Data integration and inference of gene regulation using single-cell temporal multimodal data with scTIE.

Single-cell technologies offer unprecedented opportunities to dissect gene regulatory mechanisms in context-specific ways. Although there are computational methods for extracting gene regulatory relationships from scRNA-seq and scATAC-seq data, the data integration problem, essential for accurate cell type identification, has been mostly treated as a standalone challenge. Here we present scTIE, a unified method that integrates temporal multimodal data and infers regulatory relationships predictive of cellular state changes. scTIE uses an autoencoder to embed cells from all time points into a common space by using iterative optimal transport, followed by extracting interpretable information to predict cell trajectories. Using a variety of synthetic and real temporal multimodal data sets, we show scTIE achieves effective data integration while preserving more biological signals than existing methods, particularly in the presence of batch effects and noise. Furthermore, on the exemplar multiome data set we generated from differentiating mouse embryonic stem cells over time, we show scTIE captures regulatory elements highly predictive of cell transition probabilities, providing new potentials to understand the regulatory landscape driving developmental processes.

Mouse Pramel1 regulates spermatogonial development by inhibiting retinoic acid signaling during spermatogenesis.

Spermatogenesis begins when cell fate-committed prospermatogonia migrate to the basement membrane and initiate spermatogenesis in response to retinoic acid (RA) in the neonatal testis. The underlying cellular and molecular mechanisms in this process are not fully understood. Here, we report findings on the involvement of a cancer/testis antigen, PRAMEL1, in the initiation and maintenance of spermatogenesis. By analyzing mouse models with either global or conditional Pramel1 inactivation, we found that PRAMEL1 regulates the RA responsiveness of the subtypes of prospermatogonia in the neonatal testis, and affects their homing process during the initiation of spermatogenesis. Pramel1 deficiency led to increased fecundity in juvenile males and decreased fecundity in mature males. In addition, Pramel1 deficiency resulted in a regional Sertoli cell-only phenotype during the first round of spermatogenesis, which was rescued by administration of the RA inhibitor WIN18,446, suggesting that PRAMEL1 functions as an inhibitor of RA signaling in germ cells. Overall, our findings suggest that PRAMEL1 fine-tunes RA signaling, playing a crucial role in the proper establishment of the first and subsequent rounds of spermatogenesis.

Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Decrease Portal Hypertension.

BACKGROUND & AIMS: Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in the portal vein (PV) on PH. METHODS: PH models were induced by thioacetamide injection, bile duct ligation, or partial PV ligation. HTR1A expression was detected using real-time polymerase chain reaction, in situ hybridization, and immunofluorescence staining. In situ intraportal infusion was used to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a-knockout (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a-knockout (Htr1aΔVSMC) mice were used to confirm the regulatory role of HTR1A on PP. RESULTS: HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased, but WAY-100635 decreased, the PP in rats without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMC-specific Htr1a knockout in mice prevented the development of PH. Moreover, 5-HT triggered adenosine 3',5'-cyclic monophosphate pathway-mediated PV smooth muscle cell contraction via HTR1A in the PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in rats with thioacetamide-, bile duct ligation-, and partial PV ligation-induced PH. CONCLUSIONS: Our findings reveal that 5-HT promotes PH by inducing the contraction of the PV and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment.

Exosomes isolated from TNF-α-treated bone marrow mesenchymal stem cells ameliorate pelvic floor dysfunction in rats.

Exosomes derived from bone marrow-derived mesenchymal stem cells (BMSCs) can alleviate the symptoms of pelvic floor dysfunction (PFD) in rats. However, the potential therapeutical effects of exosomes derived from BMSCs treated with tumour necrosis factor (TNF)-α on the symptoms of PFD in rats are unknown. Exosomes extracted from BMSCs treated with or without TNF-α were applied to treat PFD rats. Our findings revealed a significant elevation in interleukin (IL)-6 and TNF-α, and matrix metalloproteinase-2 (MMP2) levels in the vaginal wall tissues of patients with pelvic organ prolapse (POP) compared with the control group. Daily administration of exosomes derived from BMSCs, treated either with or without TNF-α (referred to as Exo and TNF-Exo), resulted in increased void volume and bladder void pressure, along with reduced peak bladder pressure and leak point pressure in PFD rats. Notably, TNF-Exo treatment demonstrated superior efficacy in restoring void volume, bladder void pressure and the mentioned parameters compared with Exo treatment. Importantly, TNF-Exo exhibited greater potency than Exo in restoring the levels of multiple proteins (Elastin, Collagen I, Collagen III, IL-6, TNF-α and MMP2) in the anterior vaginal walls of PFD rats. The application of exosomes derived from TNF-α-treated BMSCs holds promise as a novel therapeutic approach for treating PFD.

