Personalized embryo transfer guided by rsERT with hourly precision improves pregnancy outcomes in patients with a receptive window of implantation: a pilot study.

PURPOSE: To investigate whether personalized embryo transfer (pET) predicted by a modified RNA-sequencing-based endometrial receptivity test (rsERT) model can improve intrauterine pregnancy rate (IPR) in patients with a receptive window of implantation (WOI). DESIGN: A retrospective pilot study was conducted in the Center for Reproductive Medicine, Central South University, from January 2018 to December 2023. A total of 524 patients with receptive WOI results from rsERT were assigned into two groups based on whether they underwent conventional embryo transfer (conventional ET) or pET. Patients in the conventional ET were matched with those in the pET group at a 1:1 ratio using propensity score matching (PSM). RESULTS: Before PSM, the IPR (55.73% vs. 46.19%, P = 0.032) and implantation rate (IR) (47.51% vs. 34.03%, P = 0.000) in the pET group were significantly higher than that in the conventional ET group. However, the number and types of transferred embryos differed significantly between the two groups. After adjusting for confounding factors, IPR (57.38% vs. 44.81, P = 0.016) and IR (46.81% vs. 33.10%, P = 0.001) remained significantly higher in the pET group compared to the conventional ET group. The implantation failure rate was significantly lower in the pET group compared to controls (42.62% vs. 55.19%, P = 0.016). Additionally, the multiple-pregnancy rate was significantly higher in the pET group compared to the conventional ET group (10.29% vs. 1.68%, P = 0.001). CONCLUSIONS: Women with receptive WOI results could benefit from the receptivity-timed pET predicted by the newly refined rsERT. These findings provide a basis for future research in precision medicine for embryo transfer.

Biliary atresia: the role of gut microbiome, and microbial metabolites.

Biliary atresia (BA) is a progressive fibroinflammatory disease affecting both the extrahepatic and intrahepatic bile ducts, potentially leading to chronic cholestasis and biliary cirrhosis. Despite its prevalence, the exact mechanisms behind BA development remain incompletely understood. Recent research suggests that the gut microbiota and its metabolites may play significant roles in BA development. This paper offers a comprehensive review of the changing characteristics of gut microbiota and their metabolites at different stages of BA in children. It discusses their influence on the host's inflammatory response, immune system, and bile acid metabolism. The review also explores the potential of gut microbiota and metabolites as a therapeutic target for BA, with interventions like butyrate and gut microbiota preparations showing promise in alleviating BA symptoms. While progress has been made, further research is necessary to untangle the complex interactions between gut microbiota and BA, paving the way for more effective prevention and treatment strategies for this challenging condition.

Single cell dual-omic atlas of the human developing retina.

The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.

Evaluation of Efficacy and Safety in First-Line Treatment Methods for Extensive-Stage Small Cell Lung Cancer: A Comprehensive Comparative Study of Chemotherapy, Targeted Therapy Combined With Chemotherapy, and Immunotherapy Combined With Chemotherapy.

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive tumor with limited effectiveness in its standard chemotherapy treatment. Targeted antiangiogenic therapy and immune checkpoint inhibitors (ICIs) have demonstrated potential as alternative treatments for extensive-stage SCLC (ES-SCLC). However, there is insufficient comparative evidence available to determine the optimal first-line treatment option between ICIs plus chemotherapy and targeted antiangiogenic therapy plus chemotherapy. OBJECTIVE: This study is aimed at analyzing clinical data from ES-SCLC patients treated at the First Affiliated Hospital of Bengbu Medical College between June 2021 and June 2023. The study compared the efficacy and safety of three first-line treatment regimens: standard chemotherapy, antiangiogenic therapy combined with chemotherapy, and immune combination therapy. METHODS: Patients who met the inclusion criteria were divided into three groups: chemotherapy, immune combination therapy, and antiangiogenic therapy combined with chemotherapy. The study collected data on clinical characteristics, treatment regimens, and adverse reactions. The analysis included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and treatment safety. RESULTS: A total of 101 patients were included in the study, with 49 receiving chemotherapy alone, 19 receiving antiangiogenic therapy, and 33 receiving immune combination therapy. The ORRs were 78.9% for antiangiogenic therapy, 72.7% for immune combination therapy, and 42.9% for chemotherapy alone. The median PFS was 8.0 months for antiangiogenic therapy, 7.8 months for immune combination therapy, and 5.2 months for chemotherapy alone. Both combination therapy groups demonstrated superior efficacy compared to chemotherapy alone. CONCLUSION: Targeted combined chemotherapy and immune combination chemotherapy showed superior efficacy as first-line treatments for ES-SCLC compared to chemotherapy alone, with manageable adverse reactions.

