👤 Felix Lopez

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry. Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioural assays (locomotor activity and conditioned place preference), alcohol intake paradigms (intermittent access two-bottle choice, drinking in the dark and the alcohol deprivation effect), and molecular analyses (microdialysis, electrophysiology and proteomics) in rodents. First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release (P < 0.001). Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption (P < 0.001), prevented binge (P < 0.01) and relapse-like drinking (P < 0.001), and maintained efficacy during repeated administration (P < 0.001). Finally, tirzepatide induced sustained synaptic depression in the lateral septum (P < 0.05) and further altered histone regulatory proteins in this region (P < 0.05), suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight (P < 0.001), adipose tissue mass (P < 0.01), hepatic triglycerides (P < 0.01) and circulating pro-inflammatory cytokines (P < 0.05). Together, our findings suggest tirzepatide modulates alcohol-related behaviours through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatide's established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications. The study is supported by grants from the Swedish Research Council (2023-2600, 2020-00559, 2020-01463, 2024-03054), LUA/ALF (723941 & 1005347) from the Sahlgrenska University Hospital, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (FO2024-0048), National Institutes of Health (NIH) (P50 AA010761 & U01 AA014095), U.S. Department of Veterans Affairs Office of Research and Development (BLR&D I01BX000813 & IK6BX006299), Herbert & Karin Jacobssons Foundation (2024-Forskning-225), Adlerbertska Research Foundation (2024-791), Wilhelm & Martina Lundgren's Research Foundation (2024-SA-4698), Åke Wibergs Foundation (M24-0216), Swedish Diabetes Foundation (DIA 2024-898) and Mary von Sydow Foundation (2024-36 & 2024-185). Thaynnam A Emous held an international internship scholarship from the São Paulo Research Foundation (FAPESP), Process Number #2023/18470-5, while conducting research at the University of Gothenburg. Show less

Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium's effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment (MCI). To examine the feasibility, safety, and preliminary efficacy of lithium carbonate for delaying cognitive decline in older adults with MCI. This single-site, randomized, double-blind, placebo-controlled pilot feasibility clinical trial was conducted at the University of Pittsburgh School of Medicine from February 2018 to August 2024, with 2-year follow-up. Analyses used linear mixed-effects models in the intention-to-treat population. Adults aged 60 years or older with MCI who were free of major psychiatric or neurologic illness and contraindications to lithium were included. Of 170 individuals assessed, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). Data were analyzed from August 2024 to December 2025. Daily low-dose lithium carbonate or placebo for 2 years. Six prespecified coprimary outcomes included cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised, preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor. Among 80 participants (mean [SD] age, lithium: 72.93 [8.77] years; placebo: 71.22 [6.47] years; 56% female), none of the 6 coprimary outcomes met the prespecified significance threshold. Mean (SD) CVLT-II baseline scores were 7.95 (3.4) for lithium and 7.90 (3.9) for placebo; scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Hippocampal and cortical volumes showed a decline over time in both groups, but no significant treatment × time interactions. Serious adverse events occurred in 12 of 41 (29%) receiving lithium vs 9 of 39 (23%) receiving placebo; none were definitely treatment related. One death occurred in the placebo group. Common adverse events included increased creatinine levels (12 of 41 [29%] with lithium vs 12 of 39 [31%] with placebo), diarrhea (12 of 41 [29%] vs 6 of 39 [15%]), tiredness (12 of 41 [29%] vs 6 of 39 [15%]), and tremor occurrence (10 of 41 [24%] vs 6 of 39 [15%]). This pilot randomized clinical trial established feasibility, confirmed safety and tolerability, and generated effect size estimates for future trials of low-dose lithium in MCI. None of the coprimary outcomes met the prespecified significance threshold. ClinicalTrials.gov Identifier: NCT03185208. Show less

