The impact and inflammatory characteristics of SARS-CoV-2 infection during ovarian stimulation on the outcomes of assisted reproductive treatment.

Introduction: Despite the global prevalence of coronavirus disease 2019 (COVID-19), limited research has been conducted on the effects of SARS-CoV-2 infection on human reproduction. The aims of this study were to investigate the impact of SARS-CoV-2 infection during controlled ovarian stimulation (COS) on the outcomes of assisted reproductive treatment (ART) and the cytokine status of patients. Methods: This retrospective cohort study included 202 couples who received ART treatment, 101 couples infected with SARS-CoV-2 during COS and 101 matched uninfected couples. The parameters of ovarian stimulation and pregnancy outcomes were compared between the two groups. The All-Human Inflammation Array Q3 kit was utilized to measure cytokine levels in both blood and follicular fluid. Results: No difference was found in the number of good-quality embryos (3.3 ± 3.1 vs. 3.0 ± 2.2, P = 0.553) between the infected and uninfected groups. Among couples who received fresh embryo transfers, no difference was observed in clinical pregnancy rate (53.3% vs. 51.5%, P = 0.907). The rates of fertilization, implantation, miscarriage, ectopic pregnancy and live birth were also comparable between the two groups. After adjustments were made for confounders, regression models indicated that the quality of embryos (B = 0.16, P = 0.605) and clinical pregnancy rate (P = 0.206) remained unaffected by SARS-CoV-2 infection. The serum levels of MCP-1, TIMP-1, I-309, TNF-RI and TNF-RII were increased, while that of eotaxin-2 was decreased in COVID-19 patients. No significant difference was found in the levels of cytokines in follicular fluid between the two groups. Conclusion: Asymptomatic or mild COVID-19 during COS had no adverse effects on ART outcomes. Although mild inflammation was present in the serum, it was not detected in the follicular fluid of these patients. The subsequent immune response needs further investigation.

BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination-defective oocytes.

In the meiotic prophase, programmed DNA double-strand breaks are repaired by meiotic recombination. Recombination-defective meiocytes are eliminated to preserve genome integrity in gametes. BRCA1 is a critical protein in somatic homologous recombination, but studies have suggested that BRCA1 is dispensable for meiotic recombination. Here we show that BRCA1 is essential for meiotic recombination. Interestingly, BRCA1 also has a function in eliminating recombination-defective oocytes. Brca1 knockout (KO) rescues the survival of Dmc1 KO oocytes far more efficiently than removing CHK2, a vital component of the DNA damage checkpoint in oocytes. Mechanistically, BRCA1 activates chromosome asynapsis checkpoint by promoting ATR activity at unsynapsed chromosome axes in Dmc1 KO oocytes. Moreover, Brca1 KO also rescues the survival of asynaptic Spo11 KO oocytes. Collectively, our study not only unveils an unappreciated role of chromosome asynapsis in eliminating recombination-defective oocytes but also reveals the dual functions of BRCA1 in safeguarding oocyte genome integrity.

MHC-Fine: Fine-tuned AlphaFold for Precise MHC-Peptide Complex Prediction.

The precise prediction of Major Histocompatibility Complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFold's capabilities by fine-tuning it with a specialized dataset consisting of exclusively high-resolution Class I MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFold's original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of Class I MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora, as well as the AlphaFold multimer model. Our results demonstrate that our fine-tuned model outperforms others in terms of RMSD (median value for C-alpha atoms for peptides is 0.66 Å) and also provides enhanced predicted lDDT scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants.

