Enhancing antioxidant levels and mitochondrial function in porcine oocyte maturation and embryonic development through notoginsenoside R1 supplementation.

This study examines the impact of Notoginsenoside R1 (NGR1), a compound from Panax notoginseng, on the maturation of porcine oocytes and their embryonic development, focusing on its effects on antioxidant levels and mitochondrial function. This study demonstrates that supplementing in vitro maturation (IVM) medium with NGR1 significantly enhances several biochemical parameters. These include elevated levels of glutathione (GSH), nuclear factor erythrocyte 2-related factor 2 (NRF2) and mRNA expression of catalase (CAT) and GPX. Concurrently, we observed a decrease in reactive oxygen species (ROS) levels and an increase in JC-1 immunofluorescence, mitochondrial distribution, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and nuclear NRF2 mRNA levels. Additionally, there was an increase in ATP production and lipid droplets (LDs) immunofluorescence. These biochemical improvements correlate with enhanced embryonic outcomes, including a higher blastocyst rate, increased total cell count, enhanced proliferative capacity and elevated octamer-binding transcription factor 4 (Oct4) and superoxide dismutase 2 (Sod2) gene expression. Furthermore, NGR1 supplementation resulted in decreased apoptosis, reduced caspase 3 (Cas3) and BCL2-Associated X (Bax) mRNA levels and decreased glucose-regulated protein 78 kD (GRP78) immunofluorescence in porcine oocytes undergoing in vitro maturation. These findings suggest that NGR1 plays a crucial role in promoting porcine oocyte maturation and subsequent embryonic development by providing antioxidant levels and mitochondrial protection.

TGFBI: A novel therapeutic target for cancer.

TGFBI, an extracellular matrix protein induced by transforming growth factor ß, has been found to exhibit aberrant expression in various types of cancer. TGFBI plays a crucial role in tumor cell proliferation, angiogenesis, and apoptosis. It also facilitates invasion and metastasis in various types of cancer, including colon, head and neck squamous, renal, and prostate cancers. TGFBI, a prominent p-EMT marker, strongly correlates with lymph node metastasis. TGFBI demonstrates immunosuppressive effects within the tumor immune microenvironment. Targeted therapy directed at TGFBI shows promise as a potential strategy to combat cancer. Hence, a comprehensive review was conducted to examine the impact of TGFBI on various aspects of tumor biology, including cell proliferation, angiogenesis, invasion, metastasis, apoptosis, and the immune microenvironment. This review also delved into the underlying biochemical mechanisms to enhance our understanding of the research advancements related to TGFBI in the context of tumors.

The prognosis and treatment of newly diagnosed bone metastasis of head and neck squamous cell cancer: an analysis of racial disparity / El pronóstico y el tratamiento de las metástasis óseas recién diagnosticadas de cáncer de células escamosas de cabeza y cuello: un análisis de la disparidad racial

Objective: There is a lack of research investigating racial disparity in newly diagnosed head and neck squamous cell carcinoma with isolated bone metastases (HNSCC-BM). This study aims to investigate the clinical characteristics and prognostic factors in HNSCC-BM patients from different racial backgrounds to aid clinical decision making and management. Methods: We retrieved data from the Surveillance, Epidemiology, and End Results (SEER) database for 345 cases of HNSCC-BM that were diagnosed between 2010 and 2017. Survival was compared using univariate and multivariate Cox proportional hazards models, Kaplan–Meier analysis, and log-rank tests. We also used propensity score matching to adjust for confounders. Results: In white patients, those who were over 40 years of age had a significantly shorter survival (HR, 4.49; 95% CI 1.03–19.56; P < 0.05). Female black patients were found to survive longer compared to male patients (HR, 0.34; 95% CI 0.15–0.76; P < 0.01). Single (never married) Asians had shorter survival than married Asians (HR, 4.68; 95% CI 1.34–16.41; P < 0.05). In all three racial groups, patients who received radiotherapy in addition to chemotherapy did not survive longer than those receiving chemotherapy (P > 0.05). In Asian patients, those who underwent surgery at the primary site combined with chemoradiotherapy had significantly better survival outcomes than those who received chemoradiotherapy (HR: 0.10, 95% CI 0.01–0.88; P = 0.01). Conclusion: Prognostic factors differ between HNSCC-BM patients from different racial backgrounds.(AU)

Identification of rare variants in PTCH2 associated with non-syndromic orofacial clefts.

