COVID-19 is associated with changes in brain function and structure: A multimodal meta-analysis of neuroimaging studies.

The actual role of coronavirus disease 2019 (COVID-19) in brain damage has been increasingly reported, necessitating a meta-analysis to collate and summarize the inconsistent findings from functional imaging and voxel-based morphometry (VBM) studies. A comprehensive voxel-wise meta-analysis of the whole brain was conducted to identify alterations in functional activity and gray matter volume (GMV) between COVID-19 patients and healthy controls (HCs) by using Seed-based d Mapping software. We included 15 functional imaging studies (484 patients with COVID-19, 534 HCs) and 9 VBM studies (449 patients with COVID-19, 388 HCs) in the analysis. Overall, patients with COVID-19 exhibited decreased functional activity in the right superior temporal gyrus (STG) (extending to the right middle and inferior temporal gyrus, insula, and temporal pole [TP]), left insula, right orbitofrontal cortex (OFC) (extending to the right olfactory cortex), and left cerebellum compared to HCs. For VBM, patients with COVID-19, relative to HCs, showed decreased GMV in the bilateral anterior cingulate cortex/medial prefrontal cortex (extending to the bilateral OFC), and left cerebellum, and increased GMV in the bilateral amygdala (extending to the bilateral hippocampus, STG, TP, MTG, and right striatum). Moreover, overlapping analysis revealed that patients with COVID-19 exhibited both decreased functional activity and increased GMV in the right TP (extending to the right STG). The multimodal meta-analysis suggests that brain changes of function and structure in the temporal lobe, OFC and cerebellum, and functional or structural alterations in the insula and the limbic system in COVID-19. These findings contribute to a better understanding of the pathophysiology of brain alterations in COVID-19. SIGNIFICANCE STATEMENT: This first large-scale multimodal meta-analysis collates existing neuroimaging studies and provides voxel-wise functional and structural whole-brain abnormalities in COVID-19. Findings of this meta-analysis provide valuable insights into the dynamic brain changes (from infection to recovery) and offer further explanations for the pathophysiological basis of brain alterations in COVID-19.

METTL14 promotes lipid metabolism reprogramming and sustains nasopharyngeal carcinoma progression via enhancing m6A modification of ANKRD22 mRNA.

BACKGROUND: N6-methyladenosine (m6A) modification is essential for modulating RNA processing as well as expression, particularly in the context of malignant tumour progression. However, the exploration of m6A modification in nasopharyngeal carcinoma (NPC) remains very limited. METHODS: RNA m6A levels were analysed in NPC using m6A dot blot assay. The expression level of methyltransferase-like 14 (METTL14) within NPC tissues was analysed from public databases as well as RT-qPCR and immunohistochemistry. The influences on METTL14 expression on NPC proliferation and metastasis were explored via in vitro as well as in vivo functional assays. Targeted genes of METTL14 were screened using the m6A and gene expression profiling microarray data. Actinomycin D treatment and polysome analysis were used to detect the half-life and translational efficiency of ANKRD22. Flow cytometry, immunofluorescence and immunoprecipitation were used to validate the role of ANKRD22 on lipid metabolism in NPC cells. ChIP-qPCR analysis of H3K27AC signalling near the promoters of METTL14, GINS3, POLE2, PLEK2 and FERMT1 genes. RESULTS: We revealed METTL14, in NPC, correlating with poor patient prognosis. In vitro and in vivo assays indicated METTL14 actively promoted NPC cells proliferation and metastasis. METTL14 catalysed m6A modification on ANKRD22 messenger ribonucleic acid (mRNA), recognized by the reader IGF2BP2, leading to increased mRNA stability and higher translational efficiency. Moreover, ANKRD22, a metabolism-related protein on mitochondria, interacted with SLC25A1 to enhance citrate transport, elevating intracellular acetyl-CoA content. This dual impact of ANKRD22 promoted lipid metabolism reprogramming and cellular lipid synthesis while upregulating the expression of genes associated with the cell cycle (GINS3 and POLE2) and the cytoskeleton (PLEK2 and FERMT1) through heightened epigenetic histone acetylation levels in the nucleus. Intriguingly, our findings highlighted elevated ANKRD22-mediated histone H3 lysine 27 acetylation (H3K27AC) signals near the METTL14 promoter, which contributes to a positive feedback loop perpetuating malignant progression in NPC. CONCLUSIONS: The identified METTL14-ANKRD22-SLC25A1 axis emerges as a promising therapeutic target for NPC, and also these molecules may serve as novel diagnostic biomarkers.

