Exploring the immune escape mechanisms in gastric cancer patients based on the deep AI algorithms and single-cell sequencing analysis.

Gastric cancer is a prevalent and deadly malignancy, and the response to immunotherapy varies among patients. This study aimed to develop a prognostic model for gastric cancer patients and investigate immune escape mechanisms using deep machine learning and single-cell sequencing analysis. Data from public databases were analysed, and a prediction model was constructed using 101 algorithms. The high-AIDPS group, characterized by increased AIDPS expression, exhibited worse survival, genomic variations and immune cell infiltration. These patients also showed immunotherapy tolerance. Treatment strategies targeting the high-AIDPS group identified three potential drugs. Additionally, distinct cluster groups and upregulated AIDPS-associated genes were observed in gastric adenocarcinoma cell lines. Inhibition of GHRL expression suppressed cancer cell activity, inhibited M2 polarization in macrophages and reduced invasiveness. Overall, AIDPS plays a critical role in gastric cancer prognosis, genomic variations, immune cell infiltration and immunotherapy response, and targeting GHRL expression holds promise for personalized treatment. These findings contribute to improved clinical management in gastric cancer.

Long-Term Effectiveness and Durability of COVID-19 Vaccination Among Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.

Organo-organic interactions dominantly drive soil organic carbon accrual.

Organo-mineral interactions have been regarded as the primary mechanism for the stabilization of soil organic carbon (SOC) over decadal to millennial timescales, and the capacity for soil carbon (C) storage has commonly been assessed based on soil mineralogical attributes, particularly mineral surface availability. However, it remains contentious whether soil C sequestration is exclusively governed by mineral vacancies, making it challenging to accurately predict SOC dynamics. Here, through a 400-day incubation experiment using 13 C-labeled organic materials in two contrasting soils (i.e., Mollisol and Ultisol), we show that despite the unsaturation of mineral surfaces in both soils, the newly incorporated C predominantly adheres to "dirty" mineral surfaces coated with native organic matter (OM), demonstrating the crucial role of organo-organic interactions in exogenous C sequestration. Such interactions lead to multilayered C accumulation that is not constrained by mineral vacancies, a process distinct from direct organo-mineral contacts. The coverage of native OM by new C, representing the degree of organo-organic interactions, is noticeably larger in Ultisol (~14.2%) than in Mollisol (~5.8%), amounting to the net retention of exogenous C in Ultisol by 0.2-1.3 g kg-1 and in Mollisol by 0.1-1.0 g kg-1 . Additionally, organo-organic interactions are primarily mediated by polysaccharide-rich microbial necromass. Further evidence indicates that iron oxides can selectively preserve polysaccharide compounds, thereby promoting the organo-organic interactions. Overall, our findings provide direct empirical evidence for an overlooked but critically important pathway of C accumulation, challenging the prevailing "C saturation" concept that emphasizes the overriding role of mineral vacancies. It is estimated that, through organo-organic interactions, global Mollisols and Ultisols might sequester ~0.1-1.0 and ~0.3-1.7 Pg C per year, respectively, corresponding to the neutralization of ca. 0.5%-3.0% of soil C emissions or 5%-30% of fossil fuel combustion globally.

Protists regulate microbially mediated organic carbon turnover in soil aggregates.

Soil protists, the major predator of bacteria and fungi, shape the taxonomic and functional structure of soil microbiome via trophic regulation. However, how trophic interactions between protists and their prey influence microbially mediated soil organic carbon turnover remains largely unknown. Here, we investigated the protistan communities and microbial trophic interactions across different aggregates-size fractions in agricultural soil with long-term fertilization regimes. Our results showed that aggregate sizes significantly influenced the protistan community and microbial hierarchical interactions. Bacterivores were the predominant protistan functional group and were more abundant in macroaggregates and silt + clay than in microaggregates, while omnivores showed an opposite distribution pattern. Furthermore, partial least square path modeling revealed positive impacts of omnivores on the C-decomposition genes and soil organic matter (SOM) contents, while bacterivores displayed negative impacts. Microbial trophic interactions were intensive in macroaggregates and silt + clay but were restricted in microaggregates, as indicated by the intensity of protistan-bacterial associations and network complexity and connectivity. Cercozoan taxa were consistently identified as the keystone species in SOM degradation-related ecological clusters in macroaggregates and silt + clay, indicating the critical roles of protists in SOM degradation by regulating bacterial and fungal taxa. Chemical fertilization had a positive effect on soil C sequestration through suppressing SOM degradation-related ecological clusters in macroaggregate and silt + clay. Conversely, the associations between the trophic interactions and SOM contents were decoupled in microaggregates, suggesting limited microbial contributions to SOM turnovers. Our study demonstrates the importance of protists-driven trophic interactions on soil C cycling in agricultural ecosystems.

