Biology subjects

Shi, W.

Publications and source records attributed to Shi, W..

At least 127 records · Page 7Linked to original sources

bioRxiv2022

A Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1-mediated Trabeculation Cessation

BackgroundLeft ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. MethodsWe screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo chromodomain helicase DNA-binding protein 4 (CHD4) proband, CHD4M202I, with congenital heart defects. We engineered a patient-specific model of CHD4M202I (mouse CHD4M195I). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4M195I-mediated ventricular wall defects. ResultsCHD4M195I/M195I mice developed biventricular hypertrabeculaion and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4M195I hearts, and the excessive trabeculation was associated with accumulation of extracellular matrix (ECM) proteins and a reduction of ADAMTS1, an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4M195I protein showed augmented affinity to endocardial BRG1. This enhanced affinity resulted in failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. ConclusionsOur study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4M195I can be attenuated by the administration of ADAMTS1. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIA patient-specific mouse model of CHD4M202I develops ventricular hypertrabeculation and dies at birth. C_LIO_LIProliferation of cardiomyocytes is significantly enhanced in CHD4M195I mice. C_LIO_LIADAMTS1 is significantly downregulated in CHD4M195I mice. C_LIO_LIClose interaction between CHD4M195I and BRG1 robustly and continuously represses Adamts1 transcription, which impairs ADAMTS1-mediated termination of trabeculation in the developing mutant heart. C_LI What Are the Clinical Implications?O_LIThis study provides a unique mouse model of ventricular noncompaction cardiomyopathy that faithfully reflects human patients genetic condition without disturbing the target genes expression and localization. C_LIO_LITranscriptional repression of ECM protease ADAMTS1 by CHD4-BRG1 interaction is detrimental to ventricular wall maturation; maintaining appropriate ADAMTS1 levels in the heart could be a promising therapeutic approach for treating ventricular noncompaction cardiomyopathy. C_LI

developmental biology↗

bioRxiv2022

Redefining normal breast cell populations using long noncoding RNAs

Single-cell RNAseq has allowed unprecedented insight into gene expression across different cell populations in normal tissue and disease states. However, almost all studies rely on annotated gene sets to capture gene expression levels and sequencing reads that do not align to known genes are discarded. Here, we discover thousands of long noncoding RNAs (lncRNAs) expressed in human mammary epithelial cells and analyze their expression in individual cells of the normal breast. We show that lncRNA expression alone can discriminate between luminal and basal cell types and define subpopulations of both compartments. Clustering cells based on lncRNA expression identified additional basal subpopulations, compared to clustering based on annotated gene expression, suggesting that lncRNAs can provide an additional layer of information to better distinguish breast cell subpopulations. In contrast, these breast-specific lncRNAs poorly distinguish brain cell populations, highlighting the need to annotate tissue-specific lncRNAs prior to expression analyses. We also identified a panel of 100 breast lncRNAs that could discern breast cancer subtypes better than protein-coding markers. Overall, our results suggest that lncRNAs are an unexplored resource for new biomarker and therapeutic target discovery in the normal breast and breast cancer subtypes.

cell biology↗

bioRxiv2022

Single-cell Atlas of Human Fetal Cerebellum Decoding Medulloblastoma Origin and Oncogenesis

Medulloblastoma (MB) is the most common malignant childhood brain tumor1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3,4 or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

cancer biology↗

bioRxiv2022

Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme

The successful generation of endodermal, ectodermal, and most mesodermal lineages from pluripotent stem cells has resulted in basic discoveries and regenerative medicine clinical trials of cell-based therapies. In contrast, the derivation of tissue-specific mesenchyme via directed differentiation in vitro has markedly lagged, due in part to a limited understanding of the signaling pathways regulating in vivo mesenchymal development and a lack of specific markers or reporters able to purify such lineages. The derivation of lung-specific mesenchyme is a particularly important goal since this tissue plays important roles in lung development and respiratory disease pathogenesis. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer facilitating the tracking and purification of engineered lung-specific mesenchyme. We identify the key signaling pathways (RA and Shh) necessary to specify lung mesenchyme from lateral plate mesodermal precursors and find that mouse iPSC-derived lung mesenchyme (iLM) expresses the molecular and functional phenotypes of primary developing lung mesenchyme. Purified iLM can be recombined with separately engineered lung epithelial progenitors, self-organizing into 3-dimensional organoids featuring significantly augmented structural complexity and lineage purity, including interacting juxtaposed layers of epithelium and mesenchyme. Co-culture with iLM increases the yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional epithelial-mesenchymal crosstalk. Our iPSC-derived population thus expresses key features of developing lung mesenchyme, providing an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics.