One-year outcomes of a novel venous stent for symptomatic iliofemoral venous obstruction: prospective cohort study.

BACKGROUND: A stent with characteristics of a hybrid design may have advantages in improving the patency of symptomatic iliofemoral vein obstruction. This study assessed the safety and effectiveness of the V-Mixtent Venous Stent in treating symptomatic iliofemoral outflow obstruction. METHODS: Eligible patients had a Clinical-Etiologic-Anatomic-Physiologic (CEAP) C classification of ≥ 3 or a Venous Clinical Severity Score (VCSS) pain score of ≥ 2. The primary safety endpoint was the rate of major adverse events within 30 days. The primary effectiveness endpoint was the 12-month primary patency rate. Secondary endpoints included changes in VCSS from baseline to 6 and 12 months, alterations in CEAP C classification, Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-14) scores at 12 months, and stent durability measures. RESULTS: Between December 2020 and November 2021, 171 patients were enrolled across 15 institutions. A total of 185 endovenous stents were placed, with 91.81% of subjects receiving one stent and 8.19% receiving 2 stents. Within 30 days, only two major adverse events occurred (1.17%; 95% confidence interval [CI], 0.14-4.16%), below the literature-defined performance goal of 11% (P < .001). The 12-month primary patency rate (91.36%; 95% CI, 85.93-95.19%; P < .001) exceeded the literature-defined performance goal. VCSS changes from baseline demonstrated clinical improvement at 6 months (- 4.30 ± 3.66) and 12 months (- 4.98 ± 3.67) (P < .001). Significant reduction in symptoms, as measured by CEAP C classification and CIVIQ-14, was observed from pre-procedure to 12 months (P < .001). CONCLUSIONS: The 12-month outcomes confirm the safety and effectiveness of the V-Mixtent Venous Stent in managing symptomatic iliofemoral venous outflow obstruction, including clinical symptom improvement compared to before treatment.

Stepwise changes in flavonoids in spores/pollen contributed to terrestrial adaptation of plants.

Protecting haploid pollen and spores against UV-B light and high temperature, 2 major stresses inherent to the terrestrial environment, is critical for plant reproduction and dispersal. Here, we show flavonoids play an indispensable role in this process. First, we identified the flavanone naringenin, which serves to defend against UV-B damage, in the sporopollenin wall of all vascular plants tested. Second, we found that flavonols are present in the spore/pollen protoplasm of all euphyllophyte plants tested and that these flavonols scavenge reactive oxygen species to protect against environmental stresses, particularly heat. Genetic and biochemical analyses showed that these flavonoids are sequentially synthesized in both the tapetum and microspores during pollen ontogeny in Arabidopsis (Arabidopsis thaliana). We show that stepwise increases in the complexity of flavonoids in spores/pollen during plant evolution mirror their progressive adaptation to terrestrial environments. The close relationship between flavonoid complexity and phylogeny and its strong association with pollen survival phenotypes suggest that flavonoids played a central role in the progression of plants from aquatic environments into progressively dry land habitats.

The role of regulatory T cells in vitiligo and therapeutic advances: a mini-review.