Gut proinflammatory bacteria is associated with abnormal functional connectivity of hippocampus in unmedicated patients with major depressive disorder.

Accumulating evidence has revealed the gut bacteria dysbiosis and brain hippocampal functional and structural alterations in major depressive disorder (MDD). However, the potential relationship between the gut microbiota and hippocampal function alterations in patients with MDD is still very limited. Data of resting-state functional magnetic resonance imaging were acquired from 44 unmedicated MDD patients and 42 demographically matched healthy controls (HCs). Severn pairs of hippocampus subregions (the bilateral cornu ammonis [CA1-CA3], dentate gyrus (DG), entorhinal cortex, hippocampal-amygdaloid transition area, and subiculum) were selected as the seeds in the functional connectivity (FC) analysis. Additionally, fecal samples of participants were collected and 16S rDNA amplicon sequencing was used to identify the altered relative abundance of gut microbiota. Then, association analysis was conducted to investigate the potential relationships between the abnormal hippocampal subregions FC and microbiome features. Also, the altered hippocampal subregion FC values and gut microbiota levels were used as features separately or together in the support vector machine models distinguishing the MDD patients and HCs. Compared with HCs, patients with MDD exhibited increased FC between the left hippocampus (CA2, CA3 and DG) and right hippocampus (CA2 and CA3), and decreased FC between the right hippocampal CA3 and bilateral posterior cingulate cortex. In addition, we found that the level of proinflammatory bacteria (i.e., Enterobacteriaceae) was significantly increased, whereas the level of short-chain fatty acids producing-bacteria (i.e., Prevotellaceae, Agathobacter and Clostridium) were significantly decreased in MDD patients. Furthermore, FC values of the left hippocampal CA3- right hippocampus (CA2 and CA3) was positively correlated with the relative abundance of Enterobacteriaceae in patients with MDD. Moreover, altered hippocampal FC patterns and gut microbiota level were considered in combination, the best discrimination was obtained (AUC = 0.92). These findings may provide insights into the potential role of gut microbiota in the underlying neuropathology of MDD patients.

Aflatoxin B1 as a complicit in intestinal damage caused by Eimeria ovinoidalis in lambs: Novel insights to reveal parasite-gut battle.

Mycotoxins, unavoidable contaminants in feed and feed ingredients, have the potential to influence the incidence and severity of various diseases upon ingestion. Sheep coccidiosis is an enteric disease caused by protozoa of Eimeria spp. However, the extent to which the presence of aflatoxin b1 (AFB1) synergistically exacerbates damage to intestinal health in lambs with Eimeria remains unclear. 50-day-old female lambs were randomly assigned to a 2 × 2 factorial arrangement of treatments for 15 days to assess the impact of AFB1 exposure on lambs with or without Eimeria (E.) ovinoidalis infection. Our findings reveal that AFB1 synergistically intensifies damage to intestinal health in lambs challenged by E. ovinoidalis. This is evidenced by disruptions to the intestinal microbiota and reductions in the production of short-chain fatty acids. AFB1 further aggravates damage to the cecal mechanical barrier. Additionally, AFB1 contributes to the entry of lipopolysaccharide into the bloodstream, activating the inflammatory response. Interestingly, AFB1 exposure history results in an early peak of oocyst excretion and a decreased number of oocyst excretion in E. ovinoidalis infected lambs. This may be closely linked to the destruction of the intestinal epithelial cell structure and its apoptosis, as indicated by a decreased ratio of Bcl-2 to Bax and increased caspase-3 levels. Mechanistically, proteomics analysis identified mitochondrial dysfunction (inhibition of the oxidative phosphorylation pathway) as the primary factor intensifying intestinal epithelial cell destruction caused by coccidia, exacerbated by AFB1 through the inhibiting the conversion of NADH to NAD+ in the cecum of lambs via down-regulation of the PGC-1α/NRF1/TFAM pathway. Overall, these results offer novel insights into the AFB1 complicity in accelerating intestinal damage caused by E. ovinoidalis in lambs. Targeting the mitochondrial oxidative phosphorylation pathway of the intestine may represent a new therapeutic strategy against the detrimental effects of mycotoxin and coccidia.