Trade-off between Pore-Throat Structure and Mineral Composition in Modulating the Stability of Soil Organic Carbon.

The preservation of soil organic carbon (OC) is an effective way to decelerate the emission of CO2 emission. However, the coregulation of pore structure and mineral composition in OC stabilization remains elusive. We employed the in situ nondestructive oxidation of OC by low-temperature ashing (LTA) combined with near edge X-ray absorption fine structure (NEXAFS), high-resolution microtomography (µ-CT), field emission electron probe microanalysis (FE-EPMA) with C-free embedding, and novel Cosine similarity measurement to investigate the C retention in different aggregate fractions of contrasting soils. Pore structure and minerals contributed equally (ca. 50%) to OC accumulation in macroaggregates, while chemical protection played a leading role in C retention with 53.4%-59.2% of residual C associated with minerals in microaggregates. Phyllosilicates were discovered to be more prominent than Fe (hydr)oxides in C stabilization. The proportion of phyllosilicates-associated C (52.0%-61.9%) was higher than that bound with Fe (hydr)oxides (45.6%-55.3%) in all aggregate fractions tested. This study disentangled quantitatively for the first time a trade-off between physical and chemical protection of OC varying with aggregate size and the different contributions of minerals to OC preservation. Incorporating pore structure and mineral composition into C modeling would optimize the C models and improve the soil C content prediction.

Three new discovery effector proteins from Candidatus Liberibacter asiaticus psy62 inhibit plant defense through interaction with AtCAT3 and AtGAPA.

KEY MESSAGE: We identify three SDEs that inhibiting host defence from Candidatus Liberibacter asiaticus psy62, which is an important supplement to the pathogenesis of HLB. Candidatus Liberibacter asiaticus (CLas) is the main pathogen of citrus Huanglongbing (HLB). 38 new possible sec-dependent effectors (SDEs) of CLas psy62 were predicted by updated predictor SignalP 5.0, which 12 new SDEs were found using alkaline phosphate assay. Among them, SDE4310, SDE4435 and SDE4955 inhibited hypersensitivity reactions (HR) in Arabidopsis thaliana (Arabidopsis, At) and Nicotiana benthamiana leaves induced by pathogens, which lead to a decrease in cell death and reactive oxygen species (ROS) accumulation. And the expression levels of SDE4310, SDE4435, and SDE4955 genes elevated significantly in mild symptom citrus leaves. When SDE4310, SDE4435 and SDE4955 were overexpressed in Arabidopsis, HR pathway key genes pathogenesis-related 2 (PR2), PR5, nonexpressor of pathogenesis-related 1 (NPR1) and isochorismate synthase 1 (ICS1) expression significantly decreased and the growth of pathogen was greatly increased relative to control with Pst DC3000/AvrRps4 treatment. Our findings also indicated that SDE4310, SDE4435 and SDE4955 interacted with AtCAT3 (catalase 3) and AtGAPA (glyceraldehyde-3-phosphate dehydrogenase A). In conclusion, our results suggest that SDE4310, SDE4435 and SDE4955 are CLas psy62 effector proteins that may have redundant functions. They inhibit ROS burst and cell death by interacting with AtCAT3 and AtGAPA to negatively regulate host defense.

Exploring the Mechanism of H2S Synthesis in Male Bactrian Camel Poll Glands Based on Data Independent Acquisition Proteomics and Non-Targeted Metabolomics.

