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Abstract Background Diabetes mellitus (DM) is a major risk factor for tuberculosis (TB), However, limited research exists on their clinical and strain characteristics. This study aims to investigate the correlation between these factors in TB-DM patients in Changping District. Methods Whole genome sequencing (WGS) and drug susceptibility tests (DST) were performed on culture-positive strains. Spearman correlation analysis was used to examine risk factors and the correlation between lineage, cavities, and hemoptysis in the TB-DM population. The specificity, sensitivity, and confidence intervals for predicting phenotypic drug resistance based on genotypic resistance were calculated. Results Among the 3924 TB patients, 292 had DM, showing a doubling in the proportion of TB patients with DM over seven years. Among the 144 etiologically positive TB-DM cases treated at the Changping Institute for Tuberculosis Prevention and Treatment, 75% (108/144) of the patients exhibited tuberculosis lesions that formed cavities and 12.5% (18/144) with hemoptysis. A statistically significant difference in cavity formation across different age groups was observed (r = -0.198, P

Myocardial ischemia-reperfusion injury (MIRI) is a prevalent pathophysiological process associated with ischemic heart disease and significantly exacerbates myocardial damage, particularly in the elderly population.This condition not only poses serious risks to individual health but also brings creates substantial societal and economic burdens.Polysaccharides, natural macromolecule found in animals, plants and microorganisms, serve as active substance that confer various health benefits.Among these, polysaccharides extracted from traditional Chinese medicine(TCM) through modern scientific techniques have gained prominence in the medical field due to their safety and high efficiency, playing a vital role in the management of various cardiovascular diseases.This paper, provides a comprehensive review of the role and mechanisms of TCM-derived polysaccharide in MIRI, aiming to furnish valuable insights for the future treatment of cardiovascular diseases in the elderly.

Developing a cost-effective and environmentally friendly process for the production of valuable chemicals from abundant herbal biomass receives great attentions in recent years. Herein, taking advantage of the “lignin first” strategy, corn straw is converted to valuable chemicals including lignin monomers, furfural and 5-methoxymethylfurfural via a two steps process. The key of this research lies in the development of a green and low-cost catalytic process utilizing magnetic Raney Ni catalyst and high boiling point ethylene glycol. The utilization of neat ethylene glycol as the sole slovent under atmospheric conditions obviates the need for additional additives, thereby facilitating the entire process to be conducted in glass flasks and rendering it highly convenient for scaling up. In the initial step, depolymerization of corn straw lignin resulted in a monomer yield of 18.1 wt%. Subsequently, in a dimethyl carbonate system, the carbohydrate component underwent complete conversion in a one-pot process, yielding furfural and 5-methoxymethylfurfural as the primary products with an impressive yield of 47.7%.

Abstract Purpose To present the different findings of Chlamydia psittaci (C. psittaci) pneumonia on computed tomography (CT) according to the progression of the disease, to improve diagnostic accuracy, guide early clinical diagnosis, evaluate treatment efficacy, and reduce the mortality associated with the disease. Methods In total, 80 cases of C. psittaci pneumonia diagnosed through next-generation sequencing from January 2019 to December 2023 in multiple hospitals in China were collected according to the inclusion criteria and analyzed. The study discussed important CT findings and their dynamic changes. Results The most common manifestations of C. psittaci pneumonia are lobar pneumonia and spherical pneumonia types with interstitial changes. The most common signs are the intralobular lines, air bronchogram sign, and reverse halo sign. In addition, necrosis, cavitation, and the tree-in-bud sign are rare but often associated with pleural effusion and splenomegaly. In the ultra-early stage, vascular inflammation changes were observed on imaging, often manifesting as ground-glass opacities around small core vessels or thickening of pulmonary hilar vessels. In the early stage, secondary lobules showed high-density shadows, which rapidly fused into large areas in the progressive stage, easily forming lobar pneumonia. The repair and absorption period tended to show the formation of the reverse halo sign centrally, and the dissipation period might have led to the formation of fibrous bands. Conclusion Combining clinical manifestations, laboratory tests, contact history, and imaging findings contribute to the diagnosis of C. psittaci pneumonia.

Abstract Hydrogen is a promising clean energy source with geological reserves widely distributed globally, offering an annual flow exceeding 23 trillion grams. However, natural hydrogen extraction wells face unique safety challenges compared to conventional oil and gas wells. This paper reviews well safety concerns such as tubing/casing damage, cement/sealant failure, and excessive annular pressure buildup. Key issues include hydrogen embrittlement, microbiological corrosion, H2-cement reaction, and H2-rubber degradation, which can lead to mechanical failures. The review explores potential solutions like metal coatings, rubber fillers, and cement additives to mitigate these problems. It also emphasizes the need for further research to validate these solutions under real-world conditions. Addressing these challenges is crucial for the safe and efficient extraction of natural hydrogen.

Abstract Background Ischemia/reperfusion (I/R) is an inevitable pathophysiological process during heart transplantation, and ferroptosis is an important pathogenic mechanism. Unlike other modes of cell death, ferroptosis depends on the accumulation of iron within the cell and the oxidative degradation of polyunsaturated fatty acids. Dysregulation of this pathway has been linked to the progression of multiple pathological conditions, making it an attractive target for therapeutic intervention. Therefore, this study aims to explore the effect of ferroptosis on I/R during heart transplantation. Methods GEO2R was applied to identify differentially expressed genes (DEGs) obtained from GSE50884 data, which was involved in I/R and heart transplantation. And ferroptosis-related DEGs (FRDEGs) were screened by venn diagram with ferroptosis-related genes downloaded from FerDb database. FRDEGs was enriched and analyzed by GO and KEGG, and hub genes related to ferroptosis were screened by Cytoscape software and database STRING. Additionally, considering the relationship between ferroptosis and immunity, CIBERSORTx was to analyze the infiltration of 22 kinds of immune cells in I/R during heart transplantation, and the correlation between each immune cell and the expression of FRDEGs was also discussed. Finally, the mouse model of heart transplantation with I/R was constructed, and the hub genes was verified by RT-qPCR and western blot. Results 12 FRDEGs were identified out of 327 DEGs in GSE50844, which were mainly involved in ferroptosis and other pathways. Three hub genes (SLC7A11, PSAT1, ASNS) were obtained by the degree algorithm of cytohubba plug-in. Immunoinfiltration analysis showed that 16 of 22 immune cells changed, and the immune score of heart transplantation with I/R was higher than that without I/R. In addition, hub genes exhibited significant correlation with Eosinophils, NK cells resting, Dendritic cells resting, NK cells activated and T cells CD4 memory activated. We verified the expression of SLC7A11, PSAT1 and ASNS was higher than that in normal tissues using RT-qPCR and western blot in mouse models of heart transplantation with I/R, companied by ferroptosis aggravated is involved. Conclusions In short, ferroptosis is involved in I/R injury during heart transplantation, which is related to immune cell infiltration. Three hub genes (SLC7A11, PSAT1 and ASNS) identified in this study provide therapeutic targets for ameliorating I/R injury in heart transplantation.