Alcohol use disorder (AUD) is a significant medical problem and there is great need for developing effective treatment strategies. Brain-Derived Neurotrophic Factor (BDNF) has been shown to play a role in regulating numerous pharmacological and motivational effects of alcohol. We have shown that chronic alcohol-induced escalation of drinking is accompanied by a deficit in BDNF levels in medial prefrontal cortex (mPFC). This study examined whether exercise (wheel-running) attenuates excessive alcohol drinking via increased BDNF expression, thereby mitigating the deficit in mPFC. Adult male C57BL/6J mice were given scheduled (2-hr/day) access to a running wheel in the home-cage 1-hr following opportunity to drink alcohol for 2-hr/day. After six weeks, mice were further separated into groups that received chronic alcohol vapor or control (air) inhalation exposure. Results indicated that alcohol consumption did not alter wheel-running and exercise did not alter alcohol intake during the 6-week baseline. Exercise increased BDNF mRNA and protein expression in mPFC, reversed chronic alcohol-induced reduction in BDNF levels, and attenuated escalated alcohol drinking. Systemic administration of a TrkB receptor antagonist (ANA-12) reversed the beneficial effects of wheel-running in the model. Together, these data provide support for exercise as a potentially effective intervention strategy for treating AUD. Show less

Type 1 diabetes (T1D) is an autoimmune disease resulting in the destruction of pancreatic β-cells leading to insulin deficiency and hyperglycemia. Single cell transcriptomic analysis of human islets demonstrated profound β-cell changes and revealed heterogeneity in endocrine and exocrine cells in T1D. Pancreatic stellate cells (PSCs), the resident mesenchymal cells of the pancreas, regulate extracellular matrix homeostasis and drive fibrosis in aging, pancreatitis, and pancreatic cancer. By secreting cytokines and growth factors, PSCs contribute to local immunity and inflammation that affect pancreatic exocrine and endocrine functions. However, cell-cell communication from single cell transcriptomics analyzing the role of PSCs in T1D has not been explored. We analyzed single-cell RNA sequencing data from human pancreatic islets of 20 donors with and without T1D from the Human Pancreas Analysis Program database using the CellChat R package, focusing on activated-PSCs (aPSCs) signaling pathways. In addition, we performed aPSCs differential expression gene and gene set enrichment analyses. CellChat analysis revealed aPSCs demonstrated major changes increasing the number and strength of cellular communications in T1D compared to control pancreata. Signaling pathways upregulated in cell-to-cell communication involving aPSCs include TGFB, FGF, CXCL, ANGPTL, and NGF, and their respective ligands TGFB1/3, FGF7, CXCL12, ANGPTL4 and NGF. In contrast, PTN signaling from aPSCs was blunted in T1D. Our study revealed novel intercellular communication signatures involving aPSCs in T1D. Identification of the changes in cellular communication between aPSCs and other cells in T1D suggest a role in T1D pathogenesis or progression which might lead to the development of novel therapeutics. Show less

A signature of 16 serum proteins that were previously profiled using the aptamer-based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass-spectrometry, ELISA, Luminex, blood transcriptomics, and antibody-based Olink serum proteomics. Some of the findings were replicated in the UK Biobank using antibody-based Olink serum proteomics. This analysis replicated the association between APOB and the e2 allele of APOE, detected a new, robust pattern of association between APOE genotypes and the serum level of APOE, and discovered new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC2, APOC3, APOC4, APOE, APOF, and APOL1. In addition, 13 new proteins correlated with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease. Show less

BackgroundIdentifying genetic variants conferring resilience to Alzheimer's disease and related dementia (ADRD) may hold promise for developing therapeutics.ObjectiveTo determine genetic associations with being dementia-free at age 85 (DF85).MethodsWe examined genetic associations, using whole genome sequencing data, with DF85 in three Trans-Omics for Precision Medicine cohorts and the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium. We tested common variants individually and aggregation of rare (MAF ≤ 1%) coding and non-coding variants in DF85 participants (n = 3657) against individuals who were not DF85 (n = 20,010). We verified associations using a stricter control set who developed dementia before age 85 (n = 5552).ResultsWe observed an association at Show less

