Biology subjects

Rao, H.

Publications and source records attributed to Rao, H..

17 recordsLinked to original sources

bioRxiv2026

NSD2 deficiency disrupts the epigenetic landscape of cochlear hair cells to enhance ECM expression and to perturb cochlear hair cell function

Mammalian cochlear hair cells (HC) are crucial for hearing, and histone modifications may play an important role in HC maturation and functions. However, whether and how NSD2, a histone H3 lysine 36 (H3K36) dimethyltransferase, affects cochlear HC maturation remains unclear. Here, we established an HC-specific Nsd2 knockout mouse model and discovered that the loss of NSD2 results in severe structural defects in stereociliary bundles and profound hearing impairment. Integrated multi-omics profiling revealed that NSD2 deficiency leads to a decreased expression of H3K36me2, which in turn alters genome-wide chromatin accessibility and gene expression. Mechanistically, NSD2 deficiency triggers the aberrant upregulation of extracellular matrix (ECM) genes at the transcriptional level, causing excessive collagen accumulation and compromising tissue structure. Crucially, ECM intervention can mitigate NSD2-deficiency mediated hearing damage. Our study reveals an epigenetic mechanism by which NSD2 regulates cochlear HC maturation through inhibition of chromatin remodeling-induced ECM accumulation, and provides a potential new therapeutic direction for hearing impairment.

cell biology↗

bioRxiv2026

Intranasal Fritillaria taipaiensis nanovesicles alleviate acute lung injury via the lung-brain axis

Acute lung injury (ALI) is a severe inflammatory syndrome frequently complicated by brain injury, which worsens outcomes. Here, we explored whether regulation of the lung-brain axis represents a therapeutic strategy for the management of ALI. We show that intranasal administration of Fritillaria taipaiensis-derived exosome-like nanovesicles (Ft-ELNs) ameliorates LPS-induced ALI and ALI-associated hypothalamic inflammation in mice. Ft-ELNs preferentially accumulate in the lungs, inhibiting TRPV1 in both the lungs and the hypothalamus to establish the lung-brain axis. In parallel, Ft-ELNs primarily regulate systemic humoral immunity by inhibiting the VEGFR1/PI3K/AKT/NF?B signaling pathway. In vitro experiments further confirmed that Ft-ELNs are efficiently internalized by alveolar epithelial MLE-12 cells, exerting protective effects by suppressing VEGFR1 expression. Mechanistically, we identified Ft-miR1 of Ft-ELNs as the key functional effector that directly targets the Flt1 3'UTR to inhibit VEGFR1 expression. These data suggest that Ft-ELNs attenuate lung-brain axis inflammation by targeting VEGFR1 and may hold potential as novel therapeutic agents for the treatment of severe ALI.

immunology↗

bioRxiv2026

AnnoAudit: a marker-based protocol for auditing single-cell atlas annotations reveals annotation-driven artifacts in a widely used traumatic brain injury resource

Single-cell atlas annotations are routinely treated as ground truth but rarely validated before use. We present AnnoAudit, a marker-based audit protocol that combines four convergent checks - marker scoring, unsupervised clustering, margin-gated module scoring, and applicability-gated pretrained models - into a composite Annotation Contamination Score (ACS), plus an independent-gene discrimination step that distinguishes genuine mis-assignment from ambient-RNA detection artifacts, and a trajectory-correlation fingerprint tracing suspicious signals to their cell type of origin. Applied to CEREBRI (GSE269748), a widely used single-cell TBI atlas (73 citations; 65 citing works; six re-analysis studies, none of which validated the annotations), the audit shows that contamination is systematic: the official "glutamatergic neuron" label is 97.8% non-excitatory by markers, with at least 67.4% of its cells independently confirmed as non-neuronal (microglia-dominated); the GABAergic (46.6%), OPC (66.1%), and astrocyte (37.7%) labels are likewise contaminated by marker-confirmed microglia, whereas the microglial, oligodendrocyte, endothelial, and pericyte labels are largely clean (85-96% self-confirmed). The contamination is state-dependent: astrocyte and OPC labels are largely correct in uninjured controls (76.0% OPC self-marker; 18.5% discrimination-confirmed contamination for the astrocyte label) but collapse in the acute 24-h window (14-16% self-marker; 57-71% microglia), recovering by 6 months - so the annotation failure concentrates precisely in the window of maximal injury response. This temporal structure generates coherent false signals - a biphasic trajectory for 40 of 307 ion-channel genes, a KCNC3-specific OXPHOS signature, and an inverted KCNC3 trajectory at 7 days - whereas the corrected response is a sustained acute KCNC3 up-regulation conserved across three independent datasets and three injury models. Simulation-calibrated ACS is 82.6% for CEREBRI. In a human ALS atlas (GSE330130), an ambient-aware re-analysis shows that the official neuron labels are largely correct (1.8-6.1% contamination after discrimination), confirming that the audit does not flag well-annotated resources, and that marker-only estimates on snRNA data with high ambient RNA must be interpreted with the discrimination step. AnnoAudit needs only the deposited count matrix and a canonical panel; we propose it as a routine quality step for atlas-based re-analysis.