Background: The brominated flame retardant 2, 2′, 4, 4′-tetrabromodiphenyl ether (PBDE-47) is well known as a developmental neurotoxicant, yet the underlying mechanisms remain elusive. Increasing evidence has demonstrated that brain glucose metabolism perturbation plays a role in neural impairments. Nevertheless, whether this disturbance is involved in PBDE-47-induced neurotoxicity remains unknown. Objectives: To explore the impacts of perinatal PBDE-47 exposure on brain glucose metabolism, and its link to thyroid hormones (THs) levels as well as neurobehavioral changes. Methods: Female Sprague-Dawley rats were orally exposed to PBDE-47 at environmentally relevant levels (0.1, 1.0, and 10.0 mg/kg bw) from pre-pregnancy through weaning of offspring. The male offspring were continued to raise to 88 days after birth for follow-up experiments. Morris water maze and Open field tests were performed to assess the neurobehavioral alterations. The brain glucose metabolism was evaluated using 18F-labeled fluorodeoxyglucose (18F-FDG) positron emission tomography. Serum THs levels were measured via enzyme-linked immunosorbent assay. Results: Perinatal exposure to PBDE-47 induced neurobehavioral impairments in adult male rats as evidenced by learning and memory impairments, hyperactivity and anxiety-like behavior. Moreover, positron emission tomography showed that the glucose metabolism in the whole and the specific brain regions were markedly declined. Interestingly, variations in brain glucose metabolism were associated with the increased serum triiodothyronine (T3) levels, and both were linked to neurobehavioral disorders. Conclusion: Exposure to environmentally related levels of PBDE-47 at critical developmental stages lowers glucose metabolism in the whole brain and in various brain regions, which is associated with behavioral and cognitive deficits in adult male rats. Moreover, the association may be influenced by the disturbance of T3 homeostasis.

Abstract Background Air pollution (AP) has become a substantial environmental issue affecting human cardiorespiratory health. Physical exercise (PE) is widely accepted to promote cardiorespiratory health. There is a paucity of research on the point at which the level of polluted environment engaged in PE could be used as a preventive approach to compensate for the damages of AP. Objectives To assess the effects of acute moderate-intensity PE on the cardio-respiratory and inflammatory responses of young adults in varying levels of AP, and to determine the pollution level at which engaging in short-term PE is considered safe. Methods We constructed a real-world crossover study of 30 healthy young adults with repeated measures. Participants participated in 90 min of moderate-intensity PE in different (low, medium, high) AP exposure scenarios. Cardiorespiratory health was measured by assessing systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), mean forced expiratory flow between 25% and 75% of FVC (FEF25–75%), and fractional exhaled nitric oxide (FeNO) before and after the intervention. Blood samples were also collected simultaneously. The percentage changes in cardiorespiratory health markers after exercise in the three AP levels environments were compared using linear mixed-effects models. Results Compared to the changes observed post-exercise in the low-level AP environment, only PEF (-9.36, P = 0.018) showed a significant decrease, and eosinophils showed a significant increase in the medium-level environment (25.64, P = 0.022), with no significant differences in other indicators. Conversely, post-exercise in the high-level AP environment resulted in a significant increase in DBP (6.5, P = 0.05), lung inflammation (FeNO: 13.3, p

Abstract This study aimed to investigate the influence of sperm miRNAs on fertilization rates (FR) in in vitro fertilization (IVF) and to explore potential regulatory mechanisms in sperm-mediated fertilization and embryo development. Through high-throughput sequencing, we identified differentially expressed miRNAs in sperm, with miR-133a-3p significantly upregulated in samples associated with low FR and available embryo rate (AER). Key regulatory circRNAs and mRNAs were further identified via the Starbase database, intersected with differentially expressed RNA, and analyzed through GO, KEGG, and PPI analyses. The circMYH9/miR-133a-3p/CXCR4 axis emerged as a critical regulatory network. In vitro assays using the GC-2 spd mouse spermatogenic cell line revealed that miR-133a-3p inhibited cell growth and proliferation while promoting apoptosis. circMYH9, acting as a competing endogenous RNA (ceRNA) for miR-133a-3p, modulated CXCR4 expression, enhancing GC-2 spd cell growth and inhibiting apoptosis through the miR-133a-3p/CXCR4 axis. In vivo experiments using a mouse model confirmed that circMYH9 overexpression increased IVF success rates and promoted embryo development via this axis. Mechanistically, miR-133a-3p suppresses sperm fertilization and embryo development by targeting the circMYH9/miR-133a-3p/CXCR4 axis. These findings suggest that this regulatory network could serve as a novel biomarker for assessing fertilization potential and embryo quality in clinical settings and as a potential therapeutic target to improve IVF outcomes and address infertility. This study provides valuable insights into the molecular mechanisms governing sperm function and early embryonic development.

Abstract Background The efficacy and safety of anti-angiogenic combination therapy in patients with driver gene-negative non-small cell lung cancer (NSCLC) with brain metastases (BM) are uncertain. Methods Eighty-eight records of driver gene-negative patients with NSCLC treated with craniocerebral radiotherapy (RT) and programmed death factor-1 (PD-1) inhibitors between May 2021 and May 2023 were collected. Based on whether anti-angiogenic therapy (AT) is combined or not, patients are categorized into the AT group and the non anti-angiogenic therapy (NAT) group. The NAT group patients received craniocerebral RT and PD-1 inhibitor and those in the AT group received craniocerebral RT and PD-1 inhibitor with ≥ 4 cycles of AT. Comparing the clinical efficacy and safety in these two patient cohorts was the main goal of the study. Results By May 1, 2024, the iORR was 94.0% and 63.2% for AT and NAT group, respectively. The 1- and 2-year iLPFS for AT and NAT group were 93.6%, 80.9% and 69.7%, 36.4%, respectively. The 1- and 2-year iDPFS were 86.7%, 56.3% and 59.1%, 48.3%, respectively. The 1- and 2-year OS were 82.0%, 36.6% and 68.4%, 34.6%, respectively. Compared to the standard treatment (RT and PD-1 inhibitors), the addition of AT prolonged the median iLPFS (NR vs. 22.0 months, hazard ratio [HR] = 11.004, P

