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Identification of rapid, inexpensive, and reliable prognostic factors can improve survival estimation and guide healthcare in patients with acute heart failure (AHF). In this study, we aimed to determine the prognostic value of the platelet-to-lymphocyte ratio (PLR) in patients with AHF. A total of 443 patients from two hospitals met the inclusion criteria from January 2010 to December 2017. Univariate and multivariate Cox analyses were performed to determine the association of PLR with survival. All-cause mortality was analysed using the Kaplan-Meier method. The 6-month survival rate for patients according to PLR quartiles (<110.63, 110.63–139.23, 139.23–177.17, and >177.17) were 90.09%, 76.79%, 50.07%, and 37.27%, respectively (p < 0.001). Univariate analysis identified high PLR (>110.63), old age (≥73 years), smoking habit, low estimated glomerular filtration rate (<57), and high platelet count (≥198 × 10 9 /l) as poor prognostic factors for survival. In the multivariate analysis, after adjusting for confounding factors, the third (hazard ratio [HR] = 3.118, 95% confidence interval [CI] = 1.668–5.386, p < 0.001) and fourth (HR = 2.437, 95% CI = 1.302–3.653, p < 0.001) quartiles of PLR were identified as independent prognostic factors in patients with AHF. A higher PLR was associated with poor clinical outcomes in patients with AHF and might be a novel marker in AHF management.

Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2 Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.

Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N 6 -methyladenosine (m 6 A) demethylase that demethylates RNAs involved in energy homeostasis, though its influence on DR is not well studied. Herein, we detected elevated FTO expression in vitreous fibrovascular membranes of patients with proliferative DR. FTO promoted cell cycle progression and tip cell formation of endothelial cells (ECs) to facilitate angiogenesis in vitro, in mice, and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC–microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m 6 A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate-mediated histone lactylation. FB23-2, an inhibitor to FTO’s m 6 A demethylase activity, suppressed angiogenic phenotypes in vitro. To allow for systemic administration, we developed a nanoplatform encapsulating FB23-2 and confirmed its targeting and therapeutic efficiency in mice. Collectively, our study demonstrates that FTO is important for EC function and retinal homeostasis in DR, and warrants further investigation as a therapeutic target for DR patients. Synopsis The fat mass and obesity-associated (FTO) protein, an N 6 -methyladenosine (m 6 A) demethylase, influences endothelial cell (EC) function and retinal homeostasis in diabetic retinopathy (DR), thus providing a promising nanotherapeutic approach for DR. FTO expression is elevated in diabetic mice retinas and vitreous fibrovascular membranes of patients with proliferative DR. FTO triggers diabetes-induced microvascular dysfunction by facilitating neovascularization and regulating EC–pericyte/microglia crosstalk. FTO regulates CDK2 mRNA stability with the YTHDF2 reader in an m 6 A-dependent manner. Lactic acid regulates FTO expression via histone lactylation. FB23-2 suppresses demethylation activity of FTO to inhibit diabetes-induced EC phenotypes, showing therapeutic potential in DR in mice. The fat mass and obesity-associated (FTO) protein, an N 6 -methyladenosine (m 6 A) demethylase, influences endothelial cell (EC) function and retinal homeostasis in diabetic retinopathy (DR), thus providing a promising nanotherapeutic approach for DR.