We evaluated the accuracy of standard machine learning (ML) algorithms in predicting 1-year cognitive decline in Alzheimer's disease patients with mild cognitive impairment (ADMCI) using resting-state electroencephalographic (rsEEG) biomarkers enriched with APOE genotype, sex, age, and educational attainment data. The study analyzed datasets from 63 ADMCI patients obtained from an international archive. The ML algorithms included Simple Logistic Regression, Model Trees, Logistic Regression, K-nearest neighbor, and Support Vector Machine. Input features comprised lobar rsEEG source activities across delta (<4 Hz) to alpha (≈10-12 Hz) bands, cerebrospinal fluid (CSF Aβ1-42/p-tau), and structural magnetic resonance imaging (sMRI) biomarkers. Cognitive decline was assessed over a 1-year follow-up ("stable" vs. "decliner") based on Mini-Mental State Examination (MMSE) scores. The four independent ML algorithms accurately predicted changes in the MMSE score over a 1-year follow-up, with accuracies of 77-78% in ADMCI participants aged ≥ 70 years and 74-77% in those aged < 70 years. These findings suggest that rsEEG biomarkers in ADMCI patients may not only reveal underlying pathophysiological mechanisms affecting cortical arousal and vigilance but also hold predictive value for cognitive outcomes. Show less

BackgroundEducation promotes cognitive reserve (CR), potentially buffering Alzheimer's disease pathology (ADP). However, the education-CR relationship may differ by population and genetic background.ObjectiveTo examine education, Show less

To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1 This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred. Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials. US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche. Show less

Branched-chain α-amino acids (BCAAs) support protein synthesis and their oxidation is restrained by branched-chain α-keto acid dehydrogenase kinase (BCKDK). We previously observed that in the brains of Bckdk knockout (KO) mice, BCAAs fall while glutamate is preserved and other amino acids rise. We asked why this profile emerges and how it affects skeletal muscle versus brain during nutrient stress. Motor behavior, protein synthesis and nutrient signaling were compared in the skeletal muscle and brains of wildtype (WT) and Bckdk KO male mice. In addition, nitrogen delivery into brain from BCAAs was assessed using stable isotope tracing and mass spectrometry imaging. Bckdk KO showed normal grip strength but poor beam traversal and reduced wheel running during protein restriction. In skeletal muscle, leucine or protein-feeding stimulated and fasting suppressed mechanistic target of rapamycin complex 1 (mTORC1) signaling in both genotypes. Fasting reduced muscle protein synthesis in both strains without activating the integrated-stress response (ISR). In contrast, Bckdk KO brains exhibited ISR activation during fasting, and up-regulation of Atf4 and its target genes, including Slc7a5 mRNA. Tracer studies revealed lower serum [ Show less

Testosterone production by testicular Leydig cells (steroidogenesis) is vital to male fertility and overall male health. Information about how nutrition influences Leydig cell steroidogenesis is lacking. Branched chain amino acids (BCAAs - leucine, isoleucine, and valine) are essential amino acids and important regulators of protein synthesis and energy production. Circulating and tissue BCAA levels are tightly regulated by the enzyme branched chain a-keto acid dehydrogenase kinase (BCKDK), which inhibits their catabolism. This work explored how BCAAs, and especially leucine, modulate male fertility and testosterone production. In a mutant mouse model of Bckdk, breeding analysis showed reduced male fertility and circulating testosterone. Further, morphological evaluation demonstrated testicular and epididymal abnormalities consistent with abnormal testicular androgen signaling. Fertility was partially rescued by feeding a high protein diet while circulating testosterone was not. In wild type testes, Leydig cells were the primary cell type to express BCKDK. Leveraging a primary interstitial cell culture, cell survival and apoptosis analyses demonstrated Leydig cells are highly sensitive to leucine deprivation and this sensitivity is enhanced under steroidogenesis stimulating conditions. Lastly, using the same primary cell culture system, testosterone production was shown to be lost under leucine deprivation. In total, this work demonstrates Leydig cells are uniquely sensitive to BCAA status under steroidogenesis stimulation and that regulated BCAA catabolism may be important for optimal male fertility. Show less