Core competing endogenous RNA network based on mRNA and non-coding RNA expression profiles in chicken fatty liver.

Fatty liver disease is a common metabolic disease in chickens. This disease can lead to a decrease in egg production and increase the risk of death in chickens. Long non-coding RNAs (lncRNAs) are involved in fatty liver formation by directly targeting genes or regulating gene expression by competitively binding microRNAs. However, a large proportion of competing endogenous RNA (ceRNA) networks in fatty liver diseases are still unclear. The total of 300 Jingxing-Huang chickens were used for fatty liver model construction. Then, differentially expressed (DE) genes (DEGs) identified through whole-transcriptome sequencing from four chickens with fatty liver and four chickens without fatty liver were chosen from the F1 generation. A total of 953 DEGs were identified between the fatty liver group and the control group, including 26 DE micro (mi)RNAs and 56 DE lncRNAs. Differential expression heatmaps and volcano plots were obtained after clustering expression analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these DEGs were involved in many biological processes and signaling pathways related to fatty acid metabolism and lipid synthesis. Furthermore, cytoscape was used to construct a ceRNA network of the DE miRNAs, DE mRNAs, and DE lncRNAs. Eleven DE lncRNAs, seven DE miRNAs, and 13 DE mRNAs were found to be associated with the pathogenesis of fatty liver disease. An lncRNA-miRNA-mRNA ceRNA network was constructed to elucidate the mechanisms of fatty liver diseases, and the ENSGALT00000079786-miR-140/miR-143/miR-1a/miR-22/miR-375 network was identified. These results provide a valuable resource for further elucidating the posttranscriptional regulatory mechanisms of chicken liver and adipose fat development or deposition.

Recent progress in tyrosine kinase 2 inhibitors for atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by persistent itching. Conventional treatments for AD include topical corticosteroids and calcineurin inhibitors, but there are emerging therapies targeting the JAK-TYK2 pathway that are promising for the treatment of AD. AREAS COVERED: This review comprehensively explores the pathogenesis, triggers, clinical manifestations, and conventional treatment options for AD. In addition, we discuss novel therapeutic agents targeting alternative signaling pathways, with a focus on clinical trials evaluating tyrosine kinase 2 (TYK2) inhibitors, including systemic and topical agents. We also provide a detailed assessment of ICP-332 efficacy, safety, and potential adverse effects in moderate-to-severe AD. EXPERT OPINION: Janus kinase inhibitors that have been recently approved have shown promise for the treatment of AD, especially for patients with severe phenotypes. Preliminary findings from randomized controlled trials suggest that TYK2 inhibitors exhibit rapid efficacy and acceptable safety in the management of AD; however, additional investigations, including long-term trials, are warranted to fully understand their efficacy and safety profile.

Dihydroartemisinin restores the immunogenicity and enhances the anticancer immunosurveillance of cisplatin by activating the PERK/eIF2α pathway.