developmental biology↗

bioRxiv2022

Is cold-induced nuclear import of CBF4 regulating freezing tolerance?

C-repeat binding factors (CBFs) are crucial transcriptional activators in plant responses to low temperature. CBF4 differs by a slower, but more persistent regulation and its role in cold acclimation. Cold acclimation is of accentuated relevance for the tolerance to late spring frosts as they become progressively common as consequence of blurred seasonality in the context of global climate change. In the current study, we explore the functions of CBF4 from grapevine, VvCBF4. Overexpression of VvCBF4 fused to GFP in tobacco BY-2 cells confers cold tolerance. Furthermore, this protein shuttles from the cytoplasm to the nucleus in response to cold stress, associated with accumulation of transcripts for other CBFs and the cold responsive gene ERD10d. This response differs for chilling as compared to freezing and is regulated differently by upstream signalling involving oxidative burst, proteasome activity and jasmonate synthesis. This difference between chilling and freezing is also seen in the regulation of CBF4 transcripts in leaves from different grapevines differing in their cold tolerance. We propose the quality of cold stress is transduced by different upstream signals inducing nuclear import to regulate other CBF factor and activate COR genes.

molecular biology↗

bioRxiv2022

A multispecific antibody confers pan-reactive SARS-CoV-2 neutralization and prevents immune escape

Summary ParagraphDespite effective countermeasures, SARS-CoV-2 persists worldwide due to its ability to diversify and evade human immunity1. This evasion stems from amino-acid substitutions, particularly in the receptor-binding domain of the spike, that confer resistance to vaccines and antibodies 2-16. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different receptor binding domain (RBD) sites17,18 into multispecific antibodies. Here, we describe multispecific antibodies, including a trispecific that prevented virus escape >3000-fold more potently than the most effective clinical antibody or mixtures of the parental antibodies. Despite being generated before the evolution of Omicron, this trispecific antibody potently neutralized all previous variants of concern and major Omicron variants, including the most recent BA.4/BA.5 strains at nanomolar concentrations. Negative stain electron microscopy revealed that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated inter-spike binding. An optimized trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2 and BA.5, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. Such multispecific antibodies decrease the likelihood of SARS-CoV-2 escape, simplify treatment, and maximize coverage, providing a strategy for universal antibody therapies that could help eliminate pandemic spread for this and other pathogens.

immunology↗

bioRxiv2022

Intrinsic BMP inhibitor Gremlin regulates lung alveolar progenitor cell proliferation and differentiation

Type 1 alveolar epithelial cells (AT1s) and type 2 alveolar epithelial cells (AT2s) regulate the structural integrity and function of alveoli. AT1s mediate gas exchange, whereas AT2s serve multiple functions, including surfactant secretion and alveolar repair through proliferation and differentiation into AT1s as progenitors. However, mechanisms regulating AT2 proliferation and differentiation remain unclear. Here we demonstrate that Gremlin, an intrinsic inhibitor of bone morphogenetic protein (BMP), induces AT2 proliferation and differentiation. Transient overexpression of Gremlin in rat lungs by adenovirus vector delivery suppressed BMP signaling, induced proliferation of AT2s and the production of Bmp2, which in turn led to the recovery of BMP signaling and induced AT2 differentiation into AT1s. Gremlin was upregulated in a bleomycin-induced lung injury model. TGF-{beta} and IL-1{beta} induced Gremlin expression in fibroblasts. Taken together, our findings implicate that Gremlin expression during lung injury leads to precisely timed inhibition of BMP signaling and activates AT2s, leading to alveolar repair.

