Linker histone H1 drives heterochromatin condensation via phase separation in Arabidopsis.

In the eukaryotic nucleus, heterochromatin forms highly condensed, visible foci known as heterochromatin foci (HF). These HF are enriched with linker histone H1, a key player in heterochromatin condensation and silencing. However, it is unknown how H1 aggregates HF and condenses heterochromatin. In this study, we established that H1 facilitates heterochromatin condensation by enhancing inter- and intrachromosomal interactions between and within heterochromatic regions of the Arabidopsis (Arabidopsis thaliana) genome. We demonstrated that H1 drives HF formation via phase separation, which requires its C-terminal intrinsically disordered region (C-IDR). A truncated H1 lacking the C-IDR fails to form foci or recover HF in the h1 mutant background, whereas C-IDR with a short stretch of the globular domain (18 out of 71 amino acids) is sufficient to rescue both defects. In addition, C-IDR is essential for H1's roles in regulating nucleosome repeat length and DNA methylation in Arabidopsis, indicating that phase separation capability is required for chromatin functions of H1. Our data suggest that bacterial H1-like proteins, which have been shown to condense DNA, are intrinsically disordered and capable of mediating phase separation. Therefore, we propose that phase separation mediated by H1 or H1-like proteins may represent an ancient mechanism for condensing chromatin and DNA.

GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.

During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors.

MORE FLORET1 controls anther development by negatively regulating key tapetal genes in both diploid and tetraploid rice.

Polyploid hybrid rice (Oryza sativa) has great potential for increasing yields. However, hybrid rice depends on male fertility and its regulation, which is less well studied in polyploid rice than in diploid rice. We previously identified an MYB transcription factor, MORE FLORET1 (MOF1), whose mutation causes male sterility in neo-tetraploid rice. MOF1 expression in anthers peaks at anther Stage 7 (S7) and progressively decreases to low levels at S10. However, it remains unclear how the dynamics of MOF1 expression contribute to male fertility. Here, we carefully examined anther development in both diploid and tetraploid mof1 rice mutants, as well as lines ectopically expressing MOF1 in a temporal manner. MOF1 mutations caused delayed degeneration of the tapetum and middle layer of anthers and aberrant pollen wall organization. Ectopic MOF1 expression at later stages of anther development led to retarded cytoplasmic reorganization of tapetal cells. In both cases, pollen grains were aborted and seed production was abolished, indicating that precise control of MOF1 expression is essential for male reproduction. We demonstrated that 5 key tapetal genes, CYP703A3 (CYTOCHROME P450 HYDROXYLASE 703A3), OsABCG26 (O. sativa ATP BINDING CASSETTE G26), PTC1 (PERSISTENT TAPETAL CELL1), PKS2 (POLYKETIDE SYNTHASE 2), and OsABCG15 (O. sativa ATP BINDING CASSETTE G15), exhibit expression patterns opposite to those of MOF1 and are negatively regulated by MOF1. Moreover, DNA affinity purification sequencing (DAP-seq), luciferase activity assays, and electrophoretic mobility shift assays indicated that MOF1 binds directly to the PKS2 promoter for transcriptional repression. Our results provide a mechanistic basis for the regulation of male reproduction by MOF1 in both diploid and tetraploid rice. This study will facilitate the development of polyploid male sterile lines, which are useful for breeding of polyploid hybrid rice.

In-Bridge Stereochemistry: A Determinant of Stapled Peptide Conformation and Activity.

Peptide side chain stapling has been proven to be an effective strategy for fine-tuning peptide properties. This innovative approach leads to the creation of stapled peptides characterized by stabilized α-helical conformations, enhanced protein-binding affinity, improved cell permeability, superior enzymatic stability, and numerous other advantages. Extensive research has explored the impact of various stapling bridges on the properties of these peptides, with limited investigation into the influence of bridge chirality, until very recently. In this concise review, we provide a brief overview of the current state of knowledge regarding the stereochemistry within the bridges of stapled peptides, offering insights into the potential applications of chiral bridges in the design and development of stapled peptides.

Relationship between metabolic status, physical activity and cardiovascular disease in participants with obesity.

