Oxidative Stress Initiates Receptor-Interacting Protein Kinase-3/Mixed Lineage Kinase Domain-Like-Mediated Corneal Epithelial Necroptosis and Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Signaling during Fungal Keratitis.

Fungal keratitis remains a major cause of severe visual loss in developing countries because of limited choices of therapy. The progression of fungal keratitis is a race between the innate immune system and the outgrowth of fungal conidia. Programmed necrosis (necroptosis), a type of proinflammatory cell death, has been recognized as a critical pathologic change in several diseases. However, the role and potential regulatory mechanisms of necroptosis have not been investigated in corneal diseases. The current study showed, for the first time, that fungal infection triggered significant corneal epithelial necroptosis in human/mouse/in vitro models. Moreover, a reduction in excessive reactive oxygen species release effectively prevented necroptosis. NLRP3 knockout did not affect necroptosis in vivo. In contrast, ablation of necroptosis via RIPK3 knockout significantly delayed migration and inhibited the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in macrophages, which enhanced the progression of fungal keratitis. Taking these findings together, the study indicated that overproduction of reactive oxygen species in fungal keratitis leads to significant necroptosis in the corneal epithelium. Furthermore, the necroptotic stimuli-mediated NLRP3 inflammasome serves as a driving force in host defense against fungal infection.

Screening and evaluation of antioxidants for retinal pigment epithelial cell protection: L-ergothioneine as a novel therapeutic candidate through NRF2 activation.

The continual exposure of retinal tissues to oxidative stress leads to discernible anatomical and physiological alterations. Specifically, the onslaught of oxidative damage escalates the irreversible death of retinal pigmented epithelium (RPE) cells, pinpointed as the fundamental pathological event in dry age-related macular degeneration (AMD). There is a conspicuous lack of effective therapeutic strategies to counteract this degenerative process. This study screened a library of antioxidants for their ability to protect RPE cells against oxidative stress and identified L-ergothioneine (EGT) as a potent cytoprotective agent. L-ergothioneine provided efficient protection against oxidative stress-damaged RPE and maintained cell redox homeostasis and normal physiological functions. It maintained the normal structure of the retina in mice under oxidative stress conditions. Transcriptomic analysis revealed that EGT counteracted major gene expression changes induced by oxidative stress. It upregulated antioxidant gene expression and inhibited NRF2 translocation. The inhibition of NRF2 abolished EGT's protective effects, suggesting that NRF2 activation contributes to its mechanism of action. In conclusion, we identified EGT as a safe and effective small-molecule compound that is expected to be a novel antioxidative agent for treating AMD.

Sex-Related Gene Network Revealed by Transcriptome Differentiation of Bisexual and Unisexual Flowers of Orchid Cymbidium tortisepalum.

Despite extensive research on orchid reproductive strategies, the genetic studies of sex differentiation in the orchid family are still lacking. In this study, we compared three sexual phenotypes of Cymbidium tortisepalum bisexual flowers as well as female and male unisexual mutants. Through comparative transcriptomes, we analyzed the sex-biased differentially expressed genes (DEGs) and gene co-expression networks of sex organs (gynostemium and ovary) among them, identified the candidate genes of sex differentiation, and validated their expression by qRT-PCR. The C. tortisepalum unisexual mutants with degenerated phenotypes were compared to the bisexual plants with respect to both the flower organs and plant morphologies. Totally, 12,145, 10,789, and 14,447 genes were uniquely expressed in the female, male, and hermaphrodite sex organs, respectively. A total of 4291 sex-biased DEGs were detected among them, with 871, 2867, and 1937 DEGs in the comparisons of bisexual vs. female, bisexual vs. male, and male vs. female flowers, respectively. Two co-expressed network modules, with 81 and 419 genes were tightly correlated with female sexual traits, while two others with 265 and 135 genes were highly correlated with male sexual traits. Two female-biased hub genes (CtSDR3b and CtSDR3b-like) nested in the female modules, the homologs of maize sex determinant tasselseed2, may control the feminization of C. tortisepalum. At the same time, two male-biased hub genes (CtYAB2 and CtYAB5) nested in the male modules, the homologs of grape sex determinant VviYABBY3, may control the androphany of C. tortisepalum. This study discovered the molecular regulation networks and proposed a model for orchid sex differentiation, therefore providing for the first time the genetic basis for the sex separation in the orchid family.