Abstract Glioma refers to a highly prevalent type of brain tumor that is strongly associated with a high mortality rate. During the treatment process of the disease, it is particularly important to accurately perform segmentation of the glioma from Magnetic Resonance Imaging (MRI). However, existing methods used for glioma segmentation usually rely solely on either local or global features and perform poorly in terms of capturing and exploiting critical information from tumor volume features. Herein, we propose a local and global dual transformer with an attentional supervision U-shape network called DTASUnet, which is purposed for glioma segmentation. First, we built a pyramid hierarchical encoder based on 3D shift local and global transformers to effectively extract the features and relationships of different tumor regions. We also designed a 3D channel and spatial attention supervision module to guide the network, allowing it to capture key information in volumetric features more accurately during the training process. In the BraTS 2018 validation set, the average Dice scores of DTASUnet for the tumor core (TC), whole tumor (WT), and enhancing tumor (ET) regions were 0.845, 0.905, and 0.808, respectively. These results demonstrate that DTASUnet has utility in assisting clinicians with determining the location of gliomas to facilitate more efficient and accurate brain surgery and diagnosis.

Abstract Gastric pain has limited treatment options and the mechanisms within the central circuitry remain largely unclear. This study investigates the central circuitry in gastric pain induced by noxious gastric distension (GD) in mice. Here, we identified that the nucleus tractus solitarius (NTS) serves as the first-level center of gastric pain, primarily via the vagus nerve. The prelimbic cortex (PL) is engaged in the perception of gastric pain. The lateral parabrachial nucleus (LPB) and the paraventricular thalamic nucleus (PVT) are crucial regions for synaptic transmission from the NTS to the PL. The glutamatergic tetra-synaptic NTS–LPB–PVT–PL circuitry is necessary and sufficient for the processing of gastric pain. Overall, our finding reveals a glutamatergic tetra-synaptic NTS–LPB–PVT–PL circuitry that transmits gastric nociceptive signaling by the vagus nerve in mice. It provides an insight into the gastric pain ascending pathway and offers potential therapeutic targets for relieving visceral pain.

Abstract Type 2 diabetes mellitus (T2DM) seriously threatens human health and the quality of life, cognitive impairment is considered as a common complication of T2DM. Neuroimaging meta-analysis found brain functional and structural abnormality in patients with T2DM. Therefore, the purpose of the meta-analysis was to identify brain regions of patients with T2DM-related cognitive impairment (T2DM-CI) where functional and structural indicators changed together or could not synchronize. A literature screening of neuroimaging studies on cognitive impairment in T2DM was conducted from 1 January 2007 to 26 May 2023 in PubMed, Web of Science, Cochrane Library, and Medline databases. The functional indicators we studied were amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and degree centrality (DC), while the structural indicator was gray matter (GM), which included gray matter volume (GMV) and cerebral cortical thickness. Studies reporting ALFF, ReHo, DC and GM abnormalities between T2DM-CI and healthy controls (HCs) were selected and their significant peak coordinates (x, y, z) and effect size (t-value) were extracted to perform a meta-analysis using anisotropic effect size sign differential mapping (AES-SDM) 5.15 software. Moreover, the brain regions with significant differences obtained from meta-analysis were saved as masks and then validated in our data. Total 19 studies and 20 datasets were involved in this study. Compared to HCs, combining ALFF, ReHo, and DC measurements, the brain activity of the left anterior cingulate/paracingulate gyri (ACC.L, BA24) in T2DM-CI patients increased significantly, while the brain activity of the left lingual gyrus (LING.L, BA18) in T2DM-CI patients decreased significantly. The GM indicator of the right superior temporal gyrus (STG.R, BA42) and left inferior occipital gyrus (IOG.L, BA19) in T2DM-CI patients decreased significantly. Meta-regression analysis showed the negative relationship between the brain activity reduction in LING.L and the percentage of female patients, as well as the negative relationship between GM reduction in IOG.L and T2DM duration. Furthermore, we validated a decrease in brain activity in the LING.L of T2DM-CI patients in our independent dataset. The decrease of brain activity in LING.L and the decrease of GM in IOG.L were closely related to visual impairment in T2DM-CI patients. These abnormal brain regions may be the main targets for future research, early intervention can delay the further development of cognitive impairment in T2DM patients and improve their quality of life, which also provided early biomarkers for clarifying the mechanism of cognitive impairment in T2DM.

Abstract Epileptogenesis is the process whereby the previously normally functioning brain begins to generate spontaneous, unprovoked seizures. Status epilepticus (SE), which entails a massive release of neuronal glutamate and other neuroactive substances, is one of the best-known triggers of epileptogenesis. We here asked whether pharmacologically promoting glymphatic clearance during or after SE is beneficial and able to attenuate the subsequent epileptogenesis. We induced SE in adult male mice by intrahippocampal kainic acid (KA) infusion. Acute administration of a cocktail of adrenergic receptor antagonists (propranolol, prazosin, and atipamezole: PPA), enhanced glymphatic flow and effectively reduced the severity of spontaneous seizures in the chronic phase. The PPA treatment also reduced reactive gliosis and inhibited the loss of polarized expression of AQP4 water channels in the vascular endfeet of astrocytes. Administration of PPA after cessation of SE (30 hours post KA) also effectively suppressed epileptogenesis and improved outcome. Conversely, mice with constitutively low glymphatic transport due to genetic deletion of the aquaporin 4 (AQP4) water channel showed exacerbation of KA-induced epileptogenesis. We conclude that the pharmacological modulation of glymphatic fluid transport may represent a potential strategy to dampen epileptogenesis and the occurrence of spontaneous seizures following KA-induced SE.

Objective To investigate whether activation of PI3K/AKT/mTOR pathway can reduce inflammation in acute pancreatitis (AP) rats. Methods SD rats were grouped into sham surgery group, model group, Gln group, and Gln+LY294002 group (PI3K/AKT/mTOR pathway inhibitors). Intra-abdominal pressure (IAP), ascites volume(AS), serum amylase (AMY), diamine oxidase (DAO), interleukin(IL-1β, IL-6), Tumor necrosis factor (TNF-α) were measured. The pathological change in pancreatic and small intestinal tissues was evaluated by microscopy; The expression of PI3K, Akt and mTOR genes and cytoplasm compact linking protein (ZO-1), compact linking protein (occludin-1), PI3K, Akt and mTOR in ileum of each group were detected. Results Compared with the sham surgery group, the IAP and AS, IL-1β, IL-6, TNF-α, AMY, DAO, and pathological injury scores of pancreas and small intestine in the model group were obviously increased; The expression of PI3K mRNA,Akt mRNA, mTOR mRNA, ZO-1, occludin-1, p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR in rat ileum tissue significantly reduced (P＜0.05). Compared with the model group, the level of IAP and AS, IL-1β, IL-6, TNF-α, AMY, DAO and pathological injury scores of pancreas and small intestine in the Gln group were significantly reduced; The expression of PI3K mRNA, Akt mRNA, mTOR mRNA, ZO-1, occludin-1, p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR in rat ileum tissue was significantly increased (P＜0.05); LY294002 could specifically reverse the therapeutic effect of Gln on acute pancreatitis in rats. Conclusions Activation of PI3K/AKT/mTOR pathway may reduce inflammation and improve gastrointestinal function in rats with acute pancreatitis.