Cystic fibrosis (CF) is a genetic disorder arising from variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to multiple organ system defects. CFTR tool compounds are molecules that can modify the activity of the CFTR channel. Especially, patients that are currently not able to benefit from approved CFTR modulators, such as patients with rare CFTR variants, benefit from further research in discovering novel tools to modulate CFTR. This Review explores the development and classification of CFTR tool compounds, including CFTR blockers (CFTRinh-172, GlyH-101), potentiators (VRT-532, Genistein), correctors (VRT-325, Corr-4a), and other approved and unapproved modulators, with detailed descriptions and discussions for each compound. The challenges and future directions in targeting rare variants and optimizing drug delivery, and the potential synergistic effects in combination therapies are outlined. CFTR modulation holds promise not only for CF treatment but also for generating CF models that contribute to CF research and potentially treating other diseases such as secretory diarrhea. Therefore, continued research on CFTR tool compounds is critical.

Moxibustion for declined cardiorespiratory fitness of apparently healthy older adults: A study protocol for a randomized controlled trial.

BACKGROUND: Aging and age-related declines lead to varying degrees of decreased cardiorespiratory fitness (CRF) in apparently healthy older adults. Exercise training, the primary approach for enhancing CRF, encounters several constraints when used with elderly individuals. Existing evidence implies that moxibustion might enhance the CRF of older adults. However, clinical research in this area still needs to be improved. METHODS: This study will employ a randomized, assessor-blinded, controlled trial design involving 126 eligible participants. These participants will be stratified and randomly assigned to one moxibustion group, one sham moxibustion group, and one blank control group. Acupoints of bilateral Zusanli (ST36), Shenque (CV8), and Guanyuan (CV4) are selected for both real and sham moxibustion groups. The treatment will last 60 min per session, 5 sessions a week for 12 weeks. The blank control group will not receive any intervention for CRF improvement. Primary outcomes will be the mean change in peak oxygen uptake (VO2peak), anaerobic threshold (AT), and serum central carbon metabolites (CCB) from the baseline to observation points. Secondary outcome measures involve the six-minute walk distance (6MWD), the Short Form 36 Health Survey (SF-36), and the Qi and Blood Status Questionnaire (QBSQ). Outcome assessments will be conducted at weeks 4, 8, 12, and 24 as part of the follow-up. Adverse events will be assessed at each visit. DISCUSSION: This trial can potentially ascertain moxibustion's effectiveness and safety in enhancing CRF among apparently healthy older adults. TRAIL REGISTRATION: ChiCTR, ChiCTR2300070303. Registered on April 08, 2023.

Switched Control of HyTAQs: A Framework of Stochastic Hybrid Fuzzy Systems With Variable Dimensions.

This article is concerned with the switched control of hybrid terrestrial and aerial quadrotors (HyTAQs) via stochastic hybrid fuzzy system methodology, in which the terrestrial and aerial mode switching is subject to a Markov process with lower-bounded sojourn time. For the first time, the bimodal nonlinear attitude dynamics of HyTAQs is analyzed and modeled based on the Takagi-Sugeno (T-S) fuzzy model, and switched fuzzy controllers are developed to stabilize the hybrid fuzzy system. The characteristic of state dimension switching caused by ground contact is modeled via the singular system presentation with mode-dependent singularity matrices, based on which numerically testable criteria of stability and stabilization in the stochastic sense are derived. Compared with the previous control approaches based on Markov jump systems, the proposed one is able to describe the deterministic dwelling duration in practice and integrate multiple subsystems with algebraic equations of different dimensions, while achieving lower conservatism. Illustrative examples are provided to demonstrate the effectiveness and potential of the designed variable-dimension fuzzy controllers.

Trajectories of Body Mass Index and Waist Circumference in Relation to the Risk of Cardiac Arrhythmia: A Prospective Cohort Study.

