Role of reactive oxygen species in myelodysplastic syndromes.

Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy.

Identification of pasteurized mare milk and powder adulteration with bovine milk using quantitative proteomics and metabolomics approaches.

Adulteration in dairy products presents food safety challenges, driven by economic factors. Processing may change specific biomarkers, thus affecting their effectiveness in detection. In this study, proteomics and metabolomics approaches were to investigate the detection of bovine milk (BM) constituents adulteration in pasteurized mare milk (PMM) and mare milk powder (MMP). Several bovine proteins and metabolites were identified, with their abundances in PMM and MMP increasing upon addition of BM. Proteins like osteopontin (OPN) and serotransferrin (TF) detected adulteration down to 1 % in PMM, whereas these proteins in MMP were utilized to identify 10 % adulteration. Biotin and N6-Me-adenosine were effective in detecting adulteration in PMM as low as 10 % and 1 % respectively, while in MMP, their detection limits extend down to 0.1 %. These findings offer insights for authenticating mare milk products and underscore the influence of processing methods on biomarker levels, stressing the need to consider these effects in milk product authentication.

Novel Splicing Variants in the ARR3 Gene Cause the Female-Limited Early-Onset High Myopia.

Purpose: Variants in the ARR3 gene have been linked to early-onset high myopia (eoHM) with a unique X-linked female-limited inheritance. However, the clinical validity of this gene-disease association has not been systematically evaluated. Methods: We identified two Chinese families with novel ARR3 splicing variants associated with eoHM. Minigene constructs were generated to assess the effects of the variants on splicing. We integrated previous evidence to curate the clinical validity of ARR3 and eoHM using the ClinGen framework. Results: The variants c.39+1G>A and c.100+4A>G were identified in the two families. Minigene analysis showed both variants resulted in abnormal splicing and introduction of premature termination codons. Based on genetic and experimental evidence, the ARR3-eoHM relationship was classified as "definitive." Conclusions: Our study identified two novel splicing variants of the ARR3 gene linked to eoHM and confirmed their functional validity via minigene assay. This research expanded the mutational spectrum of ARR3 and confirmed the minigene assay technique as an effective tool for understanding variant effects on splicing mechanisms.

Aberrant splicing caused by a novel KMT2A variant in Wiedemann-Steiner syndrome.

INTRODUCTION: Wiedemann-Steiner syndrome (WSS) is a rare autosomal-dominant disorder caused by KMT2A variants. The aim of this study was to characterize a novel KMT2A variant in a child with WSS and demonstrate integrated diagnostic approaches. METHODS: A 3-year-old female with developmental delay, distinctive facial features, and anal fistula underwent whole exome sequencing (WES). RNA analysis was performed to assess splicing effects caused by a novel variant. RESULTS: WES identified novel heterozygous KMT2A c.5664+6T>C variant initially classified as a variant of uncertain significance. RNA analysis provided evidence of aberrant splicing (exon 20 skipping), allowing reclassification to likely pathogenic. The patient exhibited typical WSS features along with a potential novel finding of anal fistula. CONCLUSION: This report describes a novel non-canonical splice site variant in KMT2A associated with WSS. RNA analysis was critical for variant reclassification. Detailed phenotypic evaluation revealed common and expanded WSS manifestations. This case highlights the importance of combining clinical assessment, DNA testing, and RNA functional assays for the diagnosis of rare genetic disorders.

USP40 promotes hepatocellular carcinoma cell proliferation, migration and stemness by deubiquitinating and stabilizing Claudin1.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignant tumor that poses a major threat to people's lives and health. Previous studies have found that multiple deubiquitinating enzymes are involved in the pathogenesis of HCC. The purpose of this work was to elucidate the function and mechanism of the deubiquitinating enzyme USP40 in HCC progression. METHODS: The expression of USP40 in human HCC tissues and HCC cell lines was investigated using RT-qPCR, western blotting and immunohistochemistry (IHC). Both in vitro and in vivo experiments were conducted to determine the crucial role of USP40 in HCC progression. The interaction between USP40 and Claudin1 was identified by immunofluorescence, co-immunoprecipitation and ubiquitination assays. RESULTS: We discovered that USP40 is elevated in HCC tissues and predicts poor prognosis in HCC patients. USP40 knockdown inhibits HCC cell proliferation, migration and stemness, whereas USP40 overexpression shows the opposite impact. Furthermore, we confirmed that Claudin1 is a downstream gene of USP40. Mechanistically, USP40 interacts with Claudin1 and inhibits its polyubiquitination to stabilize Claudin1 protein. CONCLUSIONS: Our study reveals that USP40 enhances HCC malignant development by deubiquitinating and stabilizing Claudin1, suggesting that targeting USP40 may be a novel approach for HCC therapy.

DataColor: unveiling biological data relationships through distinctive color mapping.

In the era of rapid advancements in high-throughput omics technologies, the visualization of diverse data types with varying orders of magnitude presents a pressing challenge. To bridge this gap, we introduce DataColor, an all-encompassing software solution meticulously crafted to address this challenge. Our aim is to empower users with the ability to handle a wide array of data types through an assortment of tools, while simultaneously streamlining parameter selection for rapid insights and detailed enhancements. DataColor stands as a robust toolkit, encompassing 23 distinct tools coupled with over 600 parameters. The defining characteristic of this toolkit is its adept utilization of the color spectrum, allowing for the representation of data spanning diverse types and magnitudes. Through the integration of advanced algorithms encompassing data clustering, normalization, squarified layouts, and customizable parameters, DataColor unveils an abundance of insights that lay hidden within the intricate relationships embedded in the data. Whether you find yourself navigating the analysis of expansive datasets or embarking on the quest to visualize intricate patterns, DataColor stands as the comprehensive and potent solution. We extend the availability of DataColor to all users at no cost, accessible through the following link: https://github.com/frankgenome/DataColor.

Novel multi-target angiogenesis inhibitors as potential anticancer agents: Design, synthesis and preliminary activity evaluation.

Based on the crucial role of histone deacetylase (HDAC) and receptor tyrosine kinase in angiogenesis, in situ assembly, skeletal transition, molecular hybridization, and pharmacophore fusion were employed to yield seventy-six multi-target angiogenesis inhibitors. Biological evaluation indicated that most of the compounds exhibited potent proliferation inhibitory activity on MCF-7 cells, with the TH series having the highest inhibitory activity on MCF-7 cells. In addition, the IC50 values of TA11 and TH3 against HT-29 cellswere 0.078 µmol/L and 0.068 µmol/L, respectively. The cytotoxicity evaluation indicated that TC9, TA11, TM4, and TH3 displayed good safety against HEK293T cells. TH2 and TH3 could induce apoptosis of MCF-7 cells. Molecular modeling and ADMET prediction results indicated that most of target compounds showed promising medicinal properties, which was consistent with the experimental results. Our findings provided new lead compounds for the structural optimization of multi-target angiogenesis inhibitors.

Overall survival and short-term efficacy analysis of cervical squamous cell carcinoma with skeletal muscle and 18F-FDG PET/CT parameters.

2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) can provide tumor biological metabolism and skeletal muscle composition information. The aim of this study was to evaluate overall survival (OS) and short-term efficacy of cervical squamous cell carcinoma combining tumor biological metabolism and skeletal muscle composition parameters. Eighty two patients with cervical squamous cell carcinoma were included in the study, who received 18F-FDG PET/CT scans before treatment. Clinical characteristics, tumor biological metabolism parameters [standardized uptake value, metabolic tumor volume (MTV), total lesion glycolysis, heterogeneity of tumors, etc.] and body composition parameters were recorded. The survival analysis of cervical squamous cell carcinoma patients was performed by univariate and multivariate analysis. A combined model included clinical indicators, tumor metabolism parameters and sarcopenia was constructed to evaluate OS of patients. According to the Response Evaluation Criteria in Solid Tumours version 1.1, the relationship between sarcopenia with tumor metabolism parameters and short-term efficacy was investigated in subgroup. The results indicate that sarcopenia and high value of the sum of MTV of lesions and metastases (MTVtotal) were poor prognostic factors in patients with cervical squamous cell carcinoma. The combination of sarcopenia, MTVtotal and clinical factors provided an improved prediction of OS especially in the long term after treatment. Nutritional status of the patients and tumor metabolism may not affect the short-term efficacy of chemoradiotherapy in cervical squamous cell carcinoma patients.

Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide.

Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.

Loss of SHROOM3 affects neuroepithelial cell shape through regulating cytoskeleton proteins in cynomolgus monkey organoids.

Neural tube defects (NTDs) are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure. Although folate supplementation has been shown to mitigate the incidence of NTDs, some cases, often attributable to genetic factors, remain unpreventable. The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation; at present, however, the underlying mechanism remains unclear. Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate. To determine the role of SHROOM3 in early developmental morphogenesis, we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase. Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei. These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins, namely fibrous actin (F-actin), myosin II, and phospho-myosin light chain (PMLC), to the apical side of the neuroepithelial cells. Notably, these defects were not rescued by folate supplementation. RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis. In summary, we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.

High-Entropy Mn/Fe-Based Layered Cathode with Suppressed P2-P'2 Transition and Low-Strain for Fast and Stable Sodium Ion Storage.

Mn/Fe-based layered oxides are deemed to be a highly suitable cathode for sodium-ion batteries (SIBs) due to their high capacity and abundant Mn/Fe resources, but they still suffer from a complicated phase transition and large volume variation. To conquer these problems, high-entropy Mn/Fe-based layered oxide P2-Na0.67Mn0.5Fe0.334Cu0.045Mg0.014Ti0.014Al0.014Zr0.014Sn0.014O2 (Mn-Fe-HEO) is rationally designed and fabricated. When used as a cathode for SIB, high-entropy Mn-Fe-HEO exhibits much higher reversible capacity and better rate capability than low-entropy Na0.67Mn0.5Fe0.334Cu0.164O2 (Mn-Fe-LEO) within a wide voltage range of 1.5-4.3 V. Ex situ X-ray diffraction combined with diffusion kinetics tests and microstructural characterizations demonstrate that high-entropy enhanced structural stability effectively prevents the Jahn-Teller distortion of Mn3+, stabilizes the Na+ diffusion channels, and enables the smooth transfer of more working Na+. These lead to a stable and fast redox electrochemistry in high-entropy Mn-Fe-HEO. This work deepens the understanding of the relationship between high-entropy structure and performance and provides important guidance for the rational design of future high-entropy layered cathodes.

Causal relationship from heart failure to kidney function and CKD: A bidirectional two-sample mendelian randomization study.

BACKGROUND: Heart Failure (HF) is a widespread condition that affects millions of people, and it is caused by issues with the heart and blood vessels. Even though we know hypertension, coronary artery disease, obesity, diabetes, and genetics can increase the risk of HF and Chronic Kidney Disease (CKD), the exact cause of these conditions remains a mystery. To bridge this gap, we adopted Mendelian Randomization (MR), which relies on genetic variants as proxies. METHODS: We used data from European populations for our Bidirectional Two-Sample MR Study, which included 930,014 controls and 47,309 cases of HF from the HERMES consortium, as well as 736,396 controls and 51,256 cases of CKD. We also employed several MR variations, including MR-Egger, Inverse Variance Weighted (IVW), and Weighted Median Estimator (WME), to guarantee the results were accurate and comprehensive.). RESULTS: In this study, the MR analysis found that individuals with a genetic predisposition for HF have an elevated risk of CKD. Our study revealed a significant association between the genetic prediction of HF and the risk of CKD, as evidenced by the IVW method [with an odds ratio (OR) of 1.12 (95% CI, 1.03-1.21), p = 0.009] and the WME [with an OR of 1.14 (95% CI, 1.03-1.26), p = 0.008]. This causal relationship remained robust even after conducting MR analysis while adjusting for the effects of diabetes and hypertension, yielding ORs of 1.13 (IVW:95% CI, 1.03-1.23), 1.12 (MR-Egger: 95% CI, 0.85-1.48), and 1.15 (WME:95% CI, 1.04-1.27) (p = 0.008). However, in the reverse analysis aiming to explore CKD and renal function as exposures and HF as the outcome, we did not observe a statistically significant causal link between CKD and HF. CONCLUSION: Our study demonstrates the significance of HF in CKD progression, thus having meaningful implications for treatment and the potential for discovering new therapies. To better understand the relationship between HF and CKD, we need to conduct research in a variety of populations.

A patent perspective of antiangiogenic agents.

INTRODUCTION: Angiogenesis plays a crucial role in the development of numerous vascular structures and is involved in a variety of physiologic and pathologic processes, including psoriasis, diabetic retinopathy, and especially cancer. By obstructing the process of angiogenesis, these therapies effectively inhibit the progression of the disease. Consequently, anti-angiogenic agents were subsequently developed. AREAS COVERED: This review provides a comprehensive summary of the anti-angiogenic inhibitors developed in the past five years in terms of chemical structure, biochemical/pharmacological activity and potential clinical applications. A literature search was conducted using utilizing the databases Web of Science, SciFinder and PubMed with the key word 'anti-angiogenic agents' and 'angiogenesis inhibitor.' EXPERT OPINION: This is despite the fact that the concept of antiangiogenesis has been proposed for more than 50 years and angiogenesis inhibitors are extensively employed in clinical practice. However, significant challenges continue to confront them. In recent years, there has been a significant increase in the number of patents focusing on angiogenesis inhibitors. These patents aim to enhance the selectivity of drugs against VEGF/VEGFR, explore new targets to overcome drug resistance, and explore potential drug combinations, thereby expanding the therapeutic possibilities in this field.

Association of Cardiovascular Health With Risk of Incident Depression and Anxiety.

OBJECTIVE: To investigate the association between cardiovascular health (CVH), defined by the American Heart Association's Life's Essential 8 (LE8) score, and incident depression and anxiety. DESIGN: A prospective cohort study using data from UK Biobank. SETTING: Participants were enrolled from March 2006 to October 2010. PARTICIPANTS: Participants without cardiovascular diseases and common mental disorders at baseline and having complete data on metrics of LE8 were included. MEASUREMENTS: CVH was assessed by LE8 score including eight components. The overall CVH was categorized as low (LE8 score <50), moderate (50≤ LE8 score <80), and high (LE8 score ≥80). RESULTS: We included 115,855 participants (mean age: 55.7 years; female: 52.6%). During a median follow-up of 12.4 years, 3,194 (2.8%) and 4,005 (3.5%) participants had incident depression and anxiety, respectively. Compared with participants having low CVH, those having moderate and high CVH had 37% (HR = 0.63, 95% CI: 0.57-0.70) and 52% (HR = 0.48, 95% CI: 0.41-0.55) lower risk of incident depression. Similarly, moderate and high CVH were related to a lower risk of incident anxiety (HR = 0.81, 95% CI: 0.73-0.89 and HR = 0.68, 95% CI: 0.60-0.78). Restricted cubic spline showed that LE8 score was inversely related to incident depression and anxiety in a linear manner, and the risk of incident depression and anxiety decreased by 17% (HR = 0.83, 95% CI: 0.80-0.85) and 10% (HR = 0.90, 95% CI: 0.88-0.92) for 10-point increment in LE8 score, respectively. CONCLUSIONS: Higher CVH, evaluated by LE8 score, is strongly associated with a lower risk of incident depression and anxiety, suggesting the significance of optimizing CVH by adopting LE8.

Molecular mechanisms underlying human spatial cognitive ability revealed with neurotransmitter and transcriptomic mapping.

Mental rotation, one of the cores of spatial cognitive abilities, is closely associated with spatial processing and general intelligence. Although the brain underpinnings of mental rotation have been reported, the cellular and molecular mechanisms remain unexplored. Here, we used magnetic resonance imaging, a whole-brain spatial distribution atlas of 19 neurotransmitter receptors, transcriptomic data from Allen Human Brain Atlas, and mental rotation performances of 356 healthy individuals to identify the genetic/molecular foundation of mental rotation. We found significant associations of mental rotation performance with gray matter volume and fractional amplitude of low-frequency fluctuations in primary visual cortex, fusiform gyrus, primary sensory-motor cortex, and default mode network. Gray matter volume and fractional amplitude of low-frequency fluctuations in these brain areas also exhibited significant sex differences. Importantly, spatial correlation analyses were conducted between the spatial patterns of gray matter volume or fractional amplitude of low-frequency fluctuations with mental rotation and the spatial distribution patterns of neurotransmitter receptors and transcriptomic data, and identified the related genes and neurotransmitter receptors associated with mental rotation. These identified genes are localized on the X chromosome and are mainly involved in trans-synaptic signaling, transmembrane transport, and hormone response. Our findings provide initial evidence for the neural and molecular mechanisms underlying spatial cognitive ability.

Combined addition of L-carnitine and L-proline improves cryopreservation of dairy goat semen.

Cryopreservation of semen renders artificial insemination easier and cheaper compared to use of fresh semen. However, the cellular oxidative stress, toxicity of cryoprotectants, and osmotic imbalance may lead to a decline in semen quality and fertilization ability during the process of cryopreservation. L-carnitine and L-proline have been demonstrated to possess effective antioxidant properties in cryopreservation, with the latter also exhibiting excellent permeability and thus being utilized as a permeable cryoprotectant in the field. The aim of this study was to investigate the effects of LC and LP on cryopreservation of semen of dairy goats. After thawing, sperm motility, membrane integrity, and acrosome integrity rate of cryopreserved semen treated with LC (50 mM) were significantly higher compared to the untreated control samples. Based on this premise, we conducted experiments to assess the cryoprotective efficacy of different concentrations of LP. The findings demonstrated that the inclusion of 50 mM LP resulted in improved sperm motility compared to other concentrations. Furthermore, the levels of damaging reactive oxygen species and the malonyldialdehyde marker for oxidative stress were significantly lower in goat semen treated with these concentrations of LC and LP compared to semen exposed to other treatments. Semen treated with LC and LP also exhibited good fertilization ability during both in vitro fertilization and artificial insemination. Thus, LC (50 mM) and LP (50 mM) improve cryoprotection of dairy goat sperm which suggests that addition of these compounds will be highly beneficial to the development of dairy goat breeding.

Recent Advances in Electrocatalytic Hydrogenation Reactions on Copper-Based Catalysts.

Hydrogenation reactions play a critical role in the synthesis of value-added products within the chemical industry. Electrocatalytic hydrogenation (ECH) using water as the hydrogen source has emerged as an alternative to conventional thermocatalytic processes for sustainable and decentralized chemical synthesis under mild conditions. Among the various ECH catalysts, copper-based (Cu-based) nanomaterials are promising candidates due to their earth-abundance, unique electronic structure, versatility, and high activity/selectivity. Herein, recent advances in the application of Cu-based catalysts in ECH reactions for the upgrading of valuable chemicals are systematically analyzed. The unique properties of Cu-based catalysts in ECH are initially introduced, followed by design strategies to enhance their activity and selectivity. Then, typical ECH reactions on Cu-based catalysts are presented in detail, including carbon dioxide reduction for multicarbon generation, alkyne-to-alkene conversion, selective aldehyde conversion, ammonia production from nitrogen-containing substances, and amine production from organic nitrogen compounds. In these catalysts, the role of catalyst composition and nanostructures toward different products is focused. The co-hydrogenation of two substrates (e.g., CO2 and NOx n , SO3 2- , etc.) via C─N, C─S, and C─C cross-coupling reactions are also highlighted. Finally, the critical issues and future perspectives of Cu-catalyzed ECH are proposed to accelerate the rational development of next-generation catalysts.