BACKGROUND: Regulatory T cells (Tregs) play vital roles in controlling immune reactions and maintaining immune tolerance in the body. The targeted destruction of epidermal melanocytes by activated CD8+T cells is a key event in the development of vitiligo. However, Tregs may exert immunosuppressive effects on CD8+T cells, which could be beneficial in treating vitiligo. METHODS: A comprehensive search of PubMed and Web of Science was conducted to gather information on Tregs and vitiligo. RESULTS: In vitiligo, there is a decrease in Treg numbers and impaired Treg functions, along with potential damage to Treg-related signaling pathways. Increasing Treg numbers and enhancing Treg function could lead to immunosuppressive effects on CD8+T cells. Recent research progress on Tregs in vitiligo has been summarized, highlighting various Treg-related therapies being investigated for clinical use. The current status of Treg-related therapeutic strategies and potential future directions for vitiligo treatment are also discussed. CONCLUSIONS: A deeper understanding of Tregs will be crucial for advancing Treg-related drug discovery and treatment development in vitiligo.

High-Resolution Mass Spectrometry Screening of Quaternary Ammonium Compounds (QACs) in Dust from Homes and Various Microenvironments in South China.

Despite their ubiquitous use, information regarding the presence of quaternary ammonium compounds (QACs) in various microenvironments remains scarce and only a small subset of QACs has been monitored using targeted chemical analysis. In this study, a total of 111 dust samples were collected from homes and various public settings in South China during the COVID-19 pandemic and were analyzed for traditional and emerging QACs using high-resolution mass spectrometry. The total traditional QAC concentrations in residential dust (∑traditional QAC, sum of 18 traditional QACs) ranged from 13.8 to 150 µg/g with a median concentration of 42.2 µg/g. Twenty-eight emerging QACs were identified in these samples, and the composition of ∑emerging QAC (sum of emerging QACs) to ∑QAC (sum of traditional and emerging QACs) ranged from 19 to 42% across various microenvironments, indicating the widespread existence of emerging QACs in indoor environments. Additionally, dust samples from cinemas exhibited higher ∑QAC concentrations compared to homes (medians 65.9 µg/g vs 58.3 µg/g, respectively), indicating heavier emission sources of QACs in these places. Interestingly, significantly higher ∑QAC concentrations were observed in dust from the rooms with carpets than those without (medians 65.6 µg/g vs 32.6 µg/g, p < 0.05, respectively). Overall, this study sheds light on the ubiquitous occurrence of QACs in indoor environments in South China.

Exploring the phase change and structure of carbon using a deep learning interatomic potential.

Small-scale systems based on periodic boundary conditions often cannot accurately describe real-world situations, especially when conducting molecular dynamics simulations to study phase transitions, where it is very necessary to use large-scale systems. However, studying phase transitions in large-scale systems is an important and difficult task. Though ab initio molecular dynamics (AIMD), based on density functional theory (DFT), provides advantages in terms of accuracy, it is very difficult to study phase transitions in large-scale systems due to the considerable computational time required. In addition, although traditional empirical potentials are faster, their lower calculation accuracy makes it difficult to use them for phase transition studies. It is crucial to devise a method that has enabled a promising fusion of computational efficiency and precision to effectively investigate phase transitions in large-scale systems. In this work, the obtained machine learning potential function of carbon through deep neural networks not only demonstrates strong scalability but also effectively enables the study of the formation mechanisms of amorphous diamond and polycrystalline diamond using C60 crystals and graphene as precursors under high-pressure high-temperature conditions (HPHT). Furthermore, the structure search software (AIRSS) was used to generate numerous initial structures which were optimized using the machine learning potential, a process which led to finding new structural clusters of carbon. Interestingly, the predictive capabilities of the machine learning potential for symmetric and asymmetric carbon clusters aligned well with the Gaussian approximation potential (GAP), yet the former demonstrated higher computational efficiency, making it more suitable for carbon material research. The results of this work signify significant progress in the field of carbon transition study, opening up new possibilities for exploring and understanding carbon materials with improved computational efficacy.

Brønsted Acid-Mediated Conversion of Naturally Abundant Lathyrane Diterpenes: Are Rare 10,11-seco-Lathyrane Diterpenes Artifacts?

The question of whether rare 10,11-seco-lathyranes are natural products or artifacts is thoughtfully considered after a Brønsted acid-mediated chemical conversion of naturally abundant 5/11/3 lathyrane type diterpenes into 10,11-seco-lathyranes was developed. Benefiting from this concise route, a series of 10,11-seco-lathyrane products (1-14) were smoothly synthesized. The conversion may involve an acid promoted cyclopropane ring opening accompanied by a double bond shift with final trapping of carbocation. The ease of this chemical conversion under mildly acidic conditions may imply that the 10,11-seco-lathyranes isolated to date are artifacts. This work not only develops a new modular synthetic strategy for efficient constructing rare 10,11-seco-lathyranes, but also provides a promising bioactive diterpene with excellent effect against the NO production on LPS-induced BV-2 cells.

