E2F1-associated purine synthesis pathway is a major component of the MET-DNA damage response network.

Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways whose interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acids, and lipids metabolism. 5'-Phosphoribosyl-N-formylglycinamide (FGAR), a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and a METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase (GART) which catalyzes FGAR synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTPs depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTPs reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis.

Serotonergic input from the dorsal raphe nucleus shapes learning-associated odor responses in the olfactory bulb.

AIM: Neural activity in the olfactory bulb (OB) can represent odor information during different brain and behavioral states. For example, the odor responses of mitral/tufted (M/T) cells in the OB change during learning of odor-discrimination tasks and, at the network level, beta power increases and the high gamma (HG) power decreases during odor presentation in such tasks. However, the neural mechanisms underlying these observations remain poorly understood. Here, we investigate whether serotonergic modulation from the dorsal raphe nucleus (DRN) to the OB is involved in shaping activity during the learning process in a go/no-go task in mice. METHODS: Fiber photometry was used to record the population activity of DRN serotonergic neurons during a go/no-go task. In vivo electrophysiology was used to record neural activity (single units and local field potentials) in the OB during the go/no-go task. Real-time place preference (RTPP) and intracranial light administration in a specific subarea (iClass) tests were used to assess the ability of mice to encoding reward information. RESULTS: Odor-evoked population activity in serotonergic neurons in the DRN was shaped during the learning process in a go/no-go task. In the OB, neural activity from oscillations to single cells showed complex, learning-associated changes and ability to encode information during an odor discrimination task. However, these properties were not observed after ablation of DRN serotonergic neurons. CONCLUSION: The activity of neural networks and single cells in the OB, and their ability to encode information about odor value, are shaped by serotonergic projections from the DRN.

Establishing and clinically validating a machine learning model for predicting unplanned reoperation risk in colorectal cancer.

BACKGROUND: Colorectal cancer significantly impacts global health, with unplanned reoperations post-surgery being key determinants of patient outcomes. Existing predictive models for these reoperations lack precision in integrating complex clinical data. AIM: To develop and validate a machine learning model for predicting unplanned reoperation risk in colorectal cancer patients. METHODS: Data of patients treated for colorectal cancer (n = 2044) at the First Affiliated Hospital of Wenzhou Medical University and Wenzhou Central Hospital from March 2020 to March 2022 were retrospectively collected. Patients were divided into an experimental group (n = 60) and a control group (n = 1984) according to unplanned reoperation occurrence. Patients were also divided into a training group and a validation group (7:3 ratio). We used three different machine learning methods to screen characteristic variables. A nomogram was created based on multifactor logistic regression, and the model performance was assessed using receiver operating characteristic curve, calibration curve, Hosmer-Lemeshow test, and decision curve analysis. The risk scores of the two groups were calculated and compared to validate the model. RESULTS: More patients in the experimental group were ≥ 60 years old, male, and had a history of hypertension, laparotomy, and hypoproteinemia, compared to the control group. Multiple logistic regression analysis confirmed the following as independent risk factors for unplanned reoperation (P < 0.05): Prognostic Nutritional Index value, history of laparotomy, hypertension, or stroke, hypoproteinemia, age, tumor-node-metastasis staging, surgical time, gender, and American Society of Anesthesiologists classification. Receiver operating characteristic curve analysis showed that the model had good discrimination and clinical utility. CONCLUSION: This study used a machine learning approach to build a model that accurately predicts the risk of postoperative unplanned reoperation in patients with colorectal cancer, which can improve treatment decisions and prognosis.

Cyrtomiumadenotrichum (Dryopteridaceae), a new species from Guangxi, China.

Cyrtomiumadenotrichum Y. Nong & R.H. Jiang (Dryopteridaceae), a new species from Guangxi, China, is described and illustrated. This new species is similar to C.nephrolepioides (Christ) Copel., C.obliquum Ching & K. H. Shing ex K. H. Shing, C.sinningense Ching & K. H. Shing ex K. H. Shing and C.calcis Liang Zhang, N.T.Lu & Li Bing Zhang in having erect rhizomes, dense, leathery lamina and rounded sori, but it can be easily distinguishable by its stipe sparsely glandular, base obvious oblique, basiscopic base truncate, acroscopic base auriculate or ovate.