BACKGROUND: The aim of the current study was to explore the trajectories, variabilities, and cumulative exposures of body mass index (BMI) and waist circumference (WC) with cardiac arrhythmia (CA) risks. METHODS: In total, 35,739 adults from the Kailuan study were included. BMI and WC were measured repeatedly during the 2006-2010 waves. CA was identified via electrocardiogram diagnosis. BMI and WC trajectories were fitted using a group-based trajectory model. The associations were estimated using Cox proportional hazards models. RESULTS: We identified four stable trajectories for BMI and WC, respectively. Neither the BMI trajectories nor the baseline BMI values were associated with the risk of CA. Compared to the low-stable WC group, participants in the high-stable WC group had a higher risk of CA (hazard ratio (HR) = 1.40, 95% confidence interval (CI): 1.06, 1.86). Interestingly, the cumulative exposures of BMI and WC instead of their variabilities were associated with the risk of CA. In the stratified analyses, the positive associations of the high-stable WC group with the risk of CA were found in females only (HR = 1.98, 95% CI: 1.02, 3.83). CONCLUSIONS: A high-stable WC trajectory is associated with a higher risk of CA among Chinese female adults, underscoring the potential of WC rather than BMI to identify adults who are at risk.

Healthy lifestyle decreases the risk of the first incidence of non-communicable chronic disease and its progression to multimorbidity and its mediating roles of metabolic components: a prospective cohort study in China.

OBJECTIVES: To identify the influence of healthy lifestyles on the incidence of the first NCD (FNCD), multiple chronic conditions (MCCs), and the progression from FNCD to MCCs. DESIGN: cohort study. SETTING: Zhejiang, China PARTICIPANTS: 10566 subjects (55.5 ± 13.5 years, 43.1% male) free of NCDs at baseline from the Zhejiang Metabolic Syndrome prospective cohort. MEASUREMENTS: Healthy lifestyle score (HLS) was developed by 6 common healthy lifestyle factors as smoking, alcohol drinking, physical activity, body mass index (BMI) and waist-to-hip ratio (WHR). Healthy lifestyle data and metabolic biomarkers collected via a face-to-face questionnaire-based interview, clinical health examination and routine biochemical determination. Biochemical variables were determined using biochemical auto-analyzer. Participants were stratified into four group based on the levels of HLS as ≤2, 3, 4 and ≥5. Multiple Cox proportional hazards model was applied to examine the relationship between HLS and the risk of FNCD, MCCs and the progression from FNCD to MCCs. The population-attributable fractions (PAF) were used to assess the attributable role of HLS. Mediating effect was examined by mediation package in R. RESULTS: After a median of 9.92 years of follow-up, 1572 participants (14.9%) developed FNCD, and 149 (1.4%) developed MCCs. In the fully adjusted model, the higher HLS group (≥5) was associated with lower risk of FNCD (HR = 0.68 and 95% CI: 0.56-0.82), MCCs (HR = 0.31 and 95%CI: 0.14-0.69); and the progression from FNCD to MCCs (HR = 0.39 and 95%CI: 0.18-0.85). Metabolic components (TC, TG, HDL-C, LDC-C, FPG, and UA) played the mediating roles with the proportion ranging from 5.02% to 22.2% for FNCD and 5.94% to 20.1% for MCCs. PAFs (95%CI) for poor adherence to the overall healthy lifestyle (HLS ≤ 3) were 17.5% (11.2%, 23.7%) for FNCD, 42.9% (23.4%, 61.0%) for MCCs, and 37.0% (15.5%, 56.3%) for the progression from FNCD to MCCs. CONCLUSIONS: High HLS decreases the risk of FNCD, MCCs, and the progression from FNCD to MCCs. These effects are partially mediated by metabolic components. Maintaining healthy lifestyles might reduce the disease burden of common chronic diseases.

Zygotic Splicing Activation of the Transcriptome is a Crucial Aspect of Maternal-to-Zygotic Transition and Required for the Conversion from Totipotency to Pluripotency.