Orofacial clefts (OFCs) represent the most prevalent congenital craniofacial anomalies, significantly impacting patients' appearance, oral function, and psychological well-being. Among these, non-syndromic OFCs (NSOFCs) are the most predominant type, with the etiology attributed to a combination of genetic and environmental factors. Rare variants of key genes involved in craniofacial development-related signaling pathway are crucial in the occurrence of NSOFCs, and our recent studies have identified PTCH1, a receptor-coding gene in the Hedgehog signaling pathway, as a causative gene for NSOFCs. However, the role of PTCH2, the paralog of PTCH1, in pathogenesis of NSOFCs remains unclear. Here, we perform whole-exome sequencing to explore the genetic basis of 144 sporadic NSOFC patients. We identify five heterozygous variants of PTCH2 in four patients: p.L104P, p.A131G, p.R557H, p.I927S, and p.V978D, with the latter two co-occurring in a single patient. These variants, all proven to be rare through multiple genomic databases, with p.I927S and p.V978D being novel variants and previously unreported. Sequence alignment suggests that these affected amino acids are evolutionarily conserved across vertebrates. Utilizing predictive structural modeling tools such as AlphaFold and SWISS-MODEL, we propose that these variants may disrupt the protein's structure and function. In summary, our findings suggest that PTCH2 may be a novel candidate gene predicted to be associated with NSOFCs, thereby broadening the spectrum of causative genes implicated in the craniofacial anomalies.

The prognosis and treatment of newly diagnosed bone metastasis of head and neck squamous cell cancer: an analysis of racial disparity.

OBJECTIVE: There is a lack of research investigating racial disparity in newly diagnosed head and neck squamous cell carcinoma with isolated bone metastases (HNSCC-BM). This study aims to investigate the clinical characteristics and prognostic factors in HNSCC-BM patients from different racial backgrounds to aid clinical decision making and management. METHODS: We retrieved data from the Surveillance, Epidemiology, and End Results (SEER) database for 345 cases of HNSCC-BM that were diagnosed between 2010 and 2017. Survival was compared using univariate and multivariate Cox proportional hazards models, Kaplan-Meier analysis, and log-rank tests. We also used propensity score matching to adjust for confounders. RESULTS: In white patients, those who were over 40 years of age had a significantly shorter survival (HR, 4.49; 95% CI 1.03-19.56; P < 0.05). Female black patients were found to survive longer compared to male patients (HR, 0.34; 95% CI 0.15-0.76; P < 0.01). Single (never married) Asians had shorter survival than married Asians (HR, 4.68; 95% CI 1.34-16.41; P < 0.05). In all three racial groups, patients who received radiotherapy in addition to chemotherapy did not survive longer than those receiving chemotherapy (P > 0.05). In Asian patients, those who underwent surgery at the primary site combined with chemoradiotherapy had significantly better survival outcomes than those who received chemoradiotherapy (HR: 0.10, 95% CI 0.01-0.88; P = 0.01). CONCLUSION: Prognostic factors differ between HNSCC-BM patients from different racial backgrounds.

Establishment of a novel classification system for alveolar morphology in infants with unilateral complete cleft lip and palate.

OBJECTIVES: Unilateral complete cleft lip and palate (UCCLP) is one of the most severe clinical subtypes among cleft lip and palate (CLP), making repair surgery and subsequent orthodontic treatment particularly challenging. Presurgical nasoalveolar molding (PNAM) has shown conflicting and heterogeneous results in the treatment of UCCLP patients, raising questions about whether the diversity in alveolar anatomical morphology among these patients plays a role in the effectiveness of PNAM treatment. MATERIALS AND METHODS: We collected 90 digital maxillary models of infants with UCCLP and performed mathematical clustering analysis, including principal component analysis (PCA), decision tree modeling, and area under the ROC Curve (AUC) analysis, to classify alveolar morphology and identify key measurements. We also conducted clinical evaluations to assess the association between the alveolar morphology and CLP treatment outcomes. RESULTS: Using mathematical clustering analysis, we classified the alveolar morphology into three distinct types: average form, horizontal form, and longitudinal form. The decision tree model, AUC analysis, and comparison analysis revealed that four measurements (Trans ACG-ACL, ML length, MG length and Inc length) were essential for clustering the alveolar morphology of infants with UCCLP. Furthermore, the blinded clinical evaluation indicated that UCCLP patients with alveolar segments of horizontal form had the lowest treatment outcomes. CONCLUSION: Overall, our findings establish a novel quantitative classification system for the morphology of alveolar bone in infants with UCCLP and suggest that this classification may be associated with the outcomes of CLP treatment. CLINICAL RELEVANCE: The multidisciplinary CLP team should thoroughly evaluate and classify the specific alveolar morphology when administering PNAM to infants with UCCLP.

