HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis.

Background: BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. Objectives: This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation's effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. Design: This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. Methods: We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Results: Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers (p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64-1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61-1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. Conclusion: HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer.

Long-term prognosis of patients with gallbladder carcinoma after curative-intent resection based on changes in the ratio of carbohydrate antigen 19-9 to total bilirubin (CA19-9/TB): a multicenter retrospective cohort study.

BACKGROUND: The prognostic value of carbohydrate antigen 19-9 (CA19-9) is known to be affected by elevated bilirubin levels in patients with gallbladder carcinoma (GBC). The clinical significance of changes in the ratio of CA19-9 levels to total bilirubin (TB) levels in patients with GBC after curative-intent resection remains unknown. The aim of this study was to determine the prognostic value of changes in preoperative and postoperative CA19-9/TB ratio in these patients. METHODS: Prospectively colleced data on consecutive patients who underwent curative-intent resection for GBC between January 2015 and December 2020 stored in a multicenter database from 10 hospitals were analysed in this retrospective cohort study. Based on the adjusted CA19-9 defined as the ratio of CA19-9 to TB, and using 2×103 U/µmol as the upper normal value, patients were divided into a normal group (with normal preoperative and postoperative adjusted CA19-9), a normalization group (with abnormal preoperative but normal postoperative adjusted CA19-9), and a non-normalization group (with abnormal postoperative adjusted CA19-9). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). The log-rank test was used to compare OS and RFS among the groups. The Cox regression model was used to determine factors independently associated with OS and RFS. RESULTS: The normal group (n=179 patients) and the normalization group (n=73 patients) had better OS and RFS than the non-normalization group (n=65 patients) (the 3-year OS rates 72.0%, 58.4% and 24.2%, respectively; the RFS rates 54.5%, 25.5% and 11.8%, respectively; both P<0.001). There were no significant differences between the normal and the normalization groups in OS and RFS (OS, P=0.255; RFS, P=0.130). Cox regression analysis confirmed that the non-normalization group was independently associated with worse OS and RFS. Subgroup analysis revealed that the non-normalization group of patients who received adjuvant therapy had significantly improved OS and RFS as compared to those who did not receive adjuvant therapy (OS, P=0.025; RFS, P=0.003). CONCLUSIONS: Patients with GBC who underwent curative-intent surgical resection with postoperative abnormal levels of adjusted CA19-9 (the CA19-9/TB ratio) were associated with poorer long-term survival outcomes. Adjuvant therapy after surgery improved the long-term outcomes of these patients.

Changes in health-promoting metabolites associated with high-altitude adaptation in honey.

The levels of metabolites in honey are influenced by floral origin, production region, and bee species. However, how environmental factors affect honey quality remains unclear. Based on untargeted metabolomics and using UPLC Q-Orbitrap MS, we analyzed 3596 metabolites in 51 honey samples from Yunnan and Shennongjia. Comparative analysis revealed that geniposidic acid, kynurenic acid and caffieine accumulated at significantly different levels between Shennongjia and Yunnan honey. Based on cluster structure analysis, 36 Yunnan honey samples were divided into two distinct groups by altitude. Notably, quercetin, hyperoside, taxifolin, rutin, tryptophan, astragalin and phenylalanine were higher levels in high-altitude honey (>1700 m), whereas abscisic acid was higher levels in low-altitude honey (≤1700 m). Among these, significantly elevated levels of hyperoside, taxfolin, astragalin, and tryptophan were observed in honey collected from high-altitude areas in Shennongjia. Our findings highlight the effect of altitude on honey health-promoting components, providing valuable insights into honey quality.

Efficacy and safety of precision-guided transjugular extrahepatic portosystemic shunt (TEPS) in the management of cavernous transformation of the portal vein with portal hypertension: a case series.