OBJECTIVE: We aimed to investigate the independent and joint associations between metabolic status, PA (physical activity) and risk of CVD (cardiovascular disease) in participants with obesity. METHODS: We included 109,301 adults with obesity free of baseline CVD enrolled from 2006 to 2010 in the UK Biobank cohort (aged 56 ± 7.9 years). Based on metabolic status, obesity was grouped into metabolically healthy obesity (MHO; free of hypertension, hypercholesterolemia and diabetes; n = 26,989; BMI 33 ± 3.3 kg/m2) and metabolically unhealthy obesity (MUO; n = 82,312; BMI 34 ± 4.0 kg/m2). PA was categorized into four groups according to moderate-to-vigorous PA (MVPA): none, low, medium, and high. Multivariable Cox regression models were used for the main analyses adjusting for sociodemographic factors, lifestyles and comorbidities. RESULTS: There were 8,059 CVD events during a median follow-up of 8.1 years. MHO was associated with a 42% reduced risk of CVD compared with MUO (HR = 0.58, 95% CI: 0.53-0.63). A significant interaction effect between PA and metabolic status on CVD risk was found. Among MUO participants, individuals with PA had significantly decreased CVD risk when compared with no MVPA (HR = 0.87, 95% CI: 0.81-0.94 for low PA; HR = 0.85, 95% CI: 0.78-0.93 for medium PA; and HR = 0.86, 95% CI: 0.80-0.92 for high PA). The lowest CVD risk was observed in MHO & medium PA group when compared with MUO & no MVPA (HR = 0.45, 95% CI: 0.37-0.56). CONCLUSIONS: Both MHO and any MVPA were associated with reduced risk of CVD in adults with obesity, while PA could modify the relationship between metabolic status and CVD risk.

Recombinant human IL-37 attenuates acute cardiac allograft rejection in mice.

BACKGROUND: Allograft rejection remains a major obstacle to long-term graft survival. Although previous studies have demonstrated that IL-37 exhibited significant immunomodulatory effects in various diseases, research on its role in solid organ transplantation has not been fully elucidated. In this study, the therapeutic effect of recombinant human IL-37 (rhIL-37) was evaluated in a mouse cardiac allotransplantation model. METHODS: The C57BL/6 recipients mouse receiving BALB/c donor hearts were treated with rhIL-37. Graft pathological and immunohistology changes, immune cell populations, and cytokine profiles were analyzed on postoperative day (POD) 7. The proliferative capacities of Th1, Th17, and Treg subpopulations were assessed in vitro. Furthermore, the role of the p-mTOR pathway in rhIL-37-induced CD4+ cell inhibition was also elucidated. RESULTS: Compared to untreated groups, treatment of rhIL-37 achieved long-term cardiac allograft survival and effectively alleviated allograft rejection indicated by markedly reduced infiltration of CD4+ and CD11c+ cells and ameliorated graft pathological changes. rhIL-37 displayed significantly less splenic populations of Th1 and Th17 cells, as well as matured dendritic cells. The percentages of Tregs in splenocytes were significantly increased in the therapy group. Furthermore, rhIL-37 markedly decreased the levels of TNF-α and IFN-γ, but increased the level of IL-10 in the recipients. In addition, rhIL-37 inhibited the expression of p-mTOR in CD4+ cells of splenocytes. In vitro, similar to the in vivo experiments, rhIL-37 caused a decrease in the proportion of Th1 and Th17, as well as an increase in the proportion of Treg and a reduction in p-mTOR expression in CD4+ cells. CONCLUSIONS: We demonstrated that rhIL-37 effectively suppress acute rejection and induce long-term allograft acceptance. The results highlight that IL-37 could be novel and promising candidate for prevention of allograft rejection.

Glucose metabolism disorder related to follicular fluid exosomal miR-122-5p in cumulus cells of endometriosis patients.

