Sphingolipid Profiling: A Promising Tool for Stratifying the Metabolic Syndrome-Associated Risk

Metabolic syndrome (MetS) is a multicomponent risk condition that reflects the clustering of individual cardiometabolic risk factors related to abdominal obesity and insulin resistance. MetS increases the risk for cardiovascular diseases (CVD) and type 2 diabetes mellitus (T2DM). However, there still is not total clinical consensus about the definition of MetS, and its pathophysiology seems to be heterogeneous. Moreover, it remains unclear whether MetS is a single syndrome or a set of diverse clinical conditions conferring different metabolic and cardiovascular risks. Indeed, traditional biomarkers alone do not explain well such heterogeneity or the risk of associated diseases. There is thus a need to identify additional biomarkers that may contribute to a better understanding of MetS, along with more accurate prognosis of its various chronic disease risks. To fulfill this need, omics technologies may offer new insights into associations between sphingolipids and cardiometabolic diseases. Particularly, ceramides –the most widely studied sphingolipid class– have been shown to play a causative role in both T2DM and CVD. However, the involvement of simple glycosphingolipids remains controversial. This review focuses on the current understanding of MetS heterogeneity and discuss recent findings to address how sphingolipid profiling can be applied to better characterize MetS-associated risks.

The Functional Polymorphism of DDAH2 rs9267551 Is an Independent Determinant of Arterial Stiffness

Background: The association of circulating asymmetric dimethylarginine (ADMA) levels with cardiovascular risk and arterial stiffness has been reportedly demonstrated, although the causal involvement of ADMA in the pathogenesis of these conditions is still debated. Dimethylaminohydrolase 2 (DDAH2) is the enzyme responsible for ADMA hydrolysis in the vasculature, and carriers of the polymorphism rs9267551 C in the 5′-UTR of DDAH2 have been reported to have higher DDAH2 expression and reduced levels of serum ADMA.Approach and Results: We genotyped rs9267551 in 633 adults of European ancestry and measured their carotid–femoral pulse wave velocity (cfPWV), the gold-standard method to estimate arterial stiffness. cfPWV resulted significantly lower in rs9267551 C allele carriers (Δ = −1.12 m/s, P < 0.01) after correction for age, sex and BMI, and a univariate regression showed that the presence of rs9267551 C variant was negatively associated with cfPWV (β = −0.110, P < 0.01). In a multivariable regression model, subjects carrying the rs9267551 C allele manifested significantly lower cfPWV than GG carriers (β = −0.098, P = 0.01) independently from several potential confounders. We measured circulating ADMA levels in a subset of 344 subjects. A mediation analysis revealed that the effect of DDAH2 rs9267551 genotype on cfPWV was mediated by the variation in ADMA levels.Conclusions: These evidences hint that the presence of rs9267551 C allele may explain, at least in part, a reduction in vessel rigidity as measured by cfPWV, and support the attribution of a causative role to ADMA in the pathogenesis of arterial stiffness.

Genetic Risk Factors for Idiopathic Urolithiasis: The Causative Role of Genes in Stones Formation

Background: The genetic factor of urolithiasis plays an important role in the etiology. Elucidation of responsible genes can lead to better targeted gene therapy and prevention in the future. This article aims to explain various genetic factors that play a role in kidney stone formation Method: A review article on urolithiasis based on a genetic approach is reported to underlie stone formation. A total of 41 abstracts and research articles published by internationally reputed journals were selected based on the keywords genetic factors and urolithiasis. Summary: A deeper understanding of the genetic factors that play a role in the mechanisms of stone formation and advances in molecular and pharmacogenomics have revolutionized diagnosis and treatment, and paved the way for the identification of new therapeutic targets and treatment approaches based on genetic engineering.

Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone.

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGF-beta-like soluble factor, SCUBE3. In turn, osteoclasts secrete unregulated amounts of SEMA4D enhancing proliferation of mutated osteoprogenitors and arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation upon denosumab treatment, a drug that depletes osteoclasts. In contrast, gain of hTERT activity, commonly found in malignant GCT, makes neoplastic cells insensitive to osteoclasts, predicting the unresponsiveness to denosumab. We provide a mechanism for GCT initiation and its response to current treatment, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells, emphasising the importance of tumor/microenvironment bidirectional interactions in tumorigenesis.

Exploring the Effects of Greek Yogurt Supplementation and Exercise Training on Serum Lithium and Its Relationship With Musculoskeletal Outcomes in Men

Dairy products can act as a dietary source of lithium (Li), and a recent study in university-aged males demonstrated that Greek yogurt (GY) supplementation augmented gains in fat free mass, strength and bone formation after 12 weeks of resistance exercise training compared to carbohydrate (CHO) pudding supplementation. Here, we performed secondary analyses to explore whether GY would alter serum Li levels and whether changes in serum Li would associate with changes in body composition, strength, and bone turnover markers. Results show that the GY group maintained serum Li levels after exercise training, whereas the CHO group did not. Maintaining/elevating serum Li levels was also associated with greater gains in strength and reductions in bone resorption. However, controlling for other dietary factors in GY such as protein and calcium weakened these associations. Thus, future studies should assess the causative role, if any, of dietary Li alone on strength and bone resorption in humans.

Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes

DNA methylation variations are prevalent in human obesity, but evidence of a causative role in disease pathogenesis is limited. In this study, we combine epigenome-wide association and integrative genomics to investigate the impact of subcutaneous and visceral adipocyte DNA methylation variations in extreme human obesity. We identify extensive DNA methylation changes that are robustly associated with extreme obesity in combined discovery and replication analyses (N=190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P<1x10-7). Using functional interaction maps and methylation-expression association testing in human adipocytes, we connect extreme obesity-associated methylation variations to transcriptomic changes at >500 target genes. We find that disease-associated methylation variations localise to active genomic regions and transcription factor binding sites, at which DNA methylation influences transcription factor-target gene co-expression relationships. In Mendelian Randomisation analyses, we infer causal effects of DNA methylation on human obesity and obesity-induced metabolic disturbances, under genetic control, at 28 independent loci. Silencing of two target genes of causal DNA methylation variations, the PRRC2A and LIMD2 genes, further reveals novel metabolic effects in adipocytes. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal genomic and molecular mechanisms through which altered DNA methylation may impact adipocyte cellular functions.

Cigarette Smoking and Schizophrenia: Etiology, Clinical, Pharmacological, and Treatment Implications

Recent data suggests that the prevalence of smoking in schizophrenia remains high. While reports suggest that smoking increases the risk of developing schizophrenia, the potential causative role of smoking in this relationship needs further investigation. Smokers with schizophrenia are more likely to have more intense positive symptoms and lower cognitive function, but diminished intensity of extrapyramidal side effects than nonsmoking patients with schizophrenia. They were also more likely to exhibit aggressive behaviour compared to nonsmokers, which could suggest higher levels of baseline aggression. The significant cost associated with regular tobacco expenditure can detract from investment in key domains. Large-scale trials have shown that pharmacotherapy for smoking cessation is effective and does not worsen the risk of developing neuropsychiatric symptoms compared to placebo. Electronic cigarette use among schizophrenia patients is high, and there is emerging evidence supportive of its efficacy. Future improvements include large-scale trials assessing the utility, efficacy, and safety of electronic cigarettes in schizophrenia patients.

A mikroorganizmusok patogenitása és virulenciája: definíciók, példázatok és molekuláris háttérismeretek

Összefoglaló. A fertőző betegségek kóroki hátterének felderítésére irányuló törekvések hosszú időre tekintenek vissza. Fogalmakkal és követelményekkel (posztulátumokkal) igyekeztek körülírni, hogy egy mikroorganizmus mikor tekinthető egy adott fertőző betegség okozójának. Egy patogén rendszertani kategóriába tartozó mikroorganizmus kimutatása a betegből önmagában még nem elegendő bizonyíték arra, hogy a betegségnek valóban az a kórokozója. Igazolni kell a továbbiakban, hogy rendelkezik azokkal a virulenciafaktoroknak nevezett tényezőkkel, amelyek valójában képessé teszik az adott betegség kiváltására. Robert Koch idejében csak fenotípusos ismeretek álltak rendelkezésre, azok figyelembevételével fogalmazta meg posztulátumait. Később, a megszerzett molekuláris ismeretek birtokában, a posztulátumokat molekuláris szinten is értelmezték. A beteg személyét biológiai, szociális és pszichés egységként kezelő holisztikus megközelítésnek is eleget téve, a posztulátumokat a kórokozó mellett az esetben érintett gazdaszervezet egyedi tulajdonságainak figyelembevételével tovább szélesítették. A dolgozat a fenti kérdéseket példákkal illusztrálva tárgyalja, majd kitér a gyakorlati hasznosítás lehetőségeire. Orv Hetil. 2021; 162(50): 1991–1999. Summary. Efforts to explore the casual background of infectious diseases have been ambitioned for a long time. Terms and requirements (postulates) have been created to describe in which case a microorganism can be regarded as a causative agent of a given infectious disease. Demonstration of a representative of a pathogenic taxonomic category in the patient, however, does not prove its causative role in itself. It should also be verified if the microbe possesses the so-called virulence factors enabling it to trigger the given disease. At the time when Robert Koch formulated his postulates, only phenotypic characters were at his disposal. Later, in possession of a substantial genetic knowledge, the postulates have been adapted to molecular level. For having a holistic approach, the postulates have been extended also to the host’s individual biological, social and psychological attributes. This paper discusses the above issues with examples for illustration, and outlines their practical applicabilities. Orv Hetil. 2021; 162(50): 1991–1999.

Screening and Functional Analysis of TEK Mutations in Chinese Children With Primary Congenital Glaucoma

Purposes: Recent studies have suggested that loss-of-function mutations of the tunica intima endothelial receptor tyrosine kinase (TEK) are responsible for approximately 5% of primary congenital glaucoma (PCG) cases in diverse populations. However, the causative role of TEK mutations has not been studied in Chinese PCG patients. Here, we report the mutation spectrum of TEK after screening a large cohort of PCG patients of Chinese Han origin and analyze the identified variants in functional assays.Methods: TEK-targeted next-generation sequencing (NGS) was performed in 200 PCG patients. Candidate variants were prioritized by mutation type and allele frequency in public datasets. Plasmids containing wild type and identified variants of TEK were constructed and used to assess protein expression, solubility, receptor auto-phosphorylation, and response to ligand stimulation in cell-based assays.Results: Ten missense and one nonsense heterozygous variants were detected by NGS in 11 families. The clinical features of TEK variants carriers were comparable to that of TEK-mutated patients identified in other populations and CYP1B1-mutated individuals from in-house database. Functional analysis confirmed four variants involving evolutionarily conserved residues to be loss-of-function, while one variant (p.R1003H) located in tyrosine kinase domain seemed to be an activating mutation. However, our results did not support the pathogenicity of the other five variants (p.H52R, p.M131I, p.M228V, p.H494Y, and p.L888P).Conclusion: We provide evidence for TEK variants to be causative in Chinese PCG patients for the first time. Attention needs to be paid to TEK mutations in future genetic testing.

Dopamine and fear memory formation in the human amygdala

Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.