Cross-sectional and Mendelian randomization study of fibroblast growth factor 19 reveals causal associations with metabolic diseases.

BACKGROUND AND AIM: Fibroblast growth factor 19 (FGF19) is an intestinal-derived factor that plays a role in metabolic diseases. We performed a differential study of circulating FGF19 levels and investigated the causal effects of FGF19 on metabolic diseases using Mendelian randomization (MR). METHODS: Firstly, 958 subjects were included in the physical examination center of affiliated hospital from January 2019 to January 2021. Dividing the subjects into different subgroups to compare FGF19 levels. We conducted a two-sample MR analysis of genetically predicted circulating FGF19 in relation to alcohol, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available genome-wide association study summary statistics data. RESULTS: The circulating FGF19 levels in nonalcoholic fatty liver disease (NAFLD) patients were lower than those without NAFLD (P < 0.001). The FGF19 levels in participants with obese were lower than those without obese (P < 0.001). In two-sample MR analyses, genetically predicted higher circulating FGF19 levels was significantly associated with lower aspartate aminotransferase, γ-glutamyltransferase, triglycerides, total cholesterol, low-density lipoprotein, and C-reactive protein concentrations (P < 0.05) and a negative correlation with cardiovascular disease and cirrhosis whereas a positive association with type 2 diabetes mellitus (P < 0.05). CONCLUSIONS: Our study found that circulating FGF19 levels were lower in NAFLD and obese populations. Additionally, our MR research results support the causal effects of FGF19 on improved liver function, lipids, and reduced the occurrence of inflammation, cardiovascular disease, and cirrhosis. We found a positive correlation with diabetes, which may indicate a compensatory increase in regulating above FGF19 resistance states in humans.

Interaction between microglial cells and CD1C+ B dendritic cells leads to CD8+ T cells depletion during the early stages of renal clear cell carcinoma.

Renal clear cell carcinoma (RCC) is a type of malignant tumor, which, in addition to surgical resection, radiotherapy, and chemotherapy, has been widely treated through immunotherapy recently. However, the influence of the tumor microenvironment and the infiltrating immune cells within it on immunotherapy remains unclear. It is imperative to study the interactions between various immune cells of RCC. The scRNA-seq dataset from GEO's database was used to analyze the immune cells present in tumor tissue and peripheral blood samples. Through quality control, clustering, and identification, the types and proportions of infiltrating immune cells were determined. The cellular differences were determined, and gene expression levels of the differentially present cells were investigated. A protein-protein interaction network analysis was performed using string. KEGG and GO analyses were performed to investigate abnormal activities. The microglia marker CD68 and CD1C+ B dendritic cells marker CD11C were detected using multiplex immunofluorescence staining. Many depleted CD8+ T cells (exhausted CD8+ T cells) appeared in tumor tissues as well as microglia. CD1C+ B dendritic cells did not infiltrate tumor tissues. HSPA1A was correlated with DNAJB1 in microglia. Compared with Paracancer tissues, microglia increased while CD1C+ B dendritic cells decreased in pathological stages I and I-II in cancerous tissues. An altered tumor microenvironment caused by increases in microglia in RCC in the early stage resulted in an inability of CD1C+ B dendritic cells to infiltrate, resulting in CD8+ T cells being unable to receive the antigens presented by them, and in turn being depleted in large quantities.

Incompatible packaging signals and impaired protein functions hinder reassortment of bat H17N10 or H18N11 segment 7 with human H1N1 influenza A viruses.

Novel bat H17N10 and H18N11 influenza A viruses (IAVs) are incapable of reassortment with conventional IAVs during co-infection. To date, the underlying mechanisms that inhibit bat and conventional IAV reassortment remain poorly understood. Herein, we used the bat influenza M gene in the PR8 H1N1 virus genetic background to determine the molecular basis that restricts reassortment of segment 7. Our results showed that NEP and M1 from bat H17N10 and H18N11 can interact with PR8 M1 and NEP, resulting in mediating PR8 viral ribonucleoprotein (vRNP) nuclear export and formation of virus-like particles with single vRNP. Further studies demonstrated that the incompatible packaging signals (PSs) of H17N10 or H18N11 M segment led to the failure to rescue recombinant viruses in the PR8 genetic background. Recombinant PR8 viruses (rPR8psH18M and rPR8psH17M) containing bat influenza M coding region flanked with the PR8 M PSs were rescued but displayed lower replication in contrast to the parental PR8 virus, which is due to a low efficiency of recombinant virus uncoating correlating with the functions of the bat M2. Our studies reveal molecular mechanisms of the M gene that hinder reassortment between bat and conventional IAVs, which will help to understand the biology of novel bat IAVs. IMPORTANCE: Reassortment is one of the mechanisms in fast evolution of influenza A viruses (IAVs) and responsible for generating pandemic strains. To date, why novel bat IAVs are incapable of reassorting with conventional IAVs remains completely understood. Here, we attempted to rescue recombinant PR8 viruses with M segment from bat IAVs to understand the molecular mechanisms in hindering their reassortment. Results showed that bat influenza NEP and M1 have similar functions as respective counterparts of PR8 to medicating viral ribonucleoprotein nuclear export. Moreover, the incompatible packaging signals of M genes from bat and conventional IAVs and impaired bat M2 functions are the major reasons to hinder their reassortment. Recombinant PR8 viruses with bat influenza M open reading frames were generated but showed attenuation, which correlated with the functions of the bat M2 protein. Our studies provide novel insights into the molecular mechanisms that restrict reassortment between bat and conventional IAVs.

