Biology subjects

Yang, H.

Publications and source records attributed to Yang, H..

At least 235 records · Page 13Linked to original sources

bioRxiv2024

Identification of a mesodermal progenitor for the pro-definitive angio-hematopoietic lineage

Mammalian hematopoietic cells arise from mesodermal progenitors in a close developmental relationship with endothelium, and along three distinct cell lineages known as primitive, pro-definitive, and definitive hematopoiesis. However, the developmental hierarchy between mesodermal progenitors, endothelium, and blood cell lineages is incompletely understood. We report here the identification in mouse gastrula and human (h)iPSC cultures of a population of CXCR4+ primitive streak stage mesodermal progenitors that give rise to yolk sac endothelium, blood islands, yolk sac hematopoiesis, and resident macrophages, corresponding to the pro-definitive lineage. Strikingy, this progenitor does not give rise to primitive erythropoiesis or to caudal endothelium and definitive hematopoiesis. Interestingly however, the pro-definitive progenitor population also gives rise to rostral endothelium that persists in adults. Finally, pro-definitive progenitor-derived endothelium is the first and main source of macrophages in embryo and hiPSC cultures, both directly and via previously described multipotent Erythro-Myeloid Progenitors. The identification and isolation of this mesodermal progenitor defines a revised pro-definitive angio-hematopoietic lineage and provides a framework for resident macrophage and endothelial differentiation relevant to disease pathophysiology and their manipulation for therapeutic purposes. One sentence summaryIdentification in gastrulating embryo and hiPSC cultures of a mesodermal progenitor for yolk sac and rostral endothelial cells, early macrophages, and Erythro-Myeloid Progenitors characterize pro-definitive hematopoiesis and provide a revised framework for early angio-hematopoietic development. Graphical abstractSchematic represents the progeny of angio-hematopoietic progenitors at the posterior primitive streak. Developmental timing of CXCR4 expression distinguishes i) CXCR4- primitive hematopoiesis, ii) Early CXCR4+ angio-hematopoietic progenitors (EXAP) (purple) which express CXCR4 between E6.5 and E7.5 and give rise to rostral vessels and resident macrophages through YS hemogenic endothelium, and iii) late CXCR4+ intraembryonic angio-hematopoietic progenitors (blue) which acquire expression of CXCR4 around E8 and give rise to definitive hematopoiesis through an intraembryonic hemogenic endothelium. Abbreviations: E (Mouse Embryonic Day); YS (Yolk Sac); Hemog. (Hemogenic); Endo. (Endothelium); Defi. (Definitive). O_FIG O_LINKSMALLFIG WIDTH=165 HEIGHT=200 SRC="FIGDIR/small/609533v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@afb5fdorg.highwire.dtl.DTLVardef@1d4f772org.highwire.dtl.DTLVardef@c173d9org.highwire.dtl.DTLVardef@9cc17d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

PI(4)P recruits CIDE proteins to promote the formation of unilocular lipids droplets

Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. The composition of LD surface phospholipids and their impact on LD growth and function remain to be clearly defined. Phosphoinositides mark cellular organelles and regulate cell signalling and organellar function. Here, we demonstrate that PI(4)P decorates a subset of LDs to recruit and activate the CIDE proteins. Enhanced expression of ORP2 and ORP5, LD-associated lipid transfer proteins that remove PI(4)P from LDs, abolished the localization and function of CIDE proteins. Blocking the synthesis of PI(4)P on LD surface via knocking down PI4K2A also impaired the localization and function of CIDE proteins. In adipocytes, depleting PI(4)P dramatically reduced the size of LDs, as well as adipose tissue mass. In severe steatotic liver, depleting PI(4)P reduced LD accumulation. Our results thus identify a key function of LD surface PI(4)P under physiological conditions and unveil how CIDE proteins are recruited to LDs.

cell biology↗

bioRxiv2024

Orally surface engineered probiotic system for ulcerative colitis therapy via modulating gut microbiota and immune homeostasis