MiR-122-5p, high expression in follicular fluid exosomes of patients with endometriosis, impairs the glucose metabolism function of cumulus cells and may further impair oocyte quality. Endometriosis (EMs) affects fertility in women of childbearing age in many ways. However, the mechanisms are complex, including the decrease in oocyte quality, which still needs to be studied. Exosomes, small vesicles responsible for intercellular information exchange, have been found to be involved in many biological events, such as follicle development and oocyte meiosis recovery. From the perspective of follicular fluid exosomes, this study aims to elucidate the mechanism of EMs-related oocyte quality decline. Follicular fluid was collected from three groups of women: the untreated EMs group (EMs_UT), the satisfactorily treated EMs group (EMs_ST) and the control group (Ctrl). Mouse cumulus oocyte complexes (COCs) were cocultured with exosomes extracted from follicular fluid during in vitro maturation. Oocyte quality and cumulus cell function were assessed. High-throughput sequencing of miRNA in exosomes was conducted. The function of differentially expressed miRNAs was studied by using SVOG cells (human ovarian granulosa cell line) transfected with miRNA mimic and inhibitor. Our date suggest that follicular fluid exosomes from patients with untreated EMs reduce the maturation rate and damage the quality of mouse oocytes. MiR-122-5p, overexpressed in untreated EMs, inhibits the translation of key aldolase enzymes related to glucose metabolism and partially impairs cumulus cells of endometriosis patients.

Suppression of frequency-mixing effect for pm-level heterodyne interferometers based on "zero coupling" optical path length control.

Optical path length (OPL) noise resulting from stray light significantly constrains interferometry displacement measurements in the low-frequency band. This paper presents an analytical model considering the presence of stray light in heterodyne laser interferometers. Due to the cyclic nonlinear coupling effect, there will be some special OPLs of stray light, minimizing the frequency-mixing impact to zero. Consequently, we propose a noise suppression scheme that locks the OPL of stray light at the zero coupling point. Therefore, we significantly enhanced the interference displacement measurement noise within the low-frequency band. Experimental results show that the interferometer achieves a displacement noise level lower than 6 pm/Hz1/2 covering 1 mHz.

Interleukin-37 contributes to endometrial regenerative cell-mediated immunotherapeutic effect on chronic allograft vasculopathy.

BACKGROUND AIMS: Chronic allograft vasculopathy (CAV) remains a predominant contributor to late allograft failure after organ transplantation. Several factors have already been shown to facilitate the progression of CAV, and there is still an urgent need for effective and specific therapeutic approaches to inhibit CAV. Human mesenchymal-like endometrial regenerative cells (ERCs) are free from the deficiencies of traditional invasive acquisition methods and possess many advantages. Nevertheless, the exact immunomodulation mechanism of ERCs remains to be elucidated. METHODS: C57BL/6 (B6) mouse recipients receiving BALB/c mouse donor abdominal aorta transplantation were treated with ERCs, negative control (NC)-ERCs and interleukin (IL)-37-/-ERCs (ERCs with IL-37 ablation), respectively. Pathologic lesions and inflammatory cell infiltration in the grafts, splenic immune cell populations, circulating donor-specific antibody levels and cytokine profiles were analyzed on postoperative day (POD) 40. The proliferative capacities of Th1, Th17 and Treg subpopulations were assessed in vitro. RESULTS: Allografts from untreated recipients developed typical pathology features of CAV, namely endothelial thickening, on POD 40. Compared with untreated and IL-37-/-ERC-treated groups, IL-37-secreting ERCs (ERCs and NC-ERCs) significantly reduced vascular stenosis, the intimal hyperplasia and collagen deposition. IL-37-secreting ERCs significantly inhibited the proliferation of CD4+T cells, reduced the proportions of Th1 and Th17 cells, but increased the proportion of Tregs in vitro. Furthermore, in vitro results also showed that IL-37-secreting ERCs significantly inhibited Th1 and Th17 cell responses, abolished B-cell activation, diminished donor-specific antibody production and increased Treg proportions. Notably, IL-37-secreting ERCs remarkably downregulated the levels of pro-inflammatory cytokines (interferon-γ, tumor necrosis factor-α, IL-1ß, IL-6 and IL-17A) and increased IL-10 levels in transplant recipients. CONCLUSIONS: The knockdown of IL-37 dramatically abrogates the therapeutic ability of ERCs for CAV. Thus, this study highlights that IL-37 is indispensable for ERC-mediated immunomodulation for CAV and improves the long-term allograft acceptance.

Practice effects of a breathing technique on pilots' cognitive and stress associated heart rate variability during flight operations.

