Biology subjects

Tu, Z.

Publications and source records attributed to Tu, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Beyond Auditory Relay: Dissecting the Inferior Colliculus's Role in Sensory Prediction, Cognitive Decision-Making, and Reward Prediction

The Inferior Colliculus (IC) has traditionally been regarded as an important relay in the auditory pathway, primarily involved in relaying auditory information from the brainstem to the thalamus. However, this study uncovers the multifaceted role of the IC in bridging auditory processing, sensory prediction, and reward prediction. Through extracellular recordings in monkeys engaged in a sound duration-based deviation detection task, we observed a "climbing effect" in neuronal firing rates, indicative of an enhanced response over sound sequences linked to sensory prediction rather than reward anticipation. Moreover, our findings demonstrate reward prediction errors within the IC, highlighting its complex integration in auditory and reward processing. Further analysis revealed a direct correlation between IC neuronal activity and behavioral choices, suggesting its involvement in decision-making processes. This research highlights a more complex role for the IC than traditionally understood, showcasing its integral role in cognitive and sensory processing and emphasizing its importance in integrated brain functions.

neuroscience↗

bioRxiv2024

Spatiotemporal transcriptomic maps of mouse intracerebral hemorrhage at single-cell resolution

Intracerebral hemorrhage (ICH) is a severe and widespread disease that results in high mortality and morbidity. Despite significant advances made in clinical and preclinical research, the prognosis of ICH remains poor due to an incomplete understanding of the complex pathological responses. To address this challenge, we generated single-cell resolution spatiotemporal transcriptomic maps of mouse brain 1, 3, 7, 14, and 28 days after ICH. Our analysis revealed the cellular constituents and their dynamic responses following ICH. We found changes in gene expression that are indicative of active phagocytosis and lipid processing in the lesion core and identified genes associated with brain repair at the lesion border. Persistent lipid accumulation culminated in the phenotypic transition of macrophages into foam cells. Furthermore, our results demonstrate that ICH could stimulate neural stem cells in the subventricular zone, thereby enhancing neurogenesis in this niche. This study provides a spatiotemporal molecular atlas of mouse ICH that advances the understanding of both local and global responses of brain cells to ICH and offers a valuable resource that can aid the development of novel therapies for this devastating condition.

neuroscience↗

bioRxiv2024

Lipoxin A4/FPR2 signaling mitigates ferroptosis of alveolar epithelial cells via NRF2-dependent pathway during lung ischemia-reperfusion injury

BACKGROUNDPost-lung transplantation (LTx) injury can involve sterile inflammation due to ischemia-reperfusion injury (IRI). We investigated the cell-specific role of ferroptosis (excessive iron-mediated cell death) in mediating lung IRI and determined if specialized pro-resolving mediators such as Lipoxin A4 (LxA4) can protect against ferroptosis in lung IRI. METHODSSingle-cell RNA sequencing of lung tissue from post-LTx patients was analyzed. Lung IRI was evaluated in C57BL/6 (WT), formyl peptide receptor 2 knockout (Fpr2-/-) and nuclear factor erythroid 2-related factor 2 knockout (Nrf2-/-) mice using a hilar-ligation model with or without LxA4 administration. Furthermore, the protective efficacy of LxA4 was evaluated employing a murine orthotopic LTx model and in vitro studies using alveolar type II epithelial (ATII) cells. RESULTSDifferential expression of ferroptosis-related genes was observed in post-LTx patient samples compared to healthy controls. A significant increase in the levels of oxidized lipids and reduction in the levels of intact lipids were observed in mice subjected to IRI compared to shams. Furthermore, pharmacological inhibition of ferroptosis with liproxstatin-1 mitigated lung IRI and lung dysfunction. Importantly, LxA4 treatment attenuated pulmonary dysfunction, ferroptosis and inflammation in WT mice subjected to lung IRI, but not in Fpr2-/- or Nrf2-/-mice, after IRI. In the murine LTx model, LxA4 treatment increased PaO2 levels and attenuated lung IRI. Mechanistically, LxA4-mediated protection involves increase in NRF2 activation and glutathione concentration as well as decrease in MDA levels in ATII cells. CONCLUSIONSLxA4/FPR2 signaling on ATII cells mitigates ferroptosis via NRF2 activation and protects against lung IRI.

immunology↗

bioRxiv2024

Non-mechanical disruption of Bacillus subtilis spores allows sensitive and deep characterization of the minimal proteome for resuming a cellular lifestyle.

In response to extreme conditions, Bacillus subtilis generates highly resilient spores characterized by a unique multilayered structure. This confers resistance against various chemicals and enzymes yet adding complexity to the analysis of the spore proteome. As the first step in bottom-up proteomics, sample preparation poses a significant challenge. We assessed how an optimized protocol for sample preparation by easy extraction and digestion (SPEED) performed compared to previously established methods "One-pot" (OP) and single-pot, solid phase-enhanced sample-preparation (SP3) for the proteomic analysis of B. subtilis cell and spore samples. We found that SPEED outperformed both OP and SP3 in terms of peptides and proteins identified, moreover SPEED highly reproducibly quantified over 1000 proteins in limited input samples as low as 1 OD600 of B. subtilis cells and spores. SPEED was applied to analyze spore samples of different purity by applying sequential purification following harvesting of spores. Comparison of the differential abundance of proteins revealed clusters likely partially stemming from remaining vegetative cells in less purified spore samples. We show that ranking of absolute protein abundance in cellular and spore samples further enables us to rationally differentiate integral spore proteins from vegetative remnants. This is of importance in applications and organisms where highly homogenous spore samples are difficult to obtain. A deep proteomic analysis of spore and vegetative cell samples with the new approach led to the identification of 2447 proteins, 2273 of which were further quantified and compared between B. subtilis spores and cells. Our findings indicate that pathways related to peptidoglycan biosynthesis, glycolysis, carbon metabolism, and biosynthesis of secondary metabolites are shared between cells and spores. This corroborates and extends earlier work stressing that despite marked differences in their physiological states, spores preserve vegetative cell (core) proteins, essential for revival under conditions conducive to growth. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/584050v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@9ac7b1org.highwire.dtl.DTLVardef@1ac35c6org.highwire.dtl.DTLVardef@fe73a4org.highwire.dtl.DTLVardef@15a24e8_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Human brain aging heterogeneity observed from multi-region omics data reveals a subtype closely related to Alzheimer's disease

INTRODUCTION: The interconnection between brain aging and Alzheimers disease (AD) remain to be elucidated. METHODS: We investigated multi-omics (transcriptomics and proteomics) data from multiple brain regions (i.e., the hippocampus (HIPP), prefrontal cortex (PFC), and cerebellum (CRBL)) in cognitively normal individuals. RESULTS: We found that brain samples could be divided into ADL (AD-like) and NL (normal) subtypes which were correlated across brain regions. The differentially expressed genes in the ADL samples highly overlapped with AD gene signatures and the changes were consistent across brain regions (PFC and HIPP) in the multi-omics data. Intriguingly, the ADL subtype in PFC showed more differentially expressed genes than other brain regions, which could be explained by the baseline gene expression differences in the PFC NL samples. DISCUSSION: We conclude that brain aging heterogeneity widely exists, and our findings corroborate with the hypothesis that AD-related changes occur decades before the clinical manifestation of cognitive impairment in a sub-population.

neuroscience↗

bioRxiv2024

Discovery and characterization of chromosomal inversions in the arboviral vector mosquito Aedes aegypti

Chromosomal inversions play a fundamental role in evolution and have been shown to regulate epidemiologically important traits in malaria mosquitoes. However, they have never been characterized in Aedes aegypti, the major vector of arboviruses, because of the poor structure of its polytene chromosomes. In this study, we applied a Hi-C proximity ligation approach to identify chromosomal inversions in 25 strains of Ae. aegypti, acquired from its worldwide distribution, as well as in one strain of Ae. mascarensis. The study identified 21 multi-megabase inversions with uneven distributions along the three chromosomes. All chromosomal inversions, including one specific for Ae. mascarensis, were polymorphic. Nevertheless, geographic origin separated the strains into two clusters carrying African and non-African inversions suggesting their potential association with Ae. aegypti subspecies. Some of the inversions colocalized with chemoreceptor genes and quantitative trait loci associated with pathogen infection, implicating the potential role of inversions in host choice and disease transmission.

evolutionary biology↗

bioRxiv2024

A single-cell 3D spatiotemporal multi-omics atlas from Drosophila embryogenesis to metamorphosis

The development of a multicellular organism is a highly intricate process tightly regulated by numerous genes and pathways in both spatial and temporal manners. Here, we present Flysta3D, a comprehensive multi-omics atlas of the model organism Drosophila, spanning its developmental lifespan from embryo to pupa. Our datasets encompass 3D single-cell spatial transcriptomic, single-cell transcriptomic, and single-cell chromatin accessibility information. By integrating these multi-dimensional data, we constructed cell state trajectories that uncover the detailed profiles of tissue development. With a focus on the central nervous system (CNS) and midgut, we dissected the spatiotemporal dynamics of gene regulatory networks, cell type diversity, and morphological changes from a multi-omics perspective. This extensive atlas provides an unprecedentedly rich resource and serves as a systematic platform for studying Drosophila development with integrated single-cell data at an ultra-high spatiotemporal resolution.

developmental biology↗

bioRxiv2024

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant injury

ABSTRACTO_ST_ABSRationaleC_ST_ABSPatients with end stage lung diseases require lung transplantation (LTx) that can be impeded by ischemia-reperfusion injury (IRI) leading to subsequent chronic lung allograft dysfunction (CLAD) and inadequate outcomes. ObjectivesWe examined the undefined role of MerTK (receptor Mer tyrosine kinase) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis (phagocytosis of apoptotic cells) to facilitate resolution of lung IRI. MethodsSingle-cell RNA sequencing of lung tissue and BAL from post-LTx patients was analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with Balb/c (WT), cebpb-/- (MDSC-deficient), Mertk-/- or MerTK-CR (cleavage resistant) mice. Lung function, IRI (inflammatory cytokine and myeloperoxidase expression, immunohistology for neutrophil infiltration), and flow cytometry of lung tissue for efferocytosis of apoptotic neutrophils were assessed in mice. Measurements and Main ResultsA significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of CLAD patients compared to healthy subjects was observed. In the murine IRI model, significant increase in M-MDSCs, MerTK expression and efferocytosis was observed in WT mice during resolution phase that was absent in cebpb-/- Land Mertk-/- mice. Adoptive transfer of M-MDSCs in cebpb-/- mice significantly attenuated lung dysfunction, and inflammation leading to resolution of IRI. Additionally, in a preclinical murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. In vitro studies demonstrated the ability of M-MDSCs to efferocytose apoptotic neutrophils in a MerTK-dependent manner. ConclusionsOur results suggest that MerTK-dependent efferocytosis by M-MDSCs can significantly contribute to the resolution of post-LTx IRI.

immunology↗

bioRxiv2024

C-di-AMP accumulation disrupts glutathione metabolism and inhibits virulence program expression in Listeria monocytogenes

C-di-AMP is an essential second messenger in many bacteria but its levels must be regulated. Unregulated c-di-AMP accumulation attenuates the virulence of many bacterial pathogens, including those that do not require c-di-AMP for growth. However, the mechanisms by which c-di-AMP regulates bacterial pathogenesis remain poorly understood. In Listeria monocytogenes, a mutant lacking both c-di-AMP phosphodiesterases, denoted as the {Delta}PDE mutant, accumulates a high c-di-AMP level and is significantly attenuated in the mouse model of systemic infection. All key L. monocytogenes virulence genes are transcriptionally upregulated by the master transcription factor PrfA, which is activated by reduced glutathione (GSH) during infection. Our transcriptomic analysis revealed that the {Delta}PDE mutant is significantly impaired for the expression of virulence genes within the PrfA core regulon. Subsequent quantitative gene expression analyses validated this phenotype both at the basal level and upon PrfA activation by GSH. A constitutively active PrfA* variant, PrfA G145S, which mimics the GSH-bound conformation, restores virulence gene expression in {Delta}PDE but only partially rescues virulence defect. Through GSH quantification and uptake assays, we found that the {Delta}PDE strain is significantly depleted for GSH, and that c-di-AMP inhibits GSH uptake. Constitutive expression of gshF (encoding a GSH synthetase) does not restore GSH levels in the {Delta}PDE strain, suggesting that c-di-AMP inhibits GSH synthesis activity or promotes GSH catabolism. Taken together, our data reveals GSH metabolism as another pathway that is regulated by c-di-AMP. C-di-AMP accumulation depletes cytoplasmic GSH levels within L. monocytogenes that leads to impaired virulence program expression. IMPORTANCEC-di-AMP regulates both bacterial pathogenesis and interactions with the host. Although c-di-AMP is essential in many bacteria, its accumulation also attenuates the virulence of many bacterial pathogens. Therefore, disrupting c-di-AMP homeostasis is a promising antibacterial treatment strategy, and has inspired several studies that screened for chemical inhibitors of c-di-AMP phosphodiesterases. However, the mechanisms by which c-di-AMP accumulation diminishes bacterial pathogenesis are poorly understood. Such understanding will reveal the molecular function of c-di-AMP, and inform therapeutic development strategies. Here, we identify GSH metabolism as a pathway regulated by c-di-AMP that is pertinent to L. monocytogenes replication in the host. Given the role of GSH as a virulence signal, nutrient, and antioxidant, GSH depletion impairs virulence program expression and likely diminishes host adaptation.

microbiology↗

bioRxiv2023

A novel lethal cuticular structural protein, AaCPR100A and its upstream interaction protein, G12-like, function in cuticle and egg shell formation in the yellow fever mosquito, Aedes aegypti

AaCPR100A is a structural protein, found in the soft cuticle of Ae. Aegypti. RNAi of AaCPR100A resulted in high mortality in Ae. Aegypti and abnormal egg development in the surviving mosquitoes. Over thirty proteins that could interact with AaCPR100A were screened out by yeast two-hybrid assay, and subsequently, further verification by hybrid and GST pull-down assays identified that G12-like had the strongest interaction with AaCPR100A. RNAi of G12-like suggested it may be related to larva development. Interestingly, the adults in which the G12-like gene was knocked down were sensitive to low temperature, and their egg shell formation, production, and hatching were affected. G12-like has the opposite effect in the upstream expression of AaCPR100A, promoting AaCPR100A function in the larval stage and inhibiting AaCPR100A in the adult stage. In all, functional studies of AaCPR100A and its interaction protein G12-like provide insight into its involvement in cuticle development and formation and egg shell formation.

molecular biology↗

bioRxiv2022

On the origin and evolution of the mosquito male-determining factor Nix

The mosquito family Culicidae is divided into two subfamilies named the Culicinae and Anophelinae. Nix, the dominant male-determining factor, has only been found in the culicines Aedes aegypti and Ae. albopictus, two important arboviral vectors that belong to the subgenus Stegomyia. Here we performed sex-specific whole-genome sequencing and RNAseq of divergent mosquito species and explored additional male-inclusive datasets to investigate the distribution of Nix. Except for the Culex genus, Nix homologs were found in all species surveyed from the Culicinae subfamily, including 12 additional species from three highly divergent tribes comprising 4 genera, suggesting Nix originated at least 133-165 MYA. Heterologous expression of one of three divergent Nix ORFs in Ae. aegypti resulted in partial masculinization of genetic females as evidenced by morphology and doublesex splicing. It is not clear whether insufficient transgene expression or sequence divergence or both are responsible for the lack of phenotype for the other two. Phylogenetic analysis suggests Nix is related to femaleless (fle), a recently described intermediate sex-determining factor found exclusively in anopheline mosquitoes. Nix from all species has a conserved structure, including three RNA-recognition motifs (RRMs), as does fle. However, Nix has evolved at a much faster rate than fle. The RRM3 of both Nix and fle are related to the single RRM of a widely distributed and conserved splicing factor transformer-2 (tra2). RRM3-based phylogenetic analysis suggests this domain in Nix and fle may have evolved from tra2 in a common ancestor of mosquitoes. Our results provide insights into the evolution of sex-determination and homomorphic sex chromosomes in mosquitoes, and will inform broad applications of mosquito-control strategies based on manipulating sex ratios towards the non-biting males.

evolutionary biology↗

bioRxiv2021

High-resolution spatiotemporal transcriptomic maps of developing Drosophila embryos and larvae

Drosophila has long been a successful model organism in multiple fields such as genetics and developmental biology. Drosophila genome is relatively smaller and less redundant, yet largely conserved with mammals, making it a productive model in studies of embryogenesis, cell signaling, disease mechanisms, etc. Spatial gene expression pattern is critical for understanding of complex signaling pathways and cell-cell interactions, whereas temporal gene expression changes need to be tracked during highly dynamic activities such as tissue development and disease progression. Systematic studies in Drosophila as a whole are still impeded by lack of these spatiotemporal transcriptomic information. Drosophila embryos and tissues are of relatively small size, limiting the application of current technologies to comprehensively resolve their spatiotemporal gene expression patterns. Here, utilizing SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we dissected the spatiotemporal transcriptomic changes of developing Drosophila with high resolution and sensitivity. Our data recapitulated the spatial transcriptomes of embryonic and larval development in Drosophila. With these data, we identified known and previously undetected subregions in several tissues during development, and revealed known and potential gene regulatory networks of transcription factors within their topographic background. We further demonstrated that Stereo-seq data can be used for 3D reconstruction of Drosophila embryo spatial transcriptomes. Our data provides Drosophila research community with useful resources of spatiotemporally resolved transcriptomic information across developmental stages.

developmental biology↗

bioRxiv2021

In Vivo Generation of Bone Marrow from Embryonic Stem Cells in Interspecies Chimeras

Generation of bone marrow (BM) from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) promises to accelerate the development of future cell therapies for life-threatening disorders. However, such approach is limited by technical challenges to produce a mixture of functional BM progenitor cells able to replace all hematopoietic cell lineages. Herein, we used blastocyst complementation to simultaneously produce all BM hematopoietic cell lineages from mouse ESCs in a rat. Based on FACS analysis and single-cell RNA sequencing, mouse ESCs differentiated into hematopoietic progenitor cells and multiple hematopoietic cell types that were indistinguishable from normal mouse BM cells based on gene expression signatures and cell surface markers. Transplantation of ESC-derived BM cells from mouse-rat chimeras rescued lethally-irradiated syngeneic mice and resulted in long-term contribution of donor cells to hematopoietic cell lineages. Altogether, a fully functional bone marrow was generated from mouse ESCs using rat embryos as "bioreactors". KEY POINTS- We used blastocyst complementation to simultaneously produce all bone marrow hematopoietic cell lineages from mouse ESCs in a rat. - ESC-derived cells from mouse-rat chimeras were fully functional and exhibited normal gene expression signatures and cell surface markers.

developmental biology↗

bioRxiv2021

Tissue Specific Age Dependence of the Cell Receptors Involved in the SARS-CoV-2 Infection

The coronavirus disease 2019 (COVID-19) pandemic has affected tens of millions of individuals and caused hundreds of thousands of deaths worldwide. Due to its rapid surge, there is a shortage of information on viral behavior and host response after SARS-CoV-2 infection. Here we present a comprehensive, multiscale network analysis of the transcriptional response to the virus. We particularly focus on key-regulators, cell-receptors, and host-processes that are hijacked by the virus for its advantage. ACE2-controlled processes involve a key-regulator CD300e (a TYROBP receptor) and the activation of IL-2 pro-inflammatory cytokine signaling. We further investigate the age-dependency of such receptors and identify the adipose and the brain as potentially contributing tissues for the diseases severity in old patients. In contrast, several other tissues in the young population are more susceptible to SARS-CoV-2 infection. In summary, this present study provides novel insights into the gene regulatory organization during the SARS-CoV-2 infection and the tissue-specific age dependence of the cell receptors involved in COVID-19.

systems biology↗

bioRxiv2021

Transcriptomic changes highly similar to Alzheimer's disease are observed in a subpopulation of individuals during normal brain aging

Aging is a major risk factor for late-onset Alzheimers disease (LOAD). How aging contributes to the development of LOAD remains elusive. In this study, we examined multiple large-scale transcriptomic data from both normal aging and LOAD brains to understand the molecular interconnection between aging and LOAD. We found that shared gene expression changes between aging and LOAD are mostly seen in the hippocampal and several cortical regions. In the hippocampus, the expression of phosphoprotein, alternative splicing and cytoskeleton genes are commonly changed in both aging and AD, while synapse, ion transport, and synaptic vesicle genes are commonly down-regulated. Aging-specific changes are associated with acetylation and methylation, while LOAD-specific changes are more related to glycoprotein (both up- and down-regulations), inflammatory response (up-regulation), myelin sheath and lipoprotein (down-regulation). We also found that normal aging brain transcriptomes from relatively young donors (45-70 years old) clustered into several subgroups and some subgroups showed gene expression changes highly similar to those seen in LOAD brains. Using brain transcriptomic data from another cohort of older individuals (> 70 years), we found that samples from cognitively normal older individuals clustered with the "healthy aging" subgroup while AD samples mainly clustered with the "AD similar" subgroups. This may imply that individuals in the healthy aging subgroup will likely remain cognitively normal when they become older and vice versa. In summary, our results suggest that on the transcriptome level, aging and LOAD have strong interconnections in some brain regions in a subpopulation of cognitively normal aging individuals. This supports the theory that the initiation of LOAD occurs decades earlier than the manifestation of clinical phenotype and it may be essential to closely study the "normal brain aging" to identify the very early molecular events that may lead to LOAD development.

neuroscience↗

bioRxiv2021

High resolution analysis of proteome dynamics during Bacillus subtilis sporulation

Bacillus subtilis vegetative cells switch to sporulation upon nutrient limitation. To investigate the proteome dynamics during sporulation, high resolution time-lapse proteomics was performed in a cell population that was induced to sporulate synchronously. Here, we are the first to comprehensively investigate the changeover of sporulation regulatory proteins, coat proteins and other proteins involved in sporulation and spore biogenesis. Protein co-expression analysis revealed four co-expressed modules (blue, brown, green and yellow). Modules brown and green are upregulated during sporulation and contain proteins associated with sporulation. Module blue, is negatively correlated with modules brown and green, and contained ribosomal and metabolic proteins. Finally, module yellow shows co-expression with the three other modules. Notably, several proteins not belonging to any of the known transcription regulons were identified as co-expressed with modules brown and green. We speculate that they may also play roles during sporulation. Finally, levels of some coat proteins, for example morphogenetic coat proteins, decreased late in sporulation. We speculate on their possible role in guiding or helping assembly of other coat proteins, after which they can be disposed of, but such a hypothesis remains to be experimentally addressed.

microbiology↗

bioRxiv2021

Differential sphingosine-1-phosphate receptor-1 (S1PR1) protein expressions in the dorsolateral prefrontal cortex between schizophrenia Type 1 and Type 2

Understanding the etiology and treatment approaches in schizophrenia is challenged in part by the heterogeneity of this disorder. One encouraging progress is the growing evidence that there are subtypes of schizophrenia that may relate to disease duration and premorbid severity. Recent in vitro findings of messenger ribonucleic acid (mRNA) gene expression on postmortem dorsolateral prefrontal cortex (DLPFC) showed that schizophrenia has two subtypes, those with a relatively normal DLPFC transcriptome (Type 1) and those with differentially expressed genes (Type 2). Sphingosine-1-phosphate receptor-1 (S1PR1) is one of the genes that was highly upregulated in Type 2 compared to Type 1 and controls. The impact of that finding is limited because it only can be confirmed through analysis of autopsy tissue, and the clinical characteristics such as symptoms severity or illness duration was not available from that Medical Examiner based autopsy study. However, S1PR1 has great potential because it is a target gene that can be accessed via positron emission tomography (PET) in vivo using specific radioligands (starting with [11C]CS1P1) successfully developed at our center in human brain imaging. As a preliminary study to validate this PET target in schizophrenia, S1PR1 protein expression was assessed by receptor autoradiography (ARG) using [3H]CS1P1 and immunohistochemistry (IHC) in the DLPFC from patients with schizophrenia classified as Type 1 or Type 2 based on their DLPFC transcriptomes and from controls. Our analyses demonstrate that ARG S1PR1 protein expression is significantly higher in Type 2 compared to Type 1 (p < 0.05) and controls (p < 0.05), which was consistent with previous mRNA S1PR1. These findings support the possibility that PET S1PR1 can be used as a future imaging biomarker to distinguish these subgroups of schizophrenic patients during life with obvious implications for both patient management and the design of clinical trials to validate novel pharmacologic therapies.

neuroscience↗

bioRxiv2021

Marker-assisted mapping enables effective forward genetic analysis in the arboviral vector Aedes aegypti, a species with vast recombination deserts

Aedes aegypti is a major vector of arboviruses that cause dengue, chikungunya, yellow fever and Zika. Although recent success in reverse genetics has facilitated rapid progress in basic and applied research, integration of forward genetics with modern technologies remains challenging in this important species, as up-to-47% of its chromosome is refractory to genetic mapping due to extremely low rate of recombination. Here we report the development of a marker-assisted-mapping (MAM) strategy to readily screen for and genotype only the rare but informative recombinants, drastically increasing both the resolution and signal-to-noise ratio. Using MAM, we mapped a transgene that was inserted in a >100 Mb recombination desert and a sex-linked spontaneous red-eye (re) mutation just outside the region. We subsequently determined, by CRISPR/Cas9-mediated knockout, that cardinal is the causal gene of re, which is the first forward genetic identification of a causal gene in Ae. aegypti. This study provides the molecular foundation for using gene-editing to develop versatile and stable genetic sexing methods by improving upon the current re-based genetic sexing strains. MAM does not require densely populated markers and can be readily applied throughout the genome to facilitate the mapping of genes responsible for insecticide- and viral-resistance. By enabling effective forward genetic analysis, MAM bridges a significant gap in establishing Ae. aegypti as a model system for research in vector biology. As large regions of suppressed recombination are also common in other plant and animal species including those of economic significance, MAM will have broad applications beyond vector biology.

genetics↗