Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas.

Primary effusion lymphoma (PEL) caused by Kaposi sarcoma-associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.

A nanopore-based cucumber genome assembly reveals structural variations at two QTLs controlling hypocotyl elongation.

The Xishuangbanna (XIS) cucumber (Cucumis sativus var. xishuangbannanesis) is a semiwild variety that has many distinct agronomic traits. Here, long reads generated by Nanopore sequencing technology helped assembling a high-quality genome (contig N50 = 8.7 Mb) of landrace XIS49. A total of 10,036 structural/sequence variations (SVs) were identified when comparing with Chinese Long (CL), and known SVs controlling spines, tubercles, and carpel number were confirmed in XIS49 genome. Two QTLs of hypocotyl elongation under low light, SH3.1 and SH6.1, were fine-mapped using introgression lines (donor parent, XIS49; recurrent parent, CL). SH3.1 encodes a red-light receptor Phytochrome B (PhyB, CsaV3_3G015190). A ∼4 kb region with large deletion and highly divergent regions (HDRs) were identified in the promoter of the PhyB gene in XIS49. Loss of function of this PhyB caused a super-long hypocotyl phenotype. SH6.1 encodes a CCCH-type zinc finger protein FRIGIDA-ESSENTIAL LIKE (FEL, CsaV3_6G050300). FEL negatively regulated hypocotyl elongation but it was transcriptionally suppressed by long terminal repeats retrotransposon insertion in CL cucumber. Mechanistically, FEL physically binds to the promoter of CONSTITUTIVE PHOTOMORPHOGENIC 1a (COP1a), regulating the expression of COP1a and the downstream hypocotyl elongation. These above results demonstrate the genetic mechanism of cucumber hypocotyl elongation under low light.

Biological characteristics of mechanosensitive channels MscS and MscL in Actinobacillus pleuropneumoniae.

Actinobacillus pleuropneumoniae is an important respiratory pathogen that can cause porcine contagious pleuropneumonia (PCP), resulting in significant economic losses in swine industry. Microorganisms are subjected to drastic changes in environmental osmolarity. In order to alleviate the drastic rise or fall of osmolarity, cells activate mechanosensitive channels MscL and MscS through tension changes. MscL not only regulates osmotic pressure but also has been reported to secrete protein and uptake aminoglycoside antibiotic. However, MscL and MscS, as the most common mechanosensitive channels, have not been characterized in A. pleuropneumoniae. In this study, the osmotic shock assay showed that MscL increased sodium adaptation by regulating cell length. The results of MIC showed that deletion of mscL decreased the sensitivity of A. pleuropneumoniae to multiple antibiotics, while deletion of mscS rendered A. pleuropneumoniae hypersensitive to penicillin. Biofilm assay demonstrated that MscL contributed the biofilm formation but MscS did not. The results of animal assay showed that MscL and MscS did not affect virulence in vivo. In conclusion, MscL is essential for sodium hyperosmotic tolerance, biofilm formation, and resistance to chloramphenicol, erythromycin, penicillin, and oxacillin. On the other hand, MscS is only involved in oxacillin resistance.IMPORTANCEBacterial resistance to the external environment is a critical function that ensures the normal growth of bacteria. MscL and MscS play crucial roles in responding to changes in both external and internal environments. However, the function of MscL and MscS in Actinobacillus pleuropneumoniae has not yet been reported. Our study shows that MscL plays a significant role in osmotic adaptation, antibiotic resistance, and biofilm formation of A. pleuropneumoniae, while MscS only plays a role in antibiotic resistance. Our findings provide new insights into the functional characteristics of MscL and MscS in A. pleuropneumoniae. MscL and MscS play a role in antibiotic resistance and contribute to the development of antibiotics for A. pleuropneumoniae.

Foxp2 deficiency impairs reproduction by modulating the hypothalamic-pituitary-gonadal axis in zebrafish†.