Commercial pilots endure multiple stressors in their daily and occupational lives which are detrimental to psychological well-being and cognitive functioning. The Quick coherence technique (QCT) is an effective intervention tool to improve stress resilience and psychophysiological balance based on a five-minute paced breathing exercise with heart rate variability (HRV) biofeedback. The current research reports on the application of QCT training within an international airline to improve commercial pilots' psychological health and support cognitive functions. Forty-four commercial pilots volunteered in a one-month training programme to practise self-regulated QCT in day-to-day life and flight operations. Pilots' stress index, HRV time-domain and frequency-domain parameters were collected to examine the influence of QCT practice on the stress resilience process. The results demonstrated that the QCT improved psychophysiological indicators associated with stress resilience and cognitive functions, in both day-to-day life and flight operation settings. HRV fluctuations, as measured through changes in RMSSD and LF/HF, revealed that the resilience processes were primarily controlled by the sympathetic nervous system activities that are important in promoting pilots' energy mobilization and cognitive functions, thus QCT has huge potential in facilitating flight performance and aviation safety. These findings provide scientific evidence for implementing QCT as an effective mental support programme and controlled rest strategy to improve pilots' psychological health, stress management, and operational performance.

Cloning, heterologous expression, and molecular characterization of a highly active and stable non-specific endonuclease from Pseudomonas fluorescens.

Non-specific endonucleases can be used for the digestion of nucleic acids because they hydrolyze DNA/RNA into 3-5 base pairs (bp) length oligonucleotide fragments without strict selectivity. In this work, a novel non-specific endonuclease from Pseudomonas fluorescens (PfNuc) with high activities for both DNA and RNA was successfully cloned and expressed in Escherichia coli. The production of PfNuc in flask scale could be achieved to 1.73 × 106 U/L and 4.82 × 106 U/L for DNA and RNA by investigation of the culture and induction conditions. The characterization of PfNuc indicated that it was Mg2+-dependent and the catalytic activity was enhanced by 3.74 folds for DNA and 1.06 folds for RNA in the presence of 5 mM Mg2+. The specific activity of PfNuc for DNA was 1.44 × 105 U/mg at pH 8.0 and 40 °C, and 3.93 × 105 U/mg for RNA at pH 8.5 and 45 °C. The Km of the enzyme for both DNA and RNA was close to 43 µM. The Vmax was 6.40 × 105 U/mg and 1.11 × 106 U/mg for DNA and RNA, respectively. There was no observed activity loss when PfNuc was stored at 4 °C and - 20 °C after 28 days or 10 repeated freeze-thaw cycles at - 80 °C. Molecular docking revealed that PfNuc formed 17 and 19 hydrogen bonds with single-stranded RNA and double-stranded DNA, respectively. These results could explain the high activity and stability of PfNuc, suggesting its great potential applications in the industry and clinic.

Baicalin attenuates PD-1/PD-L1 axis-induced immunosuppression in piglets challenged with Glaesserella parasuis by inhibiting the PI3K/Akt/mTOR and RAS/MEK/ERK signalling pathways.

Infection of piglets with Glaesserella parasuis (G. parasuis) induces host immunosuppression. However, the mechanism underlying the immunosuppression of piglets remains unclear. Activation of the PD-1/PD-L1 axis has been shown to trigger host immunosuppression. Baicalin possesses anti-inflammatory and immunomodulatory functions. However, whether baicalin inhibits PD-1/PD-L1 activation and thus alleviates host immunosuppression has not been investigated. In this study, the effect of baicalin on the attenuation of piglet immunosuppression induced by G. parasuis was evaluated. Seventy piglets were randomly divided into the control group, infection group, levamisole group, BMS-1 group, 25 mg/kg baicalin group, 50 mg/kg baicalin group and 100 mg/kg baicalin group. Following pretreatment with levamisole, BMS-1 or baicalin, the piglets were challenged with 1 × 108 CFU of G. parasuis. Our results showed that baicalin, levamisole and BMS-1 modified routine blood indicators and biochemical parameters; downregulated IL-1ß, IL-10, IL-18, TNF-α and IFN-γ mRNA expression; and upregulated IL-2 and IL-8 mRNA expression in blood. Baicalin, levamisole and BMS-1 increased the proportions of CD3+ T cells, CD3+CD4+ T cells, CD3+CD8+ T cells and CD3-CD21+ B cells in the splenocyte population, increased the proportions of CD3+ T cells, CD3+CD4+ T cells and CD3+CD8+ T cells in the blood, and inhibited PD-1/PD-L1 and TIM-3 activation. Baicalin, levamisole and BMS-1 reduced p-PI3K, p-Akt, and p-mTOR expression, the p-MEK1/2/MEK1/2 and p-ERK1/2/ERK1/2 ratios and increased RAS expression. Baicalin, levamisole and BMS-1 provided substantial protection against G. parasuis challenge and relieved tissue histopathological damage. Our findings might provide new strategies for controlling G. parasuis infection and other immunosuppressive diseases.