A network analysis of the interrelationships between depression, anxiety, insomnia and quality of life among fire service recruits.

Background: Research on the mental health and quality of life (hereafter QOL) among fire service recruits after the end of the COVID-19 restrictions is lacking. This study explored the network structure of depression, anxiety and insomnia, and their interconnections with QOL among fire service recruits in the post-COVID-19 era. Methods: This cross-sectional study used a consecutive sampling of fire service recruits across China. We measured the severity of depression, anxiety and insomnia symptoms, and overall QOL using the nine-item Patient Health Questionnaire (PHQ-9), seven-item Generalized Anxiety Disorder scale (GAD-7), Insomnia Severity Index (ISI) questionnaire, and World Health Organization Quality of Life-brief version (WHOQOL-BREF), respectively. We estimated the most central symptoms using the centrality index of expected influence (EI), and the symptoms connecting depression, anxiety and insomnia symptoms using bridge EI. Results: In total, 1,560 fire service recruits participated in the study. The prevalence of depression (PHQ-9 ≥ 5) was 15.2% (95% CI: 13.5-17.1%), while the prevalence of anxiety (GAD-7 ≥ 5) was 11.2% (95% CI: 9.6-12.8%). GAD4 ("Trouble relaxing") had the highest EI in the whole network model, followed by ISI5 ("Interference with daytime functioning") and GAD6 ("Irritability"). In contrast, PHQ4 ("Fatigue") had the highest bridge EI values in the network, followed by GAD4 ("Trouble relaxing") and ISI5 ("Interference with daytime functioning"). Additionally, ISI4 "Sleep dissatisfaction" (average edge weight = -1.335), which was the central symptom with the highest intensity value, had the strongest negative correlation with QOL. Conclusion: Depression and anxiety were important mental health issues to address among fire service recruits in the post-COVID-19 era in China. Targeting central and bridge symptoms identified in network analysis could help address depression and anxiety among fire service recruits in the post-COVID-19 era.

Selective biosorption of Li+ in aqueous solution by lithium ion-imprinted material on the surface of chitosan/attapulgite.

The extraction of Li+ from liquid lithium resources is a pivotal focus of current research endeavors. Attapulgite (ATP), characterized by its distinctive layered structure and inherent ion exchange properties, emerges as an exceptional material for fabricating lithium-ion sieve. Ion-imprinted chitosan/ATP composite materials are successfully synthesized, demonstrating efficacy in selectively absorbing Li+. The results emphasize the rich functional groups present in H-CTP-2, enhancing its absorbability and selectivity, with an adsorption capacity of 37.56 mg•g-1. The adsorption conforms to the Langmuir and pseudo-second-order kinetic model. Li+ coordination involves amino and hydroxyl group, indicating a chemisorption process. Furthermore, the substantial pore structure and significant specific surface area of ATP significantly promote Li+ adsorption, suggesting its participation not only in chemisorption but also in physical adsorption. The fabricated ion-imprinted materials boast substantial adsorption capacity, exceptional selectivity, and rapid kinetics, highlighting their potential for effectively separating Li+ from aqueous solution.

Whole-Genome Sequencing of Two Potentially Allelopathic Strains of Bacillus from the Roots of C. equisetifolia and Identification of Genes Related to Synthesis of Secondary Metabolites.