Background/Aims: Interleukin (IL)-17A, a proinflammatory cytokine, has been implicated in several autoimmune diseases. However, it is unclear whether IL-17A is involved in diabetic retinopathy (DR), one of the most serious complications of autoimmune diabetes. This study aimed to demonstrate that IL-17A exacerbates DR by affecting retinal Müller cell function. Methods: High glucose (HG)-treated rat Müller cell line (rMC-1) was exposed to IL-17A, anti-IL-17A-neutralizing monoclonal antibody (mAb) or/and anti-IL-17 receptor (R)A-neutralizing mAb for 24 h. For in vivo study, DR was induced by intraperitoneal injections of streptozotocin (STZ). DR model mice were treated with anti-IL-17A mAb or anti-IL-17RA mAb in the vitreous cavity. Mice that were prepared for retinal angiography were sacrificed two weeks after intravitreal injection, while the rest were sacrificed two days after intravitreal injection. Results: IL-17A production and IL-17RA expression were increased in both HG-treated rMC-1 and DR retina. HG induced rMC-1 activation and dysfunction, as determined by the increased GFAP, VEGF and glutamate levels as well as the downregulated GS and EAAT1 expression. IL-17A exacerbated the HG-induced rMC-1 functional disorders, whereas either anti-IL-17A mAb or anti-IL-17RA mAb alleviated the HG-induced rMC-1 disorders. Intravitreal injections with anti-IL-17A mAb or anti-IL-17RA mAb in DR model mice reduced Müller cell dysfunction, vascular leukostasis, vascular leakage, tight junction protein downregulation and ganglion cell apoptosis in the retina. Conclusions: IL-17A aggravates DR-like pathology at least partly by impairing retinal Müller cell function. Blocking IL-17A is a potential therapeutic strategy for DR.

This study investigates the role of RASD2 (Ras Homolog Enriched In Striatum) in thyroid carcinoma progression and its modulation by microRNA‐485‐5p. Differential RASD2 expression patterns were initially identified through bioinformatic analysis of public databases. Immunohistochemical staining and quantitative reverse transcription PCR (qRT‐PCR) validated these findings in clinical specimens and cell lines. Functional characterization of RASD2 was performed through loss‐of‐function studies, examining cellular proliferation, invasion, and glycolytic parameters. The prognostic significance of RASD2 was evaluated through Kaplan–Meier analysis. Using integrated bioinformatic approaches, we identified miRNA‐485‐5p as a potential RASD2 regulator and confirmed this interaction through molecular studies. The therapeutic potential of targeting RASD2 was assessed using xenograft and pulmonary metastasis models. RASD2 showed significant upregulation in thyroid cancer tissues, with elevated expression correlating with adverse clinicopathological parameters including lymphatic metastasis, extrathyroidal invasion, and advanced TNM stage. Genetic silencing of RASD2 in IHH4 and TPC‐1 cells substantially impaired their malignant phenotypes, manifesting as decreased proliferation, invasion, and glycolytic activity. Mechanistically, we identified miRNA‐485‐5p as a crucial negative regulator of RASD2, whose overexpression recapitulated the tumor‐suppressive effects of RASD2 knockdown. In vivo studies further validated the therapeutic potential of RASD2 inhibition, demonstrating reduced tumor growth and metastatic burden. Our findings establish the miRNA‐485‐5p/RASD2 axis as a critical regulatory pathway in thyroid cancer progression, offering new insights into disease pathogenesis and potential therapeutic interventions.

The bridge arms and DC voltage of China’s Four-Terminal Flexible DC Transmission Project exhibit persistent high-frequency harmonics over the medium to long term, causing issues such as overheating losses and electromagnetic interference within the converter stations. To address this issue, this paper first introduces the structure of the Four-Terminal Flexible DC Grid and the high-frequency harmonic characteristics on the DC side, clarifying the impact of control cycles on the harmonic distribution at converter stations. Through analysis of the modulating wave, it is demonstrated that the sideband harmonics originate from the coupling effect between the control cycle and the modulating wave, inducing high-frequency sideband harmonics on the bridge arm. A discrete switching equation for bridge arm voltage was established. Based on double Fourier decomposition, a mathematical model for sideband harmonics was derived, and the flow direction of these harmonics was analyzed. A four-terminal flexible DC system was constructed using PSCAD electromagnetic transient simulation, yielding harmonic distributions in the arm and DC-side sidebands. This validated the accuracy of theoretical analysis and ultimately identified the factors influencing sideband harmonics.

Diabetic retinopathy (DR), one of the most serious complications of diabetes, has been associated with inflammatory processes. We have recently reported that interleukin (IL)-17A, a proinflammatory cytokine, is increased in the plasma of diabetic patients. Further investigation is required to clarify the role of IL-17A in DR. Ins2 Akita (Akita) diabetic mice and high-glucose (HG)-treated primary Müller cells were used to mimic DR-like pathology. Diabetes induced retinal expression of IL-17A and IL-17 receptor A (IL-17RA) in Müller cells in contrast to ganglion cells. Further evidence demonstrated that retinal Müller cells cultured in vitro increased IL-17A and IL-17RA expression as well as IL-17A secretion in the HG condition. In both the HG-treated Müller cells and Akita mouse retina, the Act1/TRAF6/IKK/NF-κB signaling pathway was activated. IL-17A further enhanced inflammatory signaling activation, whereas Act1 knockdown or IKK inhibition blocked the downstream signaling activation by IL-17A. HG- and diabetes-induced Müller cell activation and dysfunction, as determined by increased glial fibrillary acidic protein, vascular endothelial growth factor and glutamate levels and decreased glutamine synthetase and excitatory amino acid transporter-1 expression, were exacerbated by IL-17A; however, they were alleviated by Act1 knockdown or IKK inhibition. In addition, IL-17A intravitreal injection aggravated diabetes-induced retinal vascular leukostasis, vascular leakage and ganglion cell apoptosis, whereas Act1 silencing or anti-IL-17A monoclonal antibody ameliorated the retinal vascular damage and neuronal cell apoptosis. These findings establish that IL-17A exacerbates DR-like pathology by the promotion of Müller cell functional impairment via Act1 signaling. Diabetes: Investigating inflammatory mechanisms behind diabetic blindness The increase in a cytokine at high glucose concentrations impairs cellular activity in the retina, increasing the chances of blindness. A serious complication of diabetes is diabetic retinopathy (DR), a disease of the retina that results in impairment or loss of vision, but the inflammatory mechanisms behind DR remain unclear. Ao-Wang Qiu, Zheng Bian, Ping-An Mao and Qing-Huai Liu at Nanjing Medical University, China, investigated the role of a protein called interleukin-17A (IL-17A), which is implicated in autoimmune diseases. Using a mouse strain with DR, the team found that IL-17A was increased in certain cells responsible for maintaining a healthy retina. IL-17A increase caused retinal inflammation, impaired cell functioning and killed neuronal cells, accelerating DR progression. Disrupting the signalling pathway involved in IL-17A action alleviated symptoms in mice.

Asian warty treefrogs, genus Theloderma, are morphologically variable arboreal frogs endemic to Southeast Asia and Southern China. However, integrated systematic studies are lacking, and knowledge of the genus in terms of diversity, origin, and historical diversification remains limited. To address these knowledge gaps, we used three mitochondrial and five nuclear gene fragments to reconstruct the Theloderma phylogeny, estimate divergence times, and examine the biogeography of the genus. Phylogenetic and species delimitation analyses suggest that the genus Theloderma comprises three major clades corresponding to two subgenera and seven species groups, and mPTP identified at least 12 putative cryptic species, suggesting that species diversity has been underestimated. Biogeographic analyses indicated that most recent common ancestor of Theloderma originated in the Indochina Peninsula during the Middle Oligocene (ca. 27.77 Ma) and the splitting of Clade A to C occurred in the Late Oligocene (ca. 23.55–25.57 Ma). Current biogeographic patterns result from two distinct processes: in situ diversification in the Indochina Peninsula and dispersal in multiple areas, namely southward dispersal to the Malay Peninsula and Borneo, northeastward dispersal to Southern China, northward dispersal to the Himalayas, and dispersal from Southern China to the Indochina Peninsula. Ancestral character reconstruction suggests that the ancestor of Theloderma may have possessed a small body size, rough dorsal skin, and absence of vomerine teeth and hand webbing, and that these four characters have undergone multiple evolutions. Principal component analysis based on eight bioclimatic variables did not clearly distinguish the three major clades of Theloderma, suggesting that species in these clades may occupy similar climatic ecological niches. Our research highlights the importance of orogeny and paleoclimatic changes, in shaping amphibian biodiversity in mountain ecosystems. The most comprehensive nucleotide data has been applied to the genus Theloderma. Theloderma originated in the middle Oligocene Indochina Peninsula and later dispersed outward into the Malay Peninsula, Borneo, Himalayas, and Southern China. Elevational uplift drove early clade diversification, and innovations in key characteristics contributed to the outward spread of Theloderma to survive the dramatically changed early environment.

Background In sorghum ( Sorghum bicolor ), one paramount breeding objective is to increase grain quality. The nutritional quality and end use value of sorghum grains are primarily influenced by the proportions of tannins, starch and proteins, but the genetic basis of these grain quality traits remains largely unknown. This study aimed to dissect the natural variation of sorghum grain quality traits and identify the underpinning genetic loci by genome-wide association study. Results Levels of starch, tannins and 17 amino acids were quantified in 196 diverse sorghum inbred lines, and 44 traits based on known metabolic pathways and biochemical interactions amongst the 17 amino acids calculated. A Genome-wide association study (GWAS) with 3,512,517 SNPs from re-sequencing data identified 14, 15 and 711 significant SNPs which represented 14, 14, 492 genetic loci associated with levels of tannins, starch and amino acids in sorghum grains, respectively. Amongst these significant SNPs, two SNPs were associated with tannin content on chromosome 4 and colocalized with three previously identified loci for Tannin1 , and orthologs of Zm1 and TT16 genes. One SNP associated with starch content colocalized with sucrose phosphate synthase gene. Furthermore, homologues of opaque1 and opaque2 genes associated with amino acid content were identified. Using the KEGG pathway database, six and three candidate genes of tannins and starch were mapped into 12 and 3 metabolism pathways, respectively. Thirty-four candidate genes were mapped into 16 biosynthetic and catabolic pathways of amino acids. We finally reconstructed the biosynthetic pathways for aspartate and branched-chain amino acids based on 15 candidate genes identified in this study. Conclusion Promising candidate genes associated with grain quality traits have been identified in the present study. Some of them colocalized with previously identified genetic regions, but novel candidate genes involved in various metabolic pathways which influence grain quality traits have been dissected. Our study acts as an entry point for further validation studies to elucidate the complex mechanisms controlling grain quality traits such as tannins, starch and amino acids in sorghum.

Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but the underlying mechanisms that regulate vascular remodeling remain poorly understood. Here, we confirmed the specific expression of semaphorin 3G (Sema3G) in retinal endothelial cells (ECs), which was required for vascular remodeling and the amelioration of ischemic retinopathy. We found that Sema3G was elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and in the neovascularization regression phase of oxygen-induced retinopathy (OIR). Endothelial-specific Sema3G knockout mice exhibited decreased vessel density and excessive matrix deposition in the retinal vasculature. Moreover, loss of Sema3G aggravated pathological angiogenesis in mice with OIR. Mechanistically, we demonstrated that HIF-2α directly regulated Sema3G transcription in ECs under hypoxia. Sema3G coordinated the functional interaction between β-catenin and VE-cadherin by increasing β-catenin stability in the endothelium through the neuropilin-2 (Nrp2)/PlexinD1 receptor. Furthermore, Sema3G supplementation enhanced healthy vascular network formation and promoted diseased vasculature regression during blood vessel remodeling. Overall, we deciphered the endothelium-derived Sema3G-dependent events involved in modulating physiological vascular remodeling and regression of pathological blood vessels for reparative vascular regeneration. Our findings shed light on the protective effect of Sema3G in ischemic retinopathies.