During maternal-to-zygotic transition (MZT) in the embryo, mRNA undergoes complex post-transcriptional regulatory processes. However, it is unclear whether and how alternative splicing plays a functional role in MZT. By analyzing transcriptome changes in mouse and human early embryos, dynamic changes in alternative splicing during MZT are observed and a previously unnoticed process of zygotic splicing activation (ZSA) following embryonic transcriptional activation is described. As the underlying mechanism of RNA splicing, splicing factors undergo dramatic maternal-to-zygotic conversion. This conversion relies on the key maternal factors BTG4 and PABPN1L and is zygotic-transcription-dependent. CDK11-dependent phosphorylation of the key splicing factor, SF3B1, and its aggregation with SRSF2 in the subnuclear domains of 2-cell embryos are prerequisites for ZSA. Isoforms generated by erroneous splicing, such as full-length Dppa4, hinder normal embryonic development. Moreover, alternative splicing regulates the conversion of early embryonic blastomeres from totipotency to pluripotency, thereby affecting embryonic lineage differentiation. ZSA is an essential post-transcriptional process of MZT and has physiological significance in generating new life. In addition to transcriptional activation, appropriate expression of transcript isoforms is also necessary for preimplantation embryonic development.

PD-L1 expression and its correlation with clinicopathological and molecular characteristics in Chinese patients with non-small cell lung cancer.

Little is known about the relationship between programmed cell death-ligand 1 (PD-L1) expression and histologic and genetic features in real-world Chinese non-small cell lung cancer patients. From November 2017 to June 2019, tumor tissues were collected from 2674 non-small cell lung cancer patients. PD-L1 expression was detected with immunohistochemistry using the 22C3 and SP263 antibodies, and patients were stratified into subgroups based on a tumor proportion score of 1%, 1% to 49%, and ≥ 50%. Genetic alterations were profiled using targeted next-generation sequencing. In the total population, 50.5% had negative PD-L1 expression (tumor proportion score < 1%), 32.0% had low-positive expression (1%-49%), and 17.5% had high-positive expression (≥50%). The PD-L1 positive rate was 39.0% in squamous cell carcinomas and 53.6% in adenocarcinomas. PD-L1 expression was higher in squamous cell carcinomas (P < .001) and lower in adenocarcinomas (P < .001). Of the overall patient population, 11.2% had Kirsten rat sarcoma viral oncogene (KRAS) mutations, 44.9% had epidermal growth factor receptor (EGFR) mutations, 2.1% had BRAF V600E mutations, 0.3% had MET exon 14 skipping mutations, 5.4% had anaplastic lymphoma kinase translocations, and 0.9% had ROS proto-oncogene 1 translocations. Patients carrying ROS proto-oncogene 1 translocations (P = .006), KRAS (P < .001), and MET (P = .023) mutations had significantly elevated expression of PD-L1, while those harboring EGFR (P < .001) mutations had lower PD-L1 expression. In our study, PD-L1 expression was significantly higher in squamous cell carcinomas and lower in adenocarcinomas, and was positively associated with MET and KRAS mutations, as well as the wild-type EGFR gene state. Nonetheless, additional studies are needed to further validate those associations and determine the clinical significance for immune checkpoint inhibitors of these factors.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.

Changes in frailty and incident cardiovascular disease in three prospective cohorts.

