Splicing QTL analysis focusing on coding sequences reveals pathogenicity of disease susceptibility loci.

Splicing QTL (sQTL) are one of the major causal mechanisms in GWAS loci, but their role in disease pathogenesis is poorly understood. One reason is the huge complexity of alternative splicing events producing many unknown isoforms. Here, we proposed two novel approaches, namely integration and selection, for this complexity by focusing on protein-structure of isoforms. First, we integrated isoforms with the same coding sequence (CDS) and identified 369-601 integrated-isoform ratio QTLs (i2-rQTLs), which altered protein-structure, in six immune subsets. Second, we selected CDS incomplete isoforms annotated in GENCODE and identified 175-337 isoform-ratio QTL (i-rQTL). By comprehensive long-read capture RNA-seq among these incomplete isoforms, we revealed 29 full-length isoforms with novel CDSs associated with GWAS traits. Furthermore, we have shown that disease-causal sQTL genes can be identified by evaluating their trans-eQTL effects. Our approaches highlight the understudied role of protein-altering sQTLs and are broadly applicable to other tissues and diseases.

IMPROVING THE EFFECTIVENESS OF CONSERVATIVE TREATMENT OF ERECTILE DYSFUNCTION IN PATIENTS WITH PEYRONIE'S DISEASE USING THE "BTL 6000" SHOCK WAVE THERAPY APPARATUS AND THE "TIVORTIN" DRUG

Исследовалось эффективность комплексной терапии эректильной дисфункции у пациентов с болезнью Пейрони, с применением препарата "Тивортин", который является субстратом для NO-синтазы - фермента, который катализирует синтез оксида азота в эндотелиоцитах, тем самым вызывая стабилизацию скорости кровотока в артериях полового члена, а также способствует восстановлению морфологической структуры, измененной белочной оболочки; и аппарата ударно-волновой терапий "БТЛ 6000", предназначенный для дезинтеграции бляшек в стадии кальцификации, которая купирует болевые ощущения в 91% случаев и уменьшает деформацию полового члена в 31% случаев, путем ударно-волновой терапии, и улучшения микроциркуляции в кавернозных телах полового члена, тем самым повышает эффективность лечения эректильной дисфункции у больных с болезнью Пейрони. The effectiveness of complex therapy of erectile dysfunction in patients with Peyronie's disease was studied with the use of the drug "Tivortin", which is a substrate for NO-synthase, an enzyme that catalyzes the synthesis of nitric oxide in endotheliocytes, thereby causing stabilization of the blood flow rate in the arteries of the penis, and also contributes to the restoration of the morphological structure, the altered protein envelope; and the shock wave therapy apparatus "BTL 6000", designed for the disintegration of plaques in the calcification stage, which relieves pain in 91% of cases and reduces the deformation of the penis in 31% of cases, by shock wave therapy, and improves microcirculation in the cavernous bodies of the penis, thereby increasing the effectiveness of treatment of erectile dysfunction in patients with Peyronie's disease.

Altered protein secretion in Batten disease

ABSTRACT The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.

A prion accelerates proliferation at the expense of lifespan

In fluctuating environments, switching between different growth strategies, such as those affecting cell size and proliferation, can be advantageous to an organism. Trade-offs arise, however. Mechanisms that aberrantly increase cell size or proliferation—such as mutations or chemicals that interfere with growth regulatory pathways—can also shorten lifespan. Here we report a natural example of how the interplay between growth and lifespan can be epigenetically controlled. We find that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better in growth), allows cells to heritably yet reversibly alter their translational program, leading to the differential synthesis of dozens of proteins, including many that regulate proliferation and aging. Our data reveal a new role for prion-based control of an RNA-modifying enzyme in driving heritable epigenetic states that transform cell growth and survival.

Use of proteomics to identify mechanisms of hepatocellular carcinoma with the CYP2D6*10 polymorphism and identification of ANGPTL6 as a new diagnostic and prognostic biomarker

Background Although an association between the cytochrome P4502D6 (CYP2D6) *10 (100C>T) polymorphism and hepatocellular carcinoma (HCC) is known, the mechanism remains unclear. Here we aimed to explore mechanisms of CYP2D6*10 (100C>T) polymorphism conferring to HCC, and screen markers for HCC. Methods Label-free global proteome profiling with 34 normal livers and peritumor tissue from 61 HCC patients was performed, and angiopoietin-like protein-6 (ANGPTL6) was evaluated in 2 liver samples validation cohorts and 2 blood specimens validation cohorts. Results We found a significantly decreased frequency of TT in HCC patients which reduced HCC susceptibility by 69.2% and was accompanied by lowered enzymatic activity for CYP2D6. Proteomic analysis revealed 1342 differentially expressed proteins (DEPs) that were associated with HCC and 88 DEPs were identified as 100 TT-related proteins, likely underlying the susceptibility to HCC. Twenty-two upregulated DEPs and 66 downregulated DEPs were mainly related to lipid metabolism and the extracellular matrix, respectively. High ANGPTL6 was associated with a higher risk to HCC and worse prognosis. ANGPTL6 was both an independent risk factor and an independent prognostic factor for HCC and exhibited strong potential for predicting HCC occurrence, with comparable AUC values and higher sensitivity compared with alpha-fetoprotein. Conclusions The TT genotype-associated decreased risk of HCC appears to be related to lowered CYP2D6 activity and altered protein expression in the tumor microenvironment, and ANGPTL6 is a promising new diagnostic and prognostic biomarker for HCC. Our findings reveal new mechanistic insights for polymorphisms related to HCC risk and provide avenues for screening for HCC.