The coastal Casuarina equisetifolia is the most common tree species in Hainan's coastal protection forests. Sequencing the genomes of its allelopathic endophytes can allow the protective effects of these bacteria to be effectively implemented in protected forests. The goal of this study was to sequence the whole genomes of the endophytes Bacillus amyloliquefaciens and Bacillus aryabhattai isolated from C. equisetifolia root tissues. The results showed that the genome sizes of B. amyloliquefaciens and B. aryabhattai were 3.854 Mb and 5.508 Mb, respectively. The two strains shared 2514 common gene families while having 1055 and 2406 distinct gene families, respectively. The two strains had 283 and 298 allelochemical synthesis-associated genes, respectively, 255 of which were shared by both strains and 28 and 43 of which were unique to each strain, respectively. The genes were putatively involved in 11 functional pathways, including secondary metabolite biosynthesis, terpene carbon skeleton biosynthesis, biosynthesis of ubiquinone and other terpene quinones, tropane/piperidine and piperidine alkaloids biosynthesis, and phenylpropanoid biosynthesis. NQO1 and entC are known to be involved in the biosynthesis of ubiquinone and other terpenoid quinones, and rfbC/rmlC, rfbA/rmlA/rffH, and rfbB/rmlB/rffG are involved in the biosynthesis of polyketide glycan units. Among the B. aryabhattai-specific allelochemical synthesis-related genes, STE24 is involved in terpene carbon skeleton production, atzF and gdhA in arginine biosynthesis, and TYR in isoquinoline alkaloid biosynthesis. B. amyloliquefaciens and B. aryabhattai share the genes aspB, yhdR, trpA, trpB, and GGPS, which are known to be involved in the synthesis of carotenoids, indole, momilactones, and other allelochemicals. Additionally, these bacteria are involved in allelochemical synthesis via routes such as polyketide sugar unit biosynthesis and isoquinoline alkaloid biosynthesis. This study sheds light on the genetic basis of allelopathy in Bacillus strains associated with C. equisetifolia, highlighting the possible use of these bacteria in sustainable agricultural strategies for weed management and crop protection.

Soil organic matter and total nitrogen as key driving factors promoting the assessment of acid-base buffering characteristics in a tea (Camellia sinensis) plantation habitat.

The issue of soil acidification in tea plantations has become a critical concern due to its potential impact on tea quality and plant health. Understanding the factors contributing to soil acidification is essential for implementing effective soil management strategies in tea-growing regions. In this study, a field study was conducted to investigate the effects of tea plantations on soil acidification and the associated acid-base buffering capacity (pHBC). We assessed acidification, pHBC, nutrient concentrations, and cation contents in the top 0-20 cm layer of soil across forty tea gardens of varying stand ages (0-5, 5-10, 10-20, and 20-40 years old) in Anji County, Zhejiang Province, China. The results revealed evident soil acidification due to tea plantation activities, with the lowest soil pH observed in tea gardens aged 10-20 and 20-40 years. Higher levels of soil organic matter (SOM), total nitrogen (TN), Olsen phosphorus (Olsen-P), available iron (Fe), and exchangeable hydrogen (H+) were notably recorded in 10-20 and 20-40 years old tea garden soils, suggesting an increased risk of soil acidification with prolonged tea cultivation. Furthermore, prolonged tea cultivation correlated with increased pHBC, which amplified with tea stand ages. The investigation of the relationship between soil pHBC and various parameters highlighted significant influences from soil pH, SOM, cation exchange capacity, TN, available potassium, Olsen-P, exchangeable acids (including H+ and aluminum), available Fe, and available zinc. Consequently, these findings underscore a substantial risk of soil acidification in tea gardens within the monitored region, with SOM and TN content being key driving factors influencing pHBC.

Fragment-Based Anti-inflammatory Agent Design and Target Identification: Discovery of AF-45 as an IRAK4 Inhibitor to Treat Ulcerative Colitis and Acute Lung Injury.

UC and ALI are inflammatory diseases with limited treatment in the clinic. Herein, fragment-based anti-inflammatory agent designs were carried out deriving from cyclohexylamine/cyclobutylamine and several fragments from anti-inflammatory agents in our lab. AF-45 (IC50 = 0.53/0.60 µM on IL-6/TNF-α in THP-1 macrophages) was identified as the optimal molecule using ELISA and MTT assays from the 33 synthesized compounds. Through mechanistic studies and a systematic target search process, AF-45 was found to block the NF-κB/MAPK pathway and target IRAK4, a promising target for inflammation and autoimmune diseases. The selectivity of AF-45 targeting IRAK4 was validated by comparing its effects on other kinase/nonkinase proteins. In vivo, AF-45 exhibited a good therapeutic effect on UC and ALI, and favorable PK proprieties. Since there are currently no clinical or preclinical trials for IRAK4 inhibitors to treat UC and ALI, AF-45 provides a new lead compound or candidate targeting IRAK4 for the treatment of these diseases.

Exploring susceptibility factors to medication dispensing errors through a retrospective study of patient-reported dispensing errors over 11 years: are dispensing errors indeed due to personal reasons for pharmacists?