Oral probiotics have emerged as a promising therapeutical strategy for effectively managing ulcerative colitis (UC) in the world. The existing researches successfully preserve probiotic viability in the upper gastrointestinal tract, but they fall short in achieving precise release profile and effective colonization of probiotics at the site of colitis in colon as well as the understanding of therapeutic mechanism with suboptimal efficacy. This constraint poses a significant barrier to rational design and effective development of oral probiotic system. Here, we fabricate an orally layered-by-layered probiotic (Escherichia coli Nissle 1917, EcN) system (so-called CML@EcN) based on carboxymethyl modified lignin (CML) which can significantly protect EcN in gastric and small intestinal microenvironment and efficiently control release EcN in colon. Interestingly, the release and proliferation process of EcN in the colon are detected and can be modeled as a plug-flow mode. We derive a mathematical expression that highly matches the experimental results, providing a theoretical basis for quantitatively calculation of the release process. Furthermore, CML@EcN significantly alleviates symptoms in dextran sulfate sodium (DSS)-induced UC mice by modulating the multiple organ immune disorder and gut microbiota (GM)/metabolites profile as well as reconstructing the colon barrier. Importantly, we explore the mechanism of immune homeostasis regulation via metabolism from GM. Moreover, the CML armour is excreted and would not influence the process. This work not only reports a novel oral therapeutic for UC treatment with high efficacy as well as the exploration of mechanism between GM and immune homeostasis, but also provides a general approach to engineer probiotics for oral administration.

microbiology↗

bioRxiv2024

Lipid A phosphoethanolamine transferase-mediated site-selective modifications show association with colistin resistance phenotypes and fitness

Genes encoding lipid A modifying phosphoethanolamine transferases (PETs) are genetically diverse and can confer resistance to colistin and antimicrobial peptides. To better understand the functional diversity of PETs, we characterized three canonical mobile colistin resistance (mcr) alleles (mcr-1, -3, -9), one intrinsic pet (eptA), and two mcr-like genes (petB, petC). Using an isogenic expression system, we show that mcr-1 and mcr-3 are phenotypically similar by conferring colistin resistance with lower fitness costs. mcr-9, which is phylogenetically closely related to mcr-3, and eptA only provide fitness advantages in the presence of sub-inhibitory concentrations of colistin and significantly reduce fitness in media only. PET-B and PET-C were phenotypically distinct from bonafide PETs; neither conferred colistin resistance or caused considerable fitness cost in Escherichia coli. Strikingly, we found for the first time that different PETs selectively modify different phosphates of lipid A - MCR-1, MCR-3, and PET-C selectively modify the 4-phosphate, while MCR-9 and EptA modify the 1-phosphate. 4-phosphate modifications facilitated by MCR-1 and -3 are associated with high levels of colistin resistance and low toxicity. Our results suggest that PETs have a wide phenotypic diversity and that high level colistin resistance is associated with specific lipid A modification patterns that has been largely unexplored thus far. IMPORTANCERising levels of resistance to increasing numbers of antimicrobials has led to the revival of last resort antibiotic colistin. Unfortunately, resistance to colistin is also spreading in the form of mcr genes, making it essential to (i) improve identification of resistant bacteria to allow clinicians to prescribe effective drug regimens and (ii) develop new combination therapies effective at targeting resistant bacteria. Our results demonstrate that PETs, including MCR variants, are site-selective in E. coli, with site-selectivity correlating with the level of resistance and fitness costs conferred by certain PETs. Site-selectivity associated with a given PET may not only help predict colistin resistance phenotypes, but may also provide an avenue to (i) improved drug regimens and (ii) development of new combination therapies to better combat colistin resistant bacteria.

microbiology↗

bioRxiv2024

Distinct roles of prefrontal cortex neurons in set shifting

Cognitive flexibility, the ability to adjust behavioral strategies in response to changing environmental contingencies, requires adaptive processing of internal states and contextual cues to guide goal-oriented behavior, and is dependent on prefrontal cortex (PFC) functions. However, the neurophysiological underpinning of how the PFC supports cognitive flexibility is not well understood and has been under active investigation. We recorded spiking activity from single PFC neurons in mice performing the attentional set-shifting task, where mice learned to associate different contextually relevant sensory stimuli to reward. We identified subgroups of PFC neurons encoding task context, choice and trial outcome. Putative fast-spiking neurons were more involved in representing outcome and choice than putative regular-spiking neurons. Regression model further revealed that task context and trial outcome modulated the activity of choice-encoding neurons in rule-dependent and cell type-dependent manners. Together, our data provide new evidence to elucidate PFCs role in cognitive flexibility, suggesting differential cell type-specific engagement during set shifting, and that both contextual rule representation and trial outcome monitoring underlie PFCs unique capacity to support flexible behavioral switching.

neuroscience↗

bioRxiv2024

Induction of Ferroptosis by an Amalgam of Extracellular Vesicles and Iron Oxide Nanoparticles Overcomes Cisplatin Resistance in Lung Cancer

Extracellular vesicles (EVs) hold potential as effective carriers for drug delivery, providing a promising approach to resolving challenges in lung cancer treatment. Traditional treatments, such as with the chemotherapy drug cisplatin, encounter resistance in standard cell death pathways like apoptosis, prompting the need to explore alternative approaches. This study investigates the potential of iron oxide nanoparticles (IONP) and EVs to induce ferroptosis--a regulated cell death mechanism--in lung cancer cells. We formulated a novel EV and IONP-based system, namely ExoFeR, and observed that ExoFeR demonstrated efficient ferroptosis induction, evidenced by downregulation of ferroptosis markers (xCT/SLC7A11 and GPX4), increased intracellular and mitochondrial ferrous iron levels, and morphological changes in mitochondria. To enhance efficacy, tumor-targeting transferrin (TF)-conjugated ExoFeR (ExoFeRTF) was developed. ExoFeRTF outperformed ExoFeR, exhibiting higher uptake and cell death in lung cancer cells. Mechanistically, nuclear factor erythroid 2-related factor 2 (Nrf2)--a key regulator of genes involved in glutathione biosynthesis, antioxidant responses, lipid metabolism, and iron metabolism--was found downregulated in the ferroptotic cells. Inhibition of Nrf2 intracellular translocation in ExoFeRTF-treated cells was also observed, emphasizing the role of Nrf2 in modulating ferroptosis-dependent cell death. Furthermore, ExoFeR and ExoFeRTF demonstrated the ability to sensitize chemo-resistant cancer cells, including cisplatin-resistant lung cancer patient-derived tumoroid organoids. In summary, ExoFeRTF presents a promising and multifaceted therapeutic approach for combating lung cancer by intrinsically inducing ferroptosis and sensitizing chemo-resistant cells.

cancer biology↗

bioRxiv2024

Image retrieval based on closed-loop visual-semantic neural decoding

Neural decoding via the latent space of deep neural network models can infer perceived and imagined images from neural activities, even when the image is novel for the subject and decoder. Brain-computer interfaces (BCIs) using the latent space enable a subject to retrieve intended image from a large dataset on the basis of their neural activities but have not yet been realized. Here, we used neural decoding in a closed-loop condition to retrieve images of the instructed categories from 2.3 million images on the basis of the latent vector inferred from electrocorticographic signals of visual cortices. Using a latent space of contrastive language-image pretraining (CLIP) model, two subjects retrieved images with significant accuracy exceeding 80% for two instructions. In contrast, the image retrieval failed using the latent space of another model, AlexNet. In another task to imagine an image while viewing a different image, the imagery made the inferred latent vector significantly closer to the vector of the imagined category in the CLIP latent space but significantly further away in the AlexNet latent space, although the same electrocorticographic signals from nine subjects were decoded. Humans can retrieve the intended information via a closed-loop BCI with an appropriate latent space.

neuroscience↗

bioRxiv2024

Myeloid-Specific Thrombospondin-1 Deficiency Exacerbates Aortic Rupture via Broad Suppression of Extracellular Matrix Proteins

RationaleRupture of abdominal aortic aneurysms (AAA) is associated with high mortality. However, the precise molecular and cellular drivers of AAA rupture remain elusive. Our prior study showed that global and myeloid-specific deletion of matricellular protein thrombospondin-1 (TSP1) protects mice from aneurysm formation primarily by inhibiting vascular inflammation. ObjectiveTo investigate the cellular and molecular mechanisms that drive AAA rupture by testing how TSP1 deficiency in different cell populations affects the rupture event. Methods and ResultsWe deleted TSP1 in endothelial cells and macrophages --- the major TSP1-expressing cells in aneurysmal tissues ---- by crossbreeding Thbs1 flox/flox mice with VE-cadherin Cre and Lyz2-cre mice, respectively. Aortic aneurysm and rupture were induced by angiotensin II in mice with hypercholesterolemia. Myeloid-specific Thbs1 knockout, but not endothelial-specific knockout, increased the rate of lethal aortic rupture by more than 2 folds. Combined analyses of single-cell RNA sequencing and histology showed a unique cellular and molecular signature of the rupture-prone aorta that was characterized by a broad suppression in inflammation and extracellular matrix production. Visium spatial transcriptomic analysis on human AAA tissues showed a correlation between low TSP1 expression and aortic dissection. ConclusionsTSP1 expression by myeloid cells negatively regulates aneurysm rupture, likely through promoting the matrix repair phenotypes of vascular smooth muscle cells thereby increasing the strength of the vascular wall.