bioinformatics↗

bioRxiv2026

CDK1 facilitates RAD51-mediated DNA repair to protect dictyate stage arrested oocytes from genotoxic stress

Oocytes arrested at the dictyate stage of meiosis I must maintain genomic integrity for prolonged periods to preserve female fertility. During this extended arrest, DNA lesions arising from endogenous and exogenous sources threaten oocyte survival, yet the molecular mechanisms coordinating DNA repair in dormant oocytes remain poorly understood. Here, we identify cyclin-dependent kinase 1 (CDK1) as a critical regulator of the oocyte DNA damage response and homologous recombination (HR) repair under genotoxic stress. Using cisplatin-induced DNA damage models in fetal goat ovaries and neonatal mouse ovaries, we investigated repair mechanisms operating within the ovarian reserve. Label-free proteomic profiling revealed significant enrichment of DNA damage response pathways following cisplatin exposure, with CDK1 emerging as one of the most prominently upregulated kinases. Pharmacological inhibition of CDK1 had little effect on follicle survival under physiological conditions but aggravated oocyte and follicle loss following DNA damage, indicating a stress-dependent role for CDK1 in preserving ovarian follicle pool integrity. Mechanistically, DNA damage activated a Chk2-dependent signaling pathway that promoted p63 phosphorylation and altered the WEE1-CDK1 regulatory axis, resulting in reduced inhibitory CDK1 phosphorylation (Thr14/Tyr15) and increased activating phosphorylation (Thr161). Activated CDK1 was associated with enhanced RAD51 phosphorylation and accumulation at DNA damage foci, supporting homologous recombination (HR)-mediated repair in dictyate-arrested oocytes. In contrast, CDK1 inhibition reduced phospho-RAD51 levels, impaired RAD51 localization, increased persistent {gamma}H2AX accumulation, and elevated oocyte apoptosis. Notably, suppression of CDK1 was accompanied by increased expression of the non-homologous end joining (NHEJ) marker Ku80 and the nucleotide excision repair (NER) factor XPA, suggesting increased engagement of alternative DNA repair pathways. Furthermore, inhibition of Chk2 abolished the DNA damage-associated CDK1 activation signature and restored WEE1 expression, supporting a model in which CDK1 functions downstream of Chk2 signaling during the oocyte DNA damage response. Collectively, our findings identify a previously unrecognized Chk2-CDK1-RAD51 signaling axis that coordinates homologous recombination repair in dormant oocytes and safeguards ovarian follicular pool integrity under genotoxic stress. These findings provide new mechanistic insight into how dictyate-arrested oocytes maintain genome stability during prolonged meiotic arrest.

Cell Biology↗

bioRxiv2025

Chromatin priming and Hunchback recruitment integrate spatial and temporal cues in Drosophila neuroblasts

Neural stem cells generate diverse cell types by integrating spatial and temporal cues to activate neuron-specific terminal selector (TS) genes. In Drosophila neuroblasts (NBs), spatial patterning sets lineage identity, while a temporal transcription factor (TTF) cascade sets birth order. Two proposed mechanisms could integrate these inputs. In direct regulation, spatial transcription factors (STFs) and TTFs co-occupy and regulate TS enhancers within NBs. In epigenetic regulation, STFs first prime NB-specific chromatin, creating selected enhancers that can later recruit TTFs. We tested these models in the NB5-6 and NB7-4 lineages using their candidate STFs, Gooseberry (Gsb) and Engrailed (En), together with the first TTF, Hunchback (Hb). We find that En preferentially occupies pre-accessible chromatin in the NB7-4 lineage, including highly accessible En-Hb co-bound sites. This is consistent with En acting within an already established chromatin landscape whose formation likely depends on additional NB7-4 factors. In contrast, Gsb binds both accessible and less-accessible chromatin in the NB5-6 lineage and can remodel accessibility bidirectionally when ectopically expressed in NB7-4 lineage, with corresponding changes in Hb occupancy. However, Gsb binding alone does not determine which sites become accessible or recruit Hb, indicating that productive Gsb-Hb regulatory states require additional NB5-6-specific inputs. Thus, direct and epigenetic regulation are not alternative mechanisms, but distinct steps within the integration process. We therefore propose a third possibility: distributed STF code model in which these steps -- chromatin priming and direct STF-Hb engagement -- are distributed across the members of each NB-specific STF code. The STF code therefore shapes the enhancer landscape available to Hb and enables productive Hb engagement at lineage-appropriate enhancers.