During estrus, the poll glands of male Bactrian Camels (Camelus Bactrianus) become slightly raised, exuding a large amount of pale yellow watery secretion with a characteristic odor that may contain hydrogen sulfide (H2S). However, whether H2S can be synthesized in the poll glands of male Bactrian Camels and its role in inducing camel estrus remains unclear. This study aimed to identify differentially expressed proteins (DEPs) and signaling pathways in the poll gland tissues of male Bactrian Camels using data independent acquisition (DIA) proteomics. Additionally, gas chromatography-mass spectrometry (GC-MS) was performed to identify differentially expressed metabolites (DEMs) in the neck hair containing secretions during estrus in male Bactrian Camels, to explore the specific expression patterns and mechanisms in the poll glands of camels during estrus. The results showed that cystathionine-γ-lyase (CTH) and cystathionine-ß-synthase (CBS), which are closely related to H2S synthesis in camel poll glands during estrus, were mainly enriched in glycine, serine, and threonine metabolism, amino acid biosynthesis, and metabolic pathways. In addition, both enzymes were widely distributed and highly expressed in the acinar cells of poll gland tissues in camels during estrus. Meanwhile, the neck hair secretion contains high levels of amino acids, especially glycine, serine, threonine, and cystathionine, which are precursors for H2S biosynthesis. These results demonstrate that the poll glands of male Bactrian Camels can synthesize and secrete H2S during estrus. This study provides a basis for exploring the function and mechanism of H2S in the estrus of Bactrian Camels.

Global, regional and national burden of Glaucoma: an update analysis from the Global Burden of Disease Study 2019.

PURPOSE: As the epidemiological and burden trends of glaucoma are changing, it is extremely necessary to re-investigate geographical differences and trends. Here we use data from the 2019 Global burden of Disease, which aims to report the prevalence and disability-adjusted life years of glaucoma injury to assess the latest epidemiological models and trends from 1990 to 2019. METHOD: Annual case numbers, age-standardized rates of prevalence, DALYs, and their estimated annual percentage changes (EAPCs) for glaucoma between 1990 and 2019 were derived from the GBD 2019 study. The relationship between glaucoma disease burden and social demographic index (SDI) was also investigated in this study. RESULTS: In 2019, there were 7.47 million prevalent cases and 0.75 million DALYs cases, which increased by 92.53% and 69.23% compared with 1990 respectively. The global age-standardized rate of prevalence (ASPR) and age-standardized rate of DALYs (ASDR) decreased during 1990-2019 (EAPC = - 0.55 and - 1, respectively). In 2019, the highest ASPR and ASDR of Glaucoma were all observed in Mali, whereas the lowest occurred in Taiwan (Province of China). In terms of gender, males were more likely to suffer from glaucoma than females, especially the elderly. CONCLUSIONS: The global prevalence and DALYs of glaucoma had an absolute increase during the past 30 years. The disease burden caused by glaucoma is closely related to socioeconomic level, age, gender, and other factors, and these findings provide a basis for policymakers from the perspective of social management.

Symmetry of upper eyelid after unilateral blepharoptosis repair with minimally invasive conjoint fascial sheath suspension technique.

AIM: To investigate the symmetry of upper eyelid in patients with unilateral mild and moderate blepharoptosis who underwent unilateral minimally invasive combined fascia sheath (CFS) suspension. METHODS: A retrospective study of patients who underwent unilateral minimally invasive CFS suspension surgery between January 2018 and December 2021. Inclusion criteria included unilateral mild and moderate ptosis, good levator muscle function (>9 mm) and follow-up of at least 6mo. Pre- and post-operative symmetry was graded subjectively for marginal reflex distance 1 (MRD1), tarsal platform show (TPS) and eyebrow fat span (BFS). A t-test was used to evaluate MRD1, TPS and BFS asymmetry by calculating delta values. The Bézier curve tool of the Image J software was used to extract the upper eyelid contours, where the symmetry was measured by the percentage of overlapping curvatures (POC). RESULTS: Totally 105 patients (105 eyelids) were included (mild group, n=84; moderate group, n=21). Postoperatively, all patients increased MRD1 and decreased TPS in the ptotic eye while maintaining unchanged BFS. The asymmetric delta value for MRD1 was measured to be 1.48±0.86 preoperatively, and it decreased to 0.58±0.67 postoperatively in all cases (P=0.0004). In patients with mild ptosis, the asymmetry value of TPS fell significantly from 1.15±0.62 to 0.68±0.38 (P=0.0187). The symmetry of the upper eyelid contour increased in all subgroups of patients, with a POC of 59.39%±13.45% preoperatively and POC of 78.29%±13.80% postoperatively. CONCLUSION: Minimally invasive CFS suspension is proved to be an effective means of improving the symmetry of unilateral ptosis in terms of MRD1 (all subgroups), POC (all subgroups) and TPS (only mild group), whereas BFS is unaffected.