BACKGROUND AND AIMS: Previous studies found that frailty was an important risk factor for cardiovascular disease (CVD). However, previous studies only focused on baseline frailty status, not taking into consideration the changes in frailty status during follow-up. The aim of this study was to investigate the associations of changes in frailty status with incident CVD. METHODS: This study used data of three prospective cohorts: China Health and Retirement Longitudinal Study (CHARLS), English Longitudinal Study of Ageing (ELSA), and Health and Retirement Study (HRS). Frailty status was evaluated by the Rockwood frailty index and classified as robust, pre-frail, or frail. Changes in frailty status were assessed by frailty status at baseline and the second survey which was two years after the baseline. Cardiovascular disease was ascertained by self-reported physician-diagnosed heart disease (including angina, heart attack, congestive heart failure, and other heart problems) or stroke. Cox proportional hazard models were used to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) after adjusting for potential confounders. RESULTS: A total of 7116 participants from CHARLS (female: 48.6%, mean age: 57.4 years), 5303 from ELSA (female: 57.7%, mean age: 63.7 years), and 7266 from HRS (female: 64.9%, mean age: 65.1 years) were included according to inclusion and exclusion criteria. The median follow-up periods were 5.0 years in the CHARLS, 10.7 years in the ELSA, and 9.5 years in the HRS. Compared with stable robust participants, robust participants who progressed to pre-frail or frail status had increased risks of incident CVD (CHARLS, HR = 1.84, 95% CI: 1.54-2.21; ELSA, HR = 1.53, 95% CI: 1.25-1.86; HRS, HR = 1.59, 95% CI: 1.31-1.92). In contrast, frail participants who recovered to robust or pre-frail status presented decreased risks of incident CVD (CHARLS, HR = 0.62, 95% CI: 0.47-0.81; ELSA, HR = 0.49, 95% CI: 0.34-0.69; HRS, HR = 0.70, 95% CI: 0.55-0.89) when compared with stable frail participants. These decreased risks of incident CVD were also observed in pre-frail participants who recovered to robust status (CHARLS, HR = 0.66, 95% CI: 0.52-0.83; ELSA, HR = 0.65, 95% CI: 0.49-0.85; HRS, HR = 0.71, 95% CI: 0.56-0.91) when compared with stable pre-frail participants. CONCLUSIONS: Different changes in frailty status are associated with different risks of incident CVD. Progression of frailty status increases incident CVD risks, while recovery of frailty status decreases incident CVD risks.

Ovarian response determines the luteinizing hormone suppression threshold for patients following the gonadotrophin releasing hormone antagonist protocol: A retrospective cohort study.

Background: Ovarian reactivity to gonadotrophin stimulation varies, and individual adjustments to the timing and dose of gonadotrophin-releasing hormone (GnRH) antagonist administration are necessary to prevent excessive increases and decreases in luteinizing hormone (LH) levels in patients with different ovarian response following the GnRH antagonist (GnRH-A) protocol. The present study aims to investigate optimal LH suppression thresholds for patients with normal ovarian response (NOR), high ovarian response (HOR), and poor ovarian response (POR) following the GnRH-A protocol respectively. Methods: A total of 865 in vitro fertilization (IVF) cycles using a flexible or fixed GnRH-A protocol were included. Patients were categorized into the HOR, NOR, or POR group according to their anti-Müllerian hormone (AMH) levels. Then, patients in each group were stratified into one of four subgroups according to the quartile (Q1-Q4) of the basal LH level to LH on triggering day ratio (bLH/hLH). The primary outcomes were the clinical pregnancy and live birth rates, and the secondary outcomes were the number of oocytes retrieved, MII oocytes, two pronucleus (2PN) embryos, and good-quality embryos. Results: There were 526 patients with NOR, 180 with HOR, and 159 with POR. Basal LH level, LH on triggering day and bLH/hLH were identified as independent predictors of clinical pregnancy rate and live birth rate by logistics regression analysis. Compared to those with NOR, patients with POR had the lowest embryo implantation rate (22.6% vs. 32.8%, P < 0.05), clinical pregnancy rate (32.3% vs. 47.3%, P < 0.05) and live birth rate (22.6 vs. 37.8%, P < 0.05) of fresh embryo transfer (ET). The embryo implantation, clinical pregnancy and live birth rates of frozen embryo transfer (FET) were not significantly different among the three groups. In the subgroup analysis, patients with HOR had the highest embryo implantation rate (51.6%, P < 0.05), clinical pregnancy rate (68.4%, P < 0.05) and live birth rate (52.6%, P < 0.05) of ET in Q3, with a bLH/hLH ratio of 2.40-3.69. In the NOR group, the embryo implantation rate (41.9%, P < 0.05), clinical pregnancy rate (61.5%, P < 0.05) and live birth rate (50.8%, P < 0.05) of ET and live birth rate (53.1%, P < 0.05) of FET were highest in Q2, with a bLH/hLH ratio of 1.29-2.05. Patients with POR had the highest clinical pregnancy rate (57.1%, P < 0.05) and live birth rate (42.9%, P < 0.05) of ET in Q2, with a bLH/hLH ratio of 0.86-1.35. Conclusions: In the present study, the bLH/hLH ratio represented the LH suppression threshold. The subgroup analysis of HOR, NOR and POR showed that, the LH suppression threshold varies according to ovarian response. We recommend LH suppression thresholds of 2.40-3.69 for HOR, 1.29-2.05 for NOR, and 0.86-1.35 for POR to obtain the highest clinical pregnancy rate and live birth rate. This study provides comprehensive and precise references for clinicians to monitor LH levels individually during controlled ovarian stimulation (COS) according to the patient's ovarian response following the GnRH-A protocol.