molecular biology↗

bioRxiv2022

A kinetic basis for curvature sensing by septins

The ability of cells to sense and communicate their shape is central to many of their functions. Much is known about how cells generate complex shapes, yet how they sense and respond to geometric cues remains poorly understood. Septins are GTP-binding proteins that localize to sites of micron-scale membrane curvature. Assembly of septins is a multi-step and multi-scale process but it is unknown how these discrete steps lead to curvature sensing. Here we experimentally examine the time-dependent binding of septins at different curvatures and septin bulk concentrations. These experiments unexpectedly indicated that the curvature preference of septins is not absolute but rather is sensitive to the combinations of membrane curvatures present in a reaction, suggesting there is competition between different curvatures for septin binding. To understand the basis of this result, we developed a kinetic model that connects septins self-assembly and curvature sensing properties. Our experimental and modeling results are consistent with curvature-sensitive assembly being driven by cooperative associations of septin oligomers in solution with the bound septins. When combined, the work indicates septin curvature sensing is kinetically determined, sensitive to bulk concentration, and the available membrane curvatures. While much geometry-sensitive assembly in biology is thought to be guided by intrinsic material properties of molecules, this is an important example of how kinetics can drive mesoscale curvature-sensitive assembly of polymers. Significance StatementCells use their membrane curvature to coordinate the activation and spatiotemporal compartmentalization of molecules during key cellular processes. Recent works have identified different proteins that can sense or induce membrane curvature from nano- to micron-scale. Septins are nanoscopic cytoskeletal proteins that preferentially bind to membranes with a narrow range of micron-scale curvatures. Yet the sensing mechanism remains ambiguous. Using a combination of microscopy and kinetic modeling, we show that, unlike most proteins that sense curvature in a single protein scale, curvature sensing in septins is determined kinetically through their multi-step hierarchical assembly on the membrane. This introduces a novel kinetic basis of fidelity, where the same protein can be deployed for differential binding sensitivities in different cellular contexts.

biophysics↗

bioRxiv2022

Toxic effects of elevated bile acid levels on fetal myocardium in intrahepatic cholestasis of pregnancy?from a neonatal perspective

IntroductionIntrahepatic cholestasis of pregnancy (ICP) is a liver disease which may lead to a sudden fetal death. Previous studies have suggested that the fetal accident may be related to their cardiac dysfunction. However, the relationship between fetal cardiac dysfunction and their maternal bile acid levels is not clear. The objective was to clarify the relationship from a neonatal perspective and to furtherly make clear the after-effect by analysing the cardiac parameters of the older neonates. Materials and methodsIn this case-control study, patients and their neonates, managed between 10 September 2018 and 30 June 2021 at a Chinese university hospital center, were divided into severe ICP group, mild ICP group and control gestational group. The maternal bile acid levels and the cardiac paramerers of one-day-old neonates and five-day-old neonates were analysed, respectively. ResultsThe specific-myocardial enzyme(CK-MB) and left ventricular fraction shortening(FS) of neonates showed significant differences between ICP group and control group, and were meaningfully correlated with maternal bile acid levels. However, There was no significant difference in cardiac injury parameters of older neonates between the ICP and control groups. ConclusionsThe elevated maternal bile acid levels can lead to fetal myocardial injury and the injury can be recovered after removel from high concentrations of bile acid.

pharmacology and toxicology↗

bioRxiv2022

Spatiotemporal atlas of the fetal brain depicts cortical developmental gradient in Chinese population