Dissecting the Association between Gut Microbiota and Brain Structure Change Rate: A Two-Sample Bidirectional Mendelian Randomization Study.

The connection between the gut microbiota and brain structure changes is still unclear. We conducted a Mendelian randomization (MR) study to examine the bidirectional causality between the gut microbiota (211 taxa, including 131 genera, 35 families, 20 orders, 16 classes and 9 phyla; N = 18,340 individuals) and age-independent/dependent longitudinal changes in brain structure across the lifespan (N = 15,640 individuals aged 4~99 years). We identified causal associations between the gut microbiota and age-independent/dependent longitudinal changes in brain structure, such as family Peptostreptococcaceae with age-independent longitudinal changes of cortical gray matter (GM) volume and genus Faecalibacterium with age-independent average cortical thickness and cortical GM volume. Taking age-independent longitudinal changes in brain structure across the lifespan as exposures, there were causal relationships between the surface area and genus Lachnospiraceae. Our findings may serve as fundamentals for further research on the genetic mechanisms and biological treatment of complex traits and diseases associated with the gut microbiota and the brain structure change rate.

Palladium atomic layers coated on ultrafine gold nanowires boost oxygen reduction reaction.

Palladium-based nanocatalysts play an important role in catalyzing the cathode oxygen reduction reaction (ORR) for fuel cells working under alkaline conditions, but the performance still needs to be improved to meet the requirements for large-scale applications. Herein, Au@Pd core-shell nanowires have been developed by coating Pd atomic layers on ultrafine gold nanowires and display outstanding electrocatalytic performance towards alkaline ORR. It is found that Pd overlayers with atomic thickness can be coated on 3 nm Au nanowires under CO atmosphere and completely cover the surfaces. The obtained ultrafine Au@Pd nanowires exhibit an electrochemical active area (ECSA) of 68.5 m2/g and a mass activity of 0.91 A/mg (at 0.9 V vs. RHE), which is around 3.1 and 15.2 times higher than that of commercial Pd/C. The activity loss of the ultrafine Au@Pd nanowire after 10,000 cycles of accelerated degradation tests is only ∼20 %, demonstrating its much better stability compared to commercial Pd/C. Further characterizations combined with density functional theory (DFT) calculations demonstrate that the electronic interactions between Pd atomic layers and underlying Au can increase the electronic density of Pd and promote the efficient activation of oxygen, thus leading to the improved ORR performance.

Segmental and global myocardial work in hypertensive patients with different left ventricular geometry.