BACKGROUND: Immunosurveillance is pivotal in the effectiveness of anticancer therapies and tumor control. The ineffectiveness of cisplatin in activating the immunosurveillance is attributed to its lack of adjuvanticity resulting from its inability to stimulate endoplasmic reticulum stress. Dihydroartemisinin demonstrates the anti-tumor effects through various mechanisms, including the activation of the endoplasmic reticulum stress. This study aimed to develop a novel strategy to enhance the immunogenicity of dying tumor cells by combining cisplatin with dihydroartemisinin, thereby triggering effective anti-tumor immunosurveillance and improving the efficacy of cisplatin in clinical practice. METHODS: Lewis lung carcinoma (LLC) and CT26 colon cancer cell lines and subcutaneous tumor models were used in this study. The importance of immunosurveillance was validated in both immunocompetent and immunodeficient mouse models. The ability of dihydroartemisinin and cisplatin therapy to induce immunogenic cell death and tumor growth control in vivo was validated by prophylactic tumor vaccination and therapeutic tumor models. The underlying mechanism was elucidated through the pharmaceutical or genetic intervention of the PERK/eIF2α pathway in vitro and in vivo. RESULTS: Dihydroartemisinin enhanced the generation of reactive oxygen species in cisplatin-treated LLC and CT26 cancer cells. The combination treatment of dihydroartemisinin with cisplatin promoted cell death and ensured an optimal release of damage-associated molecular patterns from dying cancer cells, promoting the phagocytosis of dendritic cells. In the tumor vaccination model, we confirmed that dihydroartemisinin plus cisplatin treatment induced immunogenic cell death. Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the combination treatment suppressed the tumor growth of CT26 colon cancer and LLC lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo. Mechanistically, dihydroartemisinin restored the immunogenicity of cisplatin by activating the adjuvanticity of damage-associated molecular patterns, such as calreticulin exposure, through the PERK/eIF2α pathway. Additionally, the inhibition of eIF2α phosphorylation attenuated the anti-tumor efficiency of C + D in vivo. CONCLUSIONS: We highlighted that dihydroartemisinin acts as an immunogenic cell death rescuer for cisplatin, activating anticancer immunosurveillance in a PERK/eIF2α-dependent manner and offering a strategy to enhance the anti-tumor efficacy of cisplatin in clinical practice.

Preovulatory progesterone levels are the top indicator for ovulation prediction based on machine learning model evaluation: a retrospective study.

BACKGROUND: Accurately predicting ovulation timing is critical for women undergoing natural cycle-frozen embryo transfer. However, the precise predicting of the ovulation timing remains challenging due to the lack of consensus among different clinics regarding the definition of this significant event. OBJECTIVE: To compare the effectiveness of preovulatory serum progesterone levels (P4) versus luteinizing hormone levels (LH) in predicting ovulation time using two machine learning models. METHODS: 771 patients who underwent autologous natural cycle-frozen embryo transfer between January 2015 and February 2022 were recruited. Utilizing variables including follicle diameters, preovulatory serum levels of LH, E2, and P4, two machine learning models were constructed to predict the ovulation time, the importance of the variables in predicting ovulation timing was further ranked. RESULTS: Two machine learning models have the capability to accurately predict the timing of ovulation, specifically within 72, 48, or 24 h. The overall accuracy rates of the validation dataset, as determined by the classification trees and random forest models, were found to be 78.83% and 85.28% respectively. Notably, when predicting ovulation within 24 h, the accuracy rate of P4 ≥ 0.65ng/ml exceeded 92%. Furthermore, it was important to consider LH or E2 levels in conjunction with P4 when assessing ovulation timing in cases where P4<0.65ng/ml. CONCLUSIONS: Preovulatory serum P4 levels are better predictors of ovulation timing than LH levels and could be used as an alternative in clinical settings, and the model we developed can be used to pinpoint the day of ovulation. Ongoing research and advancements in technology are anticipated to enhance and refine the ovulation method.

Comprehensive review of indicators and techniques for optical mapping of intracellular calcium ions.

Calcium ions (Ca2+) play crucial roles in almost every cellular process, making the detection of changes in intracellular Ca2+ essential to understanding cell function. The fluorescence indicator method has garnered widespread application due to its exceptional sensitivity, rapid analysis, cost-effectiveness, and user-friendly nature. It has successfully delineated the spatial and temporal dynamics of Ca2+ signaling across diverse cell types. However, it is vital to understand that different indicators have varying levels of accuracy, sensitivity, and stability, making choosing the right inspection method crucial. As optical detection technologies advance, they continually broaden the horizons of scientific inquiry. This primer offers a systematic synthesis of the current fluorescence indicators and optical imaging modalities utilized for the detection of intracellular Ca2+. It elucidates their practical applications and inherent limitations, serving as an essential reference for researchers seeking to identify the most suitable detection methodologies for their calcium-centric investigations.