Elevated lipoprotein(a) [Lp(a)] levels are an established risk factor for atherosclerotic cardiovascular disease, but the association between Lp(a) and venous thromboembolism (VTE) remains unclear. Sex and hormonal status may modify the relationship between Lp(a) and VTE. The present study included participants from the UK Biobank with available baseline Lp(a) data. Individuals with a history of VTE or cancer, as well as those using anticoagulants, were excluded. Multivariable-adjusted Cox models were used to assess the association between Lp(a) levels ≥ 125 nmol/L and incident VTE in premenopausal women, postmenopausal women, and men. Subgroup analyses stratified premenopausal women by oral contraceptive (OCP) use and postmenopausal women by menopausal hormone therapy (MHT) use. Among 55 302 premenopausal women, 129 045 postmenopausal women, and 189 013 men, the proportions with Lp(a) ≥ 125 nmol/L were 14.0%, 19.0%, and 15.0%, respectively. Over a median (interquartile range) follow-up of 13.6 (12.9-14.4) years, 8186 VTE events occurred (cumulative incidence 2.2%). Lp(a) ≥ 125 nmol/L was associated with incident VTE in premenopausal women [adjusted hazard ratio (aHR) 1.32; 95% confidence interval (CI) 1.04-1.66; P = 0.02] but not in postmenopausal women (aHR 1.03; 95% CI 0.94-1.13; P = 0.47; Pinteraction = 0.03) or men (aHR 1.00; 95% CI 0.92-1.08; P = 0.94). OCP use did not modify the Lp(a)-VTE association among premenopausal women (Pinteraction = 0.61). However, among postmenopausal MHT users, Lp(a) ≥ 125 nmol/L was associated with higher VTE risk (aHR 1.48; 95% CI 1.03-2.12; P = 0.03; Pinteraction = 0.04). Elevated Lp(a) was associated with VTE in premenopausal women and in postmenopausal MHT users, suggesting that hormonal context may influence Lp(a)- associated thrombotic risk. Show less

Memory impairment is frequent among alcohol use disorder (AUD) patients, and we lack specific biomarkers to detect it. Certain apolipoproteins were linked to cognition, and carrying the APOE4 gene is a vulnerability factor to memory impairment in AUD patients. We explored memory deficits in alcohol-dependent male mice and humans versus controls, and their relationship to Apolipoprotein AI (APOAI), apolipoprotein B (APOB), and apolipoprotein E (APOE) plasma levels. Male C57BL/6J mice underwent voluntary alcohol drinking (two-bottle choice, 2BC) and chronic intermittent ethanol vapor exposure (CIE) as a model of alcohol dependence; memory was assessed by the Object Location Test (OLT) and Novel Object Recognition Test (NORT). Additionally, male AUD-diagnosed patients were recruited in Spain during an alcohol dishabituation program and assessed by the Wechsler Memory Scale-IV (WMS-IV). Plasma APOAI, APOB, and APOE levels were checked in mice and humans by ELISA kits and Luminex immunoassay technology. APOAI immunolabeling was quantified in mouse brain in early withdrawal and following alcohol consumption. CIE-2BC mice (n = 8) escalated alcohol consumption compared to Air-2BC controls (n = 11) and showed deficits in spatial memory (OLT) and recognition memory (NORT) while AUD patients (n = 12) showed deficits in verbal and visual memory (WMS-IV) versus controls (n = 16). Higher plasma levels of APOAI were detected in CIE-2BC mice and AUD patients, with no differences in APOB and APOE in animals and humans. Significant negative correlations were found between levels of APOAI, APOB, and APOE and memory function tests/scales in the entire sample, with APOAI showing consistent results in both animals and humans. APOAI immunoreactivity was detected in the mice subfornical organ, but the signal did not differ between experimental groups. Both CIE-2BC mice and AUD patients exhibited elevated plasma levels of APOAI during early abstinence. APOAI correlated with poorer memory performance in both species, suggesting a potential role for this apolipoprotein in the context of alcohol-induced cognitive impairment. Show less