BACKGROUND: Myocardial work acquired by echocardiography has emerged as a novel method to evaluate myocardial function. We investigated global and segmental myocardial work in hypertension (HT) among patients with different patterns of left ventricular (LV) geometry in order to analyze the contribution of segmental myocardial work to global myocardial work. METHODS AND RESULTS: One hundred twenty-five patients with HT were divided into 4 groups: normal geometry (NG), concentric remodeling (CR), concentric hypertrophy (CH) and eccentric hypertrophy (EH). Longitudinal strain (LS) and the following indices were obtained by echocardiography: myocardial work index (MWI), myocardial constructive work (MCW), myocardial wasted work (MWW), and myocardial work efficiency (MWE). The global longitudinal strain (GLS) decreased gradually among the groups: NG, CR, CH and EH (P < 0.001). Global MWI (GWI) and global MCW (GCW) did not change across the different LV remodeling groups. Global MWW (GWW) increased and global MWE (GWE) decreased in both CH and EH group (P < 0.001). The LS of basal and middle regions reduced gradually in all HT subgroups, while apical LS decreased only in the CH and EH groups (P < 0.001). Basal MWI and MCW decreased in the CH and EH groups (P = 0.025, 0.007, respectively). Apical MWI and MCW increased in the NG and CR groups (P = 0.015, 0.044, respectively), with a decreasing trend in the CH and EH groups. All segmental MWW elevated and MWE reduced significantly in the CH and EH groups (P < 0.001). Univariate and multivariate logistic regression analyses demonstrated a significant association between left atrial volume index (LAVI), GLS, GWE and LV hypertrophy. At the receiver operating characteristic (ROC) analysis, optimal cutoff values of GLS, Apical LS, GWE and Apical MWE discriminating LV hypertrophy were 0.9072, 0.8049, 0.8325 and 0.7414, respectively. CONCLUSION: Apical myocardial work increases in the early stages of LV remodeling, likely as a compensatory mechanism to maintain normal global myocardial work. Segmental myocardial work analysis offers a reliable means to explore the distribution of myocardial impairment in hypertensive patients at different LV remodeling stages.

Genome-wide by environment interaction studies of maternal smoking and educational score in UK biobank.

PURPOSE: This study aimed to investigate the associations between maternal smoking (MS) and education score in adult offspring. METHODS: To better understand this link, we performed a two-stage genome-wide by environment interaction studies (GWEIS) of MS and offspring education score in UK Biobank cohort. Specifically, 276 996 subjects from England were enrolled in the discovery study, while 24 355 subjects from Scotland and 14 526 subjects from Wales were enrolled in the replication study. GWEIS were conducted by PLINK 2.0 with MS used as an environmental risk factor. RESULTS: Significant GWEIS associations ( P  < 0.0001) between MS and offspring education score in both the discovery cohort and two replicate cohorts (Scotland population and Wales population) were identified. GWEIS identified 2 independent significant single nucleotide polymorphism-MS interaction, with one variant located in the chromosomal 16 (rs72768988, Position: 22,768,798, P  = 1.22 × 10 -8 , ß = 6.7662) and the other one located in 2q32.3 region (2 : 196424612_GT_G, Position: 196 424 612, 3.60 × 10 -9 , ß = -0.4721). CONCLUSION: Our results suggested 2q32.3 region and HECW2 gene could negatively moderate the influence of MS on offspring's educational status.

Segmental and global myocardial work in hypertensive patients with different left ventricular ejection fraction: what's the role of the apex played?

We investigated myocardial work in hypertension (HT) among patients with different left ventricular ejection fraction (LVEF) to analyze the contribution of segmental myocardial work to global myocardial work. 114 patients with HT were divided into 4 groups: HTsnEF ("supra-normal" EF, > 65%); HTnEF ("normal" EF, 60-65%); HTmEF (designed as "middle" EF, 50-60%, within an abnormal LV geometry); HTrEF (reduced EF, < 50%). Longitudinal strain (LS) and myocardial work indices were obtained by echocardiography: myocardial work index (MWI), constructive work (MCW), wasted work (MWW), myocardial work efficiency (MWE), and percentages of apical work were calculated (PApi-MWI, PApi-MCW). Global LS (GLS) and global MWE (GWE) decreased in HTmEF and HTrEF groups. Global MWI(GWI) and MCW(GCW) increased in HTsnEF and HTnEF groups, and subsequently decreased, particularly in HTrEF group (P < 0.05). GWW increased in all HT subgroups. All segmental MWI and MCW were elevated or preserved initially in HTsnEF and HTnEF groups, and subsequently decreased, obviously in basal and middle segments in HTrEF group (P < 0.05). All segmental MWW increased and MWE decreased in HTmEF and HTrEF groups (P < 0.05). PApi-MWI and PApi-MCW increased initially, and subsequently decreased in HTmEF group, and elevated significantly in HTrEF group. Correlation analysis revealed a close connection of GLS and myocardial work parameters with LVEF. Apical myocardial work increased at the early stages of hypertensive systolic dysfunction, as a compensatory mechanism. Segmental myocardial work analysis added value to explore the distribution of myocardial impairment.