A Retrospective Study from a Single Center in China to Develop a Nomogram to Predict One-Year Mortality in Patients with End-Stage Renal Disease Who Are Receiving Hemodialysis.

BACKGROUND The prognosis of end-stage renal disease (ESRD) patients receiving hemodialysis (HD) remains Poor. This retrospective study from a single center in China aimed to develop a nomogram to predict one-year mortality in patients with ESRD on HD. MATERIAL AND METHODS We enrolled 299 ethnic Han Chinese ESRD patients undergoing HD at the Second Affiliated Hospital of Nantong University from April 29, 2011 to January 30, 2021. Univariate and multivariate Cox regression analyses were used to select the predictors incorporated in the prediction model to assess the one-year mortality for ESRD patients receiving HD. We used receiver operating characteristic curves, C-index, and calibration curves to evaluate the performance of the nomogram. The predictive performance of the nomogram was also verified in different subgroup populations. RESULTS The median follow-up time was 23.30 months. The 299 ESRD patients receiving HD were divided into a death group (n=96) and a survival group (n=203), and the incidence of death was 32.11%. The main causes of death were cardiovascular disease, inflammation and cancer. A nomogram containing age, alkaline phosphatase, albumin, cystatin C, total bilirubin, and hypersensitive c-reactive protein was established. The performance of this nomogram was reflected by its moderate predictive ability, especially for patients who were male, had a primary disease of chronic glomerulonephritis, and had no history of comorbidities. CONCLUSIONS We developed and validated an easy-to-use nomogram for predicting the one-year mortality of ESRD patients undergoing HD.

Identification of seven-gene marker to predict the survival of patients with lung adenocarcinoma using integrated multi-omics data analysis.

BACKGROUND: The mechanism of cancer occurrence and development could be understood with multi-omics data analysis. Discovering genetic markers is highly necessary for predicting clinical outcome of lung adenocarcinoma (LUAD). METHODS: Clinical follow-up information, copy number variation (CNV) data, single nucleotide polymorphism (SNP), and RNA-Seq were acquired from The Cancer Genome Atlas (TCGA). To obtain robust biomarkers, prognostic-related genes, genes with SNP variation, and copy number differential genes in the training set were selected and further subjected to feature selection using random forests. Finally, a gene-based prediction model for LUAD was validated in validation datasets. RESULTS: The study filtered 2071 prognostic-related genes and 230 genomic variants, 1878 copy deletions, and 438 significant mutations. 218 candidate genes were screened through integrating genomic variation genes and prognosis-related genes. 7 characteristic genes (RHOV, CSMD3, FBN2, MAGEL2, SMIM4, BCKDHB, and GANC) were identified by random forest feature selection, and many genes were found to be tumor progression-related. A 7-gene signature constructed by Cox regression analysis was an independent prognostic factor for LUAD patients, and at the same time a risk factor in the test set, external validation set, and training set. Noticeably, the 5-year AUC of survival in the validation set and training set was all ˃ 0.67. Similar results were obtained from multi-omics validation datasets. CONCLUSIONS: The study builds a novel 7-gene signature as a prognostic marker for the survival prediction of patients with LUAD. The current findings provided a set of new prognostic and diagnostic biomarkers and therapeutic targets.

Reference genomes of the two cultivated jute species.

Cultivated jute, which comprises the two species Corchorus capsularis and C. olitorius, is the second most important natural fibre source after cotton. Here we describe chromosome-level assemblies of the genomes of both cultivated species. The C. capsularis and C. olitorius assemblies are each comprised of seven pseudo-chromosomes, with the C. capsularis assembly consisting of 336 Mb with 25,874 genes and the C. olitorius assembly containing 361 Mb with 28 479 genes. Although the two Corchorus genomes exhibit collinearity, the genome of C. olitorius contains 25 Mb of additional sequences than that of C. capsularis with 13 putative inversions, which might give a hint to the difference of phenotypic variants between the two cultivated jute species. Analysis of gene expression in isolated fibre tissues reveals candidate genes involved in fibre development. Our analysis of the population structures of 242 cultivars from C. capsularis and 57 cultivars from C. olitorius by whole-genome resequencing resulted in post-domestication bottlenecks occurred ~2000 years ago in these species. We identified hundreds of putative significant marker-trait associations (MTAs) controlling fibre fineness, cellulose content and lignin content of fibre by integrating data from genome-wide association studies (GWAS) with data from analyses of selective sweeps due to natural and artificial selection in these two jute species. Among them, we further validated that CcCOBRA1 and CcC4H1 regulate fibre quality in transgenic plants via improving the biosynthesis of the secondary cell wall. Our results yielded important new resources for functional genomics research and genetic improvement in jute and allied fibre crops.

HMGB2 regulates satellite-cell-mediated skeletal muscle regeneration through IGF2BP2.

Although the mechanism underlying modulation of transcription factors in myogenesis has been well elucidated, the function of the transcription cofactors involved in this process remains poorly understood. Here, we identified HMGB2 as an essential nuclear transcriptional co-regulator in myogenesis. HMGB2 was highly expressed in undifferentiated myoblasts and regenerating muscle. Knockdown of HMGB2 inhibited myoblast proliferation and stimulated its differentiation. HMGB2 depletion downregulated Myf5 and cyclin A2 at the protein but not mRNA level. In contrast, overexpression of HMGB2 promoted Myf5 and cyclin A2 protein upregulation. Furthermore, we found that the RNA-binding protein IGF2BP2 is a downstream target of HMGB2, as previously shown for HMGA2. IGF2BP2 binds to mRNAs of Myf5 or cyclin A2, resulting in translation enhancement or mRNA stabilization, respectively. Notably, overexpression of IGF2BP2 could partially rescue protein levels of Myf5 and cyclin A2, in response to HMGB2 decrease. Moreover, depletion of HMGB2 in vivo severely attenuated muscle repair; this was due to a decrease in satellite cells. Taken together, these results highlight the previously undiscovered and crucial role of the HMGB2-IGF2BP2 axis in myogenesis and muscle regeneration.

Comparative Profiling of Triple-Negative Breast Carcinomas Tissue Glycoproteome by Sequential Purification of Glycoproteins and Stable Isotope Labeling.

BACKGROUND: Women with triple negative breast cancers (TNBCs) have a poor prognosis due to lack of suitable targeted therapies. Changes in the protein glycosylation are increasingly being recognized as an important modification associated with cancer etiology. METHODS: In an attempt to identify TNBC biomarkers with greater diagnostic and prognostic capabilities, hydrazide- based chemistry method combined with LC-MS/MS were used to purify and identify N-linked glycopeptides or glycoproteins of tissues from TNBC patients. RESULTS: A total of 550 unique N-linked glycoproteins were identified, among these proteins, 72 unique N-linked glycoproteins were significantly regulated in tumor tissues, of which 56 proteins were upregulated and 16 proteins were downregulated. To assess the validity of the results, three selected proteins including Vascular endothelial growth factor receptor 1, Insulin receptor, Tissue factor pathway inhibitor were selected for western blot analysis, and these proteins were found as potential biomarkers of TNBC. The top three pathways of differentially expressed glycoproteins participated in were caveolar-mediated endocytosis signaling, agrin interactions at neuromuscular junction and LXR/RXR activation. CONCLUSION: This work provides potential glycoprotein markers to function as a novel tissue-based biomarker for TNBC.

Not all the number of skeletal muscle fibers is determined prenatally.

BACKGROUND: The investigation of skeletal muscle development is of importance in stock farming and biomedicine. It is still ambiguous that whether animals are born with the full set of skeletal muscle fibers or if the number of myofibers continues to increase postnatally. RESULTS: Here, an inducible lineage-tracing system was employed to monitor the changes of myofiber number in various skeletal muscles during development. We confirm that the total myofiber number of longissimus dorsi, gastrocnemius and rectus femoris is determined prenatally. However, tibialis anterior and extensor digitorum longus have a different development pattern, and their myofiber number still increases in the first postnatal week and then remains stable afterwards. CONCLUSIONS: Our results highlight different development time frames of anatomically distinct skeletal muscles.

Genetic polymorphisms in XRCC1 genes and colorectal cancer susceptibility.

BACKGROUND: The objective of this study is to investigate the association among the polymorphisms of XRCC1 gene, smoking, drinking, family history of tumors, and the risk of colorectal cancer (CRC) in the population of Han nationality in Jiangsu Province, China. METHODS: A case-control study of 320 patients with CRC and 350 cancer-free subjects as a control group was conducted. The three polymorphic sites, codons 194, 280, and 399, of XRCC1 genes were analyzed by PCR-RFLP. RESULTS: We find that heavy smoking (>500 cigarettes per year) significantly increased the susceptibility of CRC (OR=1.89, 95% confidence interval (CI) 1.27-2.84) after stratification by total smoking amount. There was also significant difference between cases and controls when family history of tumors (OR=2.96, 95% CI 1.76-4.99) was considered. Comparing with individuals carrying XRCC1 399Arg/Arg genotype, the subjects with 399Arg/Gln (OR=1.46, 95% CI 1.06-2.01) or 399Gln/Gln genotype (OR=1.93, 95% CI 1.05-3.54) had a significantly increased risk for CRC. Taking smoking and drinking habits into consideration, we found that subjects with heavy smoking history and XRCC1 194Arg allele had the significantly increased risk for CRC (OR=2.91, 95% CI 1.35-6.24). Individuals, who carry 399Gln allele and have a heavy smoking (OR=2.72, 95% CI 1.52-4.89) or drinking habit (OR=1.98, 95% CI 1.06-3.67), also have higher risk. In smoking population, 194Arg (P=0.491) and 399Gln (P=0.912) had not significantly increased risk for CRC, so did 399Gln (P=0.812) in smoking population. CONCLUSIONS: Individuals carrying XRCC1 399Gln allele with a smoking or drinking habit were in increased risk, and heavy-smoking subjects with 194Arg allele also have higher risk for CRC in the Han nationality population of Jiangsu Province, which also showed a positive correlation with exposure dose of tobacco. But XRCC1 399Gln allele or 194Arg allele were not independent risk factors for CRC in smoking or drinking population.

The single-cell transcriptomic atlas and RORA-mediated 3D epigenomic remodeling in driving corneal epithelial differentiation.

Proper differentiation of corneal epithelial cells (CECs) from limbal stem/progenitor cells (LSCs) is required for maintenance of ocular homeostasis and clear vision. Here, using a single-cell transcriptomic atlas, we delineate the comprehensive and refined molecular regulatory dynamics during human CEC development and differentiation. We find that RORA is a CEC-specific molecular switch that initiates and drives LSCs to differentiate into mature CECs by activating PITX1. RORA dictates CEC differentiation by establishing CEC-specific enhancers and chromatin interactions between CEC gene promoters and distal regulatory elements. Conversely, RORA silences LSC-specific promoters and disrupts promoter-anchored chromatin loops to turn off LSC genes. Collectively, our work provides detailed and comprehensive insights into the transcriptional dynamics and RORA-mediated epigenetic remodeling underlying human corneal epithelial differentiation.

IGF2BP2 Maintains Retinal Pigment Epithelium Homeostasis by Stabilizing PAX6 and OTX2.

Purpose: N6-methyladenosine (m6A) methylation is a chemical modification that occurs on RNA molecules, where the hydrogen atom of adenine (A) nucleotides is replaced by a methyl group, forming N6-methyladenosine. This modification is a dynamic and reversible process that plays a crucial role in regulating various biological processes, including RNA stability, transport, translation, and degradation. Currently, there is a lack of research on the role of m6A modifications in maintaining the characteristics of RPE cells. m6A readers play a crucial role in executing the functions of m6A modifications, which prompted our investigation into their regulatory roles in the RPE. Methods: Phagocytosis assays, immunofluorescence staining, flow cytometry experiments, ß-galactosidase staining, and RNA sequencing (RNA-seq) were conducted to assess the functional and cellular characteristics changes in retinal pigment epithelium (RPE) cells following short-hairpin RNA-mediated knockdown of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). RNA-seq and ultraviolet crosslinking immunoprecipitation with high-throughput sequencing (HITS-CLIP) were employed to identify the target genes regulated by IGF2BP2. adeno-associated virus (AAV) subretinal injection was performed in 6- to 8-week-old C57 mice to reduce IGF2BP2 expression in the RPE, and the impact of IGF2BP2 knockdown on mouse visual function was assessed using immunofluorescence, quantitative real-time PCR, optical coherence tomography, and electroretinography. Results: IGF2BP2 was found to have a pronounced effect on RPE phagocytosis. Subsequent in-depth exploration revealed that IGF2BP2 modulates the mRNA stability of PAX6 and OTX2, and the loss of IGF2BP2 induces inflammatory and aging phenotypes in RPE cells. IGF2BP2 knockdown impaired RPE function, leading to retinal dysfunction in vivo. Conclusions: Our data suggest a crucial role of IGF2BP2 as an m6A reader in maintaining RPE homeostasis by regulating the stability of PAX6 and OTX2, making it a potential target for preventing the occurrence of retinal diseases related to RPE malfunction.

Weighted Gene Co-Expression Network Analysis to Explore Hub Genes of Resveratrol Biosynthesis in Exocarp and Mesocarp of 'Summer Black' Grape.

Resveratrol is a polyphenol compound beneficial to human health, and its main source is grapes. In the present study, the molecular regulation of resveratrol biosynthesis in developing grape berries was investigated using weighted gene co-expression network analysis (WGCNA). At the same time, the reason for the resveratrol content difference between grape exocarp (skin) and mesocarp (flesh) was explored. Hub genes (CHS, STS, F3'5'H, PAL, HCT) related to resveratrol biosynthesis were screened with Cytoscape software. The expression level of hub genes in the exocarp was significantly higher than that in the mesocarp, and the expressions of the hub genes and the content of resveratrol in exocarp peaked at the maturity stage. While the expression levels of PAL, CHS and STS in the mesocarp, reached the maximum at the maturity stage, and F3'5'H and HCT decreased. These hub genes likely play a key role in resveratrol biosynthesis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further indicated that resveratrol biosynthesis was related to flavonoid biosynthesis, phenylalanine metabolism, phenylpropanoid biosynthesis, and stilbene biosynthesis pathways. This study has theoretical significance for exploring genes related to resveratrol biosynthesis in the exocarp and mesocarp of grapes, and provides a theoretical basis for the subsequent function and regulatory mechanism of hub genes.

Single-cell transcriptomics implicates the FEZ1-DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence.

Limbal stem/progenitor cells (LSC) represent the source of corneal epithelium renewal. LSC proliferation and differentiation are essential for corneal homeostasis, however, the regulatory mechanism remains largely unexplored. Here, we performed single-cell RNA sequencing and discovered proliferation heterogeneity as well as spontaneously differentiated and senescent cell subgroups in multiply passaged primary LSC. Fasciculation and elongation protein zeta 1 (FEZ1) and Dickkopf-1 (DKK1) were identified as two significant regulators of LSC proliferation and senescence. These two factors were mainly expressed in undifferentiated corneal epithelial cells (CECs). Knocking down the expression of either FEZ1 or DKK1 reduced cell division and caused cell cycle arrest. We observed that DKK1 acted as a downstream target of FEZ1 in LSC and that exogenous DKK1 protein partially prevented growth arrest and senescence upon FEZ1 suppression in vitro. In a mouse model of corneal injury, DKK1 also rescued the corneal epithelium after recovery was inhibited by FEZ1 suppression. Hence, the FEZ1-DKK1 axis was required for CEC proliferation and the juvenile state and can potentially be targeted as a therapeutic strategy for promoting recovery after corneal injury.

Integrated metabolome and transcriptome analyses provide insight into the effect of red and blue LEDs on the quality of sweet potato leaves.

Red and blue light-emitting diodes (LEDs) affect the quality of sweet potato leaves and their nutritional profile. Vines cultivated under blue LEDs had higher soluble protein contents, total phenolic compounds, flavonoids, and total antioxidant activity. Conversely, chlorophyll, soluble sugar, protein, and vitamin C contents were higher in leaves grown under red LEDs. Red and blue light increased the accumulation of 77 and 18 metabolites, respectively. Alpha-linoleic and linolenic acid metabolism were the most significantly enriched pathways based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A total of 615 genes were differentially expressed between sweet potato leaves exposed to red and blue LEDs. Among these, 510 differentially expressed genes were upregulated in leaves grown under blue light compared with those grown under red light, while the remaining 105 genes were expressed at higher levels in the latter than in the former. Among the KEGG enrichment pathways, blue light significantly induced anthocyanin and carotenoid biosynthesis structural genes. This study provides a scientific reference basis for using light to alter metabolites to improve the quality of edible sweet potato leaves.

ETS1-HMGA2 Axis Promotes Human Limbal Epithelial Stem Cell Proliferation.

Purpose: This study aimed to investigate the role and molecular mechanism of ETS1 in the proliferation and differentiation of human limbal epithelial stem cells (LESCs). Methods: RNA-seq and quantitative real-time PCR were used to determine gene expression changes when ETS1 and HMGA2 was knocked down using short-hairpin RNAs or overexpressed by lentivirus. Immunofluorescence and flow cytometry experiments were performed to assess the roles of ETS1 and HMGA2 in LESC proliferation. ETS1-bound cis-regulatory elements and target genes in LESCs were identified using chromatin immunoprecipitation sequencing. The epigenetic features of ETS1-binding sites were assessed by the published histone modification and chromatin accessibility profiles. Results: ETS1 was robustly expressed in LESCs but dramatically reduced on differentiation into corneal epithelial cells (CECs). ETS1 knockdown in LESCs inhibited cellular proliferation and activated CEC markers (KRT3, KRT12, CLU, and ALDH3A1). When ETS1 was overexpressed during CEC differentiation, LESC-associated genes were upregulated while CEC-associated genes were downregulated. The genome-wide binding profile of ETS1 was identified in LESCs. ETS1 occupied H3K4me3-marked promoters and H3K27ac/H3K4me1-marked enhancers. ETS1-binding sites were also enriched for chromatin accessibility signal. HMGA2 showed a consistent expression pattern with ETS1. ETS1 activates HMAG2 by binding to its promoter. Knockdown and overexpression experiments suggested that HMGA2 can promote LESC proliferation and inhibits its differentiation. Conclusions: ETS1 promotes LESC proliferation and inhibits its differentiation via activating HMGA2.

Predictive value of serum ß2-microglobulin in cardiac valve calcification in maintenance hemodialysis patients.

Background: Cardiac valve calcification (CVC) is associated with adverse cardiovascular events. We studied the risk factors of CVC in maintenance hemodialysis (MHD) patients and the value of serum ß2-microglobulin (ß2-MG) levels in predicting the incidence of CVC. ß2-MG is a middle molecular weight toxin. In recent years, researchers found that elevated blood ß2-MG was associated with coronary, thoracic, and abdominal aortic calcifications with significant correlations. ß2-MG has been emerging as a strong biomarker for cardiovascular mortality in uremic patients but its role in CVC is not well studied. This study looked specifically at CVC occurrence in relation to ß2-MG for MHD patients. Methods: Patients who underwent MHD for more than 3 months in the First People's Hospital of Nantong City from November 2012 to November 2019 with complete available data were included in the study. The patients were divided into the CVC group and the non-CVC group. The general information and clinical laboratory indicators of the patients were collected in a retrospective manner. We analyzed the risk factors for developing CVC in MHD patients using binary logistic regression method. Receiver operating characteristic (ROC) curves were used to calculate the cut-off value of ß2-MG for predicting CVC. The decision tree (DT) method was used to classify and explore the probability of CVC in patients with MHD. Results: The ß2-MG in the CVC group was significantly higher than that in the non-CVC group (t=6.750, P<0.001). Multivariate binary logistic regression analysis showed that gender, age, serum ß2-MG, and hemodialysis (HD) adequacy (Kt/V urea) were independent risk factors for CVC in MHD patients. ROC analysis showed that a ß2-MG value of 25 µg/L was the best cut-off point for predicting CVC in MHD patients. According to binary logistic regression analysis, the ß2-MG ≥25 µg/L group was 3.39 times more likely to develop CVC than the ß2-MG <25 µg/L group [odds ratio (OR), 3.39; 95% confidence interval (CI), 1.63-7.06; P=0.001]. The DT model determined that serum ß2-MG ≥25 µg/L and age >69 years were important determinants for predicting CVC in MHD patients. Conclusions: Serum ß2-MG in MHD patients has a positive correlation with the severity and occurrence of CVC.

Pistachio genomes provide insights into nut tree domestication and ZW sex chromosome evolution.

Pistachio is a nut crop domesticated in the Fertile Crescent and a dioecious species with ZW sex chromosomes. We sequenced the genomes of Pistacia vera cultivar (cv.) Siirt, the female parent, and P. vera cv. Bagyolu, the male parent. Two chromosome-level reference genomes of pistachio were generated, and Z and W chromosomes were assembled. The ZW chromosomes originated from an autosome following the first inversion, which occurred approximately 8.18 Mya. Three inversion events in the W chromosome led to the formation of a 12.7-Mb (22.8% of the W chromosome) non-recombining region. These W-specific sequences contain several genes of interest that may have played a pivotal role in sex determination and contributed to the initiation and evolution of a ZW sex chromosome system in pistachio. The W-specific genes, including defA, defA-like, DYT1, two PTEN1, and two tandem duplications of six VPS13A paralogs, are strong candidates for sex determination or differentiation. Demographic history analysis of resequenced genomes suggest that cultivated pistachio underwent severe domestication bottlenecks approximately 7640 years ago, dating the domestication event close to the archeological record of pistachio domestication in Iran. We identified 390, 211, and 290 potential selective sweeps in 3 cultivar subgroups that underlie agronomic traits such as nut development and quality, grafting success, flowering time shift, and drought tolerance. These findings have improved our understanding of the genomic basis of sex determination/differentiation and horticulturally important traits and will accelerate the improvement of pistachio cultivars and rootstocks.

Prognostic value and potential biological functions of ferroptosis-related gene signature in bladder cancer.

Bladder cancer (BC), as a genitourinary system tumor, is a highly prevalent tumor type. Ferroptosis is an iron-dependent oxidative cell death mechanism that is becoming increasingly recognized as a promising avenue for cancer therapy. However, further determination of the prospective prognostic value of ferroptosis for BC and investigation of the underlying mechanisms is required. The mRNA expression profiles and associated clinical data were downloaded from public databases such as The Cancer Genome Atlas, Gene Expression Omnibus and the IMvigor210 database. To construct a predictive formula, the least absolute shrinkage and selection operator Cox regression algorithm was used. In addition, a prognostic multigene signature was constructed using previously selected ferroptosis-related genes (FRGs). A total of 28 FRGs were differentially expressed between tumor and normal samples with |log2 fold change| >1 and adjusted P<0.05. A prognostic model was then established and it was validated in the GEO cohort using six genes: Glutamate-cysteine ligase modifier subunit, crystallin α-B, transferrin receptor, zinc finger E-box binding homeobox 1, squalene epoxidase and glucose-6-phosphate dehydrogenase (G6PD). Numerous important pathways involved in the development of the immune system and cancer were indicated to be significantly different between the two risk groups. In addition, it was discovered that G6PD expression subgroups that were associated with immunotherapy response in patients with BC had similar prognostic features to risk score subgroups. In the present study, a gene signature with a prognostic value for ferroptosis in BC was successfully developed and the potential value of G6PD was identified for future research.