FOXP2 was initially characterized as a transcription factor linked to speech and language disorders. Single-cell RNA sequencing reveals that Foxp2 is enriched in the gonadotrope cluster of the pituitary gland and colocalized with the hormones LHB and FSHB in chickens and mice, implying that FOXP2 might be associated with reproduction in vertebrates. Herein, we investigated the roles of foxp2 in reproduction in a Foxp2-deficient zebrafish model. The results indicated that the loss of Foxp2 inhibits courtship behavior in adult male zebrafish. Notably, Foxp2 deficiency disrupts gonad development, leading to retardation of follicle development and a decrease in oocytes in females at the full-growth stage, among other phenotypes. The transcriptome analysis (RNA-seq) also revealed that differentially expressed genes clustered into the estrogen signaling and ovarian steroidogenesis-related signaling pathways. In addition, we found that Foxp2 deficiency could modulate the hypothalamic-pituitary-gonadal axis, especially the regulation of lhb and fshb expression, in zebrafish. In contrast, the injection of human chorionic gonadotropin, a specific LH agonist, partially rescues Foxp2-impaired reproduction in zebrafish, suggesting that Foxp2 plays an important role in the regulation of reproduction via the hypothalamic-pituitary-gonadal axis in zebrafish. Thus, our findings reveal a new role for Foxp2 in the regulation of reproduction in vertebrates.

Role of lymphatic endothelium specific hyaluronan receptor 1 in virus infection and associated diseases.

Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) serves as a prominent marker for lymphatic endothelial cells (LECs) and is pivotal in the process of lymphangiogenesis, a critical factor in cancer development and metastasis. Overexpression of LYVE-1 has been observed in various cancers, where it is recognized as an adverse prognostic indicator. Targeting LYVE-1 has demonstrated inhibitory effects on tumor cell proliferation, migration, and the formation of lymph node metastases both in vitro and in vivo. While extensive research has focused on the role of LYVE-1 in cancer cells, its involvement in virus infection and associated diseases remains largely unexplored. This review consolidates recent findings regarding the expression of LYVE-1 and its functions in lymphangiogenesis during various viral infections and the development of related diseases, with a particular emphasis on Kaposi's sarcoma herpesvirus. Despite the limited available data, it is evident that further studies are essential to comprehensively understand the contribution of LYVE-1 to viral pathogenesis and oncogenesis.

Development of human endogenous retrovirus type K- related treatments for human diseases.

Human endogenous retroviruses (HERVs) constitute approximately 8% of the human genome and have long been regarded as silent passengers within our genomes. However, the reactivation of HERVs has been increasingly linked to a range of human diseases, particularly the HERV-K (HML-2) family. Many studies are dedicated to elucidating the potential role of HERV-K in pathogenicity. While the underlying mechanisms require further investigation, targeting HERV-K transactivation emerges as a promising avenue for treating human diseases, including cancer, autoimmune disorders, neurodegenerative conditions, and infectious diseases. In this review, we summarize recent advancements in the development of HERV-K-targeted therapeutic strategies against various human diseases, including antiretroviral drugs, immunotherapy, and vaccines.

Coinfections with additional oncoviruses in HPV+ individuals: Status, function and potential clinical implications.

Oncovirus infections account for an estimated 12%-20% of human cancers worldwide. High-risk human papillomavirus (HPV) infection is the etiological agent of some malignancies such as cervical, oropharyngeal, anal, penile, vaginal, and vulvar cancers. However, HPV infection is not the only cause of these cancers or may not be sufficient to initiate cancer development. Actually, certain other risk factors including additional oncoviruses coinfections have been reported to increase the risk of patients exposed to HPV for developing different HPV-related cancers. In the current review, we summarize recent findings about coinfections with different oncoviruses in HPV+ patients from both clinical and mechanistic studies. We believe such efforts may lead to an interesting direction for improving our understanding and developing new treatments for virus-induced cancers.

Human endogenous retrovirus type K encoded Np9 oncoprotein induces DNA damage response.

Human endogenous retrovirus sequences (HERVs) constitute up to 8% of the human genome, yet not all HERVs remain silent passengers within our genomes. Some HERVs, especially the HERV type K (HERV-K), have been found to be frequently transactivated in a variety of inflammatory diseases and human cancers. Np9, a 9-kDa HERV-K encoded protein, has been reported as an oncoprotein and found present in a variety of tumors and transformed cells. In the current study, we for the first time reported that ectopic expression of Np9 protein was able to induce DNA damage response from host cells especially through upregulation of γH2AX. Furthermore, we found that direct knockdown of Np9 by RNAi in Kaposi's Sarcoma-associated herpesvirus (KSHV) infected cells effectively reduced LANA expression, the viral major latent oncoprotein in vitro and in vivo, which may represent a novel strategy against virus-associated malignancies.

