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Selenium (Se) is an essential trace element that is necessary for various metabolic processes, including protection against oxidative stress, and proper cardiovascular function. The role of Se in cardiovascular health is generally agreed upon to be essential yet not much has been defined in terms of specific functions. Se deficiency was first associated with Keshan’s Disease, an endemic disease characterized by cardiomyopathy and heart failure. Since then, Se deficiency has been associated with multiple cardiovascular diseases, including myocardial infarction, heart failure, coronary heart disease, and atherosclerosis. Se, through its incorporation into selenoproteins, is vital to maintain optimal cardiovascular health, as selenoproteins are involved in numerous crucial processes, including oxidative stress, redox regulation, thyroid hormone metabolism, and calcium flux, and inadequate Se may disrupt these processes. The present review aims to highlight the importance of Se in cardiovascular health, provide updated information on specific selenoproteins that are prominent for proper cardiovascular function, including how these proteins interact with microRNAs, and discuss the possibility of Se as a potential complemental therapy for prevention or treatment of cardiovascular disease.

Length polymorphisms of polyglutamine (polyQs) in triplet-repeat-disease-causing genes have diversified during primate evolution despite them conferring a risk of human-specific diseases. To explain the evolutionary process of this diversification, there is a need to focus on mechanisms by which rapid evolutionary changes can occur, such as alternative splicing. Proteins that can bind polyQs are known to act as splicing factors and may provide clues about the rapid evolutionary process. PolyQs are also characterized by the formation of intrinsically disordered (ID) regions, so I hypothesized that polyQs are involved in the transportation of various molecules between the nucleus and cytoplasm to regulate mechanisms characteristic of humans such as neural development. To determine target molecules for empirical research to understand the evolutionary change, I explored protein–protein interactions (PPIs) involving the relevant proteins. This study identified pathways related to polyQ binding as hub proteins scattered across various regulatory systems, including regulation via PQBP1, VCP, or CREBBP. Nine ID hub proteins with both nuclear and cytoplasmic localization were found. Functional annotations suggested that ID proteins containing polyQs are involved in regulating transcription and ubiquitination by flexibly changing PPI formation. These findings explain the relationships among splicing complex, polyQ length variations, and modifications in neural development.

Background: Host immunity has critical roles in tumour surveillance. Tertiary lymphoid organs (TLOs) are induced in various inflamed tissues. The aim of this study was to investigate the clinicopathological and pathobiological characteristics of tumour microenvironment in pancreatic ductal carcinoma (PDC) with TLOs. Methods: We examined 534 PDCs to investigate the clinicopathological impact of TLOs and their association with tumour-infiltrating immune cells, the cytokine milieu, and tissue characteristics. Results: There were two different localisations of PDC-associated TLOs, intratumoral and peritumoral. A better outcome was observed in patients with intratumoral TLOs, and this was independent of other survival factors. The PDC tissues with intratumoral TLOs showed significantly higher infiltration of T and B cells and lower infiltration of immunosuppressive cells, as well as significantly higher expression of Th1- and Th17-related genes. Tertiary lymphoid organs developed with an association with arterioles, venules, and nerves. These structures were reduced in an association with cancer invasion in PDC tissues, except for those with intratumoral TLOs. The PDC tissues with intratumoral TLOs had capillaries consisting of mature endothelial cells covered by pericytes. Conclusions: Our results suggest that the presence of intratumoral TLOs represents a microenvironment that has an active immune reaction, and shows a relatively intact vascular network retained.

Background: The host immune reaction is represented by immune/inflammatory cell infiltrates. Here we systematically analysed tumour-infiltrating immune/inflammatory cells in pancreatic ductal carcinoma (PDC) and evaluated their clinicopathological impact. Methods: Using immunohistochemistry, we examined tumour-infiltrating CD68 + pan-macrophages, HLA-DR + CD68 + M1 macrophages (M1), CD163 + or CD204 + M2 macrophages (M2), CD66b + neutrophils (Neu), CD4 + T cells (CD4 + T), CD8 + T cells (CD8 + T), and FOXP3 + CD4 + regulatory T cells (Treg) in 212 cases of PDC, and conducted correlation and survival analyses using the Kaplan–Meier method and Cox proportional hazards model. Results: Higher levels of tumour-infiltrating pan-macrophages, M2, Neu, or the ratio of Tregs to CD4 + T (%Treg) were significantly associated with shorter survival, whereas higher levels of tumour-infiltrating CD4 + T, CD8 + T, or the ratio of M1 to pan-macrophages (%M1) were significantly associated with longer survival. Survival analysis of pairs of these variables revealed that some of the resulting patient groups had exclusively longer survival. We then connected the apparently related factors, and two significant variables emerged: tumour-infiltrating CD4 + T high /CD8 + T high /%Treg low and tumour-infiltrating %M1 high /M2 low . Multivariate survival analysis revealed that these variables were significantly correlated with longer survival and had a higher hazard ratio. Conclusion: Tumour-infiltrating CD4 + T high /CD8 + T high /%Treg low and %M1 high /M2 low are independent prognosticators useful for evaluating the immune microenvironment of PDC.

The Antarctic continental margin supplies the densest bottom water to the global abyss. From the late twentieth century, an acceleration in the long-term freshening of Antarctic Bottom Waters (AABW) has been detected in the Australian-Antarctic Basin. Our latest hydrographic observations reveal that, in the late 2010s, the freshening trend has reversed broadly over the continental slope. Near-bottom salinities in 2018–2019 were higher than during 2011–2015. Along 170° E, the salinity increase between 2011 and 2018 was greater than that observed in the west. The layer thickness of the densest AABW increased during the 2010s, suggesting that the Ross Sea Bottom Water intensification was a major source of the salinity increase. Freshwater content on the continental slope decreased at a rate of 58 ± 37 Gt/a in the near-bottom layer. The decadal change is very likely due to changes in Ross Sea shelf water attributable to a decrease in meltwater from West Antarctic ice shelves for the corresponding period.

We revisit the thermal leptogenesis scenario in the type-I seesaw framework featuring three heavy Majorana neutrinos with a hierarchical mass spectrum. We focus on low energy observables, specifically the lightest neutrino mass m ν lightest and the neutrinoless double-beta decay effective mass parameter m β β eff . In particular, we numerically calculate the minimum mass of the lightest heavy Majorana neutrino, M 1 min , required for successful leptogenesis as a function of m ν lightest and m β β eff , considering both normal and inverted light neutrino mass orderings. Flavour effects are taken into account within the flavoured density matrix formalism. We also examine the interplay between fine-tuned cancellations in the seesaw relation and M 1 min . Recent and forthcoming searches for neutrinoless double-beta decay, along with cosmological probes of the sum of neutrino masses, motivate this analysis, as they can provide key insights into the minimal scale of thermal leptogenesis and its broader implications.

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis.

The main histological features of eosinophilic granulomatosis with polyangiitis (EGPA) are tissue eosinophilia (TE), small-vessel vasculitis (SVV), and extravascular granuloma. However, the relationship between these pathological findings and treatment response is not known. To explore the associations between pathological features of TE or SVV and the clinical parameters and treatment response in EGPA patients. This is a single-center, retrospective, cohort study. Subjects who met the following were included for analysis: 1) those who fulfilled the 1990 ACR criteria and/or the 2012 revised CHCC criteria and/or the ACR/EULAR 2022 criteria, 2) those who were treated for at least 2 years in our hospital since 1/1/2010, 3) those who had undergone tissue biopsy at any site during their initial diagnostic workup. All available slides of biopsies were reviewed by a blinded pathologist expertise with vasculitis. Based on the EULAR recommendations, remission was defined as the absence of vasculitis activity (BVAS=0) with daily doses of prednisolone <=7.5mg after 2 years of treatment and refractory disease was defined as failure to attain remission. Among 37 patients diagnosed with EGPA, 30 patients were included. Total 84 biopsies (muscle 36, skin 15, nose 9, colon 8, stomach/duodenum 4, nerve 4, kidney 3, lung 2, heart 1, small intestine 1, and temporal artery 1) were reviewed. SVV, TE, and extravascular granuloma were found in 17 (56.5 %) patients, 16 (53.3 %) patients and 3 (10 %) patients, respectively. (Fig.1) SVV was associated with refractory disease (47.1 % vs 0 %, p=0.04). TE was associated with skin lesions (56.2 % vs 14.3%, p = 0.021) and inversely associated with severe peripheral neuropathy (43.8 % vs 85.8 %, p = 0.021). (Table.1) ANCA was present in 11 (36.7 %) patients. ANCA was not associated with refractory diseases (ANCA positive 36.3% vs ANCA negative 21.1%, p=0.31) In EGPA, pathological evidence of SVV may be better predict poor treatment response than ANCA positivity. NIL. NIL. None Declared. [Display omitted] Table.1Characteristics of EGPA patients with or without pathological findings.CharacteristicsSmall-vessel vasculitis (SVV)Tissue eosinophilia (TE)Pts with SVV(n=17)Pts without SVV(n=13)P valuePts with TE(n=16)Pts without TE(n=14)P valueFemale sex, n (%)9 (52.9)9 (69.2)0.4658 (50.0)10 (71.4)0.206Age, years, median (IQR)62 (55-71)57 (54-63)0.17360 (55-71)58 (50-66)0.270Anti-MPO ANCA, n (%)7 (41.2)3 (23)0.2596 (37.5)4 (28.6)0.450Anti-PR3 ANCA, n (%)1 (5.9)0 (0)0.5671 (6.3)0 (0)0.533BVAS, median (IQR)22 (13-26)18 (15-22)0.47622 (13-26)18 (15-22)0.538Clinical features, n (%)Myalgia13 (76.5)10 (76.9)0.66011 (68.8)12 (85.7)0.256Cutaneous involvement8 (47.1)3 (23.1)0.1679 (56.3)2 (14.3)0.021ENT involvement15 (88.2)8 (61.5)0.10113 (81.3)10 (71.4)0.419Cardiac involvement9 (52.9)6 (46.2)0.5009 (56.3)6 (42.9)0.358Pulmonary infiltrates10 (58.8)8 (61.5)0.5909 (56.3)9 (64.3)0.471Glomerulonephritis3 (17.6)0 (0)0.1673 (18.8)0 (0)0.167Gastrointestinal involvement3 (17.6)3 (23.1)0.5312 (12.5)4 (28.6)0.261Severe peripheral neuropathy (MMT≦3)10 (58.8)9 (69.2)0.4217 (43.8)12 (85.8)0.021Treatment response, n (%)Refractory disease8 (47.1)0 (0)0.0405 (31.2)3 (21.4)0.426

Background/Objectives: Recent progress in evolutionary genomics on human (Homo sapiens) populations has revealed complex demographic events and genomic changes. These include population expansion with complicated migration, substantial population structure, and ancient introgression from other hominins, as well as human characteristics selections. Nevertheless, the genomic regions in which such evolutionary events took place have remained unclear. Methods: Here, we focused on eight loci containing the haplotypes that were previously presented as atypical for the mutation pattern in sequence and/or geographic distribution pattern with the model of recent African origin, which constitute two major clusters: African only, and global. This was the consensus model before information regarding introgression from Neanderthal (Homo neanderthalensis) was available. We compared diversity in identical datasets of the modern human population genome, with the 1000 Genomes project among them. Results/Conclusions: This study identified representative genomic regions that show traces of various demographic events and genomic changes that modern humans have undergone by categorizing the relationships in sequence similarity and in worldwide geographic distribution among haplotypes.