BACKGROUND: Medication dispensing errors cause wastage of medicines and increase healthcare costs, with serious consequences for patients. However, few studies have systematically and completely reviewed dispensing errors, with inadequate attention to the objective regularity and risk factors for dispensing errors. OBJECTIVES: To explore the potential causes and risk factors influencing the prevalence of medication dispensing errors. METHODS: We collected patient-reported medication dispensing errors from a large tertiary care hospital in South China over 11 years. We assessed the characteristics of dispensing errors, labelled the causes, compared them with more than 25 million prescriptions from 2012 to 2022, identified the susceptibility factors for the occurrence of dispensing errors, and analysed the characteristics and patterns of the errors. RESULTS: A total of 376 patient-reported dispensing errors were recorded. It took an average of 5.2 days for a patient to find an error. Only 37.5% of errors were reviewed by the patient within 24 hours. These errors directly contributed to a medication loss of US$188 406. Of the 160 recorded pharmacists, 112 (70%) committed dispensing errors. Dispensing errors were affected by the pharmacists' use of the machine, workload and the length of monthly vacation. Of the dispensing errors, 47.9% (n=180) were caused by medication packaging or names that were similar. Antibiotics (n=32, 8.5%) were the most common types of drugs dispensed incorrectly, and traditional Chinese medicines (n=31, 8.2%) and immunosuppressants (n=21, 5.6%) were the most likely to be dispensed in inaccurate quantities. CONCLUSIONS: Organising adequate staff and using machines to prepare medicines may be necessary to reduce dispensing errors. When pharmacists have been away from work for more than 72 hours they should find their rhythm in other positions before dispensing medicines. It is more important to prioritise the differentiation of medicines with similar packaging over those with similar names when arranging drug shelving.

Correlation between serum uric acid level and atrial fibrillation in patients with hyperthyroidism on medical data analysis context of IoT.

BACKGROUND: Dysfunctions in metabolism and endocrine systems are outcomes of disruptions in human physiological processes, often leading to disease onset. External factors can hinder the human body's innate capacity for self-regulation and healing, particularly when immune responses are compromised, allowing these factors to interfere with normal bodily functions directly. OBJECTIVE: To explore the effect of uric acid expression water in blood on the occurrence of atrial fibrillation in patients with hyperthyroidism, the expression level of uric acid in the blood and other physiological indexes were compared between patients with no symptoms of atrial fibrillation and patients with hyperthyroidism with symptoms of atrial fibrillation, to find the correlation between them. METHODS: A group of 112 hyperthyroidism patients who were admitted to our hospital from September 2019 to March 2020 were chosen and split into two groups. The control group consisted of 56 individuals (21 men and 35 women) aged between 16 and 86 years old, with an average age of 46.23 years (± 7.63). The observation group consisted of 56 individuals (24 males and 32 females) between 15 and 79 years, with an average age of 53.44 years (± 8.91). RESULTS: In the patients who were not treated with drugs before hospitalization the disease course and symptoms varied. The patients' clinical medical and demographic data were recorded and the patients' physiological indexes were obtained through blood tests and analysis. The differences between the two groups were analyzed by renal function, blood lipid index, thyroid function, and cardiac ultrasound, and these influencing factors were analyzed by regression analysis. The research adhered to ethical norms and ensured clear data presentation by using a rigorous technique to compare uric acid levels and physiological indicators among various patient groups. CONCLUSION: The study concentrated on the validation, repeatability, and contextual interpretation of data to provide a robust and rigorously scientific comparison. The most common is the increase of uric acid in the blood, which can induce other diseases, and atrial fibrillation is one of the most common diseases of cardiovascular diseases.

Pharmacokinetics of nirmatrelvir/ritonavir and the drug-drug interaction with calcineurin inhibitor in renal transplant recipients.