Electrochemical oxidative selective halogenation of pyrazolones for the synthesis of 4-halopyrazolones.

An efficient and environmentally friendly electrochemical oxidative selective halogenation of pyrazolones has been developed under conditions free of metals, external oxidants, and external supporting electrolytes. The reaction demonstrates good functional group tolerance and maintains high efficiency in large-scale synthesis, yielding moderate to excellent yields of the desired 4-halopyrazolones. This method provides a green and convenient route for the direct installation of a halogen moiety into bioactive pyrazolone derivatives, which can be utilized in a myriad of applications.

Natural Attenuation of 2,4-Dichlorophenol in Fe-Rich Soil during Redox Oscillations: Anoxic-Oxic Coupling Mechanism.

Natural attenuation of organic contaminants can occur under anoxic or oxic conditions. However, the effect of the coupling anoxic-oxic process, which often happens in subsurface soil, on contaminant transformation remains poorly understood. Here, we investigated 2,4-dichlorophenol (2,4-DCP) transformation in Fe-rich soil under anoxic-oxic alternation. The anoxic and oxic periods in the alternating system showed faster 2,4-DCP transformation than the corresponding control single anoxic and oxic systems; therefore, a higher transformation rate (63.4%) was obtained in the alternating system relative to control systems (27.9-42.4%). Compared to stable pH in the alternating system, the control systems presented clear OH- accumulation, caused by more Fe(II) regeneration in the control anoxic system and longer oxygenation in the control oxic system. Since 2,4-DCP was transformed by ion exchangeable Fe(II) in soil via direct reduction in the anoxic process and induced ·OH oxidation in the oxic process, OH- accumulation was unbeneficial because it competed for proton with direct reduction and inhibited •OH generation via complexing with Fe(II). However, the alternating system exhibited OH--buffering capacity via anoxic-oxic coupling processes because the subsequent oxic periods intercepted Fe(II) regeneration in anoxic periods, while shorter exposure to O2 in oxic periods avoided excessive OH- generation. These findings highlight the significant role of anoxic-oxic alternation in contaminant attenuation persistently.

New Insights into Aggregation Behaviors of the UV-Irradiated Dissolved Biochars (DBioCs) in Aqueous Environments: Effects of Water Chemistries and Variation in the Hamaker Constant.

The aggregation behavior of ubiquitous dissolved black carbon (DBC) largely affects the fate and transport of its own contaminants and the attached contaminants. However, the photoaging processes and resulting effects on its colloidal stability remain yet unknown. Herein, dissolved biochars (DBioCs) were extracted from common wheat straw biochar as a proxy for an anthropogenic DBC. The influences of UV radiation on their aggregation kinetics were systematically investigated under various water chemistries (pH, electrolytes, and protein). The environmental stability of the DBioCs before and after radiation was further verified in two natural water samples. Hamaker constants of pristine and photoaged DBioCs were derived according to Derjaguin-Landau-Verwey-Overbeek (DLVO) prediction, and its attenuation (3.19 ± 0.15 × 10-21 J to 1.55 ± 0.07 × 10-21 J after 7 days of radiation) was described with decay kinetic models. Pearson correlation analysis revealed that the surface properties and aggregation behaviors of DBioCs were significantly correlated with radiation time (p < 0.05), indicating its profound effects. Based on characterization and experimental results, we proposed a three-stage mechanism (contended by photodecarboxylation, photo-oxidation, and mineral exposure) that DBioCs might experience under UV radiation. These findings would provide an important reference for potential phototransformation processes and relevant behavioral changes that DBC may encounter.

Fresh fruit, dried fruit, raw vegetables, and cooked vegetables consumption associated with progression trajectory of type 2 diabetes: a multi-state analysis of a prospective cohort.

PURPOSE: To examine the effects of fresh fruit, dried fruit, raw vegetables, and cooked vegetables on type 2 diabetes (T2D) progression trajectory. METHODS: We included 429,886 participants in the UK Biobank who were free of diabetes and diabetes complications at baseline. Food groups were determined using a validated food frequency questionnaire. Outcomes were T2D incidence, complications, and mortality. Multi-state model was used to analyze the effects of food groups on T2D progression. RESULTS: During a follow-up of 12.6 years, 10,333 incident T2D cases were identified, of whom, 3961 (38.3%) developed T2D complications and 1169 (29.5%) died. We found that impacts of four food groups on T2D progression varied depending on disease stage. For example, compared to participants who ate less than one piece of dried fruit per day, the hazard ratios and 95% confidence intervals for those who ate ≥ 2 pieces of dried fruit per day were 0.82 (0.77, 0.87), 0.88 (0.85, 0.92), and 0.86 (0.78, 0.95) for transitions from diabetes-free state to incident T2D, from diabetes-free state to total death, and from incident T2D to T2D complications, respectively. Higher intake of fresh fruit was significantly associated with lower risk of disease progression from diabetes-free state to all-cause death. Higher intake of raw and cooked vegetables was significantly associated with lower risks of disease progression from diabetes-free state to incident T2D and to total death. CONCLUSIONS: These findings indicate that higher intake of fresh fruit, dried fruit, raw vegetables, and cooked vegetables could be beneficial for primary and secondary prevention of T2D.

Microbial community succession and responses to internal environmental drivers throughout the operation of constructed wetlands.

Constructed wetlands (CWs) have been widely used to ensure effective domestic wastewater treatment. Microorganisms-derived CWs have received extensive attention as they play a crucial role. However, research on the succession patterns of microbial communities and the influencing mechanisms of internal environmental factors throughout entire CW operations remains limited. In this context, three parallel-operated CWs were established in this study to assess the microbial communities and their influencing environmental factors at different substrate depths throughout the operation process using 16S rRNA gene high-throughput sequencing and metagenomic sequencing. The results showed gradual reproduction and accumulation of the microbial communities throughout the CW operation. Although gradual increases in the richness and diversity of the microbial communities were found, there were decreases in the functional expression of the dominant microbial species. The excessive accumulation of microorganisms will decrease the oxidation-reduction potential (ORP) within CWs and attenuate their influence on effluent. Dissolved oxygen (DO) was the major factor influencing the microbial community succession over the CW operation. The main identified functional bacterial genera responsible for the ammonium oxidation, nitrification, and denitrification processes in the CWs were Nitrosospira, Nitrobacter, Nitrospira, Rhodanobacter, and Nakamurella. The narG gene was identified as a key functional gene linking various components of nitrogen cycling, while pH, electrical conductivity (EC), and ORP were the major environmental factors affecting the metabolism characteristics of nitrogen functional microorganisms. This study provides a theoretical basis for the effective regulation of related microbial communities to achieve long-term, efficient, and stable CW operations.

Adaptive Bayesian information borrowing methods for finding and optimizing subgroup-specific doses.

In precision oncology, integrating multiple cancer patient subgroups into a single master protocol allows for the simultaneous assessment of treatment effects in these subgroups and promotes the sharing of information between them, ultimately reducing sample sizes and costs and enhancing scientific validity. However, the safety and efficacy of these therapies may vary across different subgroups, resulting in heterogeneous outcomes. Therefore, identifying subgroup-specific optimal doses in early-phase clinical trials is crucial for the development of future trials. In this article, we review various innovative Bayesian information-borrowing strategies that aim to determine and optimize subgroup-specific doses. Specifically, we discuss Bayesian hierarchical modeling, Bayesian clustering, Bayesian model averaging or selection, pairwise borrowing, and other relevant approaches. By employing these Bayesian information-borrowing methods, investigators can gain a better understanding of the intricate relationships between dose, toxicity, and efficacy in each subgroup. This increased understanding significantly improves the chances of identifying an optimal dose tailored to each specific subgroup. Furthermore, we present several practical recommendations to guide the design of future early-phase oncology trials involving multiple subgroups when using the Bayesian information-borrowing methods.

Comparison of the clinical characteristics in parents and their children in a series of family clustered Mycoplasma pneumoniae infections.

BACKGROUND: Mycoplasma pneumoniae infections have increased in China recently, causing some evidence of familial clustering. The purpose of this study was to compare the clinical features of parents and children in cases of familial clustering of Mycoplasma pneumoniae infection. METHODS: A retrospective analysis was performed on the cases of familial clustering of Mycoplasma pneumoniae infection, and the clinical characteristics of parents and children were compared. RESULTS: We identified 63 families, of these, 57 (65.5%) adults and 65 (94.2%) children required hospitalization. Fifty-seven adults (mean age 35.1 ± 4.6 years, 80.7% female) and 55 children (mean age 6.3 ± 3.9 years, 54.5% female) were included in the analysis. The incidence of mycoplasma infection in adults had increased gradually over the past year, while the rate in children had spiked sharply since June 2023. The clinical symptoms were similar in the two groups, mainly fever and cough. The peak temperature of children was higher than that of adults (39.1 ± 0.7℃ vs 38.6 ± 0.7℃, p = 0.004). Elevated lactate dehydrogenase was more common in children than in adults (77.8% vs 11.3%, p < 0.001). Bronchial pneumonia and bilateral involvement were more common in children, while adults usually had unilateral involvement. Three (60%) adults and 21 (52.5%) children were macrolide-resistant Mycoplasma pneumoniae infected. Children were more likely to be co-infected (65.5% vs 22.8%, p < .001). Macrolides were used in most children and quinolones were used in most adults. Ten (18.2%) children were diagnosed with severe Mycoplasma pneumoniae pneumonia, whereas all adults had mild disease. Children had a significantly longer fever duration than adults ((5.6 ± 2.2) days vs (4.1 ± 2.2) days, p = 0.002). No patient required mechanical ventilation or died. CONCLUSIONS: Mycoplasma pneumoniae infection shows a familial clustering epidemic trend at the turn of summer and autumn, with different clinical characteristics between parents and children.

Developing a Predictive Model for Minimal or Mild Endometriosis as a Clinical Screening Tool in Infertile Women: Uterosacral Tenderness as a Key Predictor.

STUDY OBJECTIVE: To develop a noninvasive predictive model based on patients with infertility for identifying minimal or mild endometriosis. DESIGN: A retrospective cohort study. SETTING: This study was conducted at a tertiary referral center. PATIENTS: A total of consecutive 1365 patients with infertility who underwent laparoscopy between January 2013 and August 2020 were divided into a training set (n = 910) for developing the predictive model and a validation set (n = 455) to confirm the model's prediction efficiency. The patients were randomly assigned in a 2:1 ratio. INTERVENTIONS: Sensitivities, specificities, area under the curve, the Hosmer-Lemeshow goodness of fit test, Net Reclassification Improvement index, and Integrated Discrimination Improvement index were evaluated in the training set to select the optimum model. In the validation set, the model's discriminations, calibrations, and clinical use were tested for validation. MEASUREMENTS AND MAIN RESULTS: In the training set, there were 587 patients with minimal or mild endometriosis and 323 patients without endometriosis. The combination of clinical parameters in the model was evaluated for both statistical and clinical significance. The best-performing model ultimately included body mass index, dysmenorrhea, dyspareunia, uterosacral tenderness, and serum cancer antigen 125 (CA-125). The nomogram based on this model demonstrated sensitivities of 87.7% and 93.3%, specificities of 68.6% and 66.4%, and area under the curve of 0.84 (95% confidence interval 0.81-0.87) and 0.85 (95% confidence interval 0.80-0.89) for the training and validation sets, respectively. Calibration curves and decision curve analyses also indicated that the model had good calibration and clinical value. Uterosacral tenderness emerged as the most valuable predictor. CONCLUSION: This study successfully developed a predictive model with high accuracy in identifying infertile women with minimal or mild endometriosis based on clinical characteristics, signs, and cost-effective blood tests. This model would assist clinicians in screening infertile women for minimal or mild endometriosis, thereby facilitating early diagnosis and treatment.