Human diseases range from gene-associated to gene-non-associated disorders, including age-related diseases, neurodegenerative, neuromuscular, cardiovascular, diabetic diseases, neurocognitive disorders and cancer. Mitochondria participate to the cascades of pathogenic events leading to the onset and progression of these diseases independently of their association to mutations of genes encoding mitochondrial protein. Under physiological conditions, the mitochondrial ATP synthase provides the most energy of the cell via the oxidative phosphorylation. Alterations of oxidative phosphorylation mainly affect the tissues characterized by a high-energy metabolism, such as nervous, cardiac and skeletal muscle tissues. In this review, we focus on human diseases caused by altered expressions of ATP synthase genes of both mitochondrial and nuclear origin. Moreover, we describe the contribution of ATP synthase to the pathophysiological mechanisms of other human diseases such as cardiovascular, neurodegenerative diseases or neurocognitive disorders.

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

Cardiovascular diseases are prevalent in patients with chronic obstructive pulmonary disease (COPD). Their coexistence implies that many COPD patients require anticoagulation therapy. Although more and more replaced by direct oral anticoagulants, vitamin K antagonists (VKAs) are still widely used. VKAs induce profound deficiency of vitamin K, a key activator in the coagulation pathway. It is recognized however that vitamin K is also an essential cofactor in the activation of other extrahepatic proteins, such as matrix Gla protein (MGP), a potent inhibitor of arterial calcification. No or insufficient MGP activation by the use of VKAs is associated with a rapid progression of vascular calcification, which may enhance the risk for overt cardiovascular disease. Vitamin K consumption, on the other hand, seems to have a protective effect on the mineralization of arteries. Furthermore, vascular calcification mutually relates to elastin degradation, which is accelerated in patients with COPD associating with impaired survival. In this commentary, we hypothesize that vitamin K is a critical determinant to the rate of elastin degradation. We speculate on the potential link between poor vitamin K status and crucial mechanisms of COPD pathogenesis and raise concerns about the use of VKAs in patients with this disease. Future intervention studies are needed to explore if vitamin K supplementation is able to reduce elastin degradation and vascular calcification in COPD patients.

Background Lewy body diseases (LBDs) feature deficiency of the sympathetic neurotransmitter norepinephrine in the left ventricular myocardium and sympathetic intra-neuronal deposition of the protein alpha-synuclein (αS). LBDs therefore are autonomic synucleinopathies. Computational modeling has revealed multiple functional abnormalities in residual myocardial sympathetic noradrenergic nerves in LBDs, including decreased norepinephrine synthesis, vesicular storage, and recycling. We report an extended model that enables predictions about the progression of LBDs and effects of genetic predispositions and treatments on that progression. Methods and Results The model combines cardiac sympathetic activation with autotoxicity mediated by the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde. We tested the model by its ability to predict longitudinal empirical data based on cardiac sympathetic neuroimaging, effects of genetic variations related to particular intra-neuronal reactions, treatment by monoamine oxidase inhibition to decrease 3,4-dihydroxyphenylacetaldehyde production, and post-mortem myocardial tissue contents of catecholamines and αS. The new model generated a triphasic decline in myocardial norepinephrine content. This pattern was confirmed by empirical data from serial cardiac 18F-dopamine positron emission tomographic scanning in patients with LBDs. The model also correctly predicted empirical data about effects of genetic variants and monoamine oxidase inhibition and about myocardial levels of catecholamines and αS. Conclusions The present computational model predicts a triphasic decline in myocardial norepinephrine content as LBDs progress. According to the model, disease-modifying interventions begun at the transition from the first to the second phase delay the onset of symptomatic disease. Computational modeling coupled with biomarkers of preclinical autonomic synucleinopathy may enable early detection and more effective treatment of LBDs.

As an immune modulator, vitamin D is involved in various pathophysiological mechanisms in a plethora of diseases. This study aims to correlate the vitamin D deficiency status and clinical progression of liver diseases associated with hepatitis B virus (HBV) infection in patients in Vietnam and to compare it to healthy controls.