The Epidemiological Characteristics of Mpox Cases - China, 2023.

What is already known about this topic?: Since May 2022, a global outbreak of mpox has emerged in more than 100 non-endemic countries. As of December 2023, over 90,000 cases had been reported. The outbreak has predominantly affected men who have sex with men (MSM), with sexual contact identified as the principal mode of transmission. What is added by this report?: Since June 2023, China has faced an occurrence of mpox, predominantly affecting the MSM population. Approximately 90% of those affected reported engaging in homosexual behavior within 21 days prior to symptom onset, a trend that aligns with the global outbreak pattern. The prompt identification of cases, diligent tracing of close contacts, and the implementation of appropriate management strategies have successfully mitigated the spread of mpox virus in China. What are the implications for public health practice?: We propose that mpox is transmitted locally within China. Drawing from our experiences in controlling the virus spread, it is crucial to investigate and formulate effective surveillance and educational strategies. Importantly, we must encourage high-risk populations to promptly seek medical care upon the onset of symptoms.

Mapping the distribution of Nipah virus infections: a geospatial modelling analysis.

BACKGROUND: Nipah virus is a zoonotic paramyxovirus responsible for disease outbreaks with high fatality rates in south and southeast Asia. However, knowledge of the potential geographical extent and risk patterns of the virus is poor. We aimed to establish an integrated spatiotemporal and phylogenetic database of Nipah virus infections in humans and animals across south and southeast Asia. METHODS: In this geospatial modelling analysis, we developed an integrated database containing information on the distribution of Nipah virus infections in humans and animals from 1998 to 2021. We conducted phylodynamic analysis to examine the evolution and migration pathways of the virus and meta-analyses to estimate the adjusted case-fatality rate. We used two boosted regression tree models to identify the potential ecological drivers of Nipah virus occurrences in spillover events and endemic areas, and mapped potential risk areas for Nipah virus endemicity. FINDINGS: 749 people and eight bat species across nine countries were documented as being infected with Nipah virus. On the basis of 66 complete genomes of the virus, we identified two clades-the Bangladesh clade and the Malaysia clade-with the time of the most recent common ancestor estimated to be 1863. Adjusted case-fatality rates varied widely between countries and were higher for the Bangladesh clade than for the Malaysia clade. Multivariable meta-regression analysis revealed significant relationships between case-fatality rate estimates and viral clade (p=0·0021), source country (p=0·016), proportion of male patients (p=0·036), and travel time to health-care facilities (p=0·036). Temperature-related bioclimate variables and the probability of occurrence of Pteropus medius were important contributors to both the spillover and the endemic infection models. INTERPRETATION: The suitable niches for Nipah virus are more extensive than previously reported. Future surveillance efforts should focus on high-risk areas informed by updated projections. Specifically, intensifying zoonotic surveillance efforts, enhancing laboratory testing capacity, and implementing public health education in projected high-risk areas where no human cases have been reported to date will be crucial. Additionally, strengthening wildlife surveillance and investigating potential modes of transmission in regions with documented human cases is needed. FUNDING: The Key Research and Development Program of China.

Multiple algorithms highlight key brain genes driven by multiple anesthetics.

Anesthesia serves as a pivotal tool in modern medicine, creating a transient state of sensory deprivation to ensure a pain-free surgical or medical intervention. While proficient in alleviating pain, anesthesia significantly modulates brain dynamics, metabolic processes, and neural signaling, thereby impairing typical cognitive functions. Furthermore, anesthesia can induce notable impacts such as memory impairment, decreased cognitive function, and diminished intelligence, emphasizing the imperative need to explore the concealed repercussions of anesthesia on individuals. In this investigation, we aggregated gene expression profiles (GSE64617, GSE141242, GSE161322, GSE175894, and GSE178995) from public repositories following second-generation sequencing analysis of various anesthetics. Through scrutinizing post-anesthesia brain tissue gene expression utilizing Gene Set Enrichment Analysis (GSEA), Robust Rank Aggregation (RRA), and Weighted Gene Co-expression Network Analysis (WGCNA), this research aims to pinpoint pivotal genes, pathways, and regulatory networks linked to anesthesia. This undertaking not only enhances comprehension of the physiological changes brought about by anesthesia but also lays the groundwork for future investigations, cultivating new insights and innovative perspectives in medical practice.