pathology↗

bioRxiv2024

Characterization of bronchiolitis and vaccine-induced enhanced respiratory disease in Syrian hamsters caused by respiratory syncytial virus infection

Respiratory syncytial virus (RSV) presents a significant health risk to pediatric and old populations. The quest for developing effective RSV vaccines and immunoprophylactic measures remains highly active, while the catastrophic enhanced respiratory disease (ERD) reaction triggered by RSV vaccines poses lingering concerns. Meanwhile, as the basis of vaccine research, the development of animal models of RSV infection has shown less substantial progress, with considerable disparities in immunological and pathological responses compared to humans. The Syrian hamster, which is reported to be susceptible to RSV infection, seems promising, but the lack of in-depth studies has hampered its application. Consequently, we have refined the RSV-infected hamster model by establishing infection models at different ages, reanalyzing virological and pathological data, and applying vaccination with heat-inactivated RSV virus for ERD reaction. In general, neonatal hamsters exhibited the highest level of viral amplification, while old hamsters displayed the most severe pathological manifestations, with adult hamsters in between. Although Syrian hamsters were moderately susceptible to RSV infection, they showed typical pathological changes of bronchitis in all age groups, with adult and old animals even showing clinical signs of coughing. In addition, hamsters demonstrated the typical ERD response to heat-inactivated virus, characterized by the exacerbation of lung injury with extensive neutrophil and eosinophil infiltration, as well as TH2 polarization. Collectively, these characteristics suggest that the Syrian hamster model has significant potential for investigating the pathogenesis of RSV infection, elucidating the mechanism of ERD, and evaluating vaccine efficacy and safety. ImportanceThe Syrian hamster has been shown in our study to be a potential model for respiratory syncytial virus (RSV) infection, according to the following characteristics: Hamsters of three different age groups all developed typical pulmonary bronchiolitis following RSV infection, whereas adult and old hamsters showed typical cough symptoms, comparable to those observed in clinical patients. Hamsters of different ages showed considerable variability. Neonatal hamsters tolerated more viral replication, while old hamsters suffered the most severe pulmonary pathology. Hamsters exhibited typical ERD responses after inoculation with heat-inactivated RSV virus, including enhanced lung pathology, pulmonary eosinophilic and neutrophil infiltration, and Th2 polarization, which was remarkable and more similar to the typical characteristics of the ERD response in humans.

microbiology↗

bioRxiv2024

Alleviation of salt stress in strawberries by hydrogen-rich water: physiological, transcriptomic and metabolomic responses

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/605184v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1aa6488org.highwire.dtl.DTLVardef@1ae580borg.highwire.dtl.DTLVardef@11656bcorg.highwire.dtl.DTLVardef@1985c7b_HPS_FORMAT_FIGEXP M_FIG C_FIG With the continuous advancement of climate change and human activities, cultivable land is becoming increasingly susceptible to the influence of salt ions. Therefore, it is crucial to mitigate the salt stress on plants through various approaches. In this study, strawberry seedlings were selected as the experimental plants, and a comprehensive transcriptomic and metabolomic analysis was conducted to elucidate the effects of hydrogen-rich water (HRW) on strawberries under salt stress. The results indicated that HRW significantly promoted plant growth, particularly increasing root biomass by 49.50%. Additionally, HRW regulated the levels of soluble sugars, malondialdehyde (MDA), and antioxidant enzymes, enhancing the cellular uptake of potassium ions and the expulsion of sodium ions. The levels of Ca2+ and Mg2+ in organelles increased by 2.06 and 2.45-fold, respectively. Transcriptomic analysis revealed that HRW substantially altered gene expression in strawberry roots; under salt stress, HRW up-regulated beneficial biological processes. Furthermore, genes related to ion absorption and transport, antioxidant enzymes, and cell wall biosynthesis were screened. Meanwhile, key common pathways were identified in differentially expressed metabolites (DEMs) and differentially expressed genes (DEGs) related to phenylpropane biosynthesis, alanine, aspartate, and glutamate metabolism, amino and nucleotide sugar metabolism, and galactose metabolism. A molecular mechanism for mitigating salt stress in strawberry seedlings by HRW was provided by the integrated approaches in this research, reflecting the potential applications of hydrogen gas in agriculture.