developmental biology↗

bioRxiv2025

Sleep deprivation exhibits age-dependent effect on infra-slow global brain activity

Infra-slow (< 0.1 Hz) global brain activity, quantified by the global mean BOLD (gBOLD) signal in resting-state fMRI, is elevated during sleep and closely associated with cerebrospinal fluid (CSF) dynamics, a key mechanism for the brain waste clearance implicated in neurodegenerative disorders such as Alzheimers disease (AD). However, the effect of sleep deprivation on gBOLD activity and its interaction with aging remain poorly understood. Using a rigorously controlled in-laboratory total sleep deprivation (TSD) protocol, we demonstrate that TSD significantly increases both the amplitude of the gBOLD signal and its coupling with CSF flow, suggesting a compensatory mechanism that may enhance glymphatic clearance following acute sleep loss. Notably, these TSD-induced enhancements exhibit robust age dependency, with diminished responses in individuals at midlife (40-50 yrs). The absence of this compensatory mechanism in these midlife participants may exacerbate age-related impairments in neurotoxic clearance and increase dementia susceptibility, thereby offering mechanistic insights into the nexus between sleep disruption, aging, and neurodegeneration.

neuroscience↗

bioRxiv2025

Histone 3 lysine 36 trimethylation by SETD2 shapes an epigenetic landscape in intestinal stem cells to orchestrate lipid metabolism and prevent cell senescence.

The self-renewal capacity of intestinal stem cells (ISCs) declines with aging, leading to a loss of homeostasis and an increased susceptibility to intestinal diseases. Despite the established significance of lipid metabolism and epigenetic regulation in ISC function, the molecular mechanisms that connect these processes to aging-related ISC dysfunction remain elusive. Here, we demonstrate that Histone 3 lysine 36 trimethylation (H3K36me3) caused by SETD2 is critical for ISC stemness. We found that H3K36me3 deficiency results in reduced ISC proliferation and differentiation, disrupts fatty acid oxidation (FAO) metabolism, and induces ISC senescence. Mechanistically, the loss of H3K36me3 triggers the activity of the SWI/SNF chromatin remodeling complex and leads to increased chromatin accessibility and enhancer activation, which alters FAO- and senescence-related gene expression. Importantly, we discover that metabolic intervention can prevent the senescence of ISC due to H3K36me3 deficiency. Our findings reveal a crucial role for H3K36me3 in maintaining the epigenetic landscape that orchestrates FAO metabolism and determines intestinal stem cell functions, emphasizing the role of FAO as a key modulator between H3K36me3 and ISC aging, suggesting that metabolic intervention may help mitigate age-related ISC dysfunction.

cell biology↗

bioRxiv2025

Yeast DNA Polymerase δ Proofreading Nuclease Suppresses Translesion Synthesis and Facilitates Recombination in DNA Lesion Bypass.

Translesion synthesis (TLS) employs specialized polymerases to incorporate nucleotides opposite DNA lesions, allowing replication to continue temporarily without repairing the lesions, while sacrificing replication fidelity (1). TLS depends on a ubiquitin molecule attached to the clamp PCNA at residue Lys164 (2, 3); the precise biochemical and molecular basis how PCNA modification stimulates TLS is still elusive (4-10). In this study, we discovered that DNA polymerase {delta} (Pol {delta}) 3 to 5 "proofreading" exonuclease degrades nascent TLS synthesis opposite pyrimidine dimers and inhibits TLS on both leading and lagging strands. Rad18 E3 ligase and PCNA ubiquitylation become dispensable for TLS when Pol {delta} exonuclease is inactive. Biochemical reconstitution showed that the major UV lesion bypass polymerase Rad30 is intrinsically inefficient at bypassing thymidine dimers and requires multiple turnovers. Pol {delta} exonuclease impedes Rad30 activity both catalytically and non-catalytically during and post-lesion bypass. Importantly, PCNA and PCNA ubiquitylation enhance processivity of Rad30 after thymidine dimer bypass, a critical step for further DNA synthesis extension and overcoming Pol {delta} inhibition. Our study reveals a new paradigm how PCNA ubiquitylation facilitates TLS and the new role of Pol {delta} nuclease in lesion bypass pathway choice and replication fidelity at fork-blocking DNA lesions.