Exploring causal correlations of inflammatory biomarkers in idiopathic normal-pressure hydrocephalus: insights from bidirectional Mendelian randomization analysis.

Background and objective: Neuroinflammatory processes have been identified as playing a crucial role in the pathophysiology of various neurodegenerative diseases, including idiopathic normal-pressure hydrocephalus (iNPH). iNPH, defined as a common disease of cognitive impairment in older adults, poses major challenges for therapeutic interventions owing to the stringent methodological requirements of relevant studies, clinical heterogeneity, unclear etiology, and uncertain diagnostic criteria. This study aims to assess the relationship between circulating inflammatory biomarkers and iNPH risk using bidirectional two-sample Mendelian randomization (MR) combined with meta-analysis. Methods: In our bidirectional MR study, genetic data from a genome-wide association study (GWAS) involving 1,456 iNPH cases and 409,726 controls of European ancestry were employed. Single-nucleotide polymorphisms (SNPs) associated with exposures served as instrumental variables for estimating the causal relationships between iNPH and 132 types of circulating inflammatory biomarkers from corresponding GWAS data. Causal associations were primarily examined using the inverse variance-weighted method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode analyses. In the results, heterogeneity was assessed using the Cochran Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers test. Sensitivity analysis was conducted through leave-one-out analysis. Reverse MR analyses were performed to mitigate bias from reverse causality. Meta-analyses of identical inflammatory biomarkers from both data sources strengthened the findings. Results: Results indicated a genetically predicted association between Interleukin-16 (IL-16) [OR: 1.228, 95% CI: 1.049-1.439, p = 0.011], TNF-related apoptosis ligand (TRAIL) [OR: 1.111, 95% CI: 1.019-1.210, p = 0.017] and Urokinase-type plasminogen activator (uPA) [OR: 1.303, 95% CI: 1.025-1.658, p = 0.031] and the risk of iNPH. Additionally, changes in human Glial cell line-derived neurotrophic factor (hGDNF) [OR: 1.044, 95% CI: 1.006-1.084, p = 0.023], Matrix metalloproteinase-1 (MMP-1) [OR: 1.058, 95% CI: 1.020, 1.098, p = 0.003] and Interleukin-12p70 (IL-12p70) [OR: 0.897, 95% CI: 0.946-0.997, p = 0.037] levels were identified as possible consequences of iNPH. Conclusion: Our MR study of inflammatory biomarkers and iNPH, indicated that IL-16, TRAIL, and uPA contribute to iNPH pathogenesis. Furthermore, iNPH may influence the expression of hGDNF, MMP-1, and IL-12p70. Therefore, targeting specific inflammatory biomarkers could be promising strategy for future iNPH treatment and prevention.

miPEP31 alleviates Ang II-induced hypertension in mice by occupying Cebpα binding sites in the pri-miR-31 promoter.