Network-based pharmacology-based research on the effect and mechanism of the Hedyotis diffusa-Scutellaria Barbata pair in the treatment of hepatocellular carcinoma.

The Hedyotis diffusa-Scutellaria officinalis pair (HD-SB) has therapeutic effects on a variety of cancers. Our study was to explore the mechanism of HD-SB in the treatment of hepatocellular carcinoma (HCC). A total of 217 active ingredients of HD-SB and 1196 HCC-related targets were reserved from the TCMSP and the SwissTarget Prediction database, and we got 63 intersection targets from GeneCards. We used a Venn diagram, and Cytoscape found that the three core ingredients were quercetin, luteolin, and baicalein. The PPI analysis showed that the core targets were TP53, CDK2, XPO1, and APP. Molecular docking results showed that these core ingredients had good binding potential with the core targets. HD-SB acts simultaneously on various HCC-related signaling pathways, including proteoglycans in cancer and the P53 signaling pathway. In vitro experiments confirmed that HD-SB can inhibit HepG2 cell proliferation by increasing TP53 and APP levels and decreasing XPO1 and CDK2 levels. This study analyzed active ingredients, core targets, and central mechanisms of HD-SB in the treatment of HCC. It reveals the role of HD-SB in targeting the P53 signaling pathway in the treatment of HCC. We hope that our research could provide a new perspective to the therapy of HCC and find new anticancer drugs.

Healthy lifestyle and cancer survival: A multinational cohort study.

Lifestyle factors after a cancer diagnosis could influence the survival of cancer 60 survivors. To examine the independent and joint associations of healthy lifestyle factors with mortality outcomes among cancer survivors, four prospective cohorts (National Health and Nutrition Examination Survey [NHANES], National Health Interview Survey [NHIS], UK Biobank [UKB] and Kailuan study) across three countries. A healthy lifestyle score (HLS) was defined based on five common lifestyle factors (smoking, alcohol drinking, diet, physical activity and body mass index) that related to cancer survival. We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of individual lifestyle factors and HLS with all-cause and cancer mortality among cancer survivors. During the follow-up period of 37,095 cancer survivors, 8927 all-cause mortality events were accrued in four cohorts and 4449 cancer death events were documented in the UK and US cohorts. Never smoking (adjusted HR = 0.77, 95% CI: 0.69-0.86), light alcohol consumption (adjusted HR = 0.86, 95% CI: 0.82-0.90), adequate physical activity (adjusted HR = 0.90, 95% CI: 0.85-0.94), a healthy diet (adjusted HR = 0.69, 95% CI: 0.61-0.78) and optimal BMI (adjusted HR = 0.89, 95% CI: 0.85-0.93) were significantly associated with a lower risk of all-cause mortality. In the joint analyses of HLS, the HR of all-cause and cancer mortality for cancer survivors with a favorable HLS (4 and 5 healthy lifestyle factors) were 0.55 (95% CI 0.42-0.64) and 0.57 (95% CI 0.44-0.72), respectively. This multicohort study of cancer survivors from the United States, the United Kingdom and China found that greater adherence to a healthy lifestyle might be beneficial in improving cancer prognosis.

Fetal drug exposure after maternally administered CFTR modulators Elexacaftor/Tezacaftor/Ivacaftor in a rat model.

BACKGROUND: The potential effects of the very effective cystic fibrosis triple combination drug, Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pregnancy on prenatal development of offspring remain largely unknown. RESEARCH QUESTION: We aimed to investigate the fetal tissue distribution pattern of maternally administered ETI by placental transfer in the rat fetuses. STUDY DESIGN AND METHODS: Sprague Dawley pregnant rats were administered ETI (6.7 mg/kg/d elexacaftor + 3.5 mg/kg/d tezacaftor + 25 mg/kg/d ivacaftor) traced with [3 H]-ivacaftor in single dose acute experiments (intraperitoneal injection) or treated orally with ETI (the same dose) for 7 days in sub-chronic experiments. Fetal tissue samples were collected at embryonic day (E) 19 and analyzed using liquid scintillation counting for acute experiments or liquid chromatography-mass spectrometry for sub-chronic experiments. RESULTS: On day E19, after acute exposure, the entry of ivacaftor into fetal brain (brain/plasma concentration ratios <50%) was significantly lower than to other tissues (>100%). However, after sub-chronic exposure, the entry of all 3 components into the developing brain was comparably extensive as into other tissues (tissue/plasma ratios, 260 - 1000%). Each component of ETI accumulated in different fetal tissues to approximately equal extent. Inter-litter differences on fetal drug distribution were found in cortex for ivacaftor, muscle for tezacaftor and cortex and mid/hindbrain for elexacaftor. Fetal plasma concentrations of ETI (ng/mL) were variable between litters. The entry of ivacaftor and tezacaftor into adult brain appeared to be restricted (<100%). INTERPRETATION: Fetal rats are exposed to maternally ingested ETI after sub-chronic exposure, potentially impacting fetal development. The brain entry data highlights the need for attention be paid to any long-term potential effects ETI exposure could have on normal brain development.

Preserved Ratio Impaired Spirometry and COPD Accelerate Frailty Progression: Evidence From a Prospective Cohort Study.

BACKGROUND: COPD has been found to be associated with frailty. However, longitudinal evidence for associations of COPD with frailty progression is inadequate. Furthermore, recent studies revealed a new phenotype of lung function impairment: preserved ratio impaired spirometry (PRISm) findings. Associations of PRISm findings and their transitions with frailty progression are unclear. RESEARCH QUESTION: What are the associations of PRISm findings, transitions of PRISm findings, and COPD with frailty progression? STUDY DESIGN AND METHODS: To analyze the associations of PRISm findings and COPD with frailty progression, 5,901 patients were included from the English Longitudinal Study of Ageing. Patients were classified into three lung function patterns of normal spirometry (NS) findings, PRISm findings, and COPD. Frailty progression was assessed by repeated measurements of the frailty index (FI) during follow-up. Among these 5,901 patients, 3,765 patients were included to analyze the associations of PRISm findings transitions with frailty progression. PRISm findings transitions were assessed based on the changes of lung function patterns after a 4-year interval. Linear mixed-effect models were used for statistical analyses. RESULTS: The median follow-up periods were 9.5 years for the analyses of PRISm findings and COPD with frailty progression and 5.8 years for PRISm findings transitions with frailty progression. When compared with participants with NS findings, patients with PRISm findings and COPD demonstrated accelerated FI progression with additional annual increases of 0.301 (95% CI, 0.211-0.392; P < .001) and 0.172 (95% CI, 0.102-0.242; P < .001), respectively. Patients who transitioned from NS findings to PRISm findings also demonstrated accelerated FI progression when compared with those with stable NS findings (ß = 0.242; 95% CI, 0.008-0.476; P = .042). However, no accelerated FI progression was found in patients with PRISm findings who transitioned to NS findings (ß = 0.119; 95% CI, -0.181 to 0.418; P = .438). INTERPRETATION: Our findings indicate that PRISm findings and COPD are associated with accelerated frailty progression. Further studies are needed to elucidate the causality of the association of PRISm findings and COPD with frailty.