genetics↗

bioRxiv2024

NSD2 promotes cell durotaxis and drives the transition from PKD to tubulocystic renal cell carcinoma through integrin/FAK/AKT signaling

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. NSD2 is an H3K36-specific di-methyltransferase which has been reported to participate in diverse biological processes and human tumors. However, its role in RCC remains unclear. Here, we found that NSD2 is highly expressed in RCC, which is associated with poor survival in RCC patients. NSD2 facilitates the transition from Myc-induced polycystic kidney disease to tubulocystic renal cell carcinoma (TCRCC), which is a rare RCC subtype with distinctive clinicopathologic and genetic characterizations. The mice with kidney-specific overexpression of MYC and NSD2 (KMN) display severe cyst burden at only 6 weeks of age, and develop into TCRCC at 12 weeks of age. Mechanistically, NSD2 transcriptionally upregulates the expressions of integrins (Itga4 and Itga11), to further activate the FAK/AKT pathway. In addition, we found that NSD2 enhances the cell proliferation on the stiff matrix of PEGDA hydrogel. Moreover, inhibition of FAK signaling relieves the symptoms of KMN mice, and significantly rescues the enhanced cell proliferation caused by NSD2 overexpression in vitro. Together, our findings highlight an epigenetic mechanism by which NSD2 regulates TCRCC tumorigenesis through the integrin/FAK/AKT pathway. This study may also pave the way for the development of targeted, patient-tailored therapies for TCRCC patients with NSD2 amplification or high expression.

cancer biology↗

bioRxiv2024

Epithelial NSD2 maintains FMOs-mediated taurine biosynthesis to prevent intestinal barrier disruption

Inflammatory bowel disease (IBD) poses a significant challenge due to its intricate pathogenesis. NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, is associated with transcriptional activation. However, the precise role of NSD2 in IBD remains unexplored. In this study, we discovered a downregulation of NSD2 in both the intestinal epithelial cells (IECs) of patients and the IBD mouse model. Deficiency of NSD2 in mouse IECs aggravated epithelial barrier disruption and inflammatory response in IBD. Mechanically, NSD2 loss downregulated H3K36me2 and FMO (taurine-synthesis enzyme) mRNA in IECs, resulting in decreased taurine biosynthesis in IECs. Importantly, supplementation with taurine significantly attenuated the symptoms of NSD2 deficiency-induced IBD. These data demonstrate that NSD2 plays a pivotal role in maintaining FMOs-mediated taurine biosynthesis to prevent intestinal inflammation. Our findings also underscore the importance of NSD2-H3K36me2-mediated taurine biosynthesis in maintaining intestinal mucosal barrier homeostasis.

cell biology↗

bioRxiv2023

Multilevel regulation of NF-kappa B signaling by NSD2 suppresses Kras-driven pancreatic tumorigenesis

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase which has been reported to play a crucial role in promoting tumorigenesis. Here, we demonstrate that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. Low level of NSD2 indicates aggressive feature of PDAC. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of I{kappa}B, which inhibits the phosphorylation of p65 and NF-{kappa}B nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-{kappa}B transcriptional activity. Furthermore, inhibition of NF-{kappa}B signaling relieves the symptoms of Nsd2-deficient mice. Together, our study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study contributes to understanding the pathogenesis of pancreatic tumorigenesis and identifies a novel negative regulator of NF-{kappa}B signaling.

cancer biology↗

bioRxiv2022

Host network-based discovery of critical regulators of innate immunity, virus growth, and pathogenesis in influenza virus infection