BACKGROUND AND AIMS: Performing a Transjugular intrahepatic portal system shunt (TIPS) in patients with portal vein cavernous transformation (CTPV) poses significant challenges. As an alternative, transjugular extrahepatic portal vein shunt (TEPS) may offer a potential solution for these patients. Nonetheless, the effectiveness and safety of TEPS remain uncertain. This case series study aimed to evaluate the efficacy and safety of TEPS in treating patients with CTPV portal hypertension complications. METHODS: The study encompassed a cohort of 22 patients diagnosed with CTPV who underwent TEPS procedures. Of these, 13 patients manifested recurrent hemorrhagic episodes subsequent to conventional therapies, 8 patients grappled with recurrent or refractory ascites, and 1 patient experienced acute bleeding but refused endoscopic treatment. Comprehensive postoperative monitoring was conducted for all patients to rigorously evaluate both the technical and clinical efficacy of the intervention, as well as long-term outcomes. RESULTS: The overall procedural success rate among the 22 patients was 95.5% (21/22).During the TEPS procedure, nine patients were guided by percutaneous splenic access, three patients were guided by percutaneous hepatic access, five patients were guided by transmesenteric vein access from the abdomen, and two patients were guided by catheter marking from the hepatic artery. Additionally, guidance for three patients was facilitated by pre-existing TIPS stents. The postoperative portal pressure gradient following TEPS demonstrated a statistically significant decrease compared to preoperative values (24.95 ± 3.19 mmHg vs. 11.48 ± 1.74 mmHg, p < 0.01).Although three patients encountered perioperative complications, their conditions ameliorated following symptomatic treatment, and no procedure-related fatalities occurred. During a median follow-up period of 14 months, spanning a range of 5 to 39 months, we observed four fatalities. Specifically, one death was attributed to hepatocellular carcinoma, while the remaining three were ascribed to chronic liver failure. During the follow-up period, no instances of shunt dysfunction were observed. CONCLUSIONS: Precision-guided TEPS appears to be a safe and efficacious intervention for the management of CTPV.

Shanghai Community-Based Schizophrenia Cohort (SCS): a protocol for establishing a longitudinal cohort and research database of patients with schizophrenia receiving community-based mental health treatment.

INTRODUCTION: Drivers for remission, relapse and violence-related behaviour among patients with schizophrenia are the most complicated issue. METHODS AND ANALYSIS: This study aims to recruit a longitudinal cohort of patients with schizophrenia. Two suburban districts and two urban districts were randomly selected according to health service facilities, population, geographical region and socioeconomic status. Individuals (>18 years old) who received a diagnosis of schizophrenia following the International Classification of Diseases (10th edition) criteria within the past 3 years will be invited as participants. Assessments will be carried out in local community health centres. Data will be used to (1) establish a community-based schizophrenia cohort and biobank, (2) prospectively determine the course of multidimensional functional outcomes of patients with schizophrenia who are receiving community-based mental health treatment, and (3) map the trajectories of patients with schizophrenia and prospectively determine the course of multidimensional outcomes based on the differential impact of potentially modifiable moderators. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the Human Research Ethics Committee of Shanghai Mental Health Center (2021-67). Results of the study will be disseminated through peer-reviewed journals. If effective, related educational materials will be released to the public.

The Co-oligomers of Aß42 and Human Islet Amyloid Polypeptide Exacerbate Neurotoxicity and Alzheimer-like Pathology at Cellular Level.

The Aß hypothesis has long been central to Alzheimer's disease (AD) theory, with a recent surge in attention following drug approvals targeting Aß plaque clearance. Aß42 oligomers (AßO) are key neurotoxins. While ß-amyloid (Aß) buildup is a hallmark of AD, postmortem brain analyses have unveiled human islet amyloid polypeptide (hIAPP) deposition in AD patients, suggesting a potential role in Alzheimer's pathology. This study investigates the neurotoxic effects of co-aggregates of Aß42 and hIAPP, specifically focusing on their impact on cell survival, apoptosis, and AD-like pathology. We analyzed and compared the impact of AßO and Aß42-hIAPP on cell survival in SH-SY5Y cells, apoptosis and inducing AD-like pathology in glutamatergic neurons. Aß42-hIAPP co-oligomers exhibited significantly greater toxicity, causing 2.3-3.5 times higher cell death compared to AßO alone. Furthermore, apoptosis rates were significantly exacerbated in glutamatergic neurons when exposed to Aß42-hIAPP co-oligomers. The study also revealed that Aß42-hIAPP co-oligomers induced typical AD-like pathology in glutamatergic neurons, including the presence of Aß deposits (detected by 6E10 and 4G8 immunofluorescence) and alterations in tau protein (changes in total tau HT7, phosphorylated tau AT8, AT180). Notably, Aß42-hIAPP co-oligomers induced a more severe AD pathology compared to AßO alone. These findings provide compelling evidence for the heightened toxicity of Aß42-hIAPP co-oligomers on neurons and their role in exacerbating AD pathology. The study contributes novel insights into the pathogenesis of Alzheimer's disease, highlighting the potential involvement of hIAPP in AD pathology. Together, these findings offer novel insights into AD pathogenesis and routes for constructing animal models.

