EMBO Molecular Medicine

Mitochondria are semi-autonomous organelles whose generation and maintenance demand precise expression, processing, and assembly of >1,000 proteins encoded across two genomes. To explore this cooperativity, we performed multiomic analyses on >200 cell lines harboring mitochondrial gene perturbations, generating >26M molecular measurements. Our data reveal that mitochondrial proteome homeostasis is heavily influenced by post-transcriptional processes. Through nearest neighbor analyses, we reveal ...

The pivotal role of Kir5.1 (KCNJ16) in maintaining electrolyte and acid-base homeostasis was demonstrated by animal studies and highlighted by the identification of disease-causing mutations in KCNJ16 resulting in a complex tubulopathy with variable severity. Although the underlying molecular mechanisms remain elusive, the modus operandi of Kir5.1 is rooted in its heteromeric association with Kir4.1 (KCNJ10) and Kir4.2 (KCNJ15). The ubiquitous expression of KCNJ16 and the heterogenous clinical p...

BackgroundWhile monosodium urate (MSU) crystal deposition within coronary plaques links hyperuricemia/gout to cardiovascular risk, the existence and functional consequences of MSU deposits within the myocardial interstitium or cardiomyocytes remain unknown. MethodsForensic autopsy myocardial and renal specimens from gout patients (n=4) and controls (n=4) were analyzed for MSU crystals using compensated polarized microscopy, laser capture microdissection coupled with HPLC-MS, and cryo-electron m...

TRAF1 is a pro-survival signaling adaptor that contributes to NF-{kappa}B activation downstream of a subset of TNFR superfamily members. TRAF1 is overexpressed in many cancers of mature B cells, including chronic lymphocytic leukemia (CLL). Previous studies have established that TRAF1 S146 is a target of phosphorylation by the kinase PKN1 and that PKN1 is required to prevent cellular inhibitor of apoptosis protein (cIAP)-dependent degradation of TRAF1 in the CD40 signaling complex. The kinase in...

Aims/hypothesisImmunotherapies such as Teplizumab can preserve residual beta cell function in individuals with newly diagnosed type 1 diabetes (T1D), but treatment response is variable. Currently, no biomarker exists to identify individuals most likely to benefit from immunotherapy. We believe that baseline serum metabolomic profiles can distinguish individuals who respond to treatment from nonresponders and predict therapeutic response. MethodsBaseline serum samples from 41 individuals newly d...

AimsGestational diabetes mellitus (GDM) is the most common pregnancy-related medical complication. GDM is linked to aberrant immune responses in both mothers and offsprings, specifically, the subsequent development of inflammatory diseases. Whereas prior research has focused on specific immune cell subsets, a comprehensive overview of the impacts of GDM on maternal and fetal immune landscape is lacking. Here, we aim to comprehensively decipher how GDM modulates various immune cell populations in...

BackgroundImmune checkpoint inhibitors (ICIs) targeting the programmed death (ligand)-1 (PD-1/PD-L1) axis, like pembrolizumab, have significantly improved survival in non-small cell lung cancer (NSCLC). However, less than 50% of patients respond. Identifying early-response biomarkers is crucial to personalize therapy, thereby preventing ineffective, expensive and potentially harmful treatment. MethodsWe applied a novel ex vivo immunopharmacological bioassay to assess pembrolizumab-dependent T c...

BackgroundImmune checkpoint inhibition has transformed cancer therapy; however, many patients fail to respond to single-agent blockade, and combination strategies are often limited by toxicity. Central nervous system tumors exploit multiple immunosuppressive pathways, including the CD200 and PD-1/PD-L1 axis to evade anti-tumor immunity and support tumor aggressiveness. MethodsWe investigated ARL200, a peptide ligand targeting the CD200 activation receptor (CD200AR) using in vitro immune assays,...

Autologous CAR-T cell therapy has demonstrated remarkable clinical efficacy in hematologic malignancies, yet its broader application remains limited by complex, labor-intensive manufacturing and inconsistent product quality. We describe a novel microfluidic cell separation platform based on Deterministic Lateral Displacement (DLD), integrated into a fully automated, closed-system instrument (Curate System), capable of processing full leukopacks in under one hour. Compared to Ficoll(R)-based dens...

Background and aims Iron deficiency (ID) and myocardial iron depletion (MID) are causally linked to heart failure (HF) in the general population and in preclinical models. ID is common amongst pregnant women, but its impact on cardiac adaptations to pregnancy is unknown. This study examines that impact, and its potential relevance to peripartum cardiomyopathy (PPCM). Methods. We provided female mice with iron-replete or iron-deficient diets, and monitored cardiac function and morphology longitud...

Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease of motor neurons that leads to muscle wasting, paralysis, and death, with an average life expectancy of 2-5 years. Approximately 10-15% of ALS cases are familial (fALS), typically linked to, but not always caused by identifiable inherited genetic mutations. The remaining 85-90% are considered sporadic ALS (sALS), which typically occurs without a clear family history. It is thought to result from a combination of genetic and non-geneti...

Leber hereditary optic neuropathy (LHON) is primarily caused by pathogenic mitochondrial DNA (mtDNA) variants, most commonly the m.11778G>A variant in the MT-ND4 gene. The presence of this variant alone is insufficient to trigger disease symptoms, of which vision loss is the hallmark. Given the incomplete penetrance and inter-population variability in modifying factors, this study aimed to investigate two previously proposed genetic risk factors for LHON in the Polish population. Using quantitat...

ObjectiveTo determine alterations in circulating Tau and phosphorylated Tau (pTau) profiles in pediatric and adult patients with spinal muscular atrophy (SMA). MethodsCirculating total Tau, pTau-181, pTau-217, pTau-262, and pTau-396 concentrations were measured across three cohorts: 1) adults including healthy controls, SMA patients, and ALS patients; 2) pediatric SMA patients and age-matched controls; and 3) pediatric SMA patients treated with onasemnogene abeparvovec. ResultsDistinct alterat...

AimsThe gut microbiome has been implicated in type 2 diabetes progression, but reproducible biomarkers across studies remain limited due to technical and population heterogeneity. This study investigated whether specific gut microbiome shifts occur progressively across stages of type 2 diabetes. MethodsWe systematically reanalysed 16S rRNA datasets from 12 published studies (n=1,247 samples) after quality control, examining five groups (healthy controls, prediabetes (PD), new-onset type 2 diabe...

Regional lymph nodes (LNs) in the thoracic cavity serve as essential immunological hubs that coordinate humoral and cell-mediated responses against the development and progression of non-small cell lung cancer (NSCLC). To investigate immune dysregulation in the non-metastatic regional LNs of patients with aggressive NSCLC, we performed multimodal profiling on 36 LNs from 11 patients undergoing curative-intent resection including CITE-seq, scRNA-seq, and Imaging Mass Cytometry (IMC). Regional N1 ...

Age-defined type 1 diabetes (T1D) endotypes, T1DE1 and T1DE2, are characterized by reproducible differences in pancreatic immunopathology and clinical course. In particular, these endotypes differ in the extent and composition of lymphocytic insulitis and in the extent of loss of insulin-producing {beta} cell mass, at diagnosis. However, blood-based biomarkers that may distinguish these endotypes and inform the underlying immune-islet biology axis at diagnosis remain limited. Here, we characteri...

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are phenotypically divergent disorders arising from similar exposures (including cigarette smoke). Differences in DNA methylation may drive the exposed lung towards COPD vs. IPF. To characterize differential methylation in COPD and IPF lung tissue relative to controls, we conducted epigenome-wide association studies of COPD and IPF in lung tissue from the Lung Tissue Research Consortium (N=1029), adjusting for a...

Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where deficiency of the TGF/BMP pathways have causal roles in hereditary and idiopathic forms. It is an attractive candidate for therapeutic intervention but there is an unmet need for clinically-relevant and practical biomarkers that can measure target engagement. A major challenge has been the inaccessibility of lung tissue in disease for molecular profiling. Here we explore the surrogate capacity of peripheral blood BMP pa...

Chronic obstructive pulmonary disease (COPD) is a debilitating and progressive lung disease that affects millions of people worldwide. There is a continuing clinical need to characterize COPD at the molecular level to be able to identify the multi-omic biomarkers of its pathogenesis and to enable more accurate diagnoses and more effective treatment. We used Multi-Omics Factor Analysis (MOFA) to jointly analyze genomic, blood transcriptomic, and plasma proteomic data collected from 1,872 particip...

ATXN2 expansions of [≥]33 CAG-repeats are associated with spinocerebellar ataxia type 2, while "intermediate" length expansions have been associated with amyotrophic lateral sclerosis (ALS). Yet, no consensus is established regarding the lengths that define a true association with ALS risk, with recent studies debating between a lower limit of [≥]29 or [≥]31 repeats. Here, we assessed the risk of ALS imparted by various ATXN2 repeat lengths to establish an accepted lower limit of repeat...