Innate immunity is protective against viruses, but also can facilitate pathological infection responses. Despite intensive research, our understanding of the mechanisms that regulate innate immunity in virus infection remains incomplete. Systems biology-based data-driven modeling approaches hold substantial promise toward discovery of crucial innate immune signaling regulators, yet model-derived predictions are almost completely unexplored. Here, we carried out systematic experimental validation of candidate regulators predicted by a transcriptional association network model of influenza virus-infected cells. We identified dozens of novel innate immune signaling regulators with potent effects on the replication of influenza and other viruses, and importantly, we established the biological relevance of a validated regulator in vivo. Collectively, these findings aid in clarifying mechanisms of influenza virus pathogenicity and might lead to innovative approaches for treating influenza virus disease. Similar data-driven modeling strategies may be applicable for the study of other pathogen systems or immunological disorders.

microbiology↗

bioRxiv2020

SETD2 deficiency impairs β-catenin destruction complex to facilitate renal cell carcinoma formation

Clear cell renal cell carcinoma (ccRCC) is a largely incurable disease that is highly relevant to epigenetic regulation including histone modification and DNA methylation. SET domain-containing 2 (SETD2) is a predominant histone methyltransferase catalyzing the trimethylation of histone H3 Lysine 36 (H3K36me3) and its mutations are highly relevant to clear cell renal cell carcinoma (ccRCC). However, its physiology role in ccRCC remains largely unexplored. Here we report that Setd2 deletion impairs the {beta}-catenin destruction complex to facilitate ccRCC formation in a c-MYC-generated polycystic kidney disease (PKD) model, which can be relieved by an inhibitor of {beta}-catenin-responsive transcription. Clinically, SETD2 loss is widely observed in ccRCC samples, and negatively correlated with expression of some members of {beta}-catenin destruction complex, but positively correlated with the activation of Wnt/{beta}-catenin signaling. Our findings thus highlight a previously unrecognized role of SETD2-mediated H3K36me3 modification in regulation of Wnt/{beta}-catenin pathway in ccRCC. SummaryOur findings for the first time reveal a previously unrecognized role of the SETD2-mediated H3K36me3 modification in regulation of the Wnt/{beta}-catenin pathway in ccRCC and shed light on the molecular mechanisms underlying the formation of renal cell carcinoma with epigenetic disorders.

cancer biology↗

bioRxiv2020

The Histone Methyltransferase SETD2 Modulates Oxidative Stress to Attenuate Colonic Inflammation and Tumorigenesis in Mice

BACKGROUND & AIMSInflammatory bowel disease (IBD) is a complex and relapsing inflammatory disease, and patients with IBD exhibit a higher risk of developing colorectal cancer (CRC). Epithelial barrier disruption is one of the major causes of IBD in which epigenetic modulation is pivotal. However, the epigenetic mechanisms underlying the epithelial barrier integrity regulation remain largely unexplored. Here, we investigated how SETD2, an epigenetic modifier, maintains intestinal epithelial homeostasis and attenuates colonic in[fl]ammation and tumorigenesis. METHODSGEO public database and IBD tissues were used to investigate the clinical relevance of SETD2 in IBD. To define a role of SETD2 in the colitis, we generated mice with epithelium-specific deletion of Setd2 (Setd2Vil-KO mice). Acute colitis was induced by 2% dextran sodium sulfate (DSS), and colitis-associated CRC was induced by injecting azoxymethane (AOM), followed by three cycles of 2% DSS treatments. Colon tissues were collected from mice and analyzed by histology, immunohistochemistry and immunoblots. Organoids were generated from Setd2Vil-KO and control mice, and were stained with 7-AAD to detect apoptosis. A fluorescent probe, 2',7'-dichlorodihydro[fl]uorescein diacetate (H2DCFDA), was used to detect the levels of ROS in intestinal epithelial cells (IECs) isolated from the two types of mice. RNA-seq and H3K36me3 ChIP-seq analyses were performed to identify the mis-regulated genes modulated by SETD2. Results were validated in functional rescue experiments by N-acetyl-l-cysteine (NAC) treatment and transgenes expression in IECs. RESULTSSETD2 expression became decreased in IBD patients and DSS-treated colitis mice. Setd2Vil-KO mice displayed abnormal loss of mucus-producing goblet cells and antimicrobial peptide (AMP)-producing Paneth cells, and exhibited pre-mature intestinal inflammation development. Consistent with the reduced SETD2 expression in IBD patients, Setd2Vil-KO mice showed increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption and markedly increased intestinal permeability that subsequently facilitated in[fl]ammation-associated CRC. Mechanistically, deletion of Setd2 resulted in excess reactive oxygen species (ROS), which led to cellular apoptosis and defects in barrier integrity. NAC treatment in Setd2Vil-KO mice rescued epithelial barrier injury and apoptosis. Importantly, Setd2 depletion led to excess ROS by directly down-regulating antioxidant genes that inhibit ROS reaction. Moreover, overexpression of antioxidant PRDX6 in Setd2Vil-KO IECs largely alleviated the overproductions of ROS and improved the cellular survival. CONCLUSIONSDeficiency of Setd2 specifically in the intestine aggravates epithelial barrier disruption and inflammatory response in colitis via a mechanism dependent on oxidative stress. Thus, our results highlight an epigenetic mechanism by which Setd2 modulates oxidative stress to regulate intestinal epithelial homeostasis. SETD2 might therefore be a pivotal regulator that maintains the homeostasis of the intestinal mucosal barrier.