We previously identified a signature of 16 serum proteins that highlighted a role of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE), and in inflammation. The serum proteins were profiled using the aptamer-based Somalogic technology. Here, we validate and expand the serum protein signature of APOE using a combination of mass-spectrometry, ELISA, Luminex, antibody-based Olink proteomics, and blood transcriptomics. We replicate the association between APOB and the e2 allele of APOE, we correct the pattern of association between APOE genotypes and serum level of APOE, and we detect new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC4, APOC2, APOC3, APOE, APOF and APOL1. In addition, we discover 13 new proteins that correlate with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease. Show less

Preclinical data have shown that low levels of metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and long-term ASCVD risk is not known. We characterised the plasma metabolomic profile (1228 metabolites) of 1852 participants (58.1 ± 7.5 years old, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Logistic regression was used to assess the impact of metabolite levels on ASCVD risk (nonfatal MI, revascularisation, and cardiac mortality). We additionally explored the effect of genetic variants neighbouring ASCVD-related genes on the levels of metabolites predictive of ASCVD events. The Atherosclerosis Risk in Communities (ARIC) study (n = 4790; 75.5 ± 5.1 years old, 57.4% female, 19.5% self-identified as Black) was used as an independent validation cohort. In fully adjusted models, alpha-ketobutyrate [AKB] (OR 0.62 [95% CI, 0.49-0.80]; p < 0.001), and 1-palmitoyl-2-linoleoyl-GPI [OR, 0.62, 95% CI, 0.47-0.83; p < 0.001], two metabolites in amino acid and phosphatidylinositol lipid pathways, respectively, showed a significant protective association with incident ASCVD risk in both Heart SCORE and ARIC cohorts. Three plasmalogens and a bilirubin derivative, whose levels were regulated by genetic variants neighbouring FADS1 and UGT1A1, respectively, exhibited a significant protective association with ASCVD risk in the Heart SCORE only. Higher mid-life levels of AKB and 1-palmitoyl-2-linoleoyl-GPI metabolites may be associated with lower risk late-life ASCVD events. Further research can determine the causality and therapeutic potential of these metabolites in ASCVD. This study was funded by the Pennsylvania Department of Health (ME-02-384). The department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Additional funding was provided by National Institutes of Health (NIH) grant R01HL089292 and UL1 TR001857 (Steven Reis). Further, NIH funded R01HL141824 and R01HL168683 were used for the ARIC study validation (Bing Yu). Show less

This study used a deidentified nationwide (US-based) high-grade serous ovarian cancer (HGSOC) clinicogenomic database (CGDB) to enrich our understanding of HGSOC's genomic heterogeneity and assess the utility of comprehensive genomic profiling (CGP) in clinical settings. We conducted a retrospective observational analysis on 856 patients with HGSOC profiled with CGP genomic tests, retrieved from CGDB from January 2011 to September 2023. In addition to Overall, our study provides evidence that CGP significantly improves the identification of molecular targets in HGSOC, supporting its importance in the clinical practice to provide patients with more therapeutic options. Show less

Congenital viral infections can have severe consequences for pregnancy and fetal outcomes. Remarkably, the fetal-derived placenta serves as a robust barrier to infection through meticulous regulation by immune effectors and cytokines. Yet, the regulatory roles of many cytokines remain undefined at the maternal-fetal interface, including Interleukin-27 (IL-27). Here, we show that trophoblast organoids derived from human placentas constitutively express both IL-27 and its receptor, and restrict Zika virus infection through IL-27 signaling. Through bulk RNA-sequencing of trophoblast organoids in the absence and presence of IL-27 signaling, we demonstrate IL-27-mediated upregulation of antiviral genes. Finally, we show that IL-27 signaling is critical to restricting placental viral burdens and protecting against pathologic fetal outcomes during murine congenital Zika virus infection. In this work, we demonstrate a novel role for IL-27 in the placenta and establish IL-27 as an innate antiviral defense at the maternal-fetal interface during congenital viral infection. Show less