Prognostic value of transthoracic echocardiography score for the prognosis of continuous ambulatory peritoneal dialysis patients.

BACKGROUND: We devoted ourselves to proving that the initial transthoracic echocardiography score (TTES) had predictive significance for patients with continuous ambulatory peritoneal dialysis (CAPD). METHODS: In this retrospective analysis, 274 CAPD patients who had PD therapy were recruited sequentially. TTE exams were performed three months following the start of PD therapy. All patients were divided into two groups based on the strength of their TTES levels. TTES's predictive value for CAPD patients was then determined using LASSO regression and Cox regression. RESULTS: During a median of 52 months, 46 patients (16.8%) died from all causes, and 32 patients (11.7%) died from cardiovascular disease (CV). The TTES was computed as follows: 0.109 × aortic root diameter (ARD, mm) - 0.976 × LVEF (> 55%, yes or no) + 0.010 × left ventricular max index, (LVMI, g/m2) + 0.035 × E/e' ratio. The higher TTES value (≥ 3.7) had a higher risk of all-cause death (hazard ratio, HR, 3.70, 95% confidence index, 95%CI, 1.45-9.46, P = 0.006) as well as CV mortality (HR, 2.74, 95%CI 1.15-19.17, P = 0.042). Moreover, the TTES had an attractive predictive efficiency for all-cause mortality (AUC = 0.762, 95%CI 0.645-0.849) and CV mortality (AUC = 0.746, 95%CI 0.640-0.852). The introduced nomogram, which was based on TTES and clinical variables, exhibited a high predictive value for all-cause and CV mortality in CAPD patients. CONCLUSION: TTES is a pretty good predictor of clinical outcomes, and the introduced TTES-based nomogram yields an accurate prediction value for CAPD patients.

Clinical significance of modified unilateral puncture percutaneous vertebroplasty guided by 3D- printed guides in the treatment of osteoporotic vertebral compression fractures: a retrospective study.

OBJECTIVE: To investigate the clinical significance of using 3D printing guides in modified unilateral puncture percutaneous vertebroplasty (PVP) for the treatment of osteoporotic vertebral compression fractures (OVCF), and to explore a new method for preventing paravertebral vein leakage during PVP in conjunction with a previous study of the optimal puncture-side bone cement/vertebral volume ratio(PSBCV/VV%). METHODS: This retrospective study analyzed 99 patients who underwent unilateral puncture PVP between January 2023 and December 2023. Patients were divided into a guide plate group (46 patients) and a conventional group (53 patients). The guide plate group underwent modified unilateral puncture PVP with the guidance of 3D printing guides, while the conventional group underwent unilateral puncture PVP using the conventional pedicle approach. The distribution of bone cement, surgical outcomes, and the occurrence of cement leakage into paravertebral veins were observed in both groups. RESULTS: The guide plate group had significantly shorter operating time and required fewer fluoroscopies compared to the conventional group. The amount of bone cement volume (BCV) used in the guide plate group was higher, but the amount of bone cement volume on the puncture side(PSBCV), the PSBCV/VV%, and the rate of paravertebral vein leakage were lower in the guide plate group compared to the conventional group (P < 0.05). Within each group, significant improvements in anterior vertebral margin height, Cobb angle, visual analog scale (VAS) score, and Oswestry Disability Index (ODI) were observed at 1 day and 1 month postoperatively compared to preoperative values (P < 0.05). CONCLUSION: Using 3D printing guides in modified unilateral puncture PVP is a safe and effective method for treating OVCF. And it has the advantages of short operation time, less fluoroscopy, even distribution of bone cement, and a low rate of paravertebral vein leakage.

Visual-Inertial RGB-D SLAM with Encoder Integration of ORB Triangulation and Depth Measurement Uncertainties.

In recent years, the accuracy of visual SLAM (Simultaneous Localization and Mapping) technology has seen significant improvements, making it a prominent area of research. However, within the current RGB-D SLAM systems, the estimation of 3D positions of feature points primarily relies on direct measurements from RGB-D depth cameras, which inherently contain measurement errors. Moreover, the potential of triangulation-based estimation for ORB (Oriented FAST and Rotated BRIEF) feature points remains underutilized. To address the singularity of measurement data, this paper proposes the integration of the ORB features, triangulation uncertainty estimation and depth measurements uncertainty estimation, for 3D positions of feature points. This integration is achieved using a CI (Covariance Intersection) filter, referred to as the CI-TEDM (Triangulation Estimates and Depth Measurements) method. Vision-based SLAM systems face significant challenges, particularly in environments, such as long straight corridors, weakly textured scenes, or during rapid motion, where tracking failures are common. To enhance the stability of visual SLAM, this paper introduces an improved CI-TEDM method by incorporating wheel encoder data. The mathematical model of the encoder is proposed, and detailed derivations of the encoder pre-integration model and error model are provided. Building on these improvements, we propose a novel tightly coupled visual-inertial RGB-D SLAM with encoder integration of ORB triangulation and depth measurement uncertainties. Validation on open-source datasets and real-world environments demonstrates that the proposed improvements significantly enhance the robustness of real-time state estimation and localization accuracy for intelligent vehicles in challenging environments.

[Mechanism of ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radix regulates HIF-1α signaling pathway mediated by renal hypoxia to ameliorate renal fibrosis in DKD rats].

This study explored the mechanism of the ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radix in ameliorating renal fibrosis in the rat model of diabetic kidney disease(DKD) based on the expression of hypoxia-inducible factor-1α(HIF-1α)/vascular endothelial growth factor(VEGF) and HIF-1α/platelet-derived growth factor(PDGF)/platelet-derived growth factor receptor(PDGFR) signaling pathways in the DKD rats. After 1 week of adaptive feeding, 50 male SPF-grade Wistar rats were randomized into a blank group(n=7) and a modeling group. After 24 h of fasting, the rats in the modeling group were subjected to intraperitoneal injection of streptozocin and fed with a high-sugar and high-fat diet to establish a DKD model. After modeling, the rats were randomly assigned into model(n=7), low-dose ultrafiltration extract(n=7), medium-dose ultrafiltration extract(n=7), irbesartan(n=8), and high-dose ultrafiltration extract(n=8) groups. After intervention by corresponding drugs for 12 weeks, the general conditions of the rats were observed. The body weights and blood glucose levels of the rats were measured weekly, and the 24 h urinary protein(24hUP) was measured at the 6th and 12th weeks of drug administration. After the last drug administration, the renal function indicators were determined. Masson staining was employed to observe the pathological changes of the renal tissue. The expression of prolyl hydroxylase domain 2(PHD2) and HIF-1α in the renal tissue was detected by immunohistochemistry(IHC). Real-time qPCR was employed to determine the mRNA levels of PHD2, VEGF, PDGF, and PDGFR in the renal tissue. Western blot was employed to determine the protein levels of HIF-1α, VEGF, PDGF, and PDGFR in the renal tissue. The results showed that compared with the model group, drug administration lowered the levels of glycosylated serum protein(GSP), aerum creatinine(Scr), and blood urea nitrogen(BUN) in a dose-dependent manner(P<0.05 or P<0.01) and mitigated the pathological changes in the renal tissue. Furthermore, drug administration up-regulated mRNA level of PHD2(P<0.05 or P<0.01), down-regulated the mRNA levels of VEGF, PDGF, and PDGFR(P<0.05 or P<0.01) and the protein levels of HIF-1α, VEGF, PDGF, and PDGFR(P<0.01) in the renal tissue, and increased the rate of PHD2-positive cells(P<0.01). In conclusion, the ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radix effectively alleviated the renal fibrosis in DKD rats by inhibiting the expression of key proteins in the HIF-1α signaling pathway mediated by renal hypoxia and reducing extracellular matrix(ECM) deposition.

Structural Modulation of Covalent Organic Frameworks for Efficient Hydrogen Peroxide Electrocatalysis.