Differences in Pain Assessments Between Inpatients and Nurses Leads to Considerable Misestimated Pain.

BACKGROUND: Pain assessments are an important aspect of health care quality because the high prevalence of pain in inpatients may contribute to complications. Several studies revealed a gap in the pain intensity evaluated by nurses (PEN) and patients (PEP). The aim of the present study was to analyze the correlation and agreement between pain assessments conducted by nurses and patients, and to determine patients at high risk of misestimated pain. OBJECTIVES: To compare the difference of pain intensity between the questionnaires conducted by additional assessors and electronic records by nursing staff. STUDY DESIGN: A retrospective study. SETTING: A medical center in Taichung, Taiwan. METHODS: We approached 1,034 patients admitted from January 1, 2018 to December 31, 2018 in our hospital. We compared the assessments of pain intensity using questionnaires conducted by additional assessors with those entered into electronic records by nursing staff. Continuous data were reported as the mean (± standard deviation). The analysis of agreement and correlation were performed by kappa statistics or weighted kappa statistics, and correlation (Spearman rank correlation method). RESULTS: Among the 1,034 patients, 307 patients were excluded. Thus, the final analysis included 686 patients. Patients' median pain intensity was 5 in PEP and 1 in PEN. The patients' pain intensity was underestimated (PEN < PEP) in 539 patients (78.6%), matched (PEN = PEP) in 126 patients (18.3%), and overestimated (PEN > PEP) in 21 patients (3.1%). The surgical interventions (chi squared = 7.996, and P = 0.018) and pain in the past 24 hours (chi squared = 17.776, and P < 0.001) led to a significant difference. LIMITATIONS: The limitation of the study was the single-center and retrospective design. CONCLUSIONS: The gap in pain assessments between inpatients and nurses is an important issue in daily practice. The underestimations of pain were more common than overestimations (78.6% vs 3.1%). Surgical interventions and persistent pain lasting over 24 hours were high risk factors for underestimation, but patients' gender, receiving anesthesia, type of anesthesia, and patient-controlled analgesia did not contribute significantly to differences in pain estimation.

Precursors and formation pathways of furfural in sugarcane juice during thermal treatment.

As a potent aromatic compound, furfural may have adverse effects on sugarcane juice quality. In this study, simplified sugarcane juice models containing glucose, fructose and amino acids were used to explore the potential precursors and formation pathways of furfural. The changes of precursors and intermediates involved in furfural formation were quantified. The results indicated that fructose contributed more to furfural formation than glucose. Serine was the main amino acid precursor for furfural formation. Furfural could be generated through 3 pathways in sugarcane juice: 1) Streaker reaction of serine, 2) caramelization of glucose and fructose via 3-deoxyglucosone, 3) formed from reducing sugars (glucose or fructose) and serine via N-(1-Deoxy-d-fructos-1-yl)-l-serine intermediate, which further converted to 3-deoxyglucosone. At the first 10 min, furfural was mainly produced through the caramelization of fructose. Subsequently, furfural was produced in the above three ways. Furfural was more effectively formed by caramelization than Maillard reaction in sugarcane juice.

GluN2A Mediates PS-Induced Depressive-Like Behavior by Activating CaMKII and Inhibiting Myelinization.

BACKGROUND: Prenatal stress (PS) can induce depression in offspring, but the underlying mechanisms are still unknown. OBJECTIVE: The aim of this work was to investigate the mechanism that underlies PS-induced depressive-like behavior in offspring. METHODS: A prenatal restraint stress procedure was developed in which pregnant rats at GD14 to GD20 were placed head-first into a well-ventilated bottle three times each day and for 45 min each time. Depressive-like behavior in the male offspring was examined using the sucrose preference test (SPT) and the forced swim test (FST). The level of glutamate and the expression levels of GluN2A, p-CaMKII and myelin basic protein (MBP) in the hippocampus of PS-susceptible (PS-S) offspring were also evaluated. To clarify the mechanism by which PS leads to depression in offspring, the effects of excessive corticosterone were also investigated using an in vitro "injured neuronal" model. RESULTS: The glutamate level in the hippocampus of PS-S male offspring was significantly elevated compared to controls. The expression levels of GluN2A and p-CaMKII were also altered. In addition, the optical density of MBP staining and the expression levels of MBP mRNA and MBP protein were decreased, demonstrating impaired myelinization in the hippocampus. Treatment of PS-S offspring with the GluN2A receptor antagonist NVP-AAM077 resulted in antidepressant-like effects in the FST, as well as rescue of the MBP and p-CaMKII abnormalities. CONCLUSIONS: These findings indicate that GluN2A is a promising target in the development of pharmacotherapies for PS-induced depression.