OBJECTIVES: To describe the pharmacokinetic (PK) characteristics of nirmatrelvir/ritonavir in renal transplant recipients and explore the potential factors that related to the PK variance of nirmatrelvir/ritonavir and its interaction with calcineurin inhibitor (CNI). METHODS: Renal transplant recipients treated with CNI and nirmatrelvir/ritonavir were prospectively enrolled. Steady-state plasma concentrations of nirmatrelvir/ritonavir were determined by high-performance liquid chromatography-tandem mass spectrometry, and the PK parameters were calculated using non-compartmental analysis. Spearman correlation analysis was used for exploring influencing factors. RESULTS: A total of eight recipients were enrolled; for nirmatrelvir and ritonavir, AUC/dose was 0.24179 ± 0.14495 and 0.06196 ± 0.03767 µg·h·mL-1·mg-1. Red blood cell (RBC), hematocrit (Ht), hemoglobins (Hb), and creatinine clearance (Ccr) were negatively correlated with AUC/dose of nirmatrelvir, while Ccr, CYP3A5 genotype, and CYP3A4 genotype were related to the AUC/dose of ritonavir. Ccr was negatively correlated with the C0/dose of tacrolimus (TAC) after termination of nirmatrelvir/ritonavir (rs = -0.943, p = 0.008). CONCLUSIONS: The PK characteristics of nirmatrelvir/ritonavir vary greatly among renal transplant recipients. Factors including Ccr and CYP3A5 genotype were related to the in vivo exposure of nirmatrelvir/ritonavir. During the whole process before and after nirmatrelvir/ritonavir therapy, it is recommended to adjust the CNI basing on renal function to avoid CNI toxicity exposure.

[Prediction of quality markers of Angong Niuhuang Pills based on LC-MS and pull-down with SPR chips].

Elucidating the quality markers(Q-markers) of traditional Chinese medicines is essential for understanding the mechanisms of action and promoting the rational use of traditional Chinese medicines as well as for developing traditional Chinese medicine-derived drugs. Studies have shown that surface plasmon resonance(SPR) is promising in this field. This study proposed a method based on pull-down with SPR chips to predict the Q-markers of Angong Niuhuang pills(AGNHP). Firstly, 71 main chemical components of AGNHP were analyzed by UPLC-Q-TOF-MS, and then network pharmacology was employed to predict the potential targets of AGNHP against stroke. Secondly, the STAT3 protein chip was constructed, and the extract of AGNHP was recovered by pull-down of the SPR system for STAT3 ligand. The potential active ingredients were collected, enriched, and identified as coptisine, palmatine, epiberberine, berberine, worenine, demethyleneberberine, jatrorrhizine, tetrahydrocoptisine, baicalein, and baicalin methyl ester. Next, the affinity constants of the 10 active ingredients were determined as 44.7, 44, 58.1, 51.3, 39.7, 32.1, 49.2, 69.1, 19.7, and 24.9 µmol·L~(-1), respectively. The molecular docking results showed that the 10 compounds could compete for binding with STAT3. This is the first report that SPR combined with UPLC-Q-TOF-MS is reliable and feasible for determining the active ingredients of AGNHP at the molecular level from complex systems. STAT3 could be used as a potential target for the biological quality evaluation of AGNHP.

Role of m6A modifications in immune evasion and immunotherapy.

RNA modification has garnered increasing attention in recent years due to its pivotal role in tumorigenesis and immune surveillance. N6-methyladenosine (m6A) modification is the most prevalent RNA modification, which can affect the expression of RNA by methylating adenylate at the sixth N position to regulate the occurrence and development of tumors. Dysregulation of m6A affects the activation of cancer-promoting pathways, destroys immune cell function, maintains immunosuppressive microenvironment, and promotes tumor cell growth. In this review, we delve into the latest insights into how abnormalities in m6A modification in both tumor and immune cells orchestrate immune evasion through the activation of signaling pathways. Furthermore, we explore how dysregulated m6A modification in tumor cells influences immune cells, thereby regulating tumor immune evasion via interactions within the tumor microenvironment (TME). Lastly, we highlight recent discoveries regarding specific inhibitors of m6A modulators and the encapsulation of m6A-targeting nanomaterials for cancer therapy, discussing their potential applications in immunotherapy.

Complete genome sequences of three Porphyromonas gingivalis strains, isolated from patient with esophageal squamous cell carcinoma and healthy individual in China.

Here, we report the complete genome sequences of three Porphyromonas gingivalis, one from patient with esophageal cancer (LyEC01), and the other two from periodontally healthy individuals (LyG-1 and LyG-2) in 2021 and 2023. The genome sizes of LyEC01, LyG-1, and LyG-2 were 2,408,275, 2,411,440, and 2,411,481 bp, respectively.