The electrochemical production of hydrogen peroxide (H2O2) using metal-free catalysts has emerged as a viable and sustainable alternative to the conventional anthraquinone process. However, the precise architectural design of these electrocatalysts poses a significant challenge, requiring intricate structural engineering to optimize electron transfer during the oxygen reduction reaction (ORR). Herein, we introduce a novel design of covalent organic frameworks (COFs) that effectively shift the ORR from a four-electron to a more advantageous two-electron pathway. Notably, the JUC-660 COF, with strategically charge-modified benzyl moieties, achieved a continuous high H2O2 yield of over 1200 mmol g-1 h-1 for an impressive duration of over 85 hours in a flow cell setting, marking it as one of the most efficient metal-free and non-pyrolyzed H2O2 electrocatalysts reported to date. Theoretical computations alongside in situ infrared spectroscopy indicate that JUC-660 markedly diminishes the adsorption of the OOH* intermediate, thereby steering the ORR towards the desired pathway. Furthermore, the versatility of JUC-660 was demonstrated through its application in the electro-Fenton reaction, where it efficiently and rapidly removed aqueous contaminants. This work delineates a pioneering approach to altering the ORR pathway, ultimately paving the way for the development of highly effective metal-free H2O2 electrocatalysts.

[Clinical characteristics of 267 children with eosinophilic gastrointestinal disease: a multicenter study]. / 267ä¾‹å„¿ç«¥å—œé ¸ç²’ç»†èƒžæ€§èƒƒè‚ é“ç–¾ç— ä¸´åºŠç‰¹å¾åˆ†æžï¼šä¸€é¡¹å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To explore the clinical manifestations, endoscopic findings, histopathological changes, treatment, and prognosis of eosinophilic gastrointestinal disease (EGID) in children, with the aim of enhancing awareness among pediatricians about this condition. METHODS: Data of 267 children with EGID were prospectively collected from January 2019 to July 2022 at Jiangxi Children's Hospital, Hunan Children's Hospital, and Henan Children's Hospital. The age of onset, symptoms, physical signs, laboratory examination results, endoscopic findings, histopathological changes, and treatment outcomes were observed. RESULTS: Among the 267 children with EGID, the majority had mild (164 cases, 61.4%) or moderate (96 cases, 35.6%) clinical severity. The disease occurred at any age, with a higher prevalence observed in school-age children (178 cases). The main symptoms in infants were vomiting and hematemesis, while in toddlers, vomiting and bloody stools were prominent. Abdominal pain and vomiting were the primary symptoms in preschool and school-age children. Nearly half (49.4%) of the affected children showed elevated platelet counts on hematological examination, but there was no significant difference in platelet counts among children with mild, moderate, and severe EGID (P>0.05). Endoscopic findings in EGID children did not reveal significant specificity, and histopathological examination showed no specific structural damage. Among them, 85.0% (227 cases) received acid suppression therapy, 34.5% (92 cases) practiced dietary avoidance, 20.9% (56 cases) received anti-allergic medication, and a small proportion (24 cases, 9.0%) were treated with prednisone. Clinical symptoms were relieved in all patients after treatment, but three cases with peptic ulcers experienced recurrence after drug discontinuation. CONCLUSIONS: Mild and moderate EGID are more common in children, with no specific endoscopic findings. Dietary avoidance, acid suppression therapy, and anti-allergic medication are the main treatment methods. The prognosis of EGID is generally favorable in children.

Role of the bovine PRAMEY protein in sperm function during in vitro fertilization (IVF).