Background/purpose: Dental pulp stem cells (DPSCs) have demonstrated significant potential for neuroregeneration. However, a full understanding of the specific mechanism underpinning the neural differentiation of DPSCs is still required. The Wnt signaling is crucial for the development of the embryonic neural system and the maintenance of adult neural homeostasis. This study aimed to investigate the role of the Wnt/Ca2+ pathway in the neural differentiation of human DPSCs (hDPSCs) and its modulation of the Wnt/β-catenin pathway. Materials and methods: hDPSCs were cultured and divided into the control group and the neurogenic induction group (Neuro group). The mRNA and protein levels of neurogenic markers, Wnt/Ca2+, and Wnt/β-catenin pathway indicators were determined using Quantitative real-time PCR and Western blotting. After inhibition of the Wnt/Ca2+ pathway using a WNT5A short hairpin RNA (shRNA) plasmid and subsequent neurogenic induction, neurogenic markers and Wnt/β-catenin pathway indicators in the NC-sh-Neuro group and WNT5A-sh-Neuro group were determined using Quantitative real-time PCR and Western blotting. Results: Compared with the control group, the expression of the Wnt/Ca2+ pathway indicators (WNT5A, Frizzled 2, calmodulin-dependent protein kinase IIa, and nuclear factor of active T cells 1) decreased in the Neuro group. Conversely, the expression of WNT3A, total β-catenin and active β-catenin in the Wnt/β-catenin pathway increased. Moreover, compared with the NC-sh-Neuro group, the WNT5A-sh-Neuro group exhibited a greater level of mature neural differentiation alongside elevated expression of the Wnt/β-catenin pathway indicators. Conclusion: The Wnt/Ca2+ pathway inhibited neural differentiation of hDPSCs and has a negative effect on the Wnt/β-catenin pathway in vitro.

Abstract Immune checkpoint inhibitors (ICIs) immunotherapy facilitates new approaches to achieve precision cancer treatment. A growing number of patients with non-small cell lung cancer (NSCLC) have benefited from treatment with neoadjuvant ICIs combined with chemotherapy. However, the mechanisms and associations between the therapeutic efficacy of neoadjuvant pembrolizumab and chemotherapy (NAPC) and macrophage subsets are still unclear. We performed single-cell RNA sequencing (scRNA-seq) and identified a novel FABP4+C1q+ macrophage subtype, which exhibited stronger proinflammatory cytokine production and phagocytic ability. This subtype was found to be more abundant in tumor tissues and lymph nodes of major pathological response (MPR) patients compared to non-MPR patients, and was associated with a good efficacy of NAPC. Multiplex fluorescent immunohistochemical (mIHC) staining was subsequently used to verify our findings. Further mechanistic studies indicated that FABP4 and C1q regulate the expression of proinflammatory cytokines synergistically. In addition, FABP4 and C1q promote fatty acid synthesis, enhance anti-apoptosis ability and phagocytic ability of macrophage via the interaction of AMPK/JAK/STAT axis. This study provides novel insights into the underlying mechanisms and predictive biomarkers of NAPC. Our findings contribute to improving the prognosis of patients with NSCLC by potentially guiding more precise patient selection and treatment strategies. Novelty & Impact Statements We identified a group of macrophages (FABP4+C1q+ macrophages) related to the therapeutic efficacy of neoadjuvant chemoimmunotherapy. FABP4+C1q+ macrophages highly expressed proinflammatory cytokines-related genes and had a strong cytokine production and phagocytic ability. We believe that our study provides a novel insight into the synergistic mechanism of neoadjuvant ICI combined with chemotherapy and may lead to improved clinical outcomes in patients with NSCLC in the future.

Abstract The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

Abstract To assess the circulating characteristics of common respiratory pathogens following the complete relaxation of non-pharmaceutical interventions (NPIs) and the cessation of the dynamic zero-COVID policy. The retrospective analysis was conducted from 14,412 patients with acute respiratory infections (ARIs) from January 24, 2020, to December 31, 2023, including Influenza A virus (IFV-A), Influenza B virus (IFV-B), Respiratory Syncytial Virus (RSV), Human Rhinovirus (HRV), Human Parainfluenza Virus (HPIV), Human Metapneumovirus (HMPV), Human Coronavirus (HCoV), Human Bocavirus (HBoV), Human Adenovirus (HAdV), and Mycoplasma pneumoniae (MP). Compared with 2020–2022, Joinpoint analysis indicated a monthly increase in overall pathogen activity in 2023, rising from an average of 43.05% to an average of 68.46%. The positive rates of IFV-A, IFV-B, HMPV, HPIV, HCoV, and MP increased, while those of HRV and RSV decreased, and no differences in HAdV and HBoV. The outbreak of IFV-A and MP was observed, the positive rate of MP has surpassed pre-COVID-19 pandemic levels and the spread of RSV was interrupted by IFV-A. Infants and toddlers were primarily infected by HRV and RSV, Children and adolescents exhibited a higher prevalence of infections with MP, IFV-A, and HRV, whereas Adults and the elderly were primarily infected by IFV-A. The incidence of co-infections rose from 4.25 to 13.73%. Restricted cubic spline models showed that the susceptible age ranges for multiple pathogens expanded. These changes serve as a reminder to stay alert in the future and offer clinicians a useful guide for diagnosing and treating.

With the increasing number of remote sensing satellites, the diversification of observation modals, and the continuous advancement of artificial intelligence algorithms, historically opportunities have been brought to the applications of earth observation and information retrieval, including climate change monitoring, natural resource investigation, ecological environment protection, and territorial space planning. Over the past decade, artificial intelligence technology represented by deep learning has made significant contributions to the field of Earth observation. Therefore, this review will focus on the bottlenecks and development process of using deep learning methods for land use/land cover mapping of the Earth's surface. Firstly, it introduces the basic framework of semantic segmentation network models for land use/land cover mapping. Then, we summarize the development of semantic segmentation models in geographical field, focusing on spatial and semantic feature extraction, context relationship perception, multi-scale effects modelling, and the transferability of models under geographical differences. Then, the application of semantic segmentation models in agricultural management, building boundary extraction, single tree segmentation and inter-species classification are reviewed. Finally, we discuss the future development prospects of deep learning technology in the context of remote sensing big data.