physiology↗

bioRxiv2024

Biochar Modulates Wheat Root Metabolome and Rhizosphere Microbiome in a Feedstock-dependent Manner

BackgroundBiochar is a multifunctional soil conditioner capable of enhancing soil health and plant productivity, but the underlying mechanisms remain elusive. Here we tackled this question using wheat as a model plant and through the lens of the rhizosphere, a vital soil-plant interface continuum. We systematically examined the effects of four types of biochar (corn stover, cattle manure, pine sawdust, or wheat straw) applied at two rates (0.25% or 2.5%, w/w). ResultsEmploying untargeted metabolomics and 16S rRNA gene sequencing, we revealed both common and unique modulating effects of the tested biochar treatments on wheat root metabolites and rhizosphere microbiome structure and functioning. Biochar modulated numerous metabolic pathways in wheat roots, where amino acid metabolism was the most common one, leading to cascade effects on the dynamics of a wide range of secondary metabolites, including many plant signaling molecules (e.g., flavonoid compounds, brassinosteroids) that are known to be involved in plant-microbe interactions. All biochar treatments increased rhizosphere microbial diversity, altered community composition, enhanced microbial interactions, and resulted in functional changes. Increased Burkholderiales (denitrifying bacteria) abundance and decreased Thermoplasmata (archaeal methanogens) abundance could explain biochars widely reported effects on nitrous oxide and methane mitigation, respectively. Biochar enhanced positive correlations among microbes and network complexity, particularly modularity, suggesting local adaptation through mutualism and/or synergism and the formation of modules of functionally interrelated taxa. A large number of diverse keystone taxa from both dominant and non-dominant phyla emerged after biochar treatments, including those known to be involved in methane, nitrogen, and sulfur cycling. Besides common alterations, treatment-specific alterations also occurred, and biochar type (i.e., feedstock choice) exerted greater influence than application rate. Wheat biochar applied at a 0.25% rate showed the strongest and distinct modulating effects, resulting in orchestrated changes in both root metabolites and rhizosphere microbiome, especially those relevant to plant-microbe interactions and likely beneficial to the host plant (e.g., upregulated biosynthesis of zeatin and down-regulated limonene degradation). ConclusionsOur work contributes to a mechanistic understanding of how biochar modulates the soil-plant continuum and provides new insights into the potential of top-down rhizosphere microbiome engineering through biochar-based reprogramming of root-microbe interactions.

microbiology↗

bioRxiv2024

B cell receptor silencing reveals the origin of high-grade B cell lymphomas with MYC and BCL2 rearrangements

The B cell receptor (BCR) is essential for mature B cell lymphomas, serving as therapeutic target. Here, we show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. HGBCL-DH-BCL2 with undetectable IGH (IGHUND) differ from IGH-expressing counterparts for germinal center-zone gene programs, MYC expression and T cell infiltration. While IGH+ HGBCL-DH-BCL2 prefer IGM/IG-Kappa expression, IGHUND counterparts have completed IGH class-switching, favoring IG-Lambda (IGL) light chains. IGHUND HGBCL-DH-BCL2 preserve IGHV gene integrity, overcoming antigen-driven selection. IGH silencing precedes onset and shapes evolution of HGBCL-DH-BCL2 from Follicular Lymphoma (FL) or FL/HGBCL-DH-BCL2 common precursor. In FL/HGBCL-DH-BCL2 pairs and HGBCL-DH-BCL2 models, BCR silencing promoted RAG1/2-dependent IG light chain editing, causing t(8;22)(q24;q11)/IGL::MYC. IGH silencing protected HGBCL-DH-BCL2 models from killing by CD79B-targeting Polatuzumab-Vedotin. Collectively, HGBCL-DH-BCL2 primarily originate from BCR-silenced isotype-switched t(14;18)/IGH::BCL2-positive (pre)FL cells acquiring IGL::MYC translocations during IG light chain revision, with clinical implications. SignificanceThese findings link BCR silencing in isotype-switched t(14;18)+ Follicular Lymphoma cells (or their precursors) to RAG1/2 re-expression, promoting IGL::MYC translocations responsible for transformation into high-grade B cell lymphomas (HGBCL). Predominant silencing of the BCR complex in HGBCL with MYC and BCL2 rearrangements protects tumor cells from CD79B-directed Polatuzumab-Vedotin killing.