Magnesium plays an important role in many physiological functions. Habitually low intakes of magnesium and in general the deficiency of this micronutrient induce changes in biochemical pathways that can increase the risk of illness and, in particular, chronic degenerative diseases. The assessment of magnesium status is consequently of great importance, however, its evaluation is difficult. The measurement of serum magnesium concentration is the most commonly used and readily available method for assessing magnesium status, even if serum levels have no reliable correlation with total body magnesium levels or concentrations in specific tissues. Therefore, this review offers an overview of recent insights into magnesium from multiple perspectives. Starting from a biochemical point of view, it aims at highlighting the risk due to insufficient uptake (frequently due to the low content of magnesium in the modern western diet), at suggesting strategies to reach the recommended dietary reference values, and at focusing on the importance of detecting physiological or pathological levels of magnesium in various body districts, in order to counteract the social impact of diseases linked to magnesium deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymatic disorder, particularly prevalent in Africa, Asia and the Middle East. In the US, about 14% of black men are affected. Individuals with G6PD deficiency are often asymptomatic but may develop hemolysis following an infection or upon consumption of specific medications. Despite some evidence that G6PD deficiency affects the immune system, the long- term health risks associated with G6PD deficiency had not been studied in a large population.

A diet restricted in dairy products can cause calcium and vitamin D deficiency and, secondarily, lead to malnutrition and low bone mass. The aim of the study was to determine the incidence hypocalcemia and vitamin D deficiency in children with inflammatory bowel diseases and lactose intolerance (LI).

Lipoprotein lipase (LPL) is an enzyme that catalyzes the hydrolysis of circulating triglyceride and the transport of fatty acids into cells. Its activity is positively regulated by insulin, and insulin resistance is associated with low LPL activity and subsequent hypertriglyceridemia. The involvement of hypertriglyceridemia in chronic kidney disease (CKD) is still under the debate in a clinical setting. Therefore, we aimed to study the role of hypertriglyceridemia in the disease using mice with systemic or renal-specific LPL deficiency. Systemic LPL deficiency was characterized by hypertriglyceridemia, but not renal injury or dyslipidemia-related conditions, such as fatty liver. Furthermore, the LPL deficiency-induced hypertriglyceridemia was not associated with a worsening of the CKD phenotype or atherosclerosis, even when CKD was induced by 5/6 nephrectomy. Next, because LPL-mediated fatty acid uptake may be important for energy metabolism in proximal tubular epithelial cells (PTECs), the role of renal LPL in renal physiology was studied by generating mice lacking LPL specifically in PTECs. These mice showed no abnormalities in their histology or renal reabsorption of micro molecules. These findings suggest that systemic and renal lipid abnormalities caused by LPL deficiency do not cause or worsen the development of renal injury, and provide novel insight regarding the potential role of lipotoxicity in the pathogenesis of obesity-related kidney injury.

Although absolute (AID) and functional iron deficiency (FID) are known risk factors for patients with cardiovascular (CV) disease, their relevance for the general population is unknown. The aim was to assess the association between AID/FID with incident CV disease and mortality in the general population.

Laminin α2 deficient congenital muscular dystrophy, caused by mutations in the LAMA2 gene, is characterized by early muscle weakness associated with abnormal white matter signal on cerebral MRI.

We evaluated the overall and site-specific incidence of cancer in subjects with primary immunodeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network (USIDNET) registry compared with age-adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database.

Ku70 (Lupus Ku autoantigen p70) is essential in nonhomologous end joining DNA double-strand break repair, and ku70(-/-) mice age prematurely because of increased genomic instability and DNA damage responses. Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis. We hypothesized that Bax-mediated apoptosis would be enhanced in the absence of Ku70 and contribute to premature death observed in ku70(-/-) mice. Here, we show that ku70(-/-) bax(+/-) and ku70(-/-) bax(-/-) mice have better survival, especially in females, than ku70(-/-) mice, even though Bax deficiency did not decrease the incidence of lymphoma observed in a Ku70-null background. Moreover, we found that ku70(-/-) mice develop lung diseases, like emphysema and pulmonary arterial (PA) occlusion, by 3 months of age. These lung abnormalities can trigger secondary health problems such as heart failure that may account for the poor survival of ku70(-/-) mice. Importantly, Bax deficiency appeared to delay the development of emphysema. This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion. Furthermore, the underlying mechanisms of emphysema and pulmonary hypertension due to PA occlusion are not well understood, and therefore ku70(-/-) and Bax-deficient ku70(-/-) mice may be useful models to study these diseases.

