosome assembly regulator, interacting with multiple spliceosome proteins and localises in several membrane-less organelles. However, there is a lack of structural information on TFIP11, limiting the rationalisation of its biological role. TFIP11 has been predicted as a highly disordered protein, and more specifically concerning its N-terminal (N-TER) region. Intrinsically disordered proteins (IDPs) lack a defined tertiary structure, existing as a dynamic conformational ensemble, favouring their role as hubs in protein-protein and protein-RNA interaction networks. Furthermore, IDPs are involved in liquid-liquid phase separation (LLPS), driving the formation of subnuclear compartments.

Combining disorder prediction, molecular dynamics, and spectroscopy methods, this contribution shows the first evidence TFIP11 N-TER may be described as a polyampholytic IDP, exhibiting a structural duality with the coexistence of ordered and disordered assemblies, depending on the ionic strength of the protein environment. Increasing the salt concentration enhances the protein conformational flexibility, presenting a fuzzier conformational landscape, a more globule-like shape, and an unstructured arrangement that could favour LLPS segregation and protein-RNA interaction. The regions mostly composed of charged and hydrophilic residues are the most impacted, including the G-Patch domain which is of crucial importance to TFIP11 function.
Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells
Authors: Santiappillai Nancy T , Cao Yue , Hakeem-Sanni Mariam F , Yang Jean , Quek Lake-Ee , Hoy Andrew J
Published: February 2024

Large-scale metabolomic analyses of pan-cancer cell line panels have provided significant insights into the relationships between metabolism and cancer cell biology. Here, we took a pathway-centric approach by transforming targeted metabolomic data into ratios to study associations between reactant and product metabolites in a panel of cancer and non-cancer cell lines. We identified five clusters of cells from various tissue origins. Of these, cells in Cluster 4 had high ratios of TCA cycle metabolites relative to pyruvate, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios. This was due to more glutamine cataplerotic efflux and not glycolysis in cells of Cluster 4.In silicoanalyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of lactate and glutamine metabolism, and OXPHOS than cells in Cluster 3. Our results highlight the potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.
Single-cell multimodal profiling of monocytes reveals diverse phenotypes and alterations linked to cardiovascular disease risks
Authors: Bashore Alexander C. , Xue Chenyi , Kim Eunyoung , Yan Hanying , Zhu Lucie Y. , Pan Huize , Kissner Michael , Ross Leila S. , Zhang Hanrui , Li Mingyao , Reilly Muredach P.
Published: February 2024

Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. The Cell surface expression of CD14 and CD16 has historically identified them, however, recent single-cell studies have uncovered that they are much more heterogeneous than previously realized. We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) to describe the comprehensive transcriptional and phenotypic landscape of 437,126 monocytes. This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCIIhi, monocyte-platelet aggregates, and non-classical, as well as several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII+CD275+MHCIIhi, CD42b+monocyte-platelet aggregates, CD16+CD99-non-classical monocytes, and CD99+classical monocytes. Each subpopulation exhibited unique functions, developmental trajectories, transcriptional regulation, and tissue distribution. Moreover, we revealed alterations associated with cardiovascular disease (CVD) risk factors, including race, smoking, and hyperlipidemia, and the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol. This integrative and cross-species comparative analysis provides a unique resource to compare alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in CVD and the potential for targeted therapies.

Multimodal profiling provides a comprehensive phenotypic and transcriptional understanding of monocytes in health and cardiovascular disease risk states.
Unveiling the genes and pathways that are dysregulated in dopaminergic neurons during both familial and sporadic Parkinson’s disease
Authors: Padhan PK , Verma S.
Published: February 2024

Identification of shared dysregulated genes and molecular mechanisms responsible for dopaminergic (DA) neuronal death in familial and sporadic forms of Parkinson’s disease (PD) can offer the potential for common therapies in both types of PD. The gene expression profiles of DA neurons with sporadic and familial PD backgrounds and healthy DA neurons were obtained from the Gene Expression Omnibus database. Overlapping differentially expressed genes and hub genes were identified. These genes were subjected to Gene Ontology and Reactome pathway enrichment analyses. The roles of a select few differentially expressed genes inC. elegansDA neuron health were assessed. 40 genes, including 12 hub genes, were found dysregulated in DA neurons with sporadic and familial PD. Altering the expression of some of these genes in wild-typeCaenorhabditis eleganspromoted DA neuron degeneration and function. The study unveils shared molecular mechanisms in DA neurons for familial and sporadic PD, potentially driving DA neuron degeneration. Understanding their roles may lead to targeted therapies, early detection, and intervention.In vivoexperiments support our hypothesis, suggesting the implication of these genes in PD neurodegeneration and neuroprotection.
Aedes albopictusis not an arbovirus aficionado – Impacts of sylvatic flavivirus infection in vectors and hosts on mosquito engorgement on non-human primates
Authors: Cecilia Hélène , Althouse Benjamin M. , Azar Sasha R. , Moehn Brett A. , Yun Ruimei , Rossi Shannan L. , Vasilakis Nikos , Hanley Kathryn A.
Published: February 2024