This research evaluated cow dung compost (CDC), goose dung compost (GDC), and duck dung compost (DDC) as peat addition in growing media used for the production of pumpkin seedlings. Commercial substrate (peat: vermiculite: perlite=3:1:1, v/v) was used as the control (CK). The partial addition in peat of each waste compost in the mixtures were 10%, 20%, and 30% (v/v). The results showed that all compost in mixtures increased bulk density, total porosity, electrical conductivity, and mineral content, but negatively affected the pH and organic matter of the growing media compared to CK. CDC in mixture increased ventilation porosity and gas-water ratio and decreased water-holding porosity compared to CK, which was the opposite of the effect of GDC and DDC. The mixtures elaborated with GDC showed better growth, biomass, gas exchange parameters, and physiological indicators of seedling plants than other treatments in varying degrees, which depended on the additional amount of GDC. DDC inhibited plant growth and gas exchange parameters, especially in high addition rate; however, it had a slight promotion effect on chlorophyll content and quality because DDC was rich in minerals. GDC was better than CDC and DDC as a partial addition for peat in the cultivation of pumpkin seedlings.

AimsThis study aims to develop a simple, clinically applicable classification system to predict pCR based on carcinoembryonic antigen (CEA) trajectory during NAC.MethodsThis study included 366 AGC patients who received NAC followed by radical gastrectomy. CEA levels were measured before, during, and after NAC, with changes classified into three trajectory types: Type I (>=80% decline), Type II (>=40% but

BackgroundSevere renal ischemia and reperfusion injury (IRI) progresses to renal interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis and macrophage polarization both play important roles in this model, their specific pathogenesis and interactions have not been elucidated. Therefore, we aimed to explore the mechanisms by which ferrotosis occurs in renal tubular epithelial cells (RTECs) and ferroptotic cell-derived exosomes induce macrophage polarization in IRI-related RIF model.MethodsIn vivo, C57BL/6J mice were randomly divided into four groups: sham group, ischemia and reperfusion (IR) group, IR + Ferrostatin-1 (Fer-1) group, and IR +ATF3 knockdown (ATFKD) group. In vitro, RTECs were divided into control (CON) group, hypoxia/reoxygenation (HR) group, HR +Fer-1 group, HR + siRNA-ATF3 (siATF3) group.ResultCompared with the sham group, the IR group showed more severe kidney injury in HE staining, more collagen fibers in Masson staining, and higher α-SMA expression levels in immunohistochemistry. Total iron and MDA content increased while GSH content decreased. The IR group had more significant mitochondrial damage and higher PTGS2 and TFRC mRNA levels than those in the sham group. Compared with the IR group, the above indexes were all alleviated in the IR+Fer-1 or IR+ATF3KD groups. In addition, the protein expressions of ATF3, Nrf2 and HO-1 in the IR group were increased than those in sham group. Compared with the IR group, ATF3 expressions in the IR+Fer-1 or IR+ATF3KD groups were decreased, and the protein contents of Nrf2 and HO-1 were further increased. Moreover, there were higher levels of M2 markers (Arg1, TGF-β and IL-10 mRNA) in the IR group than those in the sham group, and lower levels in the IR+Fer-1 group or in the IR+ATF3KD group compared with the IR group. The results of in vitro experiment are consistent with those of in vivo experiment. Mechanistically, the release of exosomes carrying miR-1306-5p by the HR group promoted more M2 macrophage.ConclusionATF3 might accelerate the ferroptosis by inhibiting Nrf2/ARE pathway, and exosomes from ferroptotic cells reduced the M1/M2 macrophage ratio, promoting fibrosis.

BackgroundElucidation of immune response differences is critical for uncovering underlying mechanisms and developing potential intervention measures among adults and children with COVID-19.MethodsIn this retrospective study, we analyzed serum biochemical markers and cytokine profiles among adults and children with COVID-19 in the First People’s Hospital of Chenzhou in Hunan, China from 1 December 2022 to 13 February 2023. A case–control study was conducted using propensity score matching (PSM) to mitigate possible confounding factors.ResultsThe significant differences observed included lymphocyte exhaustion, an increased neutrophil-to-lymphocyte (NEU/LYM) ratio, high levels of C-reactive protein (CRP), and a cytokine storm, characterized by high levels of Th1 proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, IL-8, interferon type I (IFN-γ), and tumor necrosis factor (TNF-α) in the lung among severe adult COVID-19 patients. Additionally, systemic immune responses were observed in children with COVID-19.ConclusionSignificant differences in immune responses between adults and children with COVID-19 highlight the different mechanisms and potential intervention measures of COVID-19.

In the existing pixel-level prediction methods of future remote sensing images, the impact of other factors on the outbreak of cyanobacteria blooms is often ignored, and only the single factor of chlorophyll a concentration is considered. This paper comprehensively considers the impact of chlorophyll a, temperature, and phycocyanin concentration on the outbreak of cyanobacteria blooms. Based on the Pix2Pix model, a 4D-Pix2Pix model is constructed. The Conv3D-LSTM network is used to extract the two-dimensional space, one-dimensional time, and one-dimensional multi-factor features of the multi-factor remote sensing image time series. The features are processed by the 3D-Unet network with a residual structure to achieve pixel-level prediction of future multi-factor remote sensing images. 3D-PatchGAN is used for adversarial training to optimize network performance. Finally, a cyanobacteria bloom outbreak level standard based on multi-factor remote sensing images is proposed to predict the spatiotemporal distribution of cyanobacteria blooms.