BACKGROUND: Previous studies have shown that peptides encoded by noncoding RNAs (ncRNAs) can be used as peptide drugs to alleviate diseases. We found that microRNA-31 (miR-31) is involved in the regulation of hypertension and that the peptide miPEP31, which is encoded by the primary transcript of miR-31 (pri-miR-31), can inhibit miR-31 expression. However, the role and mechanism of miPEP31 in hypertension have not been elucidated. METHODS: miPEP31 expression was determined by western blot analysis. miPEP31-deficient mice (miPEP31-/-) were used, and synthetic miPEP31 was injected into Ang II-induced hypertensive mice. Blood pressure was monitored through the tail-cuff method. Histological staining was used to evaluate renal damage. Regulatory T (Treg) cells were assessed by flow cytometry. Differentially expressed genes were analysed through RNA sequencing. The transcription factors were predicted by JASPAR. Luciferase reporter and electrophoretic mobility shift assays (EMSAs) were used to determine the effect of pri-miR-31 on the promoter activity of miPEP31. Images were taken to track the entry of miPEP31 into the cell. RESULTS: miPEP31 is endogenously expressed in target organs and cells related to hypertension. miPEP31 deficiency exacerbated but exogenous miPEP31 administration mitigated the Ang II-induced systolic blood pressure (SBP) elevation, renal impairment and Treg cell decreases in the kidney. Moreover, miPEP31 deletion increased the expression of genes related to Ang II-induced renal fibrosis. miPEP31 inhibited the transcription of miR-31 and promoted Treg differentiation by occupying the Cebpα binding site. The minimal functional domain of miPEP31 was identified and shown to regulate miR-31. CONCLUSION: miPEP31 was identified as a potential therapeutic peptide for treating hypertension by promoting Treg cell differentiation in vivo. Mechanistically, we found that miPEP31 acted as a transcriptional repressor to specifically inhibit miR-31 transcription by competitively occupying the Cebpα binding site in the pri-miR-31 promoter. Our study highlights the significant therapeutic effect of miPEP31 on hypertension and provides novel insight into the role and mechanism of miPEPs.

Spinosad blocks CHRNA5 mediated EGFR signaling pathway activation to inhibit lung adenocarcinoma proliferation.

Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide, with high incidence and low survival rates. Nicotinic acetylcholine receptors play an important role in the progression of LUAD. In this study, a screening of 17 nicotinic acetylcholine receptor allosteric agents revealed that spinosad effectively suppressed the proliferation of LUAD cells. The experiments demonstrated that spinosad induced cell cycle arrest in the G1 phase and stimulated apoptosis, thereby impeding the growth of LUAD and enhancing the responsiveness to gefitinib in vitro and vivo. Mechanistic insights obtained through transcriptome sequencing, Co-IP, and protein immunoblots indicated that spinosad disrupted the interaction between CHRNA5 and EGFR, thereby inhibiting the formation of downstream complexes and activation of the EGFR signaling pathway. The supplementation of exogenous acetylcholine showed to mitigate the inhibition of LUAD cell proliferation induced by spinosad. This study elucidates the therapeutic effects and mechanisms of spinosad in LUAD, and offers a theoretical and experimental foundation for novel LUAD treatments.

Enhancing radiation-resistance and peroxidase-like activity of single-atom copper nanozyme via local coordination manipulation.

The inactivation of natural enzymes by radiation poses a great challenge to their applications for radiotherapy. Single-atom nanozymes (SAzymes) with high structural stability under such extreme conditions become a promising candidate for replacing natural enzymes to shrink tumors. Here, we report a CuN3-centered SAzyme (CuN3-SAzyme) that exhibits higher peroxidase-like catalytic activity than a CuN4-centered counterpart, by locally regulating the coordination environment of single copper sites. Density functional theory calculations reveal that the CuN3 active moiety confers optimal H2O2 adsorption and dissociation properties, thus contributing to high enzymatic activity of CuN3-SAzyme. The introduction of X-ray can improve the kinetics of the decomposition of H2O2 by CuN3-SAzyme. Moreover, CuN3-SAzyme is very stable after a total radiation dose of 500 Gy, without significant changes in its geometrical structure or coordination environment, and simultaneously still retains comparable peroxidase-like activity relative to natural enzymes. Finally, this developed CuN3-SAzyme with remarkable radioresistance can be used as an external field-improved therapeutics for enhancing radio-enzymatic therapy in vitro and in vivo. Overall, this study provides a paradigm for developing SAzymes with improved enzymatic activity through local coordination manipulation and high radioresistance over natural enzymes, for example, as sensitizers for cancer therapy.

Humoral and cellular immune responses following Omicron BA.2.2 breakthrough infection and Omicron BA.5 reinfection.