Incidence and Characteristics of Knee Ligament and Meniscal Injuries in Patients With Posterolateral Tibial Plateau Fractures.

Background: Anterior cruciate ligament (ACL) tears are commonly seen with concomitant injuries to the posterolateral tibial plateau, while the occurrence of ACL injuries in posterolateral tibial plateau fractures (PTPFs) remains unclear. Purpose: To (1) explore the incidence of knee ligament (anterior or posterior cruciate ligament, medial or lateral collateral ligament) and medial or lateral meniscus injuries in patients with PTPF and (2) find reliable PTPF-related parameters to predict the risk of knee ligament and meniscal injuries. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients diagnosed with PTPF who had computed tomography and magnetic resonance imaging (MRI) data were identified. Morphological parameters of the PTPF were measured on sagittal computed tomography images. Knee ligament and meniscal injuries were assessed using MRI. The association of ACL injuries with meniscal injuries was analyzed. Receiver operating characteristic (ROC) analysis was used to determine the value and cutoff point of the PTPF morphological parameters for diagnosing complete in-substance ACL tears. Results: Overall, 113 patients with PTPF were included. ACL injuries were present in 94 (83.2%) patients, including 43 (38.1%) avulsion fractures and 28 (24.8%) complete in-substance tears. Patients with in-substance ACL tears had a higher incidence of lateral meniscus posterior horn tears compared with the other patients (PBonferroni < .001). ROC analysis revealed that both the fracture depression angle (cutoff point, 25.5°) and the posterior articular surface loss percentage (cutoff point, 37.5%) had a sensitivity >90% and a specificity >80% for the diagnosis of complete in-substance ACL tears. Conclusion: ACL injuries were seen in 83.2% of the study patients. Complete in-substance ACL tears were associated with an increased incidence of lateral meniscus posterior horn tears. Among PTPF parameters, fracture depression angle and posterior articular surface loss percentage showed a high predictive value for the presence of complete in-substance ACL tears, thereby reducing delays in diagnosis and treatment.

A crossover study to evaluate the pharmacokinetics and bioequivalence of hydroxychloroquine tablets in healthy Chinese subjects.

AIMS: Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design. MATERIALS AND METHODS: This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration. RESULTS: A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in Cmax, AUC0-72h, and T1/2 between the test and reference preparation (p > 0.05). Food had no significant effect on Cmax and T1/2 (p > 0.05), but AUC0-72h values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax and AUC0-72h were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC0-72h values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported. CONCLUSION: The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.

Exploring non-curative endoscopic submucosal dissection: Current treatment optimization and future indication expansion.

The increasing popularity of endoscopic submucosal dissection (ESD) as a treatment for early gastric cancer has highlighted the importance of quality assessment in achieving curative resections. This article emphasizes the significance of evaluating ESD quality, not only for curative cases but also for non-curative ones. Postoperative assessment relies on the endoscopic curability (eCura) classification, but management strategies for eCuraC-1 tumour with a positive horizontal margin are unclear. Current research primarily focuses on comparing additional surgical procedures in high-risk patients, while studies specifically targeting eCuraC-1 patients are limited. Exploring management strategies and follow-up outcomes for such cases could provide valuable insights. Furthermore, the application of molecular imaging using near-infrared fluorescent tracers holds promise for precise tumour diagnosis and navigation, potentially impacting the management of early-stage gastric cancer patients. Advancing research in these areas is essential for improving the overall efficacy of endoscopic techniques and refining treatment indications.

H2S donor S-propargyl-cysteine for skin wound healing improvement via smart transdermal delivery.

Hydrogen sulfide for wound healing has drawn a lot of attention recently. In this research, the S-propargyl-cysteine (SPRC), an endogenous H2S donor, was loaded on carbomer hydrogel, and a copper sheet rat burn model was developed. Pathological changes in rat skin tissue were examined using hematoxylin-eosin (HE) and Masson staining. The immunohistochemistry (IHC) staining was performed to detect the expression of Collagen I (Col I) and Collagen III (Col III). The mRNA levels of interleukin (IL)-6, Col Iα2, Col IIIα1, tissue inhibitors of metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-ß1 were examined by quantitative real-time chain polymerase reaction. The findings demonstrated that the collagen layer was thicker in the SPRC group during the proliferative phase, SPRC hydrogel promoted VEGF expression. In the late stage of wound healing, the expression of IL-6, TIMP-1, MMP-9, and TGF-ß1 was inhibited, and the Col I content was closer to that of normal tissue. These results surface that SPRC hydrogel can promote wound healing and play a positive role in reducing scar formation. Our results imply that SPRC can facilitate wound healing and play a positive role in reducing scar formation.

Activated hedgehog gene pattern correlates with dismal clinical outcome and tumor microenvironment heterogeneity in hepatocellular carcinoma.

Background: Activation of the Hedgehog signaling pathway is linked to the initiation and development of human hepatocellular carcinoma (HCC). However, its impact on clinical outcomes and the HCC microenvironment remains unclear. Methods: We performed comprehensive analyses of Hedgehog pathway genes in a large cohort of HCC patients. Specifically, we utilized univariate Cox regression analysis to identify Hedgehog genes linked to overall survival, and the LASSO algorithm was used to construct a Hedgehog-related gene pattern. We subsequently examined the correlation between the Hedgehog pattern and the HCC microenvironment employing the CIBERSORT and ssGSEA algorithms. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the anti-PD-L1 treatment dataset (IMvigor210) are used to evaluate the clinical response of the Hedgehog pattern in predicting immune checkpoint inhibitors. Results: We found that the Hedgehog activation score (HHAS), a prognostic score based on 11 Hedgehog genes, was significantly associated with HCC patient survival. Patients exhibiting high HHAS experienced markedly reduced survival rates compared to those with low HHAS, and HHAS emerged as an independent prognostic factor for HCC. Functional enrichment analysis unveiled the association of the HHAS phenotype with functions related to the immune system, and further investigation demonstrated that HCC patients exhibiting low HHAS displayed elevated levels of anti-tumor immune activation in CD8+ T cells, while high HHAS were linked to immune escape phenotypes and increased infiltration of immune suppressive cells. In addition, in the Immune Checkpoint Inhibitor (ICI) cohort of IMvigor210, patients with higher HHAS had worse ICI treatment outcomes and shortened survival time, indicating that the HHAS is a useful indicator for predicting patient response to immunotherapy. Conclusions: In summary, our study offers valuable insights for advancing research on Hedgehog and its impact on tumor immunity, which provides an opportunity to optimize prognosis and immune therapy for HCC.

Integrated Metagenomic and Metabolomic Analysis on Two Competing Mussels, Mytella strigata and Perna viridis, in China.

Biological invasion is a primary direct driver of biodiversity loss. Recently, owing to exploitation competition with an invasive mussel, Mytella strigata (Hanley, 1843), there has been a drastic decrease in the population of native Perna viridis (Linnaeus, 1758) in several western Pacific regions. In the present study, intestinal microbiota, metabolome, and key digestive enzyme activities were compared between the two competing mussels, M. strigata and P. viridis, to elucidate the differences in intestinal microbiota and metabolic points. We observed that Proteobacteria, Firmicutes, and Bacteroidota were the three predominant bacterial phyla in the two species. The relative abundance of Bacteroidota related to carbohydrate-degrading ability was significantly higher in M. strigata than in P. viridis. Compared to P. viridis, different metabolites including maltose and trehalose were enriched in M. strigata. Lastly, higher carbohydrases activities of alpha-amylase, cellulase, and xylanase were observed in M. strigata than in P. viridis. These differences might play an important role in the adaptation process of M. strigata to the new environment. This study provides important basic knowledge for investigating the competition between M. strigata and P. viridis in terms of food resources utilization.

Bacteria-mediated resistance of neutrophil extracellular traps to enzymatic degradation drives the formation of dental calculi.

Dental calculi can cause gingival bleeding and periodontitis, yet the mechanism underlying the formation of such mineral build-ups, and in particular the role of the local microenvironment, are unclear. Here we show that the formation of dental calculi involves bacteria in local mature biofilms converting the DNA in neutrophil extracellular traps (NETs) from being degradable by the enzyme DNase I to being degradation resistant, promoting the nucleation and growth of apatite. DNase I inhibited NET-induced mineralization in vitro and ex vivo, yet plasma DNases were ineffective at inhibiting ectopic mineralization in the oral cavity in rodents. The topical application of the DNA-intercalating agent chloroquine in rodents fed with a dental calculogenic diet reverted NET DNA to its degradable form, inhibiting the formation of calculi. Our findings may motivate therapeutic strategies for the reduction of the prevalence of the deposition of bacteria-driven calculi in the oral cavity.

YTHDF1 promotes the viability and self­renewal of glioma stem cells by enhancing LINC00900 stability.

YTHDF1, an N6­methyladenosine (m6A)­binding protein, is significantly upregulated in glioma tissues. The present study investigated the molecular mechanism underlying the regulatory effects of YTHDF1 on the viability, invasion and self­renewal of glioma stem cells (GSCs). Glioma and normal brain tissues were collected, and reverse transcription­quantitative PCR and western blotting were used to measure the gene and protein expression levels, respectively. Methylated RNA immunoprecipitation­PCR was used to assess the m6A modification level of the target gene. Subsequently GSCs were induced, and YTHDF1 and LINC00900 gene regulation was carried out using lentiviral infection. The viability, invasion and self­renewal of GSCs were assessed by Cell Counting Kit­8, Transwell and sphere formation assays, respectively. Binding between YTHDF1 and LINC00900 was verified by RNA immunoprecipitation and RNA pull­down assays. The targeted binding of microRNA (miR)­1205 to the LINC00900/STAT3 3'­UTR was verified using a luciferase reporter assay. The results revealed that YTHDF1 and LINC00900 expression levels were significantly upregulated in glioma tissues, and a high m6A modification level in LINC00900 transcripts was detected in glioma tissues. Overexpression of YTHDF1 promoted GSC viability, invasion and self­renewal, whereas knockdown of YTHDF1 had the opposite effects. In addition, YTHDF1 maintained the stability of LINC00900 and upregulated its expression through binding to it, thereby promoting GSC viability, invasion and self­renewal. Furthermore, LINC00900 promoted GSC viability, invasion, self­renewal and tumor growth by regulating the miR­1205/STAT3 axis. In conclusion, YTHDF1 promotes GSC viability and self­renewal by regulating the LINC00900/miR­1205/STAT3 axis.

Effect of pretreatment with a small dose of esketamine on sufentanil-induced cough during anesthesia induction: a randomized controlled trial.

BACKGROUND: Sufentanil-induced cough is common during the induction of anesthesia. The objective of this study was to determine whether pretreatment with a small dose of esketamine is effective in treating sufentanil-induced cough. METHODS: 220 patients were screened, and 200 patients who had scheduled elective surgery and were between 18 and 70 years old were randomly divided into two groups. Before sufentanil was administered, esketamine group (group K) was injected with 0.15 mg/kg esketamine at 5 s, and control group (group C) was administered with the same volume. Within 1 min after sufentanil(0.4ug/kg) injection during induction, cough incidence and severity were evaluated. After sufentanil was injected, we recorded its hemodynamic changes and side effects. RESULTS: In the esketamine group (group K) and control group (group C), there was an incidence of cough of 5 and 34%, respectively. The esketamine group (group K) had a significantly lower incidence and severity of cough compared to the control group (group C) immediately after sufentanil injection (P < 0.05). MAP and HR did not differ significantly between the two groups during three different times of general anesthesia induction (P > 0.05). CONCLUSION: In our study, we found that sufentanil-induced cough was significantly reduced by pretreatment with 0.15 mg/kg esketamine, but with no significant changes in the hemodynamic status. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2200063821, registered date: 17/09/2022), http://www.chictr.org.cn.

Combinatorial expression of γ-protocadherins regulates synaptic connectivity in the mouse neocortex.

In the process of synaptic formation, neurons must not only adhere to specific principles when selecting synaptic partners but also possess mechanisms to avoid undesirable connections. Yet, the strategies employed to prevent unwarranted associations have remained largely unknown. In our study, we have identified the pivotal role of combinatorial clustered protocadherin gamma (γ-PCDH) expression in orchestrating synaptic connectivity in the mouse neocortex. Through 5' end single-cell sequencing, we unveiled the intricate combinatorial expression patterns of γ-PCDH variable isoforms within neocortical neurons. Furthermore, our whole-cell patch-clamp recordings demonstrated that as the similarity in this combinatorial pattern among neurons increased, their synaptic connectivity decreased. Our findings elucidate a sophisticated molecular mechanism governing the construction of neural networks in the mouse neocortex.

A genome-wide association study for resistance to Fusarium wilt (Fusarium oxysporum f. sp. vasinfectum) race 4 in diploid cotton (Gossypium arboreum) and resistance transfer to tetraploid Gossypium hirsutum.

Fusarium wilt, caused by the soilborne fungus Fusarium oxysporum f. sp. vasinfectum (FOV), is a devastating disease affecting cotton (Gossypium spp.) worldwide. Understanding the genetic basis of resistance in diploid cotton and successfully transferring the resistance to tetraploid Upland cotton (G. hirsutum) are crucial for developing resistant cotton cultivars. Although numerous studies have been conducted to investigate the genetic basis of Fusarium wilt in tetraploid cotton, little research has been conducted on diploid species. In this study, an association mapping panel consisting of 246 accessions of G. arboreum, was used to identify chromosomal regions for FOV race 4 (FOV4) resistance based on foliar disease severity ratings in four greenhouse tests. Through a genome-wide association study (GWAS) based on 7,009 single nucleotide polymorphic (SNP) markers, 24 FOV4 resistance QTLs, including three major QTLs on chromosomes A04, A06, and A11, were detected. A validation panel consisting of 97 diploid cotton accessions was employed, confirming the presence of several QTLs. Evaluation of an introgressed BC2F7 population derived from G. hirsutum/G. aridum/G. arboreum showed significant differences in disease incidence and mortality rate, as compared to susceptible and resistant controls, suggesting that the resistance in G. arboreum and/or G. aridum was transferred into Upland cotton for the first time. The identification of novel major resistance QTLs, along with the transfer of resistance from the diploid species, expands our understanding of the genomic regions involved in conferring resistance to FOV4 and contributes to the development of resilient Upland cotton cultivars.

Transcription factor OsWRKY72 controls rice leaf angle by regulating LAZY1-mediated shoot gravitropism.

Leaf angle is a major trait of ideal architecture, which is considered to influence rice (Oryza sativa) cultivation and grain yield. Although a few mutants with altered rice leaf inclination angle have been reported, the underlying molecular mechanism remains unclear. In this study, we showed that a WRKY transcription factor gene, OsWRKY72, was highly expressed in the leaf sheath and lamina joint. Phenotypic analyses showed that oswrky72 mutants have smaller leaf angles than the wild type (WT), while OsWRKY72 overexpression lines exhibited increased leaf angle. This observation suggests that OsWRKY72 functions as a positive regulator, promoting the enlargement of the leaf angle. Our bioinformatics analysis identified LAZY1 as the downstream gene of OsWRKY72. Electrophoretic mobility shift assays (EMSA) and dual luciferase analysis revealed that OsWRKY72 directly inhibits LAZY1 by binding to its promoter. Moreover, knocking out OsWRKY72 enhanced shoot gravitropism, which is in contrast to the phenotype of lazy1 plants. These results imply that OsWRKY72 regulates leaf angle through gravitropism by reducing the expression of LAZY1. In addition, OsWRKY72 could directly regulate the expression of other leaf angle-related genes, such as FLOWERING LOCUS T-LIKE 12 (OsFTL12) and WALL-ASSOCIATED KINASE 11 (OsWAK11). Our study indicates that OsWRKY72 contributes positively to the expansion of the leaf angle by interfering with shoot gravitropism in rice.

Corrigendum: Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension.

[This corrects the article DOI: 10.3389/fimmu.2023.1153573.].