Biology subjects

Moya, M.

Publications and source records attributed to Moya, M..

4 recordsLinked to original sources

bioRxiv2026

ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity

Natural Killer (NK) cell desensitization induced by persistent stimulation limits durable antitumor immunity, yet the molecular mechanisms governing this dysfunctional state remain poorly defined. To identify conserved regulators of NK cell desensitization, we performed comparative transcriptomic analyses across multiple murine models of persistent activation and dysfunction. This approach defined a shared transcriptional program of desensitization and identified Itpkb to be upregulated across multiple distinct contexts. Genetic and pharmacological inhibition of ITPKB enhanced degranulation, cytokine production, and cytotoxicity in both murine and human NK cells under multiple desensitization settings. Mechanistically, ITPKB regulated signaling downstream of persistent activation through the IP3/IP4 axis, limiting calcium mobilization and NFAT-dependent transcriptional responses in desensitized NK cells. Furthermore, inhibition or deletion of ITPKB enhanced NK-cell mediated tumor control in vivo and improved the efficacy of adoptively transferred CAR-NK cells, underscoring the translational potential of targeting this pathway. Together, these findings identify ITPKB as a cell-intrinsic regulator of NK cell desensitization and support targeting the IP3/IP4 signaling axis to enhance NK cell-mediated antitumor immunity.

immunology↗

bioRxiv2023

Reelin plasma levels predict cognitive decline in Alcohol Use Disorder: peak levels in patients expressing plasma APOE4 protein

BackgroundHuman apolipoprotein (APO)-E4 has been related to neuropsychiatric disorders such as Alzheimers disease and cognitive decline. Reelin and Clusterin share the VLDLR and ApoER2 receptors with APOE4. Here we checked the role of these components in Alcohol Use Disorder (AUD)-induced cognitive decline. MethodsThis is a cross-sectional study with AUD-diagnosed patients (DSM-5) (n=24) recruited from an outpatient Alcohol Programme and matched controls (n=34). Participants were assessed by the validated Test of Detection of Cognitive Impairment in Alcoholism (TEDCA). APOE4 presence in plasma (distinguishing APOE4 carriers and no carriers subjects) and its levels were performed by e4Quant technique. The rest of biological markers were tested by Enzyme-Linked Immunosorbent Assay kits. ResultsPlasma APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively. Quantification analyses revealed that APOE4 reached similar plasma levels in carriers independently if they were AUD subjects or controls. Circulant plasma APOE4 had a negative effect on AUDs cognition, specifically affecting Memory/Learning (p<0.01, {eta}2=0.15). Plasma Clusterin and Reelin increased in patients but, interestingly, Reelin plasma levels peaked in patients expressing APOE4 (p<0.05, {eta}2=0.09), who showed reduced VLDL and ApoER2 expression in peripheral blood mononuclear cells (PBMCs). Reelin was a good predictor of cognitive loss in patients, accounting for the 42.3% and 54.0% of general intelligence and executive function impairments, respectively. ConclusionsReelin plasma levels are increased in AUD patients who express the APOE4 isoform, predicting cognitive deterioration to a great extent. Remarkably, plasma Reelin helps to differentiate between AUD patients with and without cognitive decline. Significance StatementFinding biological markers that predict a worse evolution in neuropsychiatric disorders may help to assist vulnerable patients appropriately. In this sense, in this study we found a biological marker, Reelin, which is elevated in patients with diagnosis of alcohol use disorder (AUD) that underwent an outpatient treatment. Interestingly, Reelin plasma levels were elevated in patients that also express APOE4, an aberrant protein present only in a small percentage of the population which is related to neuroinflammation and cognitive impairment (i.e. it is involved in Alzheimers disease). We observed that Reelin plasma levels negatively correlate with cognitive scores, being Reelin a good predictor of cognitive impairment in patients. These results may have implications for the follow-up of AUD patients in outpatient treatment.

neuroscience↗

bioRxiv2022

Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke's encephalopathy: findings in preclinical models and in a postmortem human case

Wernickes encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder (AUD) its main risk factor. WE patients present limiting motor, cognitive and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has been proposed as one of the phenomena contributing to brain damage. Our previous studies provide evidence for the involvement of the innate immune receptor Toll-like (TLR) 4 in the inflammatory response induced in the frontal cortex and cerebellum in TD animal models (animals fed with TD diet and receiving pyrithiamine). However, the effects of the combination of chronic alcohol consumption and TD on TLR4 and their specific contribution to the pathogenesis of WE are currently unknown. Additionally, no studies on TLR4 have been conducted on WE patients since brains from these patients are difficult to achieve. Here, we used rat models of chronic alcohol (CA; 9 months of forced consumption of 20% (w/v) alcohol), TD hit (TDD; TD diet + daily 0.25 mg/kg i.p. pyrithiamine during 12 days), or a combined treatment (CA+TDD) to check the activation of the proinflammatory TLR4/MyD88 pathway and related markers in the frontal cortex and the cerebellum. In addition, we characterized for the first time the TLR4 and its co-receptor MyD88 signature, along with other markers of this proinflammatory signaling such as phospo-NF{kappa}B p65 and I{kappa}B, in the post-mortem human frontal cortex and cerebellum (gray and white matter) of an alcohol-induced WE patient, comparing it with negative (no disease) and positive (aged brain with Alzheimers disease) control subjects for neuroinflammation. We found an increase in the cortical TLR4 and its adaptor molecule MyD88, together with an upregulation of the proinflammatory signaling molecules p-NF-B and IB in the CA+TDD animal model. In the patient diagnosed with alcohol-induced WE we observed cortical and cerebellar upregulation of the TLR4/MyD88 pathway. Thus, our findings provide evidence, both in the animal model and the human postmortem brain, of the upregulation of the TLR4/MyD88 proinflammatory pathway in WE related to alcohol consumption.

neuroscience↗

bioRxiv2020

An ATM-MYBL2-CDC7 axis regulates replication initiation and prevents replication stress in pluripotent stem cells

Replication stress, a major cause of genome instability in cycling cells, is mainly prevented by the ATR-dependent replication stress response pathway in somatic cells. However, the replication stress response pathway in embryonic stem cells (ESCs) may be substantially different due to alterations in cell cycle phase length. The transcription factor MYBL2, which is implicated in cell cycle regulation, is expressed between hundred to thousand-fold more highly in ESCs compared to somatic cells. Here we show that MYBL2 functions to activate ATM and suppress replication stress in ESCs. Consequently, loss of MYBL2 or inhibition of ATM or Mre11 in ESCs, results in replication fork slowing, increased fork stalling and elevated origin firing. Additionally, we demonstrate that inhibition of CDC7 activity rescues replication stress induced by MYBL2 loss and ATM inhibition, suggesting that uncontrolled new origin firing may underlie the replication stress phenotype resulting from loss/inhibition of MYBL2 and ATM. Overall, this study proposes that in addition to ATR, a MYBL2-MRN-ATM replication stress response pathway functions in ESCs to control DNA replication initiation and prevent genome instability.

cell biology↗