The emergence of novel Omicron subvariants has raised concerns regarding the efficacy of immunity induced by prior Omicron subvariants breakthrough infection (BTI) or reinfection against current circulating Omicron subvariants. Here, we prospectively investigated the durability of antibody and T cell responses in individuals post Omicron BA.2.2 BTI, with or without subsequent Omicron BA.5 reinfection. Our findings reveal that the emerging Omicron subvariants, including CH.1.1, XBB, and JN.1, exhibit extensive immune evasion induced by previous infections. Notably, the level of IgG and neutralizing antibodies were found to correlate with subsequent Omicron BA.5 reinfection. Fortunately, T cell responses recognizing both Omicron BA.2 and CH.1.1 peptides were observed. Furthermore, Omicron BA.5 reinfection may alleviate immune imprinting induced by WT-vaccination, bolster virus-specific ICS+ T cell responses, and promote the phenotypic differentiation of virus-specific memory CD8+ T cells. Antigen-updated or T cell-conserved vaccines are needed to control the transmission of diverse emerging SARS-CoV-2 variants.

Class â ¡ ferroptosis inducers are a novel therapeutic approach for t(4;14)-positive multiple myeloma.

Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by genetic heterogeneity. The cytogenetic abnormality t(4;14) strongly predicts poor outcome in MM patients even in the era of novel drugs. Ferroptosis is a new approach to antitumor therapy, but the relationship between ferroptosis and MM cytogenetic abnormalities remains largely unclear. Here, we show that t(4;14)-positive but not t(4;14)-negative MM cells are susceptible to class II ferroptosis inducers (FINs) in a preclinical setting, which is dependent on the significant upregulation of the MM SET domain-containing protein (MMSET). Mechanistically, MMSET upregulates acyl-CoA synthetase long-chain family member 4 (ACSL4) transcription by binding to its promoter region, leading to increased polyunsaturated fatty acid (PUFA) levels and enhanced sensitivity of t(4;14)-positive MM to ferroptosis. Supplementation of PUFAs efficiently restores ferroptosis susceptibility of t(4;14)-negative MM. In addition, combination treatment of class II FINs and bortezomib in t(4;14)-positive MM attenuates cellular glutathione and induces both apoptosis and ferroptosis levels by inhibiting the increase of solute carrier family 7 member 11, demonstrating synergistic anti-tumor activity in vitro and in a xenograft model. Taken together, our findings suggest that targeting ferroptosis with class II FINs is a novel and promising therapeutic approach to improve the outcome of t(4;14)-positive MM.

Application of Modified Early Warning Score in Patients with Hypertensive Intracerebral Hemorrhage After Neurosurgery.

Background: Hypertensive intracerebral hemorrhage (HICH) is one of serious complications of hypertension. Therefore, early identification of postoperative deterioration of patients and timely intervention measures are needed. Objective: To evaluate the application of Modified Early Warning Score (MEWS) in HICH patients after neurosurgery. Design: Retrospective study. Participants: 82 HICH patients admitted to the neurosurgery department of our hospital from July 2022 to January 2023 were enrolled as subjects. Interventions: The MEWS score and the early warning score of postoperative deterioration of HICH patients were evaluated every hour. The respiratory rate, heart rate, systolic blood pressure, and blood oxygen saturation were monitored by a bedside multi-parameter monitor. The consciousness was evaluated by the Glasgow Coma Scale (GCS) score. Primary Outcome Measures: The receiver operator characteristic (ROC) curve was drawn to compare the predictive effect of the early warning scale and the MEWS on the prognosis of postoperative deterioration in patients with HICH. Results: The area under the ROC curve of early warning score predicted the postoperative deterioration of patients to be 0.9660, the best cutoff value was 3.9 points, the sensitivity was 98.35%, the specificity was 86.67%, and the Yoden index was 0.784. The area under the ROC curve of the MEWS for postoperative deterioration of HICH patients was 0.869, the best cutoff value was 3.9, the sensitivity was 83.33%, the specificity was 71.67%, and the Yoden index was 0.517. However, unlike early warning scoring scale, MEWS score was only used to evaluate vital signs with high frequency of clinical monitoring, and the threshold range of heart rate, systolic blood pressure and consciousness score set was not fully applicable to patients after HICH. Conclusion: The early warning scoring scale for postoperative deterioration of HICH patients has good predictive efficacy and strong operability.

Sophora subprostrate polysaccharide targets LncRNA MSTRG.5823.1 to suppress PCV2-mediated immunosuppression via TNF/NF-κB signaling.

Current evidence suggests that porcine circovirus type 2 (PCV2) infection induces immunosuppression in piglets. Sophora subprostrate polysaccharide (SSP) exhibits various pharmacological activities, including immunoregulatory, anti-inflammatory, antiviral, and antioxidant properties. However, the acts of lncRNAs in regulating the therapeutic effects of SSP on PCV2-infected RAW264.7 cells remains poorly understood. This study aimed to investigate the molecular mechanisms by which lncRNAs regulate PCV2-induced immunosuppression during SSP treatment. Our findings revealed that 1699 mRNAs, 373 lncRNAs, and 129 miRNAs were differentially expressed in PCV2-infected RAW264.7 cells. Additionally, 359 mRNAs, 271 lncRNAs, and 79 miRNAs exhibited differential expression in SSP-treated PCV2-infected RAW264.7 cells. GO and KEGG analyses indicated that the candidate genes were enriched in the TNF/NF-κB signaling pathway. Furthermore, based on GO and KEGG pathway analysis, a ceRNA network involving chemokine (C-X-C motif) ligand 2 (CXCL2), miR-217-x, and MSTRG.5823.1 was constructed. We demonstrated that lncRNA MSTRG.5823.1 localized to the cytoplasm. Moreover, we found that silencing or overexpressing lncRNA MSTRG.5823.1 significantly modulated PCV2-induced immunosuppression by regulating the activation of the TNF/NF-κB signaling pathway. Specifically, lncRNA MSTRG.5823.1 overexpression increased the expression of TNF/NF-κB signaling pathway-related genes and proteins in PCV2-infected RAW264.7 cells. Conversely, silencing lncRNA MSTRG.5823.1 decreased their expression. Rescue assays further revealed that the suppressive effects of miR-217-x overexpression on TNF/NF-κB signaling pathway-related genes and proteins could be reversed by MSTRG.5823.1 overexpression. These findings highlight the critical role of lncRNA MSTRG.5823.1 in PCV2 infection progression and suggest a new strategy for the prevention and treatment of PCV2 infection.

Necroptosis enhances 'don't eat me' signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 'don't eat me' signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial-mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.

Mapping the distribution of sandflies and sandfly-associated pathogens in China.

BACKGROUND: Understanding and mapping the distribution of sandflies and sandfly-associated pathogens (SAPs) is crucial for guiding the surveillance and control effort. However, their distribution and the related risk burden in China remain poorly understood. METHODS: We mapped the distribution of sandflies and SAPs using literature data from 1940 to 2022. We also mapped the human visceral leishmaniasis (VL) cases using surveillance data from 2014 to 2018. The ecological drivers of 12 main sandfly species and VL were identified by applying machine learning, and their distribution and risk were predicted in three time periods (2021-2040, 2041-2060, and 2061-2080) under three scenarios of climate and socioeconomic changes. RESULTS: In the mainland of China, a total of 47 sandfly species have been reported, with the main 12 species classified into three clusters according to their ecological niches. Additionally, 6 SAPs have been identified, which include two protozoa, two bacteria, and two viruses. The incidence risk of different VL subtypes was closely associated with the distribution risk of specific vectors. The model predictions also revealed a substantial underestimation of the current sandfly distribution and VL risk. The predicted areas affected by the 12 major species of sandflies and the high-risk areas for VL were found to be 37.9-1121.0% and 136.6% larger, respectively, than the observed range in the areas. The future global changes were projected to decrease the risk of mountain-type zoonotic VL (MT-ZVL), but anthroponotic VL (AVL) and desert-type zoonotic VL (DT-ZVL) could remain stable or slightly increase. CONCLUSIONS: Current field observations underestimate the spatial distributions of main sandfly species and VL in China. More active surveillance and field investigations are needed where high risks are predicted, especially in areas where the future risk of VL is projected to remain high or increase.

Recent Advances in the Domino Annulation Reaction of Quinone Imines.

Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.

Early Postnatal Exposure to Midazolam Causes Lasting Histological and Neurobehavioral Deficits via Activation of the mTOR Pathway.

Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.