Introduction Metastasis remains a major cause of death among patients with malignant tumors. Radiotherapy is one of the main modalities of cancer treatment. The rapid development of radiotherapy technology has enabled the widespread application of hypofractionated radiotherapy (HFRT) in clinical practice. This study aimed to evaluate the effect of HFRT on the survival and safety of patients with oligometastatic tumors. Methods We conducted a retrospective study that involved 65 patients with well-controlled primary tumors and 1–5 metastatic foci treated at the study site between January 2020 and December 2022. Patients were aged >18 years and had a ≥ 6-month life expectancy. The patients received standard treatments plus HFRT for all metastatic foci. The dose fractionation regimen was adjusted according to the location and size of the patient’s metastatic foci. The planning gross tumor volume of HFRT was 82.93 cm 3 (range: 10.12-562.80 cm 3 ), and the radiation dose range was 20 Gy/5 F–60 Gy/15 F. Progression-free survival (PFS), overall survival (OS), local control rates, and incidence of adverse events of the patients were observed. Results Among the 65 patients, the median follow-up time, PFS, and OS were 26 months (95% CI: 0.80-37.50), 15 months (95% CI: 9.36-20.64), and 28 months (95% CI: 16.71-39.29), respectively. The 1- and 2-year PFS were 53.8% and 40.0%, respectively, while the 1- and 2-year OS rates were 73.8% and 56.9%, respectively. In total, 13.8%, 55.4%, 20.0%, and 13.8% of patients showed complete response, partial response, stable disease, and progressive disease, respectively. Four patients developed grade 3 or worse adverse events, and no treatment-related deaths occurred. Conclusions HFRT showed favorable clinical efficacy and safety in patients with oligometastatic tumors, generally achieving a good OS rate. Further randomized trials should be conducted.

IntroductionPharmacists are increasingly adopting patient-centered roles, improving healthcare outcomes by reducing medication errors and costs. In China, recent healthcare reforms recognize and compensate for pharmacy services. However, patient awareness of these services and their willingness to pay (WTP) remain underexplored. Therefore, this study aims to examine inpatient understanding of pharmacy services, their WTP in Hebei Province, and the factors affecting it.MethodsBetween July and August 2024, a questionnaire was used to survey inpatients from 22 medical institutions across 11 prefecture-level cities in Hebei Province regarding their awareness of WTP for pharmacy services. Further investigation targeted inpatients unwilling to pay. The survey results were analyzed descriptively, with frequencies and percentages (%) used for categorical data and continuous data were presented as mean ± standard deviation (X ± SD). The chi-square test was used to determine statistically significant influences, and logistic regression analysis was performed to identify significant factors affecting inpatient WTP for pharmacy services. A column-line graph was validated using receiver operating characteristic curves and calibration graph analysis.ResultsIn total, 464 questionnaires were distributed, with 432 valid responses, yielding a 93.10% effective response rate. Most inpatients (89.58%) viewed hospital pharmacists as primarily responsible for dispensing medication, while only 5.79% were aware of broader pharmacy services. Despite this, 72.69% of the inpatients were willing to receive pharmacy services, and 95.38% of those who had received such services found them beneficial. Half of the inpatients (216, or 50.00%) indicated WTP for pharmacy services. Among those initially unwilling to pay (216 inpatients), 102 indicated they would consider payment if a doctor recommended clinical pharmacist guidance. Of the 318 inpatients who were WTP, 315 (99.06%) chose health insurance reimbursement as a payment method. Key factors influencing inpatient WTP included literacy level, preferred source of medication counseling, prior pharmacy service experience, understanding of pharmacy service policies, and readiness to recommend these services (P < 0.05).ConclusionMost inpatients lacked knowledge and trust in clinical pharmacists, with limited awareness of the value of pharmacy services. However, they demonstrated high acceptance and WTP for these services, with nearly all inpatients preferring health insurance reimbursement. Integrating pharmacy service fees into health insurance is crucial for promoting these services.

Ascaris lumbricoides (AL), a prevalent nematode causing ascariasis, infects millions worldwide, with a higher risk in preschool and school-aged children. Though infections are usually mild, rare and life-threatening complications like gastrointestinal perforation exist. This article documents a case involving a 61-year-old deaf-mute man who presented with a month-long history of epigastric pain accompanied by nausea, anorexia, and constipation. The pain exacerbated, eventually extended to encompass the entire abdomen 4 h prior to being diagnosed with hollow viscus perforation. During the surgical procedure, three live ascarids were discovered within the abdominal cavity, and the jejunum was found to be filled with a large number of ascarids, accompanied by a perforation in the gastric antrum. Subsequently, the ascarids were extracted, and the perforated area was repaired. Postoperatively, the patient underwent anti-infection therapy, acid suppression, gastric mucosa protection, and nutritional support. On postoperative day (POD) 1, a single dose of 400 mg albendazole was administered. Fecal samples on POD 3, 5, and 6 tested positive for AL eggs. The patient recovered smoothly with no evidence of peptic ulcer disease on one-month follow-up endoscopy. Additionally, fecal tests conducted over three consecutive days did not detect any AL eggs. This case highlights the crucial importance of recognizing ascariasis-associated complications and underscores the paramount role of timely surgical intervention in such cases. Meanwhile, this article combines cases of gastrointestinal perforation caused by AL documented in the literature since 1903, elaborates on the epidemiological characteristics, pathogenesis, diagnosis, treatment, and prevention of ascariasis, and analyzes the reasons for the occurrence of such complications.

Mechanical snap-through instability of bi-stable structures may find many practical applications such as state switching and energy transforming. Although there exist diverse bi-stable structures capable of snap-through instability, it is still difficult for a structure with high slenderness to undergo the axial snap-through instability with a large stroke. Here, an elastic structure with high slenderness is simply constructed by a finite number of identical, conventional bi-stable units with relatively low slenderness in series connection. For realizing the axial snap-through instability with a large stroke, common scissors mechanisms are further introduced as rigid constraints to guarantee the synchronous snap-through instability of these bi-stable units. The global feature of the large-stroke snap-through instability realized here is robust and even insusceptible to the local out-of-synchronization of individual units. The present design provides a simple and feasible way to achieve the large-stroke snap-through instability of slender structures, which is expected to be particularly useful for state switching and energy transforming in narrow spaces.

The Yellow River is the main source of water for urban and rural area and agricultural irrigation in northern China. Herein, the distribution and risk assessment of perfluoroalkyl acids (PFAAs) were investigated from the Yellow River in Shandong Province, China. The total concentration of PFAAs (∑PFAAs) in surface water and sediments were 37.5–2128 ng/L (mean: 167 ng/L) and not detected−6.95 ng/g dry weight (dw) (mean: 1.02 ng/g dw), respectively. Short-chain PFAAs-perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), and perfluorobutane sulfonic acid (PFBS) were the most prevalent PFAAs in surface water. Source analysis showed that firefighting foam (proportion: 31.3 %) and textile treatments and food packaging (proportion: 30.3 %) were the main sources of PFAAs in water. Based on the concentration of PFAAs in water, ecological and potential human health risks were assessed. Perfluorooctanoic acid (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA) and perfluoroundecanoic acid (PFUnDA) posed nonnegligible ecological risk for some aquatic organisms. Levels of PFAAs (e.g., PFOA, PFNA, and PFDA etc.) in some water samples were higher than the advisory guidelines of PFAAs concentrations in water worldwide, indicating a potential human health risk. Therefore, PFOA, PFNA, PFDA, and PFUnDA are the key focus of pollutants in the water of the Yellow River in Shandong Province, and the standards and limits of these PFAAs in environments including surface water and sediment should be promoted.