cancer biology↗

bioRxiv2024

BOOST: a robust ten-fold expansion method on hour-scale

Expansion microscopy (ExM) enhances the microscopy resolution by physically expanding biological specimens and improves the visualization of structural and molecular details. Numerous ExM techniques and labeling methods have been developed and refined over the past decade to cater to specific research needs. Nonetheless, a shared limitation among current protocols is the extensive time required for sample processing, particularly for challenging-to-expand biological specimens (e.g., formalin-fixed paraffin-embedded (FFPE) sections and large three-dimensional specimens). Here, we have developed a rapid and robust ExM workflow named BOOST, which leverages a series of novel microwave (MW)-accelerated ExM chemistry, resulting in a single-step linear expansion of [~]10x. Specifically, BOOST facilitates a [~]10-fold expansion of cultured cells, tissue sections, and even the challenging-to-expand FFPE sections under merely 90 minutes with heat and surfactant-based protein denaturation. Furthermore, BOOST employs microwave-assisted proteomic staining and immunostaining to facilitate high-resolution visualization of structural and molecular details with significantly enhanced throughput. Noteworthily, BOOST has pioneered a [~]10-fold expansion of large millimeter-sized three-dimensional specimens in approximately three hours. BOOST offers an easily adaptable workflow based on stable and common reagents, thus boosting the potential adoption of ExM methods in biological investigations.

bioengineering↗

bioRxiv2024

Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response in mice and humans

Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy has been experimentally challenging because of variations in both host and tumor genomes, differences in the microbiome, and patient life exposures. Utilizing the Collaborative Cross (CC) multi-parent mouse genetic resource population, we developed an approach that fixes the tumor genomic configuration while varying host genetics. With this approach, we discovered that response to anti-PD-1 (aPD1) immunotherapy was significantly heritable in four distinct murine tumor models (H2 between 0.18-0.40). For the MC38 colorectal carcinoma system (H2 = 0.40), we mapped four significant ICI response quantitative trait loci (QTL) localized to mouse chromosomes (mChr) 5, 9, 15 and 17, and identified significant epistatic interactions between specific QTL pairs. Differentially expressed genes within these QTL were highly enriched for immune genes and pathways mediating allograft rejection and graft vs host disease. Using a cross species analytical approach, we found a core network of 48 genes within the four QTLs that showed significant prognostic value for overall survival in aPD1 treated human cohorts that outperformed all other existing validated immunotherapy biomarkers, especially in human tumors of the previously defined immune subtype 4. Functional blockade of two top candidate immune targets within the 48 gene network, GM-CSF and high affinity IL-2/IL-15 signaling, completely abrogated the MC38 tumor transcriptional response to aPD1 therapy in vivo. Thus, we have established a powerful cross species in vivo platform capable of uncovering host genetic factors that establish the tumor immune microenvironment configuration propitious for ICI response.

cancer biology↗

bioRxiv2024

Neuron synchronization analyzed through spatial-temporal attention

Across diverse organisms, the temporal dynamics of spiking responses between neurons, the neural synchrony, is crucial for encoding different stimuli. Neural synchrony is especially important in the insect antennal (olfactory) lobe (AL). Previous studies on synchronization, however, rely on pair-wise synchronization metrics including the cross-correlogram and cos-similarity between kernelized spikes train. These pair-wise analyses overlook an important aspect of synchronization which is the interaction at the population neuron level. There are also limited modeling techniques that incorporate the synchronization between neurons in modeling population spike trains. Inspired by recent advancements in machine learning, we leverage a modern attention mechanism to learn a generative normalizing flow that captures neuron population synchronization. Our method not only reveals the spiking mechanism of neurons in the AL region but also produces semi-interpretable attention weights that characterize neuron interactions over time. These automatically learned attention weights allow us to elucidate the known principles of neuron synchronization and further shed light on the functional roles of different cell types (the local interneurons (LNs), and projection neurons (PNs)) in the dynamic neural network in the AL. By varying the balance of excitation and inhibition in this neural circuit, our method further uncovers the pattern between the strength of synchronization and the ratio of an odorant in the mixture. Author SummaryThe olfactory system can accurately compute the mixture of volatile compounds emitted from distant sources, enabling the foraging species to exhibit fast and effective decisions. However, altering ratios of one of the compounds in the mixture could be perceived as a different odor. Leveraging the current understanding of neural synchronization on sensory neural regions of insects, we construct a spatial-temporal attention normalizing flow, which partially replicates the AL regions functionality by learning the spiking mechanics of neurons. Beyond providing insights of the spiking mechanism of neurons in the AL region, our method also produces semi-interpretable attention weights that characterize neuron interaction over time. These automatically learned attention weights allow us to dissect out the principles of neuron synchronization and interaction mechanisms between projection neurons (PNs) and local neurons (LNs). Utilizing our accurate model of these AL functionality, we show evidence that the behavioral relevant compounds are closely clustered together while varying the intensities of one of the behavioral compounds in the mixture could attenuate the synchronization

neuroscience↗

bioRxiv2024

Body size and light environment modulate flight speed and saccadic behavior in free flying Drosophila melanogaster

For flying insects, visual control relies on acquiring adequate light, but many circumstances limit this, such as dim environments, high image speeds, or eyes of modest light gathering power. To determine these effects on vinegar flies, we limited light by either placing them in dim conditions, or generating individuals with developmentally smaller eyes, then examined activity levels and three-dimensional flight paths. When simulating dawn and dusk light periods, walking flies increase activity, reflecting their crepuscular nature, and this is stronger for flies with larger eyes. When light switches abruptly, similar to many lab settings, activity associated with crepuscular periods diminishes, as does activity associated with greater facet size. During free flight, we find flight speed decreases similarly in both dim light and small eye conditions, but excess light induces smaller individuals to restore their flight speed. Through a machine learning approach, we confirmed that two features, translational speed and saccade distance, are sufficient to classify treatment groups by light niche, size, and age. Together, these imply that flight changes in smaller individuals result from visual deficits, rather than other elements of body structure.

animal behavior and cognition↗

bioRxiv2024

Extracellular vesicle-derived miRNA-mediated cell-cell communication inference for single-cell transcriptomic data with miRTalk

MicroRNAs are released from cells in extracellular vesicles (EVs), representing an essential mode of cell-cell communication (CCC) via an inhibitory effect on gene expression. The advent of single-cell RNA-sequencing (scRNA-seq) technologies has ushered in an era of elucidating EV-derived miRNA-mediated CCC. However, the lack of computational methods to infer such CCC poses an outstanding challenge. Herein, we present miRTalk (https://github.com/multitalk/miRTalk), a pioneering framework for inferring EV-derived miRNA-mediated CCC with a probabilistic model and a curated database, miRTalkDB, which includes EV-derived miRNA-target associations. The benchmarking against simulated and real-world datasets demonstrated the remarkable accuracy and robustness of miRTalk. Subsequently, we employed miRTalk to uncover the in-depth CCC mechanisms underlying three disease scenarios. In summary, miRTalk represents the first approach for inferring EV-derived miRNA-mediated CCC with scRNA-seq data, providing invaluable insights into the CCC dynamics underpinning biological processes.

bioinformatics↗

bioRxiv2024

Unsilenced inhibitory cortical ensemble gates remote memory retrieval

Acquired information can be consolidated to remote memory for storage but persists in a dormant state until its retrieval. However, it remains unknown how dormant memory is reactivated. Using a combination of simultaneous two-photon calcium imaging and holographic optogenetics in the anterior cingulate cortex (ACC) in vivo, we discover a subset of GABAergic neurons that are specifically associated with dormant memory retrieval. These interneurons display persistent activity and inter-neuronal synchronization at the remote memory stage. In the absence of natural contextual cues, directly activating these interneurons reliably recalls cortical ensembles relevant to remote memory retrieval with context specificity. Conversely, targeted volumetric inactivation of these interneurons suppresses context-induced memory retrieval. Our results reveal an unexpected role of unsilenced inhibitory cortical ensembles in causally gating the retrievability of dormant remote memory.

neuroscience↗