Traditional Chinese medicine formulates treatment according to body constitution (BC) differentiation. Different constitutions have specific metabolic characteristics and different susceptibility to certain diseases. This study aimed to assess the characteristic genes of gan-shen Yin deficiency constitution in different diseases. Fifty primary liver cancer (PLC) patients, 94 hypertension (HBP) patients, and 100 diabetes mellitus (DM) patients were enrolled and classified into gan-shen Yin deficiency group and non-gan-shen Yin deficiency group according to the body constitution questionnaire to assess the clinical manifestation of patients. The mRNA expressions of 17 genes in PLC patients with gan-shen Yin deficiency were different from those without gan-shen Yin deficiency. However, considering all patients with PLC, HBP, and DM, only MLH3 was significantly lower in gan-shen Yin deficiency group than that in non-gen-shen Yin deficiency. By ROC analysis, the relationship between MLH3 and gan-shen Yin deficiency constitution was confirmed. Treatment of MLH3 (-/- and -/+) mice with Liuweidihuang wan, classical prescriptions for Yin deficiency, partly ameliorates the body constitution of Yin deficiency in MLH3 (-/+) mice, but not in MLH3 (-/-) mice. MLH3 might be one of material bases of gan-shen Yin deficiency constitution.

In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune-mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN-γ, a key pro-inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE. While evidence suggests activation of the ATF6α branch of the UPR in oligodendrocytes under normal and disease conditions, the effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases remain unknown. Herein, we showed that ATF6α deficiency had no effect on oligodendrocytes under normal conditions. Interestingly, we showed that ATF6α deficiency exacerbated ER stressed-induced myelinating oligodendrocyte death and subsequent myelin loss in the developing CNS of IFN-γ-expressing mice. Moreover, we found that ATF6α deficiency increased EAE severity and aggravated EAE-induced oligodendrocyte loss and demyelination, without affecting inflammation. Thus, these data suggest the protective effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases.

Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of immunity underlying an absence of blood myeloid mononuclear cells, intracerebral calcifications, and multiple infections. Only three unrelated patients have been reported.

IgM deficiency has been reported in patients with many autoimmune diseases treated with Rituximab (RTX). It has not been studied, in detail, in autoimmune mucocutaneous blistering diseases (AIMBD). Our objectives were: (i) Examine the dynamics of IgM levels in patients with and without RTX. (ii) Influence of reduced serum IgM levels on clinical and laboratory parameters. (iii) Explore the possible molecular and cellular basis for reduced serum IgM levels. This retrospective study that was conducted in a single-center from 2000 to 2020. Serial IgM levels were studied in 348 patients with five AIMBD (pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, and ocular cicatricial pemphigoid) and found decreased in 55 patients treated with RTX, IVIG, and conventional immunosuppressive therapy (CIST). Hence the incidence of decreased serum IgM is low. The incidence of decreased IgM in patients treated with RTX was 19.6%, in patients treated with IVIG and CIST, it was 52.8% amongst the 55 patients. IgM levels in the post-RTX group were statistically significantly different from the IVIG group (p<0.018) and CIST group (p<0.001). There were no statistically significant differences between the groups in other clinical and laboratory measures. Decreased serum IgM did not affect depletion or repopulation of CD19+ B cells. Patients in the three groups achieved clinical and serological remission, in spite of decreased IgM levels. Decrease in IgM was isolated, since IgG and IgA were normal throughout the study period. Decreased IgM persisted at the same level, while the patients were in clinical remission, for several years. In spite of persistent decreased IgM levels, the patients did not develop infections, tumors, other autoimmune diseases, or warrant hospitalization. Studies on IgM deficiency in knockout mice provided valuable insights. There is no universally accepted mechanism that defines decreased IgM levels in AIMBD. The data is complex, multifactorial, sometimes contradictory, and not well understood. Nonetheless, data in this study provides novel information that enhances our understanding of the biology of IgM in health and disease.

Dental status is one of the main indicators of overall health. We examined it in children aged 6-15 years who live in conditions of biogeochemical fluorine and iodine deficiency (Transcarpathian region, Ukraine), to improve the quality of dental care.

Epigenetic modifications affect the differentiation of T cell subsets and the pathogenesis of autoimmune diseases, but many mechanisms of epigenetic regulation of T cell differentiation are unclear. Here we show reduced expression of the transcription factor RFX1 in CD4+ T cells from patients with systemic lupus erythematosus, which leads to IL-17A overexpression through increased histone H3 acetylation and decreased DNA methylation and H3K9 tri-methylation. Conditional deletion of Rfx1 in mice exacerbates experimental autoimmune encephalomyelitis and pristane-induced lupus-like syndrome and increases induction of Th17 cells. In vitro, Rfx1 deficiency increases the differentiation of naive CD4+ T cells into Th17 cells, but this effect can be reversed by forced expression of Rfx1. Importantly, RFX1 functions downstream of STAT3 and phosphorylated STAT3 can inhibit RFX1 expression, highlighting a non-canonical pathway that regulates differentiation of Th17 cells. Collectively, our findings identify a unique role for RFX1 in Th17-related autoimmune diseases.