Epidemiology of gout - Global burden of disease research from 1990 to 2019 and future trend predictions.

Background: Understanding the global burden of gout in the past and future can provide important references for optimizing prevention and control strategies in healthcare systems. Objectives: This study aimed to report variations in the global disease burden and risk factors of gout in 204 countries and territories from 1990 to 2019. Design: We conducted a retrospective analysis of gout based on the latest Global Burden of Disease (GBD) 2019 database. Methods: We collected data on the prevalence, incidence, and disability-adjusted life years (DALYs) of gout from 1990 to 2019. The data were then stratified by age, sex, and economic development level. Decomposition analysis, frontier analysis, and prediction models were used to analyze the changes and influencing factors influencing each indicator. Results: Globally, there were 53,871,846.4 [95% uncertainty interval (UI): 43,383,204.6-66,342,327.3] prevalent cases, 92,228,86.8 (95% UI: 7419,132.1-11,521,165) incident cases, and 1673,973.4 (95% UI: 1,068,061.1-2,393,469.2) cases of DALYs of gout in 2019, more than double those in 1990. Moreover, the pace of increase in the age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR), and age-standardized DALY rate (ASDR) accelerated during 1990-2019, with estimated annual percentage changes (EAPC) of 0.94 [95% confidence interval (CI): 0.85-1.03], 0.77 (95% CI: 0.69-0.84), and 0.93 (95% CI: 0.84-1.02), respectively, especially among men. The disease burden of gout has increased in all the other 20 GBD regions in the past 30 years, except Western Sub-Saharan Africa. The highest risk of high body mass index (BMI) and kidney dysfunction was in high-income countries such as North America and East Asia. The global prevalence rate, incidence rate, and DALYs rate of gout in 2030 will reach 599.86, 102.96 per 100,000 population, and 20.26 per 100,000 population, respectively, roughly the same as in 2019. Conclusion: With the development of society, the disease burden of gout will become increasingly severe. It is very important to study the accurate epidemiological data on gout for clinical diagnosis and treatment and health policy.

Sex Differences in Cochlear Transcriptomes in Horseshoe Bats.

Sexual dimorphism of calls is common in animals, whereas studies on the molecular basis underlying this phenotypic variation are still scarce. In this study, we used comparative transcriptomics of cochlea to investigate the sex-related difference in gene expression and alternative splicing in four Rhinolophus taxa. Based on 31 cochlear transcriptomes, we performed differential gene expression (DGE) and alternative splicing (AS) analyses between the sexes in each taxon. Consistent with the degree of difference in the echolocation pulse frequency between the sexes across the four taxa, we identified the largest number of differentially expressed genes (DEGs) and alternatively spliced genes (ASGs) in R. sinicus. However, we also detected multiple DEGs and ASGs in taxa without sexual differences in echolocation pulse frequency, suggesting that these genes might be related to other parameters of echolocation pulse rather than the frequency component. Some DEGs and ASGs are related to hearing loss or deafness genes in human or mice and they can be considered to be candidates associated with the sexual differences of echolocation pulse in bats. We also detected more than the expected overlap of DEGs and ASGs in two taxa. Overall, our current study supports the important roles of both DGE and AS in generating or maintaining sexual differences in animals.

Ripks and Neuroinflammation.

Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).

Simultaneous Quantification of Vancomycin, Linezolid and Voriconazole in Human Plasma by UHPLC-MS/MS: Application in Therapeutic Drug Monitoring.

OBJECTIVE: Individual differences challenge the treatment of vancomycin, linezolid and voriconazole in severe infections. This study aimed to build a simple and economical method for simultaneous determination of the three antibiotics in human plasma by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and provided a reference for therapeutic drug monitoring (TDM) of infected patients. METHODS: The plasma samples were precipitated by acetonitrile and detected and separated on a shim-pack GIST C18 column following the gradient elution within 5 min. Mass quantification was performed on multiple reaction monitoring mode under positive electrospray ionization. RESULTS: The linear ranges of vancomycin, linezolid and voriconazole were 1.00-100.00, 0.10-15.00 and 0.10-20.00 µg·mL-1, respectively, with good linearity (R2 > 0.99). The accuracy and precision, matrix effect, extraction recovery and stability were validated, and the results all meet the acceptance criteria of China Food and Drug Administration (CFDA) guidelines. CONCLUSION: The UHPLC-MS/MS method was established and validated for the simultaneous determination of vancomycin, linezolid and voriconazole in human plasma and successfully applied to routine TDM for individualized treatment.

High expression of ARPC1B correlates with immune infiltration and poor outcomes in glioblastoma.

Objective: To investigate the role of ARPC1B in GBM and its prognostic value. Methods: mRNA and protein expression of ARPC1B in GBM was analyzed using the TCGA; TIMER2 and the HPA databases, and protein expression differences were detected using immunohistochemistry. K-M analysis and Cox regression analysis were performed on high and low ARPC1B expression groups in the TCGA database. The relationship between immune cells and ARPC1B expression was explored using the TIMER2 database. GO and KEGG analyses were conducted to investigate the functions of ARPC1B-related genes in GBM. Results: ARPC1B was highly expressed in both GBM tissues and cell lines, and it was demonstrated as a prognostic biomarker for GBM. ARPC1B expression levels showed associations with immune cell populations within the GBM microenvironment. Conclusion: ARPC1B can regulating immune infiltration in the GBM microenvironment, indicating its potential as a novel therapeutic target for GBM.

From bench to bedside: Advancing towards therapeutic treatment of vestibular schwannomas.

Vestibular schwannomas are rare intracranial tumors originating from Schwann cells of the vestibular nerve. Despite their benign nature, these tumors can exert significant mass effects and debilitating symptoms, including gradual hearing loss, vertigo, facial nerve dysfunction, and headaches. Current clinical management options encompass wait-and-scan, surgery, radiation therapy, and off-label medication. However, each approach exhibits its own challenges and harbors limitations that underscore the urgent need for therapeutic treatments. Over the past 2 decades, extensive elucidation of the molecular underpinnings of vestibular schwannomas has unraveled genetic anomalies, dysregulated signaling pathways, downstream of receptor tyrosine kinases, disrupted extracellular matrix, inflammatory tumor microenvironment, and altered cerebrospinal fluid composition as integral factors in driving the development and progression of the disease. Armed with this knowledge, novel therapeutic interventions tailored to the unique molecular characteristics of those conditions are actively being pursued. This review underscores the urgency of addressing the dearth of Food and Drug Administration-approved drugs for vestibular schwannoma, highlighting the key molecular discoveries and their potential translation into therapeutics. It provides an in-depth exploration of the evolving landscape of therapeutic development, which is currently advancing from bench to bedside. These ongoing efforts hold the promise of significantly transforming the lives of vestibular schwannoma patients in the future.

Importance of soil ecoenzyme stoichiometry for efficient polycyclic aromatic hydrocarbon biodegradation.

Efficient remediation of soil contaminated by polycyclic aromatic hydrocarbons (PAHs) is challenging. To determine whether soil ecoenzyme stoichiometry influences PAH degradation under biostimulation and bioaugmentation, this study initially characterized soil ecoenzyme stoichiometry via a PAH degradation experiment and subsequently designed a validation experiment to answer this question. The results showed that inoculation of PAH degradation consortia ZY-PHE plus vanillate efficiently degraded phenanthrene with a K value of 0.471 (depending on first-order kinetics), followed by treatment with ZY-PHE and control. Ecoenzyme stoichiometry data revealed that the EEAC:N, vector length and angle increased before day five and decreased during the degradation process. In contrast, EEAN:P decreased and then increased. These results indicated that the rapid PAH degradation period induced more C limitation and organic P mineralization. Correlation analysis indicated that the degradation rate K was negatively correlated with vector length, EEAC:P, and EEAN:P, suggesting that C limitation and relatively less efficient P mineralization could inhibit biodegradation. Therefore, incorporating liable carbon and acid phosphatase or soluble P promoted PAH degradation in soils with ZY-PHE. This study provides novel insights into the relationship between soil ecoenzyme stoichiometry and PAH degradation. It is suggested that soil ecoenzyme stoichiometry be evaluated before designing bioremeiation stragtegies for PAH contanminated soils.

The clinical impact of plasma estrogen receptor-1 mutation in patients with metastatic breast cancer: A meta-analysis.

BACKGROUND: The relevance of the discovered plasma ESR1 mutations in positive metastatic breast cancer (BC) patients who had progressing disease after aromatase inhibitor (AI)-based therapy is still being debated. OBJECTIVES: We conducted this meta-analysis to explore the prognostic and predictive role of plasma ESR1 mutations in patients with progressive BC who have previously received AI therapy. MATERIAL AND METHODS: We searched for relevant studies in the PubMed, Embase and Cochrane Library databases to be included in the meta-analysis. This study was performed to compute combined hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the progression-free survival (PFS) rate and overall survival (OS) rate. Subgroup and sensitivity analyses were also performed. The heterogeneity between studies was evaluated using the I2 statistic. RESULTS: In this meta-analysis, a total of 1,844 patients with metastatic BC and positive for estrogen receptors (ERs) were enrolled from 8 articles. The analysis revealed that patients with circulating ESR1 mutations had significantly worse PFS (HR: 1.34; 95% CI: 1.17-1.55; p < 0.001) and OS (HR: 1.59; 95% CI: 1.31-1.92; p < 0.001) compared to wild-type ESR1 patients. Subgroup analysis showed that the types of plasma ESR1 mutations were associated with differences in the prognosis of metastatic BC. The D538G mutation showed a statistically significant lower PFS (p = 0.03), while the Y537S mutation was not significantly correlated with PFS (p = 0.354). CONCLUSION: According to the findings of this meta-analysis, the assessment for plasma ESR1 mutations may provide prognostic and clinical guidance regarding subsequent endocrine therapy decisions for ER-positive, metastatic BC patients who had received prior therapy with AIs.

Brain regions differences in amyloid-ß and gene expression in early APP/PS1 mice and identification of Npas4 as a key molecule in Alzheimer's disease.

Distinct brain regions are differentially affected during the various stages of Alzheimer's disease (AD). While the hippocampus and cortex are known to play significant roles, the involvement of the cerebellum has received less attention. Understanding the changes in diverse brain regions is essential to unravel the neuropathological mechanism in early-stage AD. Our research aimed to explore and compare amyloid-ß (Aß) pathology and gene expression profiles across the hippocampus, cortex, and cerebellum in the early stages of the Amyloid Precursor Protein/Presenilin-1 (APP/PS1) mouse model. By 7 months of age, significant Aß plaque accumulation was observed in the hippocampus and cortex of APP/PS1 mice, while no such deposits were found in the cerebellum. Gene expression analysis revealed predominant effects on immune response pathways in the hippocampus and cortex. Even in the absence of Aß deposition, notable gene expression changes were observed in the cerebellum of APP/PS1 mice. Intriguingly, Neuronal PAS Domain protein 4 (Npas4) expression was consistently down-regulated across all brain regions, independent of Aß plaque presence. Our findings reveal distinct transcriptomic alterations and Aß pathology in select cerebral regions during the initial phase of AD. Notably, the diminished expression of the Npas4 across three brain regions implies that Npas4 could play a pivotal role in the early pathogenesis of AD.

Prenatal diagnosis and molecular cytogenetic characterization of fetuses with central nervous system anomalies using chromosomal microarray analysis: a seven-year single-center retrospective study.

Few existing reports have investigated the copy number variants (CNVs) in fetuses with central nervous system (CNS) anomalies. To gain further insights into the genotype-phenotype relationship, we conducted chromosomal microarray analysis (CMA) to reveal the pathogenic CNVs (pCNVs) that were associated with fetal CNS anomalies. We enrolled 5,460 pregnant women with different high-risk factors who had undergone CMA. Among them, 57 subjects with fetal CNS anomalies were recruited. Of the subjects with fetal CNS anomalies, 23 were given amniocentesis, which involved karyotype analysis and CMA to detect chromosomal abnormalities. The other 34 cases only underwent CMA detection using fetal abortive tissue. In this study, we identified five cases of chromosome aneuploid and nine cases of pCNVs in the fetuses, with a chromosomal aberration detection rate of 24.56% (14/57). In the 23 cases that were given both karyotype and CMA analysis, one case with trisomy 18 was detected by karyotyping. Moreover, CMA revealed a further three cases of pCNVs, including the 1p36.33p36.31, 7q11.23, and 1q21.1q21.2 microdeletions, with a 13.04% (3/23) increase in CMA yield over the karyotype analysis. Additionally, three cases of trisomy 13, one case of trisomy 21, and six cases of pCNVs were detected in the other 34 fetuses where only CMA was performed. Furthermore, a higher chromosomal aberration detection rate was observed in the extra CNS anomaly group than in the isolated CNS anomaly group (40.91% vs 14.29%). In conclude, several pathogenic CNVs were identified in the fetuses with CNS anomalies using CMA. Among the detected CNVs, ZIC2, GNB1, and NSUN5 may be the candidate genes that responsible for fetal CNS anomalies. Our findings provides an additional reference for genetic counseling regarding fetal CNS anomalies and offers further insight into the genotype-phenotype relationship.

Sources and transformations of riverine nitrogen across a coastal-plain river network of eastern China: New insights from multiple stable isotopes.

Riverine nitrogen pollution is ubiquitous and attracts considerable global attention. Nitrate is commonly the dominant total nitrogen (TN) constituent in surface and ground waters; thus, stable isotopes of nitrate (δ15N/δ18O-NO3-) are widely used to differentiate nitrate sources. However, δ15N/δ18O-NO3- approach fails to present a holistic perspective of nitrogen pollution for many coastal-plain river networks because diverse nitrogen species contribute to high TN loads. In this study, multiple isotopes, namely, δ15N/δ18O-NO3-, δ18O-H2O, δ15N-NH4+, δ15N-PN, and δ15Nbulk/δ18O/SP-N2O in the Wen-Rui Tang River, a typical coastal-plain river network of Eastern China, were investigated to identify transformation processes and sources of nitrogen. Then, a stable isotope analysis in R (SIAR) model-TN source apportionment method was developed to quantify the contributions of different nitrogen sources to riverine TN loads. Results showed that nitrogen pollution in the river network was serious with TN concentrations ranging from 1.71 to 8.09 mg/L (mean ± SD: 3.77 ± 1.39 mg/L). Ammonium, nitrate, and suspended particulate nitrogen were the most prominent nitrogen components during the study period, constituting 45.4 %, 28.9 %, and 19.9 % of TN, respectively. Multiple hydrochemical and isotopic analysis identified nitrification as the dominant N cycling process. Biological assimilation and denitrification were minor N cycling processes, whereas ammonia volatilization was deemed negligible. Isotopic evidence and SIAR modeling revealed municipal sewage was the dominant contributor to nitrogen pollution. Based on quantitative estimates from the SIAR model, nitrogen source contributions to the Wen-Rui Tang River watershed followed: municipal sewage (40.6 %) ≈ soil nitrogen (39.5 %) > nitrogen fertilizer (9.7 %) > atmospheric deposition (2.8 %) during wet season; and municipal sewage (59.1 %) > soil nitrogen (30.4 %) > nitrogen fertilizer (4.1 %) > atmospheric deposition (1.0 %) during dry season. This study provides a deeper understanding of nitrogen dynamics in eutrophic coastal-plain river networks, which informs strategies for efficient control and remediation of riverine nitrogen pollution.