The fetal brains experience rapid and complex development in utero during the second and third trimesters. MRI atlas of the fetal brain in this period enables us to quantify the normal fetal brain development in the spatiotemporal domain. In this study, we constructed a high quality spatiotemporal atlas between 23-38 weeks gestational age (GA) from 90 healthy Chinese fetuses using a pairwise and groupwise registration-based pipeline. We quantified the fetal cortical morphology and characterized the developmental trajectories of each morphological index. The cortical thickness exhibited a biphasic growth pattern; the developmental trend of curvature fitted well into the Gompertz model; sulcal depth increased linearly while surface area expanded exponentially. The cortical thickness and curvature trajectories consistently pointed to a characteristic time-point during development around 31 weeks of GA. The characteristic GA and growth rate obtained from individual cortical regions suggested a central-to-peripheral developmental gradient, with the earliest development in the parietal lobe, and we also observed within-lobe regional orders, which may be linked to biophysical events such as dendritic arborization and thalamocortical fibers ingrowth. The proposed atlas was also compared with an existing fetal atlas from a Caucasian/mixed population. Finally, we examined the structural asymmetry of the fetal brains and found extensive asymmetry that dynamically changed with development. The current study depicted a comprehensive profile of fetal cortical development and the established atlas could be used as a normative reference for neurodevelopmental and diagnostic purposes, especially in the Chinese population.

bioengineering↗

bioRxiv2022

Structural and functional characteristics of SARS-CoV-2 Omicron subvariant BA.2 spike

The Omicron subvariant BA.2 has become the dominant circulating strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in many countries. We have characterized structural, functional and antigenic properties of the full-length BA.2 spike (S) protein and compared replication of the authentic virus in cell culture and animal model with previously prevalent variants. BA.2 S can fuse membranes more efficiently than Omicron BA.1, mainly due to lack of a BA.1-specific mutation that may retard the receptor engagement, but still less efficiently than other variants. Both BA.1 and BA.2 viruses replicated substantially faster in animal lungs than the early G614 (B.1) strain in the absence of pre-existing immunity, possibly explaining the increased transmissibility despite their functionally compromised spikes. As in BA.1, mutations in the BA.2 S remodel its antigenic surfaces leading to strong resistance to neutralizing antibodies. These results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility for the Omicron subvariants.

microbiology↗

bioRxiv2022

The Gene Knockout of Angiotensin II Type 1a Receptor Improves High-fat Diet-Induced Obesity in rat via Promoting Adipose Lipolysis

AimsThe renin-angiotensin system (RAS) is over-activated and the serum angiotensin II (Ang II) level increased in obese patients, while their correlations were incompletely understood. This study aims to explore the role of Ang II in diet-induced obesity by focusing on adipose lipolysis. MethodsRat model of AT1aR gene knockout were established to investigate the special role of Ang II. Wild-type (WT) and AT1aR gene knockout (AT1aR-/-) SD rats were fed with normal diet or high-fat diet for 12 weeks. Adipose morphology and adipose lipolysis were examined. ResultsAT1aR deficiency activated lipolysis-related enzymes and increased the levels of NEFAs and glycerol released from adipose tissue in high-fat diet rats, while did not affect triglycerides synthesis. Besides, AT1aR knockout promoted energy expenditure and fatty acids oxidation in adipose tissue. cAMP levels and PKA phosphorylation in the adipose tissue were significantly increased in AT1aR-/- rats fed with high-fat. Activated PKA could promote adipose lipolysis and thus improved adipose histomorphology and insulin sensitivity in high-fat diet rats. ConclusionsAT1aR deficiency alleviated adipocyte hypertrophy in high-fat diet rats by promoting adipose lipolysis via cAMP/PKA pathway, and thereby delayed the onset of obesity and related metabolic diseases.

physiology↗

bioRxiv2022

NSMCE2, a Novel Super-Enhancer Regulated Gene, is Linked to Poor Prognosis and Therapy Resistance in Breast Cancer

In this study, we identified two novel super-enhancer associated genes: NSMCE2 and MAL2, highly upregulated in breast tumors, for which high RNA levels significantly and specifically correlate with breast cancer patients poor prognosis. To approach this, we took advantage of existing datasets containing super-enhancers associated genes identified in primary breast tumors and public databases comprising gene expression, genomic and clinical outcomes for patients diagnosed with breast cancer. Through in-vitro pharmacological super-enhancer disruption assays in breast cancer cells we confirmed that super-enhancers are involved in NSMCE2 and MAL2 transcript upregulation and through bioinformatics we found that high levels of NSMCE2 strongly associate with poor response to chemotherapy. This was observed especially for patients diagnosed with aggressive triple negative and HER2 positive tumor types. Finally, we showed that treating breast cancer cells with chemotherapeutic agents while simultaneously decreasing NSMCE2 gene expression by super-enhancer blockade or by directly silencing it, reduces cell viability thus increasing the effectiveness of chemotherapy. Our results indicate that moderating the transcript levels of the novel identified super-enhancer associated gene NSMCE2 could improve patients response to standard chemotherapy and, consequently, may improve disease outcome. In summary by mining existing public breast cancer datasets, our work demonstrates that searching for super-enhancer regulated genes and their association to patients survival and response to treatment, could be an effective method for identifying a signature of tumor specific -not frequently mutated, but super-enhancer dysregulated genes. Our approach offers a new avenue to identify novel biomarkers of poor prognosis and potential pharmacological targets for improving cancer treatment.

cancer biology↗

bioRxiv2022

Convergent epitope specificities, V gene usage and public clones elicited by primary exposure to SARS-CoV-2 variants

An important consequence of infection with a SARS-CoV-2 variant is protective humoral immunity against other variants. The basis for such cross-protection at the molecular level is incompletely understood. Here we characterized the repertoire and epitope specificity of antibodies elicited by Beta, Gamma and ancestral variant infection and assessed their cross-reactivity to these and the more recent Delta and Omicron variants. We developed a high-throughput approach to obtain immunoglobulin sequences and produce monoclonal antibodies for functional assessment from single B cells. Infection with any variant elicited similar cross-binding antibody responses exhibiting a remarkably conserved hierarchy of epitope immunodominance. Furthermore, convergent V gene usage and similar public B cell clones were elicited regardless of infecting variant. These convergent responses despite antigenic variation may represent a general immunological principle that accounts for the continued efficacy of vaccines based on a single ancestral variant.

immunology↗

bioRxiv2022

Transcriptome of epibiont Saccharibacteria Nanosynbacter lyticus strain TM7x during establishment of symbiosis

Saccharibacteria Nanosynbacter lyticus strain TM7x is a member of the broadly distributed Candidate Phylum Radiation. These bacteria have ultrasmall cell size, reduced genomes and live as epibionts on the surface of other bacteria. The mechanisms by which they establish and maintain this relationship are not yet fully understood. The transcriptomes of the epibiont TM7x and its host bacteria Schaalia odontolyticus strain XH001 were captured across the establishment of symbiosis during both the initial interaction and stable symbiosis. The results showed a dynamic interaction with large shifts in gene expression for both species between the initial encounter and stable symbiosis, notably transporter genes. During stable symbiosis, the host XH001 showed higher gene expression for peptidoglycan biosynthesis, mannosylation, cell cycle and stress related genes, but lower expression of chromosomal partitioning genes. This was consistent with the elongated cell shape seen in XH001 infected with TM7x and our discovery that infection resulted in thickened cell walls. Within TM7x, increased pili, type IV effector gene, and arginine catabolism/biosynthesis gene expression during stable symbiosis implied a key role for these functions in the interaction. Consistent with its survival and persistence in the human microbiome as an obligate epibiont with reduced de novo biosynthetic capacities, TM7x also showed higher levels for energy production and peptidoglycan biosynthesis but lower expression of stress related genes during stable symbiosis. These results imply that TM7x and its host bacteria keep a delicate balance in order to sustain an episymbiotic lifestyle. IMPORTANCENanosynbacter lyticus type strain TM7x is the first cultivated member of the Saccharibacteria and the Candidate Phyla Radiation (CPR). It was discovered to have ultrasmall cell size with a highly reduced genome that establishes an obligate epibiotic relationship with its host bacterium. The CPR, now formally proposed as the Patescibacteria super-phylum, is a large monophyletic radiation of diverse bacteria with reduced genomes that includes Saccharibacteria. The vast majority of the CPR have yet to be cultivated in the laboratory and our insights into these unique organisms to date has been derived from only a few Saccharibacteria species. It is unknown however how these small obligate parasitic Saccharibacteria, that are missing many de novo biosynthetic pathways, are maintained at high prevalence within the human microbiome as well as in the environment. When TM7x infects its host bacterium there are distinct temporal phases, including an initial interaction, a killing phase, recovery phase, and finally stable symbiosis. Here we captured the gene expression of the host bacterium and epibiont during this dynamic interaction which represents the initial insights into the mechanisms of how these unique microbes may survive and persist.