Congenital viral infections can have severe consequences for pregnancy and fetal outcomes. Remarkably, the fetal-derived placenta serves as a robust barrier to infection through meticulous regulation by immune effectors and a diverse repertoire of cytokines. Yet, the regulatory roles of many cytokines remain undefined at the maternal-fetal interface. Interleukin 27 (IL-27) is a highly expressed cytokine in the placenta whose functional consequence during congenital infection is unknown. Here, we utilized trophoblast organoids (TO) derived from primary human placentas and a mouse model of congenital viral infection to uncover the functional role of IL-27 signaling during pregnancy. We show that TOs constitutively express IL-27 and its receptor, IL-27RA, and demonstrate that IL-27 signaling restricts Zika virus (ZIKV) infection of TOs. Through bulk RNA-sequencing of TOs in the absence and presence of IL-27 signaling, we demonstrate IL-27-mediated upregulation of antiviral genes. Finally, we show that IL-27 signaling is critical within the context of congenital murine ZIKV infection, as IL-27 restricts placental ZIKV burdens and protects against pathologic fetal outcomes early in gestation. These findings collectively demonstrate a novel role for IL-27 in the placenta and establish IL-27 as an innate antiviral defense at the maternal-fetal interface during congenital viral infection. Show less

Despite advances in therapies that target low-density lipoprotein (LDL), atherosclerotic cardiovascular disease (ASCVD) remains a major cause of morbidity and mortality. This has led to the investigation of other biomarkers, including lipoprotein(a) [Lp(a)]. Lp(a) is a variant of LDL that is genetically determined, has proatherogenic, proinflammatory, and prothrombotic effects, and has a linear correlation with ASCVD risk. Approximately 20%-30% of the global population has elevated serum Lp(a). Recommendations for increased Lp(a) testing has heightened the need for effective medications to target this biomarker. Although traditional antilipemic agents have demonstrated negligible effects on Lp(a), multiple targeted therapies are emerging, including antisense oligonucleotides, small interfering RNA agents, and small molecules. The efficacy of these novel agents observed in early clinical trials and the development of alternate treatment modalities, including gene editing and RNA-based innovations, signal a promising new era of ASCVD prevention via non-LDL pathways. SIGNIFICANCE STATEMENT: Lipoprotein(a) is a genetically determined biomarker that significantly impacts atherosclerotic risk. The development of novel therapies that lower lipoprotein(a) warrants a broad understanding to increase comfortability and optimize utilization upon market approval. Show less

Aberrant G-protein coupled receptor (GPCR) expression is highly prevalent in cortisol-secreting primary bilateral macronodular adrenal hyperplasia (PBMAH) and unilateral adenomas. The aberrant expression of diverse GPCRs and their ligands play an important role in the over-function of various endocrine tumours. Examples include aberrant expression of MC2R, 5-HT4R, AVPR1A, LHCGR, and GnRHR in primary aldosteronism; GCGR, LHCGR, and 5-HT4R in phaeochromocytomas and paragangliomas; TRHR, GnRHR, GIPR, and GRP101 in pituitary somatotroph tumours; AVPR2, D2DR, and SSTR5 in pituitary corticotroph tumours; GLP1R, GIPR, and somatostatin receptors in medullary thyroid carcinoma; and SSTRs, GLP1R, and GIPR in other neuroendocrine tumours. The genetic mechanisms causing the ectopic expression of GIPR in cortisol-secreting PBMAHs and unilateral adenomas have been identified, but distinct mechanisms are implicated in other endocrine tumours. Development of functional imaging targeting aberrant GPCRs should be useful for identification and for specific therapies of this wide spectrum of tumours. The aim of this review is to show that the regulation of endocrine tumours by aberrant GPCR is not restricted to cortisol-secreting adrenal lesions, but also occurs in tumours of several other organs. Show less