Increased incidence risks of cardiovascular disease among cancer patients: Evidence from a population-based cohort study in China.

BACKGROUND: Cardiovascular disease (CVD) is becoming a major concern among cancer patients, leading to the development of a new field named cardio-oncology. However, previous studies were mainly based on the western population and focused on CVD mortality. Evidence from the Chinese population is limited. Furthermore, few studies investigated the incidence risks of CVD among cancer patients. METHODS: 85,787 eligible cancer patients were included from Hangzhou city, China. Age-standardized standard incidence ratio (SIR) was used to reflect the incidence risks of CVD among cancer patients as compared with the standard population, which was defined as all residents in Hangzhou city during the same period. RESULTS: After three years of follow-up, cancer patients showed elevated incidence risks of CVD (SIR = 1.41, 95%CI: 1.35-1.47) as compared with the standard population. The elevated risks of CVD were highest in the first year after cancer diagnosis (SIR = 1.68, 95%CI: 1.58-1.78), then followed by the second (SIR = 1.21, 95%CI: 1.11-1.31) and the third (SIR = 1.18, 95%CI: 1.07-1.29) year. These results were consistent in males and females. Furthermore, different risks of CVD were observed among different cancer sites. Patients with pancreatic cancer showed the highest risks of CVD, then followed by liver cancer, lung cancer, kidney cancer, gastric cancer, bladder cancer, prostate cancer, and colorectal cancer. CONCLUSIONS: Cancer patients have increased incidence risks of CVD, especially in the first year after cancer diagnosis. The increased risks of CVD vary by different cancer sites. Our findings highlight the importance of paying close attention to the CVD risks among cancer patients.

Downregulation of homeobox A1 in human granulosa cells is involved in diminished ovarian reserve through promoting cell apoptosis and mitochondrial dysfunction.

Granulosa cell apoptosis contributes to the occurrence of diminished ovarian reserve (DOR). HOXA1, belonging to the HOX gene family, is involved in regulating cancer cell apoptosis. However, whether HOXA1 participates in the granulosa cell apoptosis in DOR patients remains to be elucidated. In the current study, we demonstrated the differential transcriptomic landscape of granulosa cells in DOR patients compared to that in the controls and identified decreased expression of the HOXA1 gene. Meanwhile, we found that HOXA1 was a gonadotropin-response gene, in which FSH could promote its expression, whereas LH inhibited HOXA1 expression in human granulosa cells. CCK-8 assay, flow cytometry and TUNEL staining results showed that inhibition of endogenous HOXA1 expression promoted human granulosa cell apoptosis. Moreover, knockdown of HOXA1 increased Bax while reducing Bcl2 protein expression. Furthermore, we found a total of 947 differentially expressed genes (DEGs), including 426 upregulated genes and 521 downregulated genes using transcriptome sequencing technology. Enrichment analysis results showed that the DEGs were involved in apoptosis and mitochondrial function-related signaling pathways. Knockdown of HOXA1 impaired mitochondrial functions, exhibiting increased reactive oxygen species (ROS) and cytoplasmic Ca2+ levels, decreased mitochondrial membrane potential, ATP production and mitochondrial DNA (mtDNA) copy number, and abnormal mitochondrial cristae. Our findings demonstrated that aberrantly reduced HOXA1 expression induced granulosa cell apoptosis in DOR patients and impaired mitochondrial function, which highlighted the potential role of HOXA1 in the occurrence of DOR and provided new insight for the treatment of DOR.

MHC-Fine: Fine-tuned AlphaFold for Precise MHC-Peptide Complex Prediction.

The precise prediction of Major Histocompatibility Complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFold's capabilities by fine-tuning it with a specialized dataset comprised by exclusively high-resolution MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFold's original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora [13], as well as the AlphaFold multimer model [8]. Our results demonstrate that our fine-tuned model outperforms both in terms of RMSD (median value is 0.65 Å) but also provides enhanced predicted lDDT scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.