GBM is one of the most malignant tumor in central nervous system. The resistance to temozolomide (TMZ) is inevitable in GBM and the characterization of TMZ resistance seriously hinders clinical treatment. It is worthwhile exploring the underlying mechanism of aggressive invasion and TMZ resistance in GBM treatment. Bioinformatic analysis was used to analyze the association between RND1 and a series of EMT-related genes. Colony formation assay and cell viability assay were used to assess the growth of U87 and U251 cells. The cell invasion status was evaluated based on transwell and wound-healing assays. Western blot was used to detect the protein expression in GBM cells. Treatment targeted RND1 combined with TMZ therapy was conducted in nude mice to evaluate the potential application of RND1 as a clinical target for GBM. The overexpression of RND1 suppressed the progression and migration of U87 and U251 cells. RND1 knockdown facilitated the growth and invasion of GBM cells. RND1 regulated the EMT of GBM cells via inhibiting the phosphorylation of AKT and GSK3-β. The promoted effects of RND1 on TMZ sensitivity was identified both in vitro and in vivo. This research demonstrated that the overexpression of RND1 suppressed the migration and EMT status by downregulating AKT/GSK3-β pathway in GBM. RND1 enhanced the TMZ sensitivity of GBM cells both in vitro and in vivo. Our findings may contribute to the targeted therapy for GBM and the understanding of mechanisms of TMZ resistance in GBM.

Background: Relapse was the major cause of treatment failure in patients with myeloid malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients who still suffer from the disease while cannot be detected by morphological analysis can be identified by the minimal residual disease (MRD) monitoring. The most used first-line regimens for MRD are immunotherapies. However, for patients who were ineligible for or failed in first-line immunotherapies, options were limited.Methods: A total of 20 patients with myeloid malignancies with recurrent MRD after allo-HSCT were included in this study. The safety and efficacy of venetoclax-based regimens were analyzed.Results: There were 13 patients (65%) treated with venetoclax combined with hypomethylating agents concomitantly and seven patients (35%) treated with venetoclax monotherapy. After venetoclax-based regimens, MRD was eliminated in 11 patients (55%) with 6 subsequently developing recurrent MRD and 5 remaining in molecular remission. MRD declined in two patients (10%), and no responses in seven patients (35%). Among the two patients with declined MRD, one patient finally eliminated MRD after two cycles of the venetoclax-based regimen, and the other patient’s MRD further declined after the second regimen. The objective response rate (ORR) was 65%. The median duration of response was 103 (12–313) days. The incidences of grades 3–4 neutropenia, anemia, and thrombocytopenia independently of pretreatment status were 30%, 20% and 20%, respectively.Conclusion: Venetoclax-based regimens are efficient and safe for MRD in patients with myeloid malignancies ineligible for or failed in the first-line immunotherapies after allo-HSCT.

Abstract Background The role of tumor inflammatory microenvironment in the advancement of cancer, particularly prostate cancer, is widely acknowledged. ELL-associated factor 2 (EAF2), a tumor suppressor that has been identified in the prostate, is often downregulated in prostate cancer. Earlier investigations have shown that mice with EAF2 gene knockout exhibited a substantial infiltration of inflammatory cells into the prostatic stroma. Methods A cohort comprising 38 patients who had been diagnosed with prostate cancer and subsequently undergone radical prostatectomy (RP) was selected. These patients were pathologically graded according to the Gleason scoring system and divided into two groups. The purpose of this selection was to investigate the potential correlation between EAF2 and CD163 using immunohistochemistry (IHC) staining. Additionally, in vitro experimentation was conducted to verify the relationship between EAF2 expression, macrophage migration and polarization. Results Our study demonstrated that in specimens of human prostate cancer, the expression of EAF2 was notably downregulated, and this decrease was inversely associated with the number of CD163-positive macrophages that infiltrated the cancerous tissue. Cell co-culture experiments revealed that the chemotactic effect of tumor cells towards macrophages was intensified and that macrophages differentiated into tumor-associated macrophages (TAMs) when EAF2 was knocked out. Additionally, the application of cytokine protein microarray showed that the expression of chemokine macrophage migration inhibitory factor (MIF) increased after EAF2 knockout. Conclusions Our findings suggested that EAF2 was involved in the infiltration of CD163-positive macrophages in prostate cancer via MIF. Graphical abstract

Abstract Background Acute ischemic stroke (AIS) is a major global public health issue. There is limited research on the relationship between ambient temperature and AIS hospital admissions, and the results are controversial. Our objective is to assess the short-term impact of ambient temperature on the risk of AIS hospital admissions in Yancheng, China. Methods We collected data on daily AIS hospital admissions, meteorological factors, and air quality in Yancheng from 2014 to 2019. We used Poisson regression to fit generalized linear models and distributed lag non-linear models to explore the association between ambient temperature and AIS hospital admissions. The effects of these associations were evaluated by stratified analysis by sex and age. Results From 2014 to 2019, we identified a total of 13,391 AIS hospital admissions. We observed that the influence of extreme cold and heat on admissions for AIS manifests immediately on the day of exposure and continues for a duration of 3–5 days. Compared to the optimal temperature (24.4 °C), the cumulative relative risk under extreme cold temperature (-1.3 °C) conditions with a lag of 0–5 days was 1.88 (95%CI: 1.28, 2.78), and under extreme heat temperature (30.5 °C) conditions with a lag of 0–5 days was 1.48 (95%CI: 1.26, 1.73). Conclusions There is a non-linear association between ambient temperature and AIS hospital admission risk in Yancheng, China. Women and older patients are more vulnerable to non-optimal temperatures. Our findings may reveal the potential impact of climate change on the risk of AIS hospital admissions.