cell biology↗

bioRxiv2019

A non-canonical role for p27Kip1 in restricting proliferation of corneal endothelial cells during development

The cell cycle regulator p27Kip1 is a critical factor controlling cell number in many lineages. While its anti-proliferative effects are well-established, the extent to which this is a result of its function as a cyclin-dependent kinase (CDK) inhibitor or through other known molecular interactions is not clear. To genetically dissect its role in the developing corneal endothelium, we examined mice harboring two loss-of-function alleles, a null allele (p27-) that abrogates all protein function and a knockin allele (p27CK-) that targets only its interaction with cyclins and CDKs. Whole-animal mutants, in which all cells are either homozygous knockout or knockin, exhibit identical proliferative increases ([~]0.6-fold) compared with wild-type tissues. On the other hand, use of mosaic analysis with double markers (MADM) to produce infrequently-occurring clones of wild-type and mutant cells within the same tissue environment uncovers a roughly three- and six-fold expansion of individual p27CK-/CK- and p27-/- cells, respectively. Mosaicism also reveals distinct migration phenotypes, with p27-/- cells being highly restricted to their site of production and p27CK-/CK- cells more widely scattered within the endothelium. Using a density-based clustering algorithm to quantify dispersal of MADM-generated clones, a four-fold difference in aggregation is seen between the two types of mutant cells. Overall, our analysis reveals that, in developing mouse corneal endothelium, p27 regulates cell number by acting cell autonomously, both through its interactions with cyclins and CDKs and through a cyclin-CDK-independent mechanism(s). Combined with its parallel influence on cell motility, it constitutes a potent multi-functional effector mechanism with major impact on tissue organization.

developmental biology↗

bioRxiv2019

Di-Ras2 Promotes Renal Cell Carcinoma Formation by Activating the MAPK Pathway in the Absence of VHL

Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal human urological malignancies in the world. The pathological drivers for ccRCC are still poorly understood. One of them is the Ras family of small GTPases that function as \"molecular switches\" in many diseases including ccRCC. Among them, Di-Ras2 encodes a 26-kDa GTPase that shares 60% homology to Ras and Rap. Yet little is known about the biological function(s) of Di-Ras2. In this study, we found that Di-Ras2 was upregulated in ccRCC, and promoted the proliferation, migration and invasion of human ccRCC cells in the absence of von Hippel-Lindau (VHL). Mechanistically, Di-Ras2 induces and regulates ccRCC formation by modulating phosphorylation of the downstream effectors and activating the MAPK signaling pathway. Moreover, Di-Ras2 interacts with E3 ubiquitin ligase, VHL, which facilitates the ubiquitination and degradation of Di-Ras2. Together, these results indicate a potential function of Di-Ras2 as an oncogene and biomarker in ccRCC, and these data provide a new perspective of the relationship between VHL and the MAPK pathway in ccRCC tumorigenesis.

cancer biology↗

bioRxiv2019

Preserved global cerebral blood flow accounts for youthful processing speed in older adults

Preserved cognitive performance is one of the key contributors to successful aging. The processing speed theory and prefrontal executive theory - are competing theories regarding the general causes of cognitive aging. Here, we used a theoretically-driven framework to investigate the neural correlates of older adults with preserved processing speed. Older adults with youth-like processing speed (SuperAgers) were compared with normal aged adults (TypicalAgers) using neuroimaging methods. Global cerebral blood flow (CBF) accounted for approximately 45% of the variance in processing speed, while neither regional CBF nor other structural measures predicted additional variance. In addition, despite having significantly cortical thinning, SuperAgers still shown comparable global CBF levels with young adults. These results support the global mechanism suggested by processing speed theory and indicate that global CBF may serve as a biomarker of cognitive aging.

neuroscience↗