Exploring gut-lung axis crosstalk in SARS-CoV-2 infection: Insights from a hACE2 mouse model.

Based on the forefront of clinical research, there is a growing recognition that the gut microbiota, which plays a pivotal role in shaping both the innate and adaptive immune systems, may significantly contribute to the pathogenesis of coronavirus disease 2019 (COVID-19). Although an association between altered gut microbiota and COVID-19 pathogenesis has been established, the causative mechanisms remain incompletely understood. Additionally, the validation of the precise functional alterations within the gut microbiota relevant to COVID-19 pathogenesis has been limited by a scarcity of suitable animal experimental models. In the present investigation, we employed a newly developed humanized ACE2 knock-in (hACE2-KI) mouse model, capable of recapitulating critical aspects of pulmonary and intestinal infection, to explore the modifications in the gut microbiota following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Examination of fecal samples using 16S rRNA gene profiling unveiled a notable reduction in species richness and conspicuous alterations in microbiota composition at 6 days postinfection (dpi). These alterations were primarily characterized by a decline in beneficial bacterial species and an escalation in certain opportunistic pathogens. Moreover, our analysis entailed a correlation study between the gut microbiota and plasma cytokine concentrations, revealing the potential involvement of the Lachnospiraceae_NK4A136_group and unclassified_f_Lachnospiraceae genera in attenuating hyperinflammatory responses triggered by the infection. Furthermore, integration of gut microbiota data with RNA-seq analysis results suggested that the increased presence of Staphylococcus in fecal samples may signify the potential for bacterial coinfection in lung tissues via gut translocation. In summary, our hACE2-KI mouse model effectively recapitulated the observed alterations in the gut microbiota during SARS-CoV-2 infection. This model presents a valuable tool for elucidating gut microbiota-targeted strategies aimed at mitigating COVID-19.

Anti-diabetic and anti-inflammatory indole diterpenes from the marine-derived fungus Penicillium sp. ZYX-Z-143.

Seven new indole-diterpenoids, penpaxilloids A-E (1-5), 7-methoxypaxilline-13-ene (6), and 10-hydroxy-paspaline (7), along with 20 known ones (8-27), were isolated from the marine-derived fungus Penicillium sp. ZYX-Z-143. Among them, compound 1 was a spiro indole-diterpenoid bearing a 2,3,3a,5-tetrahydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-1-one motif. Compound 2 was characterized by a unique heptacyclic system featuring a rare 3,6,8-trioxabicyclo[3.2.1]octane unit. The structures of the new compounds were established by extensive spectroscopic analyses, NMR calculations coupled with the DP4 + analysis, and ECD calculations. The plausible biogenetic pathway of two unprecedented indole diterpenoids, penpaxilloids A and B (1 and 2), was postulated. Compound 1 acted as a noncompetitive inhibitor against protein tyrosine phosphatase 1B (PTP1B) with IC50 value of 8.60 ± 0.53 µM. Compound 17 showed significant α-glucosidase inhibitory activity with IC50 value of 19.96 ± 0.32 µM. Moreover, compounds 4, 8, and 22 potently suppressed nitric oxide production on lipopolysaccharide-stimulated RAW264.7 macrophages.

Nocturnal urination is associated with the presence of higher ventilatory chemosensitivity in patients with obstructive sleep apnea.

