Biology subjects

Wang, X.-L.

Publications and source records attributed to Wang, X.-L..

5 recordsLinked to original sources

bioRxiv2023

A novel supplemental circadian feedback loop in CA1 mediates mood-related behaviors

Traditional circadian clock feedback loops include positive branches and negative branches. Per genes belong to the negative branches. There are three subtypes of Per genes named Per1, Per2 and Per3. The relationship among these subtypes has been rarely reported. In this study, we aimed to explore the action between Per1 and Per2 genes, which are known to be critical in the pathogenesis of mood disorder. We revealed that Per1 has a positive action on the expression of Per2, while Per2 shows a negative effect on Per1 expression. This forms a novel feedback loop. Besides, both knockdown and over-expression of Per1 exhibit a pro-depressive effect, indicating a potential mediation in the pathogenesis of major depressive disorder. Correspondingly, knockdown of Per2 induces mania-like behavior, while, over-expression of Per2 produces a pro-depressive effect, suggesting its involvement in the pathophysiology of bipolar disorder. This research may provide an advance in the differential diagnosis between the two diseases in the future. HighlightsO_LIPer1 promotes the expression of Per2, while Per2 inhibit the expression of Per1 in CA1, forming a negative feedback loop. C_LIO_LIBoth knockdown and over-expression of Per1 in CA1 induce depression-like behaviors, while Per2 involves in both mania and depression-like behaviors. C_LI

neuroscience↗

bioRxiv2022

Single-cell Sequencing Highlights Heterogeneity and Malignant Progression in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To comprehensively delineate the underlying mechanisms for the whole progression from normal skin to AK to invasive cSCC, we performed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomes of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC and their matched normal tissues, covering comprehensive clinical courses of cSCC. We identified diverse cell types, including important subtypes with different gene expression profiles and functions in major keratinocytes. In SCCIS, we discovered the malignant subtypes of basal cells with differential proliferative and migration potential. Differentially expressed genes (DEGs) analysis screened out multiple key driver genes including transcription factors (TFs) along AK to cSCC progression. Immunohistochemistry (IHC) / immunofluorescence (IF) experiments and single-cell ATAC sequencing (scATAC-seq) data verified the expression changes of these genes. The functional experiments confirmed the important roles of these genes in regulating cell proliferation, apoptosis, migration and invasion in cSCC tumor. Furthermore, we comprehensively described the tumor microenvironment (TME) landscape and potential keratinocyte-TME crosstalk in cSCC providing theoretical basis for immunotherapy. Together, our findings provide a valuable resource for deciphering the progression from AK to cSCC and identifying potential targets for anticancer treatment of cSCC.

cancer biology↗

bioRxiv2022

pCREB-Per2 pathway in hippocampal CA1 region mediates the transition of depression and mania-like behaviors in rats

Little is known about the mechanisms underlying the transition between mania and depression. We found here that ouabain decreased pCREB and PER2 levels in CA1 and induced mania-like behavior, which was attenuated by lithium and overexpression of Per2 in this region. Furthermore, knockdown of Per2 in CA1 induced mania-like behavior, in contrast, overexpression of Per2 resulted in depression-like behavior. Similar results were found in manipulations of Creb1 in CA1. Western blot analyses revealed that upregulations of CREB or PER2 can increase each others levels, besides pCREB, and vice versa. Therefore, the CREB- pCREB-PER2 pathway forms a positive feedback loop that mediates the transition between manic and depressive phenotypes. One-Sentence SummaryA novel molecular loop underlies phase inversion of bipolar disorder

neuroscience↗

bioRxiv2021

Interferon-induced transmembrane protein 3 (IFITM3) limits lethality of SARS-CoV-2 in mice

Interferon-induced transmembrane protein 3 (IFITM3) is a host antiviral protein that alters cell membranes to block fusion of viruses. Published reports have identified conflicting pro- and antiviral effects of IFITM3 on SARS-CoV-2 in cultured cells, and its impact on viral pathogenesis in vivo remains unclear. Here, we show that IFITM3 knockout (KO) mice infected with mouse-adapted SARS-CoV-2 experienced extreme weight loss and lethality, while wild type (WT) mice lost minimal weight and recovered. KO mice had higher lung viral titers and increases in lung inflammatory cytokine levels, CD45-positive immune cell infiltration, and histopathology, compared to WT mice. Mechanistically, we observed disseminated viral antigen staining throughout the lung tissue and pulmonary vasculature in KO mice, while staining was observed in confined regions in WT lungs. Global transcriptomic analysis of infected lungs identified upregulation of gene signatures associated with interferons, inflammation, and angiogenesis in KO versus WT animals, highlighting changes in lung gene expression programs that precede severe lung pathology and fatality. Corroborating the protective effect of IFITM3 in vivo, K18-hACE2/IFITM3 KO mice infected with non-adapted SARS-CoV-2 showed enhanced, rapid weight loss and early death compared to control mice. Increased heart infection was observed in both mouse models in the absence of IFITM3, indicating that IFITM3 constrains extrapulmonary dissemination of SARS-CoV-2. Our results establish IFITM3 KO mice as a new animal model for studying severe SARS-CoV-2 infection of the lung and cardiovascular system, and overall demonstrate that IFITM3 is protective in SARS-CoV-2 infections of mice.

immunology↗

bioRxiv2021

Clock genes Period1 and Period2 in the hippocampal CA1 mediate depression-like behaviors and rapid antidepressant response

Accumulated reports have indicated that circadian rhythm is closely related to the pathogenesis of major depressive disorder (MDD). Recently, adenosine has been identified to modulate circadian clock via adenosine A1 and A2A receptor signaling pathways. Cyclic AMP-response element binding protein (CREB) is a convergent point that plays a critical role in the pathogenesis of depression and is a downstream molecule of adenosine A1 receptor signaling pathway as an endpoint that can regulate the expression of circadian genes Period1 (Per1) and Period2 (Per2). However, whether Per mediates the development of MDD via CREB has not been elucidated. We used chronic unpredictable stress (CUS) to induce depression-like behaviors and found that it could induce decrease in p-CREB and PER1 levels in the hippocampal CA1 region in rats. Both depression-like behaviors and the decreased protein levels could be rapidly rescued by the administration of adenosine A1 receptor agonist 2-Choro-N6-cyclopentyladenosine (CCPA). Furthermore, knockdown of Per1 in hippocampal CA1 region could also induce depression-like behaviors, which could also be rescued by CCPA. Interestingly, Per2 knockdown in hippocampal CA1 region resulted in potential antidepressant-like effect. In addition, knockout of CRE sequence in the promoter regions of either Per1 or Per2 led to depression-like behaviors, which could not be rescued by CCPA. These results indicated that clock genes Per1 and Per2 play critical roles in the pathophysiology of depression and CRE sequences in the promoter regions of Per1 and Per2 may be a critical antidepressant target. HighlightsO_LICUS induces both depression-like behaviors and decreases in the expression of p-CREB and PER1 levels in the hippocampal CA1 region in rats, which can be rapidly rescued by 2-Choro-N6-cyclopentyladenosine (CCPA). C_LIO_LIKnockdown of clock gene Per1 in the hippocampal CA1 brain region leads to depression-like behaviors in rats, which can be also rescued by CCPA. C_LIO_LIKnockdown of clock gene Per2 in the hippocampal CA1 brain region may have potential antidepressant-like effect. C_LIO_LIKnockout of the CRE sequence on the promoter region of the clock genes Per1 and Per2 produces depression-like behaviors, which cannot be rescued by CCPA. C_LI

neuroscience↗