Developing a Research Network of Early Warning Systems for Infectious Diseases Transmission Between China and Australia.

This article offers a thorough review of current early warning systems (EWS) and advocates for establishing a unified research network for EWS in infectious diseases between China and Australia. We propose that future research should focus on improving infectious disease surveillance by integrating data from both countries to enhance predictive models and intervention strategies. The article highlights the need for standardized data formats and terminologies, improved surveillance capabilities, and the development of robust spatiotemporal predictive models. It concludes by examining the potential benefits and challenges of this collaborative approach and its implications for global infectious disease surveillance. This is particularly relevant to the ongoing project, early warning systems for Infectious Diseases between China and Australia (NetEWAC), which aims to use seasonal influenza as a case study to analyze influenza trends, peak activities, and potential inter-hemispheric transmission patterns. The project seeks to integrate data from both hemispheres to improve outbreak predictions and develop a spatiotemporal predictive modeling system for seasonal influenza transmission based on socio-environmental factors.

Comparison of clinical outcomes between mineral trioxide aggregate and bioceramic materials in pulpotomy for treating early chronic pulpitis in deciduous teeth.

This study aims to elucidate the clinical efficacy of Mineral Trioxide Aggregate (MTA) and Bioceramic Materials in pulpotomy procedures for early-stage chronic pulpitis in deciduous teeth. The clinical data of 100 children with early chronic pulpitis in deciduous teeth treated at our institution between January 2021 and January 2023 were included retrospectively, which were divided into an experimental group (n = 50) and a control group (n = 50) according to the treatment methods. Experimental group received pulpotomy with Thera Cal LC as bioceramic pulp-capping material versus control group with MTA as pulp-capping agent. Comparative studies were conducted to assess the clinical effectiveness and differences between both pulp-capping techniques. At 12 months postoperatively, the experimental group showed a significantly higher success rate than the control group (96.00% vs. 80.00%, p < 0.05). Post-treatment inflammatory markers (Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6) and Interleukin-8 (IL-8)) were substantially lower in the experimental group (p < 0.05). Furthermore, significantly lower pain scores and higher comfort and satisfaction scores were obtained in the experimental group (p < 0.05). Experimental group adverse reactions were also lower in the experimental group (p < 0.05). TheraCal LC bioceramic material treats early chronic pulpitis in deciduous teeth effectively. Clinically, it is an excellent therapeutic option for emergence of permanent dentition, pain relief, comfort and improvement of patient satisfaction.

Serum inflammatory markers in children with Mycoplasma pneumoniae pneumonia and their predictive value for mycoplasma severity.

BACKGROUND: Mycoplasma pneumoniae pneumonia (MPP) significantly impacts pediatric health, necessitating markers for early severe disease identification. AIM: To investigate the correlation between serum inflammatory marker and the severity of MPP in children. METHODS: A prospective study was carried out from January 2023 to November 2023. A total of 160 children with MPP who underwent treatment were selected: 80 had severe MPP and 80 had mild MPP. Clinical and laboratory data were collected at the time of hospital admission and during hospitalization. Receiver operating characteristic curves were utilized to assess the diagnostic and prognostic for severe MPP. RESULTS: Fever duration and length of hospitalization in pediatric patients with severe MPP exceeded those with mild MPP. The incidence of pleural effusion, lung consolidation, and bronchopneumonia on imaging was markedly elevated in the severe MPP cohort compared to the mild MPP cohort. In contrast to the mild cohort, there was a notable increase in C-reactive protein (CRP), procalcitonin (PCT), erythrocyte sedimentation rate, lactic dehydrogenase, D-dimer, and inflammatory cytokines [interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] in the severe MPP group were significantly higher. CONCLUSION: Serum inflammatory markers (CRP, PCT, IL-6, D-dimer, IL-10 and TNF-α) were considered as predictors in children with severe MPP.

Intratumoral microbiota associates with systemic immune inflammation state in nasopharyngeal carcinoma.