PURPOSE: Chemosensitivity is an essential part of the pathophysiological mechanisms of obstructive sleep apnea (OSA). This study aims to use the rebreathing method to assess hypercapnic ventilatory response (HCVR) and analyze the association between chemosensitivity and certain symptoms in patients with OSA. METHODS: A total of 104 male patients with diagnosed OSA were enrolled. The HCVR was assessed using rebreathing methods under hypoxia exposure to reflect the overall chemosensitivity. Univariate and multivariate linear regression were used to explore the association with chemosensitivity. Participants were enrolled in the cluster analysis using certain symptoms, basic characteristics, and polysomnographic indices. RESULTS: At similar baseline values, the high chemosensitivity group (n = 39) demonstrated more severe levels of OSA and nocturnal hypoxia than the low chemosensitivity group (n = 65). After screening the possible associated factors, nocturnal urination, rather than OSA severity, was found to be positively associated with the level of chemosensitivity. Cluster analysis revealed three distinct groups: Cluster 1 (n = 32, 34.0%) held younger, obese individuals with nocturnal urination, elevated chemosensitivity level, and very severe OSA; Cluster 2 (41, 43.6%) included middle-aged overweighted patients with nocturnal urination, increased chemosensitivity level, but moderate-severe OSA; and Cluster 3 (n = 21, 22.3%) contained middle-aged overweighted patients without nocturnal urination, with a lowered chemosensitivity level and only moderate OSA. CONCLUSION: The presence of nocturnal urination in male patients with OSA may be a sign of higher levels of ventilatory chemosensitivity, requiring early therapy efforts independent of AHI levels.

Influence of Rehabilitation Training-Based Procedural Follow-up on Pulmonary Function and Quality of Life in Patients Undergoing Coronary Angiography and Stenting.

Objective: This study aims to investigate the impact of procedural follow-up through rehabilitation training on enhancing postoperative pulmonary function and quality of life (QOL) in patients who have undergone coronary angiography and stenting. Methods: A total of 160 patients diagnosed with coronary heart disease (CHD) and having undergone percutaneous coronary intervention (PCI) between January 1, 2020, and December 31, 2021, were selected for the study. The random number method was employed to divide them into a control group and an experimental group. The control group (80 patients) received routine post-discharge follow-ups, while the experimental group (80 patients) underwent procedural follow-ups based on rehabilitation training. Pulmonary function and quality of life were assessed at discharge, 6 months post-discharge, and 12 months post-discharge using the Jaeger spirometer and the Assessment Scale of Quality of Life in Patients with CHD. Results: No statistically significant differences in pulmonary function and quality of life were observed between the two groups at the time of discharge (P > .05). However, 6 and 12 months post-discharge, the experimental group exhibited higher values for FEV1, FEV1%, FEV1/FVC, and VO2max compared to the control group. Additionally, total QOL scores, psychological function, and knowledge of CHD prevention and treatment were higher in the experimental group. However, there were no statistically significant differences in physical function and social adaptation ability. Conclusions: Procedural follow-ups based on rehabilitation training have the potential to improve postoperative cardiopulmonary function and quality of life in patients with coronary heart disease, thereby promoting recovery.

Peroxiredoxin 1 of Procambarus clarkii govern immune responses during pathogen infection.

Members of the peroxiredoxin family are involved in a wide variety of physiological processes, including the ability to combat the effects of oxidative stress and immune responses, among others. Here, we cloned the cDNA of Procambarus clarkii Peroxiredoxin 1 (designated as PcPrx-1) and investigated its biological role in immune system functions in relation to microbial pathogens. The PcPrx-1 cDNA had 744 base pairs in an open reading frame that encoded 247 amino acid residues and contained a PRX_Typ2cys domain. The analysis of tissue specific expression patterns revealed that PcPrx-1 expression was ubiquitous in all tissues. In addition, the mRNA transcript of PcPrx-1 was found to be highest in the hepatopancreas. There was a significant upregulation of PcPrx-1 gene transcripts after exposure to LPS, PGN, and Poly I:C, but the transcription patterns were different after pathogen challenge. Double-stranded RNA was used to knockdown PcPrx-1, which resulted in a striking change in the expression of all the tested P. clarkii immune-associated genes, including lectin, Toll, cactus, chitinase, phospholipase, and sptzale. On the whole, these results suggest that PcPrx-1 is important to confer innate immunity against pathogens by governing the expression of critical transcripts that encode immune-associated genes.

Molecular cloning and functional characterization of peroxinectin from red swamp crayfish, Procambarus clarkii.

Peroxinectin, which has both peroxidase and cell adhesion activities, is crucial for invertebrate innate immune responses. In this study, we first cloned the full-length cDNA of Procambarus clarkii Peroxinectin (denoted as Pc-Px) and evaluated its immune roles. The Pc-Px cDNA had 2460 base pairs (bp) and 819 amino acid residues, including peroxidase domain and a putative integrin-binding motif. Pc-Px tissue expression was found to be ubiquitous in all examined tissues under normal physiological conditions. Pc-Px mRNA levels were highest in hemocytes, followed by gills and heart, and were lowest in the gut. The LPS, PGN, and Poly I:C treatment significantly up-regulated the transcript level of Pc-Px gene, but the expression trends were different after the microbials component treatments. Pc-Px knockdown using double-stranded RNA altered the transcription profiles of various immune-related genes in hepatopancreas of P. clarkii. Taken together, Pc-Px is an important component of immune system that likely to modulate immune function of P. clarkii via regulating immune-associated genes.

Characterization of the Microbial Community Structures, Soil Chemical Properties, and Enzyme Activity of Stellera chamaejasme (Thymelaeaceae) and Its Associated Forages in Alpine Grassland of Northwestern China.

The invasion of toxic weeds was detrimental to the growth of original vegetation and speed up the degraded grasslands. The purpose of this study was to explore the difference in microbial community, soil physicochemical properties, and enzyme activity in the rhizosphere of Stellera chamaejasme and its associated forages (Stipa purpurea and Polygonum viviparum). The rhizosphere soil microbial communities of S. chamaejasme and its associated forages were determined by high-throughput sequencing technology, the physicochemical properties, and enzyme activities were also measured using soil chemical methods. We performed biological statistical analyses to explore the correlation of rhizosphere micro-ecological environment between the invading poisonous herb S. chamaejasme and its associated forages. The Ascomycota community in the rhizosphere soil of S. chamaejasme was significantly decreased when compared with its associated forages. S. chamaejasme and S. purpurea had a similar bacterial composition, while the rhizosphere of P. viviparum was associated with more Acidobacteria and Bacteroidetes. The RDA analysis showed S. chamaejasme had highly correlated with acid proteinase, invertase, polyphenol oxidase, cellulose, and neutral protease and S. purpurea had highly associated with N-acetyl-beta-D-glucosaminidase, ß-D-Glucosidase, and the P. viviparum had highly associated with total phosphorus, total nitrogen, ammonium nitrogen, soil organic matter, pH, acid phosphatase, and catalase. Along with the invasion of S. chamaejasme, the microbial composition, soil physicochemical properties, and enzyme activity of the growing area changed considerably compared with the associated forages. Taken together, our results suggested that the composition and diversity of microbial communities associated with S. chamaejasme and its associated forages exhibited different patterns, and the rhizosphere soil microbial communities in different plants were regulated by different environmental factors in this alpine grassland ecosystem.

Factors associated with quality of life in Chinese people with psoriasis: a cross-sectional study.

BACKGROUND: The ultimate goal of medical care is to eradicate disease and restore normality to a person's life. Quality of life (QOL) is a concern as dermatologists and researchers strive to find better drug treatments. However, there have been few reports on the factors associated with QOL among Chinese people with psoriasis. METHODS: A total of 185 people with psoriasis were surveyed to assess their sociodemographic status, disease-related information, psychosocial status, and QOL. The questionnaires included a sociodemographic questionnaire, the Athens Insomnia Scale, the Hospital Anxiety and Depression Scale, the Perceived Social Support Scale, the Psychosocial Adaptation Questionnaire of Chronic Skin Disease and the Dermatology Life Quality Index. Multiple stepwise regression and path analysis were used to study the factors associated with QOL among Chinese people with psoriasis and to analyse the relationship between them. RESULTS: The results showed that the presence of anxiety/depression, lesion area, sleep disorders, psychosocial adaptation, and sex could jointly predict 62.1% of the variance in QOL among Chinese people with psoriasis. According to previous theories and the literature, a path model was established for five variables. Four internal variables could be effectively explained. The values of the explanatory variables were 62.1% (F(1056) = 61.020, p = 0.000) for QOL, 71.8% (F(2433) = 117.370, p = 0.000) for anxiety/depression, 44.0% (F(660) = 36.935, p = 0.000) for sleep disorders, and 66.9% (F(6886) = 93.556, p = 0.000) for psychosocial adaptation. The path analysis confirmed that 9 paths were consistent with the predicted path, and 3 paths were not confirmed. CONCLUSION: To improve QOL among Chinese people with psoriasis, attention should be given to the presence of anxiety/depression, lesion area, sleep disorders, psychosocial adaptation and sex differences. Therefore, health care programs for psoriasis should include physical, psychological and social aspects.

Effects of Multi-Dimensional Nursing Based on HAPA Theory on Self-Care Ability and Cardiac Function in Patients with Coronary Heart Failure and Heart Failure.

Objective: This study aimed to investigate the effects of multi-dimensional nursing based on the Health Action Process Approach (HAPA) theory on self-care ability and cardiac function in patients with coronary heart disease (CHD) and heart failure. To explore the effects of multi-dimensional nursing based on the health action process approach (HAPA) theory on self-care ability and cardiac function in patients with coronary heart disease (CHD) and heart failure. Methods: A total of 94 patients with CHD and heart failure admitted to the hospital were enrolled between January 2021 and October 2022. The random number table method divided them into a control group (47 cases, routine nursing in cardiology department) and observation group (47 cases, multi-dimensional nursing based on HAPA theory, which is a mental model used to explain and predict the health behavior of individuals). Before and after the intervention, self-care ability, negative emotions, cardiac function and quality of life in both groups were evaluated by the exercise of self-care agency scale (ESCA), self-rating anxiety scale (SAS), self-rating depression scale (SDS), 6-minute walking test, left ventricular ejection fraction (LVEF) and Minnesota living with heart failure questionnaire (MLWHFQ). Results: During the study period, at discharge, self-care ability in both groups was improved, which was better in the observation group than the control group (P < .05). At discharge, SAS and SDS scores in both groups were decreased, which were lower in the observation group than control group (P < .05). At 6 weeks after discharge, cardiac function (LVEF, 6 min walking distance) in both groups was improved, and the improvement effect was better in the observation group than control group (P < .05). There was no significant difference in the quality of life at discharge and 6 weeks after discharge in the observation group (P > .05), but it was worse in the control group at 6 weeks after discharge (P < .05). Conclusions: Multi-dimensional nursing based on HAPA theory can significantly improve self-care ability, improve cardiac function, and quality of life in patients with CHD and heart failure.

The association of left ventricular fraction shortening with cardiovascular events in peritoneal dialysis patients.

BACKGROUND: Peritoneal dialysis (PD) patients have a high incidence of cardiovascular events (CVEs). Left ventricular fraction shortening (LVFS), one of the echocardiographic parameters, is an independent risk factor for mortality in previous studies. The aim of this study was to evaluate associations between LVFS and CVEs in PD patients. METHODS: This was a single-center observational cohort study. Seven hundred and eighty-four PD patients were enrolled from 1 January 2012 to 1 June 2021 and followed until 1 June 2022. The primary outcome was the incidence of CVEs. PD patients were categorized into three groups according to the tertiles of LVFS levels (tertile 1-tertile 3). Kaplan-Meier method, Cox proportional hazard models and competing risk regression models were used for survival analysis. The areas under the curve (AUC) of receiver-operating characteristic analysis was used to determine the predictive values of LVFS for CVEs. A preplanned subgroup analysis was assessed according to age, gender, and the presence of hypertension and dyslipidemia, etc. RESULTS: During a median follow-up period of 42.3 months (interquartile range 24.0-79.0 months), 259 CVEs occurred. Compared to the other two groups respectively, patients in tertile 3 group had the lowest incidence of CVEs (24.5% vs 31.6% vs 43.0%, respectively, p < 0.05). After multiple adjustments, the tertile 3 group was associated with the 45.1% decrease in the CVEs hazard compared to that of the tertile1 group (SHR = 0.549, 95%CI: 0.395-0.762, p < 0.001). Subgroup analysis demonstrated that tertile 1 group as the reference, the association between LVFS and CVEs in tertile 3 group was robust among female patients (HR = 0.506, 95%CI: 0.309-0.829, p = 0.007), aged < 45 years (HR = 0.496, 95%CI: 0.331-0.744, p = 0.001), history of hypertension (HR = 0.586, 95%CI: 0.349-0.872, p = 0.008) and combined with dyslipidemia (HR = 0.464, 95%CI: 0.269-0.799, p = 0.006). CONCLUSIONS: This study suggests that LVFS is independently associated with the increased risk of CVEs in PD patients, especially those with aged < 45 years, female, with hypertension and dyslipidemia.

Adaptations to Optimized Interval Training in Soccer Players: A Comparative Analysis of Standardized Methods for Individualizing Interval Interventions.

Accurately prescribing supramaximal interval training facilitates targeting desired physiological adaptations. This study compared the homogeneity of adaptations in cardiorespiratory parameters to supramaximal [i.e., intensities beyond maximal aerobic speed (MAS)] interval interventions prescribed using anaerobic speed reserve (ASR), the speed attained at the end of 30-15 Intermittent Fitness Test (VIFT), and MAS. Using repeated-measures factorial design, and during the off-season phase of the athletes' yearly training cycle, thirty national-level soccer players (age = 19 ± 1.6 years; body mass = 78.9 ± 1.6 kg; height = 179 ± 4.7 cm; Body fat = 11 ± 0.9%) were randomized to interventions consisting of 2 sets of 6, 7, 8, 7, 8, and 9-min intervals (from 1st to 6th week), including 15 s running at Δ%20ASR (MAS + 0.2 × ASR), 120%MAS, or 95%VIFT followed by 15 s passive recovery. All ASR, VIFT, and MAS programs sufficiently stimulated adaptive mechanisms, improving relative maximal oxygen uptake [V̇O2max (p < 0.05; ES = 1.6, 1.2, and 1.1, respectively)], absolute V̇O2max (p < 0.05; ES = 1.5, 1.1, and 0.7), ventilation [V̇E (p < 0.05; ES = 1.6, 1.1, and 1.1)], O2 pulse [V̇O2/HR (p < 0.05; ES = 1.4, 1.1, and 0.6)], first and second ventilatory threshold [VT1 (p < 0.05; ES = 0.7, 0.8, and 0.7) and VT2 (p < 0.05; ES = 1.1, 1.1, and 0.8)], cardiac output [Q̇max (p = 1.5, 1.0, and 0.7)], and stroke volume [SVmax (p < 0.05; ES = 0.9, 0.7, and 0.5)]. Although there was no between-group difference for the change in the abovementioned variables over time, supramaximal interval training prescribed using ASR and VIFT resulted in a lower coefficient of variation [CV (inter-individual variability)] in physiological adaptations compared to exercise intensity determined as a proportion of MAS. Expressing the intensity of supramaximal interval programs according to the athlete's ASR and VIFT would assist in accurately prescribing interventions and facilitate imposing mechanical and related physiological stimulus according to the athletes' physiological ceiling. Such an approach leads to identical stimulation across athletes with differing profiles and potentially facilitates more homogenized adaptations.

Enhancement of Visible-Light-Driven Hydrogen Evolution Activity of 2D π-Conjugated Bipyridine-Based Covalent Organic Frameworks via Post-Protonation.

Photocatalytic hydrogen (H2 ) evolution represents a promising and sustainable technology. Covalent organic frameworks (COFs)-based photocatalysts have received growing attention. A 2D fully conjugated ethylene-linked COF (BTT-BPy-COF) was fabricated with a dedicated designed active site. The introduced bipyridine sites enable a facile post-protonation strategy to fine-tune the actives sites, which results in a largely improved charge-separation efficiency and increased hydrophilicity in the pore channels synergically. After modulating the degree of protonation, the optimal BTT-BPy-PCOF exhibits a remarkable H2 evolution rate of 15.8 mmol g-1 h-1 under visible light, which surpasses the biphenyl-based COF 6 times. By using different types of acids, the post-protonation is proved to be a potential universal strategy for promoting photocatalytic H2 evolution. This strategy would provide important guidance for the design of highly efficient organic semiconductor photocatalysts.