The contact structure between vertebrate hosts and arthropod vectors plays a key role in the spread of arthropod-borne viruses (arboviruses); thus, it is important to determine whether arbovirus infection of either host or vector alters vector feeding behavior. Here we leveraged a study of the replication dynamics of two arboviruses isolated from their ancestral cycles in paleotropical forests, sylvatic dengue-2 (DENV-2) and Zika (ZIKV), in one non-human primate (NHP) species from the paleotropics (cynomolgus macaques,Macaca fascicularis) and one from the neotropics (squirrel monkeys,Saimiri boliviensis) to test the effect of both vector and host infection with each virus on completion of blood feeding (engorgement) of the mosquitoAedes albopictus. Although mosquitoes were starved and given no choice of hosts, engorgement rates varied dramatically, from 0% to 100%. While neither vector nor host infection systematically affected engorgement, NHP species and body temperature at the time of feeding did. We also interrogated the effect of repeated mosquito bites on cytokine expression and found that epidermal growth factor (EGF) and macrophage migration inhibitory factor (MIF) concentrations were dynamically associated with exposure to mosquito bites. This study highlights the importance of incorporating individual-level heterogeneity of vector biting in arbovirus transmission models.
Host 5-HT affectsPlasmodiumtransmission in mosquitoes via modulating mosquito mitochondrial homeostasis
Authors: Gao Li , Zhang Benguang , Feng Yuebiao , Yang Wenxu , Zhang Shibo , Wang Jingwen
Published: February 2024

Malaria parasites hijack the metabolism of their mammalian host during the blood-stage cycle.Anophelesmosquitoes depend on mammalian blood to survive and to transmit malaria parasites. However, it remains understudied whether changes in host metabolism affect parasite transmission in mosquitoes. In this study, we discovered thatPlasmodiuminfection significantly decreased the levels of the tryptophan metabolite, 5-hydroxytryptamine (5-HT), in both humans and mice. The reduction led to the decrease of 5-HT in mosquitoes. Oral supplementation of 5-HT toAnopheles stephensienhanced its resistance toPlasmodium bergheiinfection by promoting the generation of mitochondrial reactive oxygen species. This effect was due to the accumulation of dysfunctional mitochondria caused by 5-HT-mediated inhibition of mitophagy. Elevating 5-HT levels in mouse serum significantly suppressed parasite infection in mosquitoes. In summary, our data highlight the critical role of metabolites in animal blood in determining the capacity of mosquitoes to control parasite infection.
GATAD2B containing NuRD complex drives R-loop dependent chromatin boundary formation at double strand breaks
Authors: Liu Zhichao , Ajit Kamal , Wu Yupei , Zhu Wei-Guo , Gullerova Monika
Published: February 2024

Double-strand breaks (DSBs) are the most lethal form of DNA damage. Transcriptional activity at DSBs, as well as transcriptional repression around DSBs, are both required for efficient DNA repair. The chromatin landscape defines and coordinates these two opposing events. However, the regulation of the open and condensed chromatin architecture is still unclear. In this study, we show that the GATAD2B-NuRD complex associates with DSBs in a transcription- and R-loop-dependent manner, to promote histone deacetylation and chromatin condensation, creating a temporal boundary between open and closed chromatin. This boundary is necessary for correct DNA end resection termination. The lack of the GATAD2B-NuRD complex leads to chromatin hyper-relaxation and extended DNA end resection, resulting in HR repair failure. Our results suggest that the GATAD2B-NuRD complex is a key coordinator of the dynamic interplay between transcription and chromatin landscape and underscore its biological significance in the RNA-dependent DNA damage response.
Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition
Authors: Flower Cameron T. , Liu Chunmei , Chuang Hui-Yu , Ye Xiaoyang , Cheng Hanjun , Heath James R. , Wei Wei , White Forest M.
Published: February 2024

A major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing to capture molecular snapshots within the first minutes, hours, and days of BRAF kinase inhibitor exposure in a humanBRAF-mutant melanoma model of adaptive therapy resistance. By enriching specific phospho-motifs associated with mitogenic kinase activity, we monitored the dynamics of thousands of growth- and survival-related protein phosphorylation events under oncogenic BRAF inhibition and drug removal. We observed early and sustained inhibition of the BRAF-ERK axis, gradual downregulation of canonical cell cycle-dependent signals, and three distinct and reversible phase transitions toward quiescence. Statistical inference of kinetically-defined signaling and transcriptional modules revealed a concerted response to oncogenic BRAF inhibition and a dominant compensatory induction of SRC family kinase (SFK) signaling, which we found to be at least partially driven by accumulation of reactive oxygen species via impaired redox homeostasis. This induction sensitized cells to co-treatment with an SFK inhibitor across a panel of patient-derived melanoma cell lines and in an orthotopic mouse xenograft model, underscoring the translational potential for measuring the early temporal dynamics of signaling and transcriptional networks under therapeutic challenge.
Heat Stable and Intrinsically Sterile Liquid Protein Formulations
Authors: Lawanprasert Atip , Pimcharoen Sopida , Singh Harminder , González Vargas Mariangely , Dewan Arshiya , Kirimanjeswara Girish S. , Medina Scott
Published: February 2024

Over 80% of biologic drugs, and 90% of vaccines, require temperature-controlled conditions throughout the supply chain to minimize thermal inactivation and contamination. This cold chain is costly, requires stringent oversight, and is impractical in remote environments. Here, we report chemical dispersants that non-covalently solvate proteins within fluorous liquids to alter their thermodynamic equilibrium and reduce conformational flexibility. This generates non-aqueous, fluorine-based liquid protein formulations that biochemically rigidify protein structure to yield thermally stable biologics at extreme temperatures (up to 90°C). These non-aqueous formulations are impervious to contamination by microorganismal pathogens, degradative enzymes, and environmental impurities, and display comparable pre-clinical serum half-life and safety profiles to standard saline protein samples. As a result, we deliver a fluorochemical formulation paradigm that may limit the need for cold chain logistics of protein reagents and biopharmaceuticals.
Enhanced stimulus-induced and stimulus-free gamma in open-eye meditators
Authors: Biswas Ankan , Aggarwal Srishty , Sharma Kanishka , Ray Supratim
Published: February 2024

Visual stimuli induce “narrowband” gamma oscillations (30-70 Hz) that are linked to attention/binding and attenuate with aging and neurodegeneration. In contrast, meditation increases power in a broad frequency range (>25 Hz). However, the effect of meditation on stimulus-induced gamma is unknown. We recorded EEG from meditators and controls performing open-eye meditation while gamma-inducing stimuli were presented before, during and after meditation. We found that stimulus-induced gamma, like stimulus-free gamma, was stronger in meditators. Interestingly, both gamma signatures co-existed during meditation but were unrelated and prominent in occipital and fronto-temporal regions, respectively. Further, power spectral density (PSD) slope, which becomes shallower with aging, was steeper for meditators. Meditation could boost inhibitory mechanisms leading to stronger gamma and steeper PSDs, potentially providing protection against aging and neurodegeneration.

One line summary

Stimulus-induced and stimulus-free gamma are stronger in open-eye meditators.
Investigating the Intradermal Irritation Test of Hydrogel: A Study on Domestic Production
Authors: Odelabu Kehinde , Racheal Christianah
Published: February 2024

This study employs the intradermal injection method to assess the skin irritation potential of domestically produced medical hydrogel. Healthy white rabbits received intradermal injections of 0.5% sodium chloride solution (control), 0.5% sodium chloride extract, and olive oil extract as test samples. Erythema and edema were observed at 24 and 72 hours post-injection, and the primary irritation index was determined. Results revealed a primary irritation index of 0 for domestically produced hydrogel, indicating no skin irritation response.
A Neural Mechanism for Optic Flow Parsing in Macaque Visual Cortex
Authors: Peltier Nicole E. , Anzai Akiyuki , Moreno-Bote Ruben , DeAngelis Gregory C.
Published: February 2024

For the brain to compute object motion in the world during self-motion, it must discount the global patterns of image motion (optic flow) caused by self-motion. Optic flow parsing is a proposed visual mechanism for computing object motion in the world, and studies in both humans and monkeys have demonstrated perceptual biases consistent with the operation of a flow parsing mechanism. However, the neural basis of flow parsing remains unknown. We demonstrate, at both the individual unit and population levels, that neural activity in macaque area MT is biased by peripheral optic flow in a manner that can at least partially account for perceptual biases induced by flow parsing. These effects cannot be explained by conventional surround suppression mechanisms or choice-related activity, and have a substantial neural latency. Together, our findings establish the first neural basis for the computation of scene-relative object motion based on flow parsing.
Compositional transformations can reasonably introduce phenotype-associated values into sparse features
Authors: Austin George I. , Korem Tal
Published: February 2024

It was recently argued1that an analysis of tumor-associated microbiome data2is invalid because features that were originally very sparse (genera with mostly zero read counts) became associated with the phenotype following batch correction1. Here, we examine whether such an observation should necessarily indicate issues with processing or machine learning pipelines. We show counterexamples using the centered log ratio (CLR) transformation, which is often used for analysis of compositional microbiome data3. The CLR transformation has similarities to Voom-SNM4,5, the batch-correction method brought into question1,2, yet is a sample-wise operation that cannot, in itself, “leak” information or invalidate downstream analyses. We show that because the CLR transformation divides each value by the geometric mean of its sample, common imputation strategies for missing or zero values result in transformed features that are associated with the geometric mean. Through analyses of both synthetic and vaginal microbiome datasets we demonstrate that when the geometric mean is associated with a phenotype, sparse and CLR-transformed features will also become associated with it. We re-analyze features highlighted by Gihawi et al.1and demonstrate that the phenomenon of sparse features becoming phenotype-associated can also be observed after a CLR transformation, which serves as a counterexample to the claim that such an observation necessarily means information leakage. While we do not intend to address other concerns regarding tumor microbiome analyses1,6, validate Poore et al.’s2results, or evaluate batch-correction pipelines, we conclude that because phenotype-associated features that were initially sparse can be created by a sample-wise transformation that cannot artifactually inflate machine learning performance, their detection is not independently sufficient to demonstrate information leakage in machine learning pipelines. Microbiome data is multivariate, and as such, a value of zero carries a different meaning for each sample. Many transformations, including CLR and other batch-correction methods, are likewise multivariate, and, as these issues demonstrate, each individual feature should be interpreted with caution.
Hepatocyte differentiation requires anisotropic expansion of bile canaliculi
Authors: Belicova Lenka , Bebelman Maarten , Gralinska Elzbieta , Jumel Tobias , Lahree Aparajita , Shevchenko Andrej , Zatsepin Timofei , Kalaidzidis Yannis , Vingron Martin , Zerial Marino
Published: February 2024

During liver development, bipotential progenitor cells called hepatoblasts differentiate into hepatocytes or cholangiocytes. Hepatocyte differentiation is uniquely associated with multi-axial polarity, enabling the anisotropic expansion of apical lumina between adjacent cells and formation of a three-dimensional network of bile canaliculi (BC). Cholangiocytes, the cells forming the bile ducts, exhibit the vectorial polarity common to epithelial cells. Whether and how cell polarization feeds back on the gene regulatory pathways governing hepatoblast differentiation is unknown. Here, we used primary hepatoblasts to investigate the contribution of anisotropic apical expansion to hepatocyte differentiation. Silencing of the small GTPase Rab35 caused isotropic lumen expansion and formation of multicellular cysts with the vectorial polarity of cholangiocytes. Gene expression profiling revealed that these cells express reduced levels of hepatocyte markers and upregulate genes associated with cholangiocyte identity. Time-course RNA sequencing demonstrated that loss of lumen anisotropy precedes these transcriptional changes. Independent alterations in apical lumen morphology induced either by modulation of the subapical actomyosin cortex or increased intraluminal pressure caused similar transcriptional changes. These findings suggest that cell polarity and lumen morphogenesis feedback to hepatoblast-to-hepatocyte differentiation.

Summary statement

Differentiation of liver progenitors to functional hepatocytes requires anisotropic elongation of their nascent apical surfaces into tubular bile canaliculi.
A Telescopic Independent Component Analysis on Functional Magnetic Resonance Imaging Data Set
Authors: Mirzaeian Shiva , Faghiri Ashkan , Calhoun Vince D. , Iraji Armin
Published: February 2024

Brain function can be modeled as the dynamic interactions between functional sources at different spatial scales, and each spatial scale can contain its functional sources with unique information, thus using a single scale may provide an incomplete view of brain function. This paper introduces a novel approach, termed “telescopic independent component analysis (TICA),” designed to construct spatial functional hierarchies and estimate functional sources across multiple spatial scales using fMRI data. The method employs a recursive ICA strategy, leveraging information from a larger network to guide the extraction of information about smaller networks. We apply our model to the default mode network (DMN), visual network (VN), and right frontoparietal network (RFPN). We investigate further on DMN by evaluating the difference between healthy people and individuals with schizophrenia. We show that the TICA approach can detect the spatial hierarchy of DMN, VS, and RFPN. In addition, TICA revealed DMN-associated group differences between cohorts that may not be captured if we focus on a single-scale ICA. In sum, our proposed approach represents a promising new tool for studying functional sources.

Author summary

Our study introduces “telescopic independent component analysis (TICA)”, a novel approach using a recursive ICA strategy for exploring brain function across multiple spatial scales using fMRI data. TICA constructs spatial hierarchies and identifies functional sources such as default mode network (DMN), visual network (VN), and right frontoparietal network (RFPN). By applying TICA, we uncovered hierarchical structures within these networks and revealed differences in the DMN between healthy individuals and those with schizophrenia. This approach offers a promising new tool for studying function dynamics comprehensively.
Stability of N-type inactivation and the coupling between N-type and C-type inactivation in theAplysiaKv1 channel
Authors: Iwamuro Tokunari , Itohara Kazuki , Furukawa Yasuo
Published: February 2024

The voltage-dependent potassium channels (Kv channels) show several different types of inactivation. N-type inactivation is a fast inactivating mechanism, which is essentially an open pore blockade by the amino-terminal structure of the channel itself or the auxiliary subunit. There are several functionally discriminatable slow inactivation (C-type, P-type, U-type), the mechanism of which is supposed to include rearrangement of the pore region. In some Kv1 channels, the actual inactivation is brought about by coupling of N- type and C-type inactivation (N-C coupling). In the present study, we focused on the N-C coupling of theAplysiaKv1 channel (AKv1). AKv1 shows a robust N-type inactivation, but its recovery is almost thoroughly from C-type inactivated state owing to the efficient N-C coupling. In the I8Q mutant of AKv1, we found that the inactivation as well as its recovery showed two kinetic components apparently correspond to N-type and C-type inactivation. Also, the cumulative inactivation which depends on N-type mechanism in AKv1 was hindered in I8Q, suggesting that N-type inactivation of I8Q is less stable. We also found that Zn2+specifically accelerates C-type inactivation of AKv1, and that H382 in the pore turret is involved in the Zn2+binding. Because the region around Ile8(I8) in AKv1 has been suggested to be involved in the pre-block binding of the amino-terminal structure, our results strengthen a hypothesis that the stability of the pre-block state is important for stable N-type inactivation as well as the N-C coupling in the Kv1 channel inactivation.
β2 integrins impose a mechanical checkpoint on macrophage phagocytosis
Authors: Settle Alexander H. , Winer Benjamin Y. , de Jesus Miguel M. , Seeman Lauren , Wang Zhaoquan , Chan Eric , Romin Yevgeniy , Li Zhuoning , Miele Matthew M. , Hendrickson Ronald C. , Vorselen Daan , Perry Justin S. A. , Huse Morgan
Published: February 2024

Phagocytosis is an intensely physical process that depends on the mechanical properties of both the phagocytic cell and its chosen target. Here, we employed differentially deformable hydrogel microparticles to examine the role of cargo rigidity in the regulation of phagocytosis by macrophages. Whereas stiff cargos elicited canonical phagocytic cup formation and rapid engulfment, soft cargos induced an architecturally distinct response, characterized by filamentous actin protrusions at the center of the contact site, slower cup advancement, and frequent phagocytic stalling. Using phosphoproteomics, we identifiedβ2 integrins and their downstream effectors as critical mediators of this mechanically regulated phagocytic switch. Indeed, comparison of wild type andβ2 integrin deficient macrophages indicated that integrin signaling acts as a mechanical checkpoint by shaping filamentous actin to enable distinct phagocytic engulfment strategies. Collectively, these results illuminate the molecular logic of leukocyte mechanosensing and reveal potential avenues for modulating phagocyte function in immunotherapeutic contexts.
ABCA1 deficiency causes tissue-specific dysregulation of the SREBP2 pathway in mice
Authors: Yamauchi Yoshio , Abe-Dohmae Sumiko , Iwamoto Noriyuki , Sato Ryuichiro , Yokoyama Shinji
Published: February 2024

The ATP-binding cassette transporter ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL) by mediating phospholipid and cholesterol efflux to apolipoprotein A-I. In humans, loss-of-function mutations in theABCA1gene cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients andAbca1-/-mice exhibit the cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others have shown that ABCA1 deficiency causes hyperactivation of the sterol regulatory element-binding protein 2 (SREBP2) pathwayin vitro. In this work, we investigate whether ABCA1 deficiency affects SREBP2-dependent cholesterol homeostatic responsesin vivo. We show that SREBP2 response gene expression is partly downregulated in the liver ofAbca1-/-mice compared to wild-type mouse livers in the steady-state condition. In contrast, we find that in fasted or refed condition, the expression of SREBP2 target genes is upregulated in multiple tissues ofAbca1-/-mice. Correspondently, SREBP2 processing is also increased in select tissues of these mice. Altogether, our results suggest that ABCA1 deficiency is associated with the tissue-specific dysregulation of the SREBP2 pathway in a manner dependent on nutritional status. Lack of ABCA1 thus causes not only HDL deficiency but also dysregulation of the SREBP2 pathway in multiple tissues, which may underlie the pathophysiology of TD.
Pangenome mining of theStreptomycesgenus redefines their biosynthetic potential
Authors: Mohite Omkar S. , Jørgensen Tue S. , Booth Thomas , Charusanti Pep , Phaneuf Patrick V. , Weber Tilmann , Palsson Bernhard O.
Published: February 2024

Background

Streptomycesis a highly diverse genus known for the production of secondary or specialized metabolites with a wide range of applications in the medical and agricultural industries. Several thousand complete or nearly-completeStreptomycesgenome sequences are now available, affording the opportunity to deeply investigate the biosynthetic potential within these organisms and to advance natural product discovery initiatives.

Result

We performed pangenome analysis on 2,371Streptomycesgenomes, including approximately 1,200 complete assemblies. Employing a data-driven approach based on genome similarities, theStreptomycesgenus was classified into 7 primary and 42 secondary MASH-clusters, forming the basis for a comprehensive pangenome mining. A refined workflow for grouping biosynthetic gene clusters (BGCs) redefined their diversity across different MASH-clusters. This workflow also reassigned 2,729 known BGC families to only 440 families, a reduction caused by inaccuracies in BGC boundary detections. When the genomic location of BGCs is included in the analysis, a conserved genomic structure (synteny) among BGCs becomes apparent within species and MASH-clusters. This synteny suggests that vertical inheritance is a major factor in the acquisition of new BGCs.

Conclusion

Our analysis of a genomic dataset at a scale of thousands of genomes refined predictions of BGC diversity using MASH-clusters as a basis for pangenome analysis. The observed conservation in the order of BGCs’ genomic locations showed that the BGCs are vertically inherited. The presented workflow and the in-depth analysis pave the way for large-scale pangenome investigations and enhance our understanding of the biosynthetic potential of theStreptomycesgenus.
Allelic DNA synthesis followed by template switching underlies BRCA1-linked tandem duplication
Authors: Huang Zhi-Cheng , Feng Yi-Li , Liu Qian , Chen Ruo-Dan , Liu Si-Cheng , Wang Meng , Xie An-Yong
Published: February 2024

Microhomology-mediated short tandem duplication (TD) is among specific mutational signatures associated withBRCA1-deficient tumors. Several mechanisms have been proposed for its generation, but may not be applicable in repeat-less regions of the human genome. We thus developed a repeat-less TD reporter and a PCR-based site-specific TD assay to analyze short TDs induced by one-ended DNA double strand breaks (DSBs) converted from DNA nicks inBrca1-deficient cells. We found that short TDs induced by DNA nicks are significantly stimulated inBrca1-deficient cells. Analysis of TD products revealed that the TD formation is partly mediated by template switching of displaced nascent strand after allelic DNA synthesis. This suggests either allelic DNA synthesis or the strand annealing step of allelic break-induced replication might be more easily aborted inBrca1-deficient cells, thus promoting TD. Neither depletion ofRad51orBrca2nor inactivation of the Brca1 coiled-coil domain stimulated nick-induced TD, indicating that RAD51 loading by BRCA1 is dispensable for BRCA1-mediated TD suppression. These results together provide novel insights into the mechanisms underlyingBRCA1-linked TD formation in cancer.