Identification of hub genes associated with neutrophils in chronic rhinosinusitis with nasal polyps.

Neutrophil infiltration plays a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). However, pertinent mechanisms remain poorly elucidated. Here, we obtained the data from gene expression omnibus (GEO) and gene set enrichment analysis (GSEA) to identify and validate neutrophil-associated hub genes in CRSwNP. We found that four neutrophil-associated hub genes, namely ICAM1, IL-1ß, TYROBP, and BCL2A1, were markedly upregulated and positively correlated with neutrophil infiltration levels in patients with CRSwNP. Subsequently, this was confirmed by real-time quantitative PCR. In conclusion, we identified the role of neutrophil infiltration in the pathophysiology of CRSwNP, which may be the potential targets for the diagnosis and treatment of CRSwNP.

The links between symptom burden, illness perception, psychological resilience, social support, coping modes, and cancer-related worry in Chinese early-stage lung cancer patients after surgery: a cross-sectional study.

OBJECTIVES: This study aims to investigate the links between the clinical, demographic, and psychosocial factors and cancer-related worry in patients with early-stage lung cancer after surgery. METHODS: The study utilized a descriptive cross-sectional design. Questionnaires, including assessments of cancer-related worry, symptom burden, illness perception, psychological resilience, coping modes, social support and participant characteristics, were distributed to 302 individuals in early-stage lung cancer patients after surgery. The data collection period spanned from January and October 2023. Analytical procedures encompassed descriptive statistics, independent Wilcoxon Rank Sum test, Kruskal-Wallis- H- test, Spearman correlation analysis, and hierarchical multiple regression. RESULTS: After surgery, 89.07% had cancer-related worries, with a median (interquartile range, IQR) CRW score of 380.00 (130.00, 720.00). The most frequently cited concern was the cancer itself (80.46%), while sexual issues were the least worrisome (44.37%). Regression analyses controlling for demographic variables showed that higher levels of cancer-related worry (CRW) were associated with increased symptom burden, illness perceptions, and acceptance-rejection coping modes, whereas they had lower levels of psychological resilience, social support and confrontation coping modes, and were more willing to obtain information about the disease from the Internet or applications. Among these factors, the greatest explanatory power in the regression was observed for symptom burden, illness perceptions, social support, and sources of illness information (from the Internet or applications), which collectively explained 52.00% of the variance. CONCLUSIONS: Healthcare providers should be aware that worry is a common issue for early stage lung cancer survivors with a favorable prognosis. During post-operative recovery, physicians should identify patient concerns and address unmet needs to improve patients' emotional state and quality of life through psychological support and disease education.

Erratum: Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

[This corrects the article DOI: 10.1016/j.isci.2024.109122.].

Combined effects of climate and land-use changes on the alpha and beta functional diversities of terrestrial mammals in China.

Climate and land-use changes are predicted to impact biodiversity, threatening ecosystem services and functions. However, their combined effects on the functional diversity of mammals at the regional scale remain unclear, especially at the beta level. Here, we use projected climate and land-use changes in China to investigate their potential effects on the alpha and beta functional diversities of terrestrial mammals under low- and high-emission scenarios. In the current projection, we showed strong positive spatial correlations between functional richness and species richness. Functional evenness (FEve), functional specialization (FSpe), and functional originality (FOri) decreased with species richness, and functional divergence (FDiv) increased first and then plateaued. Functional beta diversity was dominated by its nestedness component, in contrast to the taxonomic facet. Potential changes in species richness are more strongly influenced by land-use change under the low-emission scenario, while under the high-emission scenario, they are more strongly influenced by climate change. Changes in functional richness (FRic) were inconsistent with those in species richness, with a magnitude of decreases greater than predicted from species richness. Moreover, mammal assemblages showed potential functional differentiation (FD) across the country, and the trends exceeded those towards taxonomic differentiation (TD). Our findings help us understand the processes underlying biodiversity responses to global changes on multiple facets and provide new insight for conservation plans.