Case report: Identification of three novel compound heterozygous SGLT2 variants in three Chinese pediatric patients with familial renal glucosuria.

Familial renal glucosuria (FRG) is a rare genetic condition featured by isolated glucosuria without hyperglycemia or other kidney diseases. It is caused by pathogenic mutations of the SGLT2 (Sodium-Glucose Cotransporter 2) gene, whose protein product is responsible for reabsorbing the majority of glucose in the early proximal convoluted tubule. Hitherto, quite an array of variants of SGLT2 have been identified in patients of FRG. In this study, we performed whole exome sequencing on three Chinese pediatric patients with FRG and uncovered three compound heterozygous variants of SGLT2: c.1333C > T (p.Q445X) and c.1130-5 C > G; c.1438G > T (p.V480F) and c.346G > A (p.V116M); c.1175C > G (p.S392C) and c.1333C > T (p.Q445X). Among the total of five variants, c.1333C > T (p.Q445X), c.1438G > T (p.V480F) and c.1175C > G (p.S392C) represented novel variants that had not been reported in any genetic databases. All five variants had extremely low allele frequencies and the amino acids loci affected by missense variants were highly conserved in vertebrate species. Bioinformatic tools predicted that all five variants might disrupt the function of SGLT2, which were likely to be causal for FRG in these patients. Our findings expand the variant spectrum of SGLT2 associated with FRG and provide novel insights into mechanism of action of this transporter, which will aid in the development of novel SGLT2 inhibitors for treatment of type 2 diabetes and cardiovascular diseases.

Sustaining Improvements of Surgical Site Infections by Six Sigma DMAIC Approach.

BACKGROUND: SSIs (surgical site infections) are associated with increased rates of morbidity and mortality. The traditional quality improvement strategies focusing on individual performance did not achieve sustainable improvement. This study aimed to implement the Six Sigma DMAIC method to reduce SSIs and to sustain improvements in surgical quality. The surgical procedures, clinical data, and surgical site infections were collected among 42,233 hospitalized surgical patients from 1 January 2019 to 31 December 2020. Following strengthening leadership and empowering a multidisciplinary SSI prevention team, DMAIC (Define, Measure, Analyze, Improve, and Control) was used as the performance improvement model. An evidence-based prevention bundle for reduction of SSI was adopted as performance measures. Environmental monitoring and antimicrobial stewardship programs were strengthened to prevent the transmission of multi-drug resistant microorganisms. Process change was integrated into a clinical pathway information system. Improvement cycles by corrective actions for the risk events of SSIs were implemented to ensure sustaining improvements. We have reached the targets of the prevention bundle elements in the post-intervention period in 2020. The carbapenem resistance rates of Enterobacteriaceae and P. aeruginosa were lower than 10%. A significant 22.2% decline in SSI rates has been achieved, from 0.9% for the pre-intervention period in 2019 to 0.7% for the post-intervention period in 2020 (p = 0.004). Application of the Six Sigma DMAIC approach could significantly reduce the SSI rates. It also could help hospital administrators and quality management personnel to create a culture of patient safety.

A392V and R945X mutations cause orofacial clefts via impairing PTCH1 function.