microbiology↗

bioRxiv2022

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

Despite the demonstrated immense potential of immune checkpoint inhibitors in various types of cancers, only a minority of patients respond to these therapies. Immunocytokines designed to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME) and block the immune checkpoint simultaneously may provide a strategic advantage over the combination of two single agents. To increase response rate to checkpoint blockade, in this study we developed a novel immunocytokine (LH01) composed of the antibody against programmed death-ligand 1 (PD-L1) fused to IL-15 receptor alpha-sushi domain/IL-15 complex. We demonstrate that LH01 efficiently binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. In syngeneic mouse models, LH01 showed improved antitumor efficacy and safety versus anti-PD-L1 plus LH02 (Fc-Sushi-IL15) combination and overcame resistance to anti-PD-L1 treatment. Mechanistically, the dual anti-immunosuppressive function of LH01 led to activation of both the innate and adaptive immune response and decreased levels of transforming growth factor-{beta}1 (TGF-{beta}1) within the TME. Furthermore, combination therapy with LH01 and bevacizumab exerts synergistic antitumor effects in HT29 colorectal xenograft model. Collectively, our results provide supporting evidence that fusion of anti-PD-L1 and IL-15 might be a potent strategy to treat patients with cold tumors or resistance to checkpoint blockade.

immunology↗

bioRxiv2022

Genome-wide in vivo CRISPR screens identify GATOR1 as a TP53 induced tumour suppressor

Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC (which is abnormally highly expressed in [~]70% of human cancers) we have used a genome-wide CRISPR knockout screen in E{micro}-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo. We discovered that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerated c-MYC-driven lymphoma development in mice. Low expression of the GATOR1 complex genes correlated with poor survival outcomes for human patients with high MYC- expressing cancers. Murine lymphomas lacking GATOR1 were highly sensitive to mTOR inhibitors as a single agent therapy, both in vitro and in vivo. These findings identify inhibition of mTORC1 as a potent tumor suppressive mechanism in c-MYC-driven lymphomagenesis and suggest a new avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition. Key PointsO_LIIn vivo CRISPR/Cas9 whole genome knockout screens identified the GATOR1 complex as a potent suppressor of c-MYC-driven lymphomagenesis. C_LIO_LIGATOR1 deficiency in MYC-driven lymphomas confers sensitivity to mTOR inhibition, suggesting a novel therapeutic approach. C_LI

cancer biology↗

bioRxiv2022

Anatomical connectivity profile development constrains medial-lateral topography in the dorsal prefrontal cortex

The prefrontal cortex (PFC) is a highly variable, evolutionarily expanded brain region that is engaged in multiple cognitive processes. The subregions of the PFC mature relatively late compared with other brain regions, and the maturation times vary between these subregions. Among these, the dorsomedial and dorsolateral prefrontal cortex (dmPFC and dlPFC) share a parallel topographic pattern of functional connectivity, while participating in different types of complex behaviors. However, the developmental trajectories of the two areas remain obscure. In this study, we uncovered differences in the developmental trends of the dmPFC and dlPFC. These differences were mainly caused by structural and functional changes in the medial area of the superior frontal gyrus (SFG). The developmentally different arealization patterns were verified using multiple parcellation approaches with multimodal data, including structural magnetic resonance imaging (sMRI), diffusion MRI (dMRI), resting state functional MRI (rfMRI), and a publicly available transcriptomic dataset. Human brain gene expression data was also used to perform downstream analyses, which could inform us about the potential biological mechanisms underlying the developmentally different arealizations. Furthermore, behavioral analyses hinted at the effects of regionalization on ontogeny. In brief, this study revealed a tendency toward a medial-lateral prefrontal division and can provide a fuller understanding of the potential underlying genetic underpinnings as well as of the potential effects on developmental behavior.

neuroscience↗