Rhodium(I)-Catalyzed Annulation of Bicyclo[1.1.0]butyl-Substituted Dihydroquinolines and Dihydropyridines.

Bicyclo[1.1.0]butane-containing compounds feature a unique chemical reactivity, trigger "strain-release" reaction cascades, and provide novel scaffolds with considerable utility in the drug discovery field. We report the synthesis of new bicyclo[1.1.0]butane-linked heterocycles by a nucleophilic addition of bicyclo[1.1.0]butyl anions to 8-isocyanatoquinoline, or, alternatively, iminium cations derived from quinolines and pyridines. The resulting bicyclo[1.1.0]butanes are converted with high regioselectivity to unprecedented bridged heterocycles in a rhodium(I)-catalyzed annulative rearrangement. The addition/rearrangement process tolerates a surprisingly large range of functional groups. Subsequent chemo- and stereoselective synthetic transformations of urea, alkene, cyclopropane, and aniline moieties of the 1-methylene-5-azacyclopropa[cd]indene scaffolds provide several additional new heterocyclic building blocks. X-ray structure-validated quantum mechanical DFT calculations of the reaction pathway indicate the intermediacy of rhodium carbenoid and metallocyclobutane species.

Identification of Root Canal Morphology in Fused-rooted Mandibular Second Molars From X-ray Images Based on Deep Learning.

INTRODUCTION: Understanding the intricate anatomical morphology of fused-rooted mandibular second molars (MSMs) is essential for root canal treatment. The present study utilized a deep learning approach to identify the three-dimensional root canal morphology of MSMs from two-dimensional X-ray images. METHODS: A total of 271 fused-rooted MSMs were included in the study. Micro-computed tomography reconstruction images and two-dimensional X-ray projection images were obtained. The ground truth of three-dimensional root canal morphology was determined through micro-computed tomography images, which were classified into merging, symmetrical, and asymmetrical types. To amplify the X-ray image dataset, traditional augmentation techniques from the python package Augmentor and a multiangle projection method were employed. Identification of root canal morphology was conducted using the pretrained VGG19, ResNet18, ResNet50, and EfficientNet-b5 on X-ray images. The classification results from convolutional neural networks (CNNs) were then compared with those performed by endodontic residents. RESULTS: The multiangle projection augmentation method outperformed the traditional approach in all CNNs except for EfficientNet-b5. ResNet18 combined with the multiangle projection method outperformed all other combinations, with an overall accuracy of 79.25%. In specific classifications, accuracies of 81.13%, 86.79%, and 90.57% were achieved for merging, symmetrical, and asymmetrical types, respectively. Notably, CNNs surpassed endodontic residents in classification performance; the average accuracy for endodontic residents was only 60.38% (P < .05). CONCLUSIONS: CNNs were more effective than endodontic residents in identifying the three-dimensional root canal morphology of MSMs. The result indicates that CNNs possess the capacity to employ two-dimensional images effectively in aiding three-dimensional diagnoses.

Anlotinib synergizes with venetoclax to induce mitotic catastrophe in acute myeloid leukemia.

Venetoclax is a BCL2-targeted drug employed in treating various cancers, particularly hematologic malignancies. Venetoclax combination therapies are increasingly recognized as promising treatment strategies for acute myeloid leukemia (AML). In this study, we conducted an unbiased drug screen and identified anlotinib, a promising multi-targeted receptor tyrosine kinase inhibitor with oral activity currently utilized in the treatment of solid tumor, as a potent enhancer of venetoclax's anticancer activity in AML. Our investigation encompassed AML cell lines, primary cells, and mouse models, demonstrating effective low-dose combination therapy of anlotinib and venetoclax with minimal cytopenia or organ damage. Proteomic analysis revealed abnormal mitotic signals induced by this combination in AML cells. Mechanistically, anlotinib synergized with venetoclax by suppressing ARPP19 protein, leading to sustained activation of PP2A-B55δ. This inhibited AML cells from entering the mitotic phase, culminating in mitotic catastrophe and apoptosis. Additionally, we identified a specific synthetic lethal vulnerability in AML involving an ARPP19 mutation at S62 phosphorylation. These findings underscore the therapeutic potential of anlotinib and venetoclax combination therapy in AML, warranting further clinical investigation.