Abstract Background This study was designed to compare the diagnostic efficacy of mSEPT9 to four blood markers (CEA, CA19-9, platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR)). In addition, we aimed to determine the combined diagnostic efficacy of mSEPT9, CEA, CA19-9, PLR and NLR in colorectal cancer. Methods A total of 567 participants were enrolled in the study, including 308 CRC patients, 61 colorectal polyp patients and 198 healthy subjects confirmed by colonoscopy and/or tissue biopsy. Plasma samples were collected for tests. Results The positive rate of mSEPT9 in CRC (71.8%) was markedly higher than that in either the colorectal polyps group (27.9%) or the healthy controls (6.1%) (P

Abstract We evaluate the value of oral contrast-enhanced gastric ultrasonography (OCUS) by comparing it with conventional gastroscopy in diagnosing and staging benign peptic ulcer. From July 2018 to December 2020, 44 patients with gastroscopy-confirmed benign peptic ulcers (a total of 45 ulcers were detected), who also received OCUS, were retrospectively reviewed. Each patient’s ultrasound images were compared with gastroscopy and pathology findings. The characteristics of ultrasonic images of different stages of ulcer were analysed. A total of 43 ulcers were detected by OCUS in 44 patients with benign peptic ulcers. There were no false positive results among the OCUS exams, but two ulcers were misdiagnosed. OCUS for benign peptic ulcer staging also shows acceptable clinical practice results. OCUS is useful for detecting and staging benign peptic ulcer, and may be considered an alternative method for conventional gastroscopy. OCUS is especially useful in the follow-up of BPU treatment, but futher study is needed to improve the diagnostic accuracy of benign and malignant ulcers.

Objective: To study the relationships of serum 25-hydroxyvitamin D [25(OH)D] with dental caries and periodontitis in a general Norwegian adult population. Methods: We analysed a subsample of 1605 participants from the Trøndelag Health Study (HUNT) in Norway that had serum 25(OH)D levels measured in HUNT3 (2006-08) and oral health assessed in the HUNT4 Oral Health Study (2017-19). Negative binomial and Poisson regression models were used to estimate the ratios of means (RMs; for count oral outcomes) and prevalence ratios (PRs; for dichotomous oral outcomes). Results: Serum 25(OH)D was inversely associated with the number of decayed teeth in a dose-response gradient (

Abstract Limited studies have triangulated the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and systolic blood pressure (SBP), diastolic blood pressure (DBP) or hypertension risk utilizing both observational and Mendelian randomization (MR) approaches. We employed data from the Norwegian Trøndelag Health Study (HUNT) to conduct cross-sectional (n = 5854) and prospective (n = 3592) analyses, as well as one-sample MR (n = 86,324). We also used largest publicly available data for two-sample MR. Our cross-sectional analyses showed a 25 nmol/L increase in 25(OH)D was associated with a 1.73 mmHg decrease in SBP (95% CI − 2.46 to − 1.01), a 0.91 mmHg decrease in DBP (95% CI − 1.35 to − 0.47) and 19% lower prevalence of hypertension (OR 0.81, 95% CI 0.74 to 0.90) after adjusting for important confounders. However, these associations disappeared in prospective analyses. One-sample and two-sample MR results further suggested no causal relationship between serum vitamin D levels and blood pressure or hypertension risk in the general population.

Chemical optimization of ribose has significantly advanced nucleic acid therapeutics (NATs) by improving the stability, specificity, and safety of therapies like small interfering RNAs, CRISPR-Cas9 guide RNAs, and GAPmers. Recent research has extended this approach to splice-switching oligonucleotides (SSOs), which target splicing events. Our study identifies a set of mixed-modification patterns—combining 2′-O-Methyl, 2′-MethOxyEthyl, 2′-Locked Nucleic Acid, and 2′-Constrained Ethyl ribose moieties (2′OMe, 2′MOE, LNA, and cET)—that enhance SSO potency. We term this strategy lateral mixed positional configuration, which improves SSO efficacy across various sequences and could reduce the trial-and-error process in SSO development. This advancement is supported by NAT Unlabeled Reporter Assay (NATURA), a novel platform for high-throughput quantification of NATs' functional delivery and potency. NATURA uses a reporter gene system and a comprehensive sequence library to test modifications and delivery methods, validated in a transgenic mouse model. This approach aims to accelerate NAT development and address challenges in delivering these therapies to patients.

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BackgroundRecent studies have indicated the role of the gut microbiota in the progression of osteoarticular diseases, however, the causal relationship between the gut microbiota and pyogenic arthritis remains unclear. There is also a lack of theoretical basis for the application of the gut microbiota in the treatment of pyogenic arthritis.MethodsIn our study, we utilized the largest genome-wide association study (GWAS) data from the MiBioGen Consortium involving 13,400 participants and extracted summary statistical data of the microbiota metabolic pathways of 7,738 participants of European descent from the Dutch Microbiome Project (DMP) The data of pyogenic arthritis were derived from the FinnGen R10 database, including 1,086 patients and 147,221 controls. We employed the two-sample Mendelian randomization approach to investigate the causal association between the gut microbiota and pyogenic arthritis. Our methods comprised inverse variance weighting, Mendelian Randomization Egger regression, weighted median, and weighted modal methods. Subsequently, polygenic and heterogeneity analyses were conducted.ResultsAt the class level, β-proteobacteria is positively correlated with the risk of pyogenic arthritis. At the order level, Burkholderia is positively associated with the disease. At the genus level, the unclassified genus of Sutterellaceae is positively correlated with the disease, while the unnamed genus of Lachnospiraceae, Rothia, and the unnamed genus of Erysipelotrichaceae are negatively correlated with the disease. In addition, Faecalibacterium and Finegoldia are also negatively correlated with the disease. Sensitivity analysis did not show any abnormal evidence.ConclusionThis study indicates that β-proteobacteria, Burkholderiales, and the unclassified genus of Sutterellaceae are associated with an increased risk of the disease, while the unnamed genus of Lachnospiraceae, Rothia, the unnamed genus of Erysipelotrichaceae, Faecalibacterium, and Finegoldia are related to a reduced risk. Future studies are needed to elucidate the specific mechanisms by which these specific bacterial groups affect pyogenic arthritis.

Summary: The hypothalamic supramammillary nucleus (SuM) projects heavily to the hippocampus to regulate hippocampal activity and plasticity. Although the projections from the SuM to the dentate gyrus (DG) and CA2 have been extensively studied, whether the SuM projects to CA1, the main hippocampal output region, is unclear. Here, we report a glutamatergic pathway from the SuM that selectively excites CA1 interneurons in the border between the stratum radiatum (SR) and the stratum lacunosum-moleculare (SLM). We find that the SuM projects selectively to a narrow band in the CA1 SR/SLM and monosynaptically excites SR/SLM interneurons, including vasoactive intestinal peptide-expressing (VIP+) and neuron-derived neurotrophic factor-expressing (NDNF+) cells, but completely avoids making monosynaptic contacts with CA1 pyramidal neurons (PNs) or parvalbumin-expressing (PV+) or somatostatin-expressing (SOM+) cells. Moreover, SuM activation drives spikes in most SR/SLM interneurons to suppress CA1 PN excitability. Taken together, our findings reveal that the SuM can directly regulate hippocampal output region CA1, bypassing CA2, CA3, and the DG.