Preferentially expressed antigen in melanoma (PRAME) is a cancer/testis antigen (CTA) that is predominantly expressed in normal male gonad tissues and a variety of tumors. PRAME proteins are present in the acrosome and sperm tail, but their role in sperm function is unknown. The objective of this study was to examine the function of the bovine Y-linked PRAME (PRAMEY) during spermatozoal capacitation, the acrosome reaction (AR), and fertilization. Freshly ejaculated spermatozoa were induced to capacitate and undergo AR in vitro. Western blotting results revealed a decrease in the PRAMEY protein in capacitated spermatozoa, and the release of the PRAMEY protein from the acrosome during the AR, suggesting its involvement in sperm capacitation and AR. IVF was performed using in vitro matured bovine oocytes and cauda epididymal spermatozoa either treated with PRAMEY antibody, rabbit IgG, or DPBS. Sperm-egg binding and early embryos were examined at 6 and 45 h post IVF, respectively. The number of spermatozoa that bound per oocyte was nearly two-fold greater in the PRAMEY antibody treatment group (34.4) when compared to both the rabbit IgG (17.6) and DPBS (18.1) controls (P < 0.01). Polyspermy rate in the antibody-treated group (18.9%) was three-fold greater than the rabbit IgG control (6.0%) (P < 0.01). The results indicate that PRAMEY may play a role in anti-polyspermy defense. This study thus provides the initial evidence for the involvement of the PRAME protein family in sperm function and fertilization.

The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction.

Diabetes mellitus is a metabolic disease characterized by long-term hyperglycaemia, which leads to microangiopathy and macroangiopathy and ultimately increases the mortality of diabetic patients. Endothelial dysfunction, which has been recognized as a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy, is characterized by a reduction in NO bioavailability. Oxidative stress, which is the main pathogenic factor in diabetes, is one of the major triggers of endothelial dysfunction through the reduction in NO. In this review, we summarize the four sources of ROS in the diabetic vasculature and the underlying molecular mechanisms by which the pathogenic factors hyperglycaemia, hyperlipidaemia, adipokines and insulin resistance induce oxidative stress in endothelial cells in the context of diabetes. In addition, we discuss oxidative stress-targeted interventions, including hypoglycaemic drugs, antioxidants and lifestyle interventions, and their effects on diabetes-induced endothelial dysfunction. In summary, our review provides comprehensive insight into the roles of oxidative stress in diabetes-induced endothelial dysfunction.

Strategic nanoparticle-mediated plant disease resistance.

Nanotechnology is a promising means for development of sustainable agriculture while the study of nanoparticle-mediated plant disease resistance is still in its primary stage. Nanotechnology has shown great promise in regulating: the content of secondary metabolites, inducing disease resistance genes, delivering hormones, delivering biomolecules (such as: nucleotides, proteins, and activators), and obtaining transgenic plants to resist plant diseases. In this review, we conclude its versatility and applicability in disease management strategies and diagnostics and as molecular tools. With the advent of new biotechnologies (e.g. de novo regeneration, CRISPR/Cas9, and GRF4-GIF1 fusion protein), we discuss the potential of nanoparticles as an optimal platform to deliver biomolecules to plants for genetic engineering. In order to ensure the safe use and social acceptance of plant nanoparticle technology, its adverse effects are discussed, including the risk of transferring nanoparticles through the food chain.

Hyperglycemia-induced STING signaling activation leads to aortic endothelial injury in diabetes.

Hyperglycaemia-induced endothelial dysfunction is a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy. STING, which is a newly discovered regulator of innate immunity, has also been reported to play an important role in various metabolic diseases. However, the role of STING in diabetes-induced endothelial cell dysfunction is unknown. In this study, we established a diabetic macroangiopathy mouse model by streptozotocin (STZ) injection combined with high-fat diet (HFD) feeding and a glucotoxicity cell model in high glucose (HG)-treated rat aortic endothelial cells (RAECs). We found that STING expression was specifically increased in the endothelial cells of diabetic arteries, as well as in HG-treated RAECs. Moreover, genetic deletion of STING significantly ameliorated diabetes-induced endothelial cell dysfunction and apoptosis in vivo. Likewise, STING inhibition by C-176 reversed HG-induced migration dysfunction and apoptosis in RAECs, whereas STING activation by DMXAA resulted in migration dysfunction and apoptosis. Mechanistically, hyperglycaemia-induced oxidative stress promoted endothelial mitochondrial dysfunction and mtDNA release, which subsequently activated the cGAS-STING system and the cGAS-STING-dependent IRF3/NF-kB pathway, ultimately resulting in inflammation and apoptosis. In conclusion, our study identified a novel role of STING in diabetes-induced aortic endothelial cell injury and suggested that STING inhibition was a potential new therapeutic strategy for the treatment of diabetic macroangiopathy. Video Abstract.