Global prevalence of major depressive disorder in LGBTQ+ samples: A systematic review and meta-analysis of epidemiological studies.

BACKGROUND: LGBTQ+ populations have been reported to have higher rates of depression compared with their heterosexual peers. Such data provided us the impetus to conduct a meta-analysis on the worldwide prevalence of major depressive disorder (MDD) in LGBTQ+ populations and moderating factors that contributed to differences in prevalence estimates between studies. METHODS: A systematic literature search was performed in major international (PubMed, PsycINFO, Web of Science, EMBASE) and Chinese (Chinese Nation Knowledge Infrastructure (CNKI) and WANFANG) databases from dates of inception to 10 December 2021. RESULTS: 48 articles comprising 4,616,903 individuals were included in the meta-analysis. The overall prevalence of MDD was 32.2 % (95%CI: 30.8-33.6 %, I2 = 99.6 %, τ2 = 0.284). MDD prevalence was higher in the LGBTQ+ samples from the United States than other countries, though the difference was not significant in moderator analyses. Moderator analyses indicated point and lifetime prevalence of MDD were significantly higher than estimates based on the past year (Q = 6.270, p = 0.043). Furthermore, studies that relied on convenience sampling had a higher prevalence of MDD than those based on other sampling methods (Q = 8.159, p = 0.017). In meta-regression analyses, mean age (B = 0.03, z = 9.54, p < 0.001) and study quality assessment score (B = 0.24, z = 67.64, p < 0.001) were positively associated with pooled prevalence of MDD while mediation data of year of study (B = -0.08, z = -72.55, p < 0.001) and sample size (B = -1.46, z = -37.83, p < 0.001) were negatively associated with pooled prevalence of MDD in LGBTQ+ samples. CONCLUSIONS: MDD is common among in LGBTQ+ individuals. Considering the negative consequences MDD has on daily life and well-being, appropriate prevention and treatment measures should be provided to vulnerable members of these populations. The findings of this meta-analysis could facilitate identifying at-risk subgroups, developing relevant health policy for LGBTQ+ individuals and allocating health resources from an intersectionality perspective.

Prevalence and network structure of depression, insomnia and suicidality among mental health professionals who recovered from COVID-19: a national survey in China.

Psychiatric syndromes are common following recovery from Coronavirus Disease 2019 (COVID-19) infection. This study investigated the prevalence and the network structure of depression, insomnia, and suicidality among mental health professionals (MHPs) who recovered from COVID-19. Depression and insomnia were assessed with the Patient Health Questionnaire (PHQ-9) and Insomnia Severity Index questionnaire (ISI7) respectively. Suicidality items comprising suicidal ideation, suicidal plan and suicidal attempt were evaluated with binary response (no/yes) items. Network analyses with Ising model were conducted to identify the central symptoms of the network and their links to suicidality. A total of 9858 COVID-19 survivors were enrolled in a survey of MHPs. The prevalence of depression and insomnia were 47.10% (95% confidence interval (CI) = 46.09-48.06%) and 36.2% (95%CI = 35.35-37.21%), respectively, while the overall prevalence of suicidality was 7.8% (95%CI = 7.31-8.37%). The key central nodes included "Distress caused by the sleep difficulties" (ISI7) (EI = 1.34), "Interference with daytime functioning" (ISI5) (EI = 1.08), and "Sleep dissatisfaction" (ISI4) (EI = 0.74). "Fatigue" (PHQ4) (Bridge EI = 1.98), "Distress caused by sleep difficulties" (ISI7) (Bridge EI = 1.71), and "Motor Disturbances" (PHQ8) (Bridge EI = 1.67) were important bridge symptoms. The flow network indicated that the edge between the nodes of "Suicidality" (SU) and "Guilt" (PHQ6) showed the strongest connection (Edge Weight= 1.17, followed by "Suicidality" (SU) - "Sad mood" (PHQ2) (Edge Weight = 0.68)). The network analysis results suggest that insomnia symptoms play a critical role in the activation of the insomnia-depression-suicidality network model of COVID-19 survivors, while suicidality is more susceptible to the influence of depressive symptoms. These findings may have implications for developing prevention and intervention strategies for mental health conditions following recovery from COVID-19.