Coping with family function changes: A qualitative study of couples facing advanced lung cancer.

Objective: This study aimed to explore the experiences of couples with advanced lung cancer in coping with changes in their family functioning. Methods: This study included patients with advanced lung disease and their spouses who were hospitalized in a tertiary hospital in Shanghai, China. Data were collected through interviews that focused on three key areas: (1) patient coping, (2) spousal coping, and (3) dyadic coping. Semi-structured qualitative interviews were conducted in Chinese and analyzed using Braun-Clarke thematic analysis. Results: A total of 15 couples participated in the study (12 male and 3 female patients). The average age of the patients was 63.73 years, and that of their partners was 63.20 years. Marriage duration ranged from 25 to 53 years. Three distinct themes emerged from the data: individual patient coping was expressed in four areas: struggle, acceptance of reality, cherishing the present and regaining hope, and rebuilding family life; spousal coping was expressed in three areas: acceptance and understanding of the patient, providing active support, and adjusting roles and sharing of family responsibilities; and dyadic coping was expressed in three areas: cognitive consistency of changes in family functioning, stress communication, and family adjustment and adaptation based on shared cognition. A relationship diagram of patients with advanced lung cancer and their spouses in coping with post-cancer changes in family functioning was constructed. Conclusions: Post-cancer coping with changes in family functioning in couples with advanced lung cancer is a continuous developmental and gradual evolutionary process, and there is a close relationship between the two that influences each other. Early assistance for couples to form consistent cognition and communicate effectively with the stress caused by the disease can help improve the family functioning of both partners and, in turn, improve the quality of life of patients. Therefore, it is recommended that clinicians conduct family- or couple-centered intervention studies aimed at improving the post-cancer quality of life of patients with advanced lung cancer.

Simplification of the Acidithiobacillus ferrooxidans Culture Process for Expanding the Field of Biomachining.

Biomachining is an eco-friendly metal processing method with broad application potential. Nevertheless, the bacterial culture methods that are currently involved in biomachining require the intensive use of chemical reagents, especially FeSO4, specialized equipment, and professional-level skills in the field of biology. Herein, the differences between two cultures with and without sterilization were evaluated. Acidithiobacillus ferrooxidans was cultured with iron instead of FeSO4 in the culture medium. The chemical and biochemical parameters of the culture were analyzed by studying the area of exposed iron and continuously regulating the pH. Eliminating the sterilization and sterile inoculation of the medium is feasible for culturing A. ferrooxidans. The key to achieving a high bacterial density in culture with iron was to maintain the solution pH. The possibility of mass culturing A. ferrooxidans with steel cuttings was evaluated in a custom bioreactor, and the bacterial concentration reached 9 × 107 cells/mL.

Long-Term Efficacy and Safety of Stapokibart in Adults with Moderate-to-Severe Atopic Dermatitis: An Open-Label Extension, Nonrandomized Clinical Trial.

BACKGROUND: Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials. OBJECTIVE: We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis. METHODS: Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300 mg every 2 weeks up to 52 weeks. Efficacy outcomes included the proportions of patients with ≥ 50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale. RESULTS: In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week 52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥ 2-point reduction was achieved in 39.3% of patients at week 16, increasing to 58.9% at week 52. The proportions of patients with ≥ 3-point and ≥ 4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week 52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events. CONCLUSIONS: Long-term treatment with stapokibart for 52 weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021).

Genetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies disease models.

Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which may lead to the development of rhesus disease models. Through phenotyping of macaques carrying a pathogenic OPA1:p.A8S variant, we identify a genetic model of autosomal dominant optic atrophy. Finally, we present a public website housing variant and genotype data from over two thousand rhesus macaques.