Independent risk factors of left ventricular hypertrophy in non-diabetic individuals in Sierra Leone - a cross-sectional study.

BACKGROUND: Left ventricular hypertrophy (LVH) is a critical factor in heart failure and cardiovascular event-related mortality. While the prevalence of LVH in diabetic patients is well-documented, its occurrence and risk factors in non-diabetic populations remain largely unexplored. This study addresses this issue by investigating the independent risk factors of LVH in non-diabetic individuals. METHODS: This cross-sectional study, conducted meticulously, utilized data from a robust and comprehensive source, DATADRYAD, in the Sierra Leone database, collected between October 2019 and October 2021, including LVH and various variables. All variables were described and screened using univariate analysis, Spearman correlation, and principal component analysis (PCA). The lipid profile, including total cholesterols (TC), triglycerides (TG), high-density lipoprotein (HDL-C), non-high-density lipoprotein (Non-HDL-C), and low-density lipoprotein cholesterol (LDL-C), TC/HDL-C ratio, TG/HDL-C ratio, Non-HDL-C /HDL-C ratio and LDL-C/HDL-C ratio, which quartiles were treated as categorical variables, with the lowest quartile serving as the reference category. Three adjusted models were constructed to mitigate the influence of other variables. To ensure the robustness of the model, receiver operating characteristic (ROC) curves were used to calculate the cutoff values by analyzing the ROC curves. A sensitivity analysis was performed to validate the findings further. RESULTS: The dataset encompasses information from 2092 individuals. After adjusting for potential factors that could influence the results, we found that TC (OR = 2.773, 95%CI: 1.805-4.26), Non-HDL-C (OR = 2.74, 95%CI: 1.7723-4.236), TC/HDL-C ratio (OR = 2.237, 95%CI: 1.445-3.463), Non-HDL-C/HDL-C ratio (OR = 2.357, 95%CI: 1.548-3.588), TG/HDL-C ratio (OR = 1.513, 95%CI: 1.02-2.245) acts as independent risk factors of LVH. ROC curve analysis revealed the predictive ability of blood lipids for LVH, with Non-HDL-C exhibiting area under the curve (AUC = 0.6109), followed by TC (AUC = 0.6084). CONCLUSIONS: TC, non-HDL-C, TC/HDL-C ratio, Non-HDL-C/HDL-C ratio, and TG/HDL-C ratio were independent risk factors of LVH in non-diabetic people. Non-HDL-C and TC were found to be essential indicators for predicting the prevalence of LVH.

Deep serum lipidomics identifies evaluative and predictive biomarkers for individualized glycemic responses following low-energy diet-induced weight loss: a PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World (PREVIEW) substudy.

BACKGROUND: Weight loss through lifestyle interventions, notably low-energy diets, offers glycemic benefits in populations with overweight-associated prediabetes. However, >50% of these individuals fail to achieve normoglycemia after weight loss. Circulating lipids hold potential for evaluating dietary impacts and predicting diabetes risk. OBJECTIVES: This study sought to identify serum lipids that could serve as evaluative or predictive biomarkers for individual glycemic changes following diet-induced weight loss. METHODS: We studied 104 participants with overweight-associated prediabetes, who lost ≥8% weight via a low-energy diet over 8 wk. High-coverage lipidomics was conducted in serum samples before and after the dietary intervention. The lipidomic recalibration was assessed using differential lipid abundance comparisons and partial least squares discriminant analyses. Associations between lipid changes and clinical characteristics were determined by Spearman correlation and Bootstrap Forest of ensemble machine learning model. Baseline lipids, predictive of glycemic parameters changes postweight loss, were assessed using Bootstrap Forest analyses. RESULTS: We quantified 439 serum lipid species and 9 related organic acids. Dietary intervention significantly reduced diacylglycerols, ceramides, lysophospholipids, and ether-linked phosphatidylethanolamine. In contrast, acylcarnitines, short-chain fatty acids, organic acids, and ether-linked phosphatidylcholine increased significantly. Changes in certain lipid species (e.g., saturated and monounsaturated fatty acid-containing glycerolipids, sphingadienine-based very long-chain sphingolipids, and organic acids) were closely associated with clinical glycemic parameters. Six baseline bioactive sphingolipids primarily predicted changes in fasting plasma glucose. In addition, a number of baseline lipid species, mainly diacylglycerols and triglycerides, were predictive of clinical changes in hemoglobin A1c, insulin and homeostasis model assessment of insulin resistance. CONCLUSIONS: Newly discovered serum lipidomic alterations and the associated changes in lipid-clinical variables suggest broad metabolic reprogramming related to diet-mediated glycemic control. Novel lipid predictors of glycemic outcomes could facilitate early stratification of individuals with prediabetes who are metabolically less responsive to weight loss, enabling more tailored intervention strategies beyond 1-size-fits-all lifestyle modification advice. The PREVIEW lifestyle intervention study was registered at clinicaltrials.gov as NCT01777893 (https://clinicaltrials.gov/study/NCT01777893).

Mendelian randomization of circulating proteome identifies IFN-γ as a druggable target in aplastic anemia.

BACKGROUND: Aplastic anemia (AA) is a kind of bone marrow failure (BMF) characterized by pancytopenia with hypoplasia/aplasia of bone marrow. Immunosuppressive therapy and bone marrow transplantation are effective methods to treat severe aplastic anemia. However, the efficacy is limited by complications and the availability of suitable donors. This study aimed to determine whether any circulating druggable protein levels may have causal effects on AA and provide potential novel drug targets for AA. METHODS: Genetic variants strongly associated with circulating druggable protein levels to perform Mendelian randomization (MR) analyses were used. The effect of these druggable protein levels on AA risk was measured using the summary statistics from a large-scale proteomic genome-wide association study (GWAS) and FinnGen database ( https://www.finngen.fi/en/access_results ). Multivariable MR analyses were performed to statistically adjust for potential confounders, including platelet counts, reticulocyte counts, neutrophil counts, and proportions of hematopoietic stem cells. RESULTS: The data showed that higher level of circulating IFN-γ levels was causally associated with AA susceptibility. The causal effects of circulating IFN-γ levels on the AA were broadly consistent, when adjusted for platelet counts, reticulocyte counts, neutrophil counts and proportions of hematopoietic stem cells. CONCLUSIONS: High levels of circulating IFN-γ levels might increase the risk of AA and might provide a potential novel target for AA.

ReTimeML: a retention time predictor that supports the LC-MS/MS analysis of sphingolipids.

The analysis of ceramide (Cer) and sphingomyelin (SM) lipid species using liquid chromatography-tandem mass spectrometry (LC-MS/MS) continues to present challenges as their precursor mass and fragmentation can correspond to multiple molecular arrangements. To address this constraint, we developed ReTimeML, a freeware that automates the expected retention times (RTs) for Cer and SM lipid profiles from complex chromatograms. ReTimeML works on the principle that LC-MS/MS experiments have pre-determined RTs from internal standards, calibrators or quality controls used throughout the analysis. Employed as reference RTs, ReTimeML subsequently extrapolates the RTs of unknowns using its machine-learned regression library of mass-to-charge (m/z) versus RT profiles, which does not require model retraining for adaptability on different LC-MS/MS pipelines. We validated ReTimeML RT estimations for various Cer and SM structures across different biologicals, tissues and LC-MS/MS setups, exhibiting a mean variance between 0.23 and 2.43% compared to user annotations. ReTimeML also aided the disambiguation of SM identities from isobar distributions in paired serum-cerebrospinal fluid from healthy volunteers, allowing us to identify a series of non-canonical SMs associated between the two biofluids comprised of a polyunsaturated structure that confers increased stability against catabolic clearance.

Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation. METHODS: Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. RESULTS: SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner. CONCLUSIONS: This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.

Demographic history and divergence of sibling grouse species inferred from whole genome sequencing reveal past effects of climate change.

BACKGROUND: The boreal forest is one of the largest biomes on earth, supporting thousands of species. The global climate fluctuations in the Quaternary, especially the ice ages, had a significant influence on the distribution of boreal forest, as well as the divergence and evolution of species inhabiting this biome. To understand the possible effects of on-going and future climate change it would be useful to reconstruct past population size changes and relate such to climatic events in the past. We sequenced the genomes of 32 individuals from two forest inhabiting bird species, Hazel Grouse (Tetrastes bonasia) and Chinese Grouse (T. sewerzowi) and three representatives of two outgroup species from Europe and China. RESULTS: We estimated the divergence time of Chinese Grouse and Hazel Grouse to 1.76 (0.46-3.37) MYA. The demographic history of different populations in these two sibling species was reconstructed, and showed that peaks and bottlenecks of effective population size occurred at different times for the two species. The northern Qilian population of Chinese Grouse became separated from the rest of the species residing in the south approximately 250,000 years ago and have since then showed consistently lower effective population size than the southern population. The Chinese Hazel Grouse population had a higher effective population size at the peak of the Last Glacial Period (approx. 300,000 years ago) than the European population. Both species have decreased recently and now have low effective population sizes. CONCLUSIONS: Combined with the uplift history and reconstructed climate change during the Quaternary, our results support that cold-adapted grouse species diverged in response to changes in the distribution of palaeo-boreal forest and the formation of the Loess Plateau. The combined effects of climate change and an increased human pressure impose major threats to the survival and conservation of both species.

Singular PT-symmetry broken point with infinite transmittance and reflectance-a classical analytical demonstration.

To demonstrate the existence of singular parity-time symmetry (PT-symmetry) broken point in optics system, we designed a one-dimensional PT symmetric structure including N unit-cell with loss and gain materials in half. We performed an analytical deduction to obtain the transmittance and reflectance of the structure basing on Maxwell's equations. We found that with the exact structure unit-cell number and the imaginary part of refraction index, the transmittance and reflectance are both close to infinite. Such strict condition is called the singular point in this study. At the singular point position, both the transmission and reflection are direction-independent. Away from the singular point, the transmittance and reflectance become finite. In light of classical wave optics, the single unit and total structure both become the resonance units. The infinite transmittance and reflectance result from the resonance matching of single unit and total structure. In light of quantum theory, the singular point corresponds to the single eigenvalue of electromagnetic scattering matrix. The infinite transmittance and reflectance mean a huge energy transformation from pumping source to light waves. Numerical calculation and software simulation both demonstrate the result.

Genomic analysis of demographic history and ecological niche modeling in the endangered Chinese Grouse Tetrastes sewerzowi.

BACKGROUND: The Quaternary had worldwide consequences in forming the contemporary diversity of many populations, species and communities, which is characterized by marked climatic oscillations between glacial and interglacial periods. The origin and evolution of biodiversity in mountainous areas are highly dependent on historical orogenesis and associated climatic changes. The Chinese grouse Tetrastes sewerzowi is a forest-dwelling species endemic to the mountains to the east of the Qinghai-Tibet Plateau, which has been listed as Near Threatened with a decreasing trend by the IUCN because of ongoing deforestation and fragmentation of coniferous forests. It is important to place current population status into a broader ecological and evolutionary context to understand their demographic history. RESULTS: Analyses of the Chinese Grouse genome revealed fluctuations throughout the Pleistocene in effective population size. Populations decreased during early to middle Pleistocene but showed an expansion during late Pleistocene which was then followed by a sharp decline during the last glacial maximum (LGM). Ecological niche modeling indicated that a suitable habitat shift between high altitude regions to low altitude regions was due to a changing climate. This result parallels patterns of population size change in Chinese Grouse estimated from PSMC modelling, which suggested an expansion in population size from the last interglacial period (LIG) and then a peak and a bottleneck occurring at the last glacial maximum (LGM). Furthermore, the present-day distribution of Chinese Grouse is greatly reduced and fragmented. It will likely become even more fragmented in the future since coniferous forest cover is threatened in the region of their distribution and the availability of such habitat restricts their ecological niche. CONCLUSIONS: The Chinese Grouse have experienced substantial population size changes from the beginning to the LIG and reached a peak before the LGM. A sharp decrease and bottleneck occurred during the LGM, when the coniferous forests were subjected to extensive loss. The results inferred from the whole genome sequencing and species distribution models both support historical population fluctuations. The distribution of the Chinese Grouse is strongly dependent on the coniferous forest cover. To protect the fragmented coniferous forests is an essential action to protect the Chinese Grouse.