BACKGROUND: The nasopharynx serves as a crucial niche for the microbiome of the upper respiratory tract. However, the association between the intratumoral microbiota and host systemic inflammation and immune status in nasopharyngeal carcinoma (NPC) remain uncertain. METHODS: We performed 5R 16S rDNA sequencing on NPC tissue samples, followed by diversity analysis, LEfSe differential analysis, and KEGG functional prediction. The analyses were based on indices such as AISI, SIRI, PAR, PLR, and NAR. Correlation analyses between microbes and these indices were performed to identify microbes associated with inflammation and immune status. Additionally, regression analysis based on tumor TNM stage was performed to identify key microbes linked to tumor progression. The head and neck squamous cell carcinoma (HNSC) transcriptome and the paired HNSC microbiome data from TCGA were utilized to validate the analyses. RESULTS: The Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes were the most enriched phyla in NPC tissues. Microbes within these phyla demonstrated high sensitivity to changes in host systemic inflammation and immune status. Proteobacteria and Firmicutes showed significant differences between inflammation groups. Actinobacteria varied specifically with platelet-related inflammatory indices, and Bacteroidetes genera exhibited significant differences between NAR groups. Corynebacterium and Brevundimonas significantly impacted the T stage of tumors, with a high load of Corynebacterium within tumors associated with a better prognosis CONCLUSION: Our analysis indicates that Proteobacteria play a crucial role in the inflammatory state of NPC, while Bacteroidetes are more sensitive to the tumor immune status.

Quercetin slow-release system delays starch digestion via inhibiting transporters and enzymes.

This study investigates the potential of a quercetin-based emulsion system to moderate starch digestion and manage blood glucose levels, addressing the lack of in vivo research. By enhancing quercetin bioaccessibility and targeting release in the small intestine, the emulsion system demonstrates significant inhibition of starch digestion and glucose spikes through both in vitro and in vivo experiments. The system inhibits α-amylase and α-glucosidase via competitive and mixed inhibition mechanisms, primarily involving hydrogen bonds and van der Waals forces, leading to static fluorescence quenching. Additionally, this system downregulates the protein expression and gene transcription of SGLT1 and GLUT2. These findings offer a novel approach to sustaining glucose equilibrium, providing a valuable foundation for further application of quercetin emulsion in food science.

Recent Advances in Electrolytes for Magnesium Batteries: Bridging the Gap Between Chemistry and Electrochemistry.

Rechargeable magnesium batteries (RMBs) have the potential to provide a sustainable and long-term solution for large-scale energy storage due to high theoretical capacity of magnesium (Mg) metal as an anode, its competitive redox potential (Mg/Mg2+: -2.37 V vs. SHE) and high natural abundance. To develop viable magnesium batteries with high energy density, the electrolytes must meet a range of requirements: high ionic conductivity, wide electrochemical potential window, chemical compatibility with electrode materials and other battery components, favourable electrode-electrolyte interfacial properties and cost-effective synthesis. In recent years, significant progress in electrolyte development has been made. Herein, a comprehensive overview of these advancements is presented. Beginning with the early developments, we particularly focus on the chemical aspects of the electrolytes and their correlations with electrochemical properties. We also highlight the design of new anions for practical electrolytes, the use of electrolyte additives to optimize anode-electrolyte interfaces and the progress in polymer electrolytes.

microRNA-125b-5p alleviated CCI-induced neuropathic pain and modulated neuroinflammation via targeting SOX11.

BACKGROUND: Increasing evidence demonstrated the involvement of microRNAs (miRNAs) in the onset and development of neuropathic pain (NP). Exploring the molecular mechanism underlying NP and identifying key molecules could provide potential targets for the therapy of NP. The function and mechanism of miR-125b-5p in regulating NP have been studied, aiming to find a potential therapeutic target for NP. METHODS: NP rat models were established by the chronic constriction injury (CCI) method. The paw withdrawal threshold and paw withdrawal latency were assessed to evaluate the establishment and recovery of rats. Highly aggressive proliferating immortalized (HAPI) micoglia cell, a rat microglia cell line, was treated with lipopolysaccharide (LPS). The M1/M2 polarization and inflammation were evaluated by enzyme-linked immunosorbent assay and western blotting. RESULTS: Decreasing miR-125b-5p and increasing SOX11 were observed in CCI rats and LPS-induced HAPI cells. Overexpressing miR-125b-5p alleviated mechanical allodynia and thermal hyperalgesia and suppressed inflammation in CCI rats. LPS induced M1 polarization and inflammation of HAPI cells, which was attenuated by miR-125b-5p overexpression. miR-125-5p negatively regulated the expression of SOX11 in CCI rats and LPS-induced HAPI cells. Overexpressing SOX11 reversed the protective effects of miR-125b-5p on mechanical pain in CCI rats and the polarization and inflammation in HAPI cells, which was considered the mechanism underlying miR-125b-5p. CONCLUSION: miR-125b-5p showed a protective effect on NP by regulating inflammation and polarization of microglia via negatively modulating SOX11.