The Hedgehog (HH) signaling plays key roles in embryogenesis and organogenesis, and its dysfunction causes a variety of human birth defects. Orofacial cleft (OFC) is one of the most common congenital craniofacial defects, and its etiology is closely related to mutations in multiple components in the HH pathway, including the PTCH1 receptor. A quantity of PTCH1 variants have been associated with OFC, but the pathogenicity and underlying mechanism of these variants have not been functionally validated. In our previous studies, we identified two PTCH1 variants (A392V and R945X) in two families with hereditary OFC. Here we explore the functional consequences of these two variants. In zebrafish embryos, microinjection of wild type PTCH1 mRNA causes curved body axis and craniofacial anomalies. In contrast, microinjection of A392V and R945X PTCH1 mRNAs results in much milder phenotypes, suggesting these two variants are loss-of-function mutations. In mammalian cells, A392V and R945X mutations reverse the inhibitory effect of PTCH1 on HH signaling. Biochemically, the two mutants PTCH1 show lower expression levels and shortened half-life, indicting these mutations decrease the stability of PTCH1. A392V and R945X mutations also appear to cause PTCH1 to localize away from vesicles. Taken together, our findings indicate that A392V and R945X variants are loss-of-function mutations that disrupt the function of PTCH1 and thus cause dysregulation of HH signaling, leading to the pathogenesis of OFC.

Comparative Phosphoproteomic Profiling in the Prefrontal Cortex of Prenatally Stressed Male Offspring Rats.

Many investigations have indicated that prenatal stress (PS) causes depressive-like disturbances in offspring rats. However, the underlying pathogenic mechanisms have not yet been fully elucidated. The prefrontal cortex (PFC) has been shown to play a role in susceptibility to stress during fetal development; thus, we focused our attention on differential protein phosphorylation in this region of PS-S (susceptibility to PS) offspring rats. The sucrose preference test was used to screen for susceptibility to PS. The validity of the prenatally stressed model was verified by other common depression-like behaviors. We used MS-based TMT quantitative proteomics in combination with the phosphopeptide enrichment method to compare phosphoproteomic profiling in the PFC of PS-S and control male offspring rats. In total, 3,418 phosphoproteins, 8,404 phosphopeptides, and 12,175 phosphosites were identified in this analysis. According to the screening criteria, 902 phosphopeptides increased and 609 decreased in the PFC of the PS-S group compared to the control rats. Gene ontology enrichment analysis indicated that the main enriched terms in the cellular component category were "synapse part," "myelin sheath," "synapse," "neuron part," and "axon." The phosphoproteins enriched in the molecular function and biological process categories were mainly related to cytoskeleton- and projection morphogenesis-associated proteins. KEGG pathway enrichment analyses identified 30 significant KEGG pathways; the top five pathways included salivary secretion, endocrine and other factor-regulated calcium reabsorption, pancreatic secretion, and insulin secretion. Motifs such as ……_S_P…RR, ……S_PE……, ……_S_PV……, ……_S_P.H……, and …S…_S_PT…. were the top five motifs enriched in phosphorylated sites. PS may induce depressive-like behaviors in male offspring rats by regulating the phosphorylation of proteins mainly related to synapses, myelin sheaths, neurons, and the cytoskeleton. The phosphorylation of related proteins may act as key pathogenic hits. Data are available via ProteomeXchange with identifier PXD026563.

GmNAC181 promotes symbiotic nodulation and salt tolerance of nodulation by directly regulating GmNINa expression in soybean.

Soybean (Glycine max) is one of the most important crops world-wide. Under low nitrogen (N) condition, soybean can form a symbiotic relationship with rhizobia to acquire sufficient N for their growth and production. Nodulation signaling controls soybean symbiosis with rhizobia. The soybean Nodule Inception (GmNINa) gene is a central regulator of soybean nodulation. However, the transcriptional regulation of GmNINa remains largely unknown. Nodulation is sensitive to salt stress, but the underlying mechanisms are unclear. Here, we identified an NAC transcription factor designated GmNAC181 (also known as GmNAC11) as the interacting protein of GmNSP1a. GmNAC181 overexpression or knockdown in soybean resulted in increased or decreased numbers of nodules, respectively. Accordingly, the expression of GmNINa was greatly up- and downregulated, respectively. Furthermore, we showed that GmNAC181 can directly bind to the GmNINa promoter to activate its gene expression. Intriguingly, GmNAC181 was highly induced by salt stress during nodulation and promoted symbiotic nodulation under salt stress. We identified a new transcriptional activator of GmNINa in the nodulation pathway and revealed a mechanism by which GmNAC181 acts as a network node orchestrating the expression of GmNINa and symbiotic nodulation under salt stress conditions.