The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) ε4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention. Show less

Neurodegenerative proteinopathies such as Alzheimer's Disease are characterized by abnormal protein aggregation and neurodegeneration. Neuroresilience or regenerative strategies to prevent neurodegeneration, preserve function, or restore lost neurons may have the potential to combat human proteinopathies; however, the adult human brain possesses a limited capacity to replace lost neurons. In contrast, axolotls ( Show less

Hepatic proteomes are intricately controlled through biosynthesis, extracellular secretion, and intrahepatic degradation. Autophagy governs lysosome-mediated intrahepatic degradation and the hepatic proteome. When autophagy is impaired, it leads to the accumulation of intrahepatic proteins, causing proteinopathy. This study investigates whether autophagy can modulate the hepatic proteome non-degradatively. Utilizing conditional, inducible, and hepatotoxin models of hepatic autophagy impairment, we assessed the overall hepatic proteome expression using Coomassie brilliant blue (CBB) staining and liquid chromatography-tandem mass spectrometry (LC/MS). We pinpointed and confirmed four specific hepatic proteins-Cps1, Ahcy, Ca3, and Gstm1-that were selectively modified in autophagy-deficient livers. Expression of Cps1, Ahcy, and Ca3 were significantly reduced, while Gstm1 expression increased in livers with autophagy impairment. Interestingly, these changes in hepatic protein levels were not due to defective autophagic degradation but were associated with alterations in mRNA transcript levels. Moreover, as a result of autophagic dysfunction, sustained activation of the nuclear erythroid-derived 2-like 2 (Nrf2) transcription factor, transcriptionally regulated the mRNA levels of these proteins. Our findings indicate that autophagy can influence hepatic proteins not solely via traditional degradative routes but also through non-degradative transcriptional processes by modulating Nrf2. Show less

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined were subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads and discordant read pairs. Polymerase Chain Reaction (PCR) followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. A total of 16 candidate pathogenic SVs were identified in 16 families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS and PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions. Show less

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined was subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY, and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads, and discordant read pairs. PCR followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. In total, sixteen candidate pathogenic SVs were identified in sixteen families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive, and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in Show less

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion ( Show less

One SNP in exon 9 (r5883) has been involved with high risk of cardiovascular disease in hypertensive subjects. The goal of the present study was to test the role of this genetic variant on lipid levels and Metabolic Syndrome (MS) in menopausal obese females. The study enrolled a sample of 112 menopausal obese females. Measurements of adiposity parameters, blood pressure, fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), lipid profile, C reactive protein and prevalence of MS were recorded. Genotype of CETP gene polymorphism (rs5883) was studied. The distribution of the rs5883 polymorphism in this menopausal obese population was 83.9% (n=94) (CC), 15.2% (n=17) (CT) and 0.9% (n=1) (TT). Adiposity parameters, blood pressure, fasting glucose levels, insulin levels, HOMA-IR, C reactive protein, total cholesterol, LDL-cholesterol and triglycerides were similar in both genotype groups (CC vs. CT+TT). Moreover, HDL cholesterol (8.5+1.2 mg/dl; p=0.01) and ratio total cholesterol/HDL-cholesterol (0.5±0.2; p=0.04) were higher in T allele carriers (dominant model). MS percentage was similar in both genotypes (37.6% vs. 27.2%; p=0.43). Logistic regression analysis showed a decreased risk of low-HDL cholesterol in T allele carriers (OR=0.18, 95% CI=0.02-0.77, p=0.03) after adjusting by dietary fatty acid intakes, body mass index and age. The results reported here support that CETP variant rs5883 is related with HDL-cholesterol levels and ratio total cholesterol/HDL-cholesterol. Show less

The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk. To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia. This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019. Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ. Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (β coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline. Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, β coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, β coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: β coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: β coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes. In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia. Show less

Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer's disease pathology. Show less