Elucidating the degradation mechanisms of perfluorooctanoic acid and perfluorooctane sulfonate in various environmental matrices: a review of green degradation pathways.

Given environmental persistence, potential for bioaccumulation, and toxicity of Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), the scientific community has increasingly focused on researching their toxicology and degradation methods. This paper presents a survey of recent research advances in the toxicological effects and degradation methods of PFOA and PFOS. Their adverse effects on the liver, nervous system, male reproductive system, genetics, and development are detailed. Additionally, the degradation techniques of PFOA and PFOS, including photochemical, photocatalytic, and electrochemical methods, are analyzed and compared, highlighted the potential of these technologies for environmental remediation. The biotransformation pathways and mechanisms of PFOA and PFOS involving microorganisms, plants, and enzymes are also presented. As the primary green degradation pathway for PFOA and PFOS, Biodegradation uses specific microorganisms, plants or enzymes to remove PFOA and PFOS from the environment through redox reactions, enzyme catalysis and other pathways. Currently, there has been a paucity of research conducted on the biodegradation of PFOA and PFOS. However, this degradation technology is promising owing to its specificity, cost-effectiveness, and ease of implementation. Furthermore, novel materials/methods for PFOA and PFOS degradation are presented in this paper. These novel materials/methods effectively improve the degradation efficiency of PFOA and PFOS and provide new ideas and tools for the degradation of PFOA and PFOS. This information can assist researchers in identifying flaws and gaps in the field, which can facilitate the formulation of innovative research ideas.

Phylogenetic indices and temporal and spatial scales shape the neighborhood effect on seedling survival in a mid-mountain moist evergreen broad-leaved forest, Gaoligong Mountains, Southwestern China.

Density dependence and habitat filtering have been proposed to aid in understanding community assembly and species coexistence. Phylogenetic relatedness between neighbors was used as a proxy for assessing the degree of ecological similarity among species. There are different conclusions regarding the neighborhood effect in previous studies with different phylogenetic indices or at different spatiotemporal scales. However, the effects of density dependence, neighbor phylogenetic relatedness, and habitat filtering on seedling survival with different phylogenetic indices or at different temporal and spatial scales are poorly understood. We monitored 916 seedlings representing 56 woody plant species within a 4-ha forest dynamics plot for 4 years (from 2020 to 2023) in a subtropical mid-mountain moist evergreen broad-leaved forest in the Gaoligong Mountains, Southwestern China. Using generalized linear mixed models, we tested whether and how four phylogenetic indices: total phylogenetic distance (TOTPd), average phylogenetic distance (AVEPd), relative average phylogenetic distance (APd'), and relative nearest taxon phylogenetic distance (NTPd'), three temporals (1, 2, and 3 years), and spatial scales (1, 2, and 4 ha) affect the effect of density dependence, phylogenetic density dependence, and habitat filtering on seedling survival. We found evidence of the effect of phylogenetic density dependence in the 4-ha forest dynamics plot. The effects of density dependence, phylogenetic density dependence, and habitat filtering on seedling survival were influenced by phylogenetic indices and temporal and spatial scales. The effects of phylogenetic density dependence and habitat filtering on seedling survival were more conspicuous only at 1-year intervals, compared with those at 2- and 3-year intervals. We did not detect any effects of neighborhood or habitat factors on seedling survival at small scales (1 and 2 ha), although these effects were more evident at the largest spatial scale (4 ha). These findings highlight that the effects of local neighborhoods and habitats on seedling survival are affected by phylogenetic indices as well as temporal and spatial scales. Our study suggested that phylogenetic index APd', shortest time scale (1 year), and largest spatial scales (4 ha) were suitable for neighborhood studies in a mid-mountain moist evergreen broad-leaved forest in Gaoligong Mountains. Phylogenetic indices and spatiotemporal scales have important impacts on the results of the neighborhood studies.

Association between neutrophil-to-lymphocyte ratio and epidural-related maternal fever in Chinese parturients: a prospective cohort study.

OBJECTIVE: Epidural analgesia could increase the risk of maternal fever during labor, and the potential mechanisms involved inflammation. Neutrophil-to-lymphocyte ratio (NLR) was a sensitive inflammatory composite indicator and related to adverse outcomes in parturients. This study aimed to investigate the association between NLR levels and epidural related maternal fever (ERMF). METHODS: This prospective cohort study included 614 parturients who underwent epidural analgesia at the Women's Hospital School of Medicine Zhejiang University from November 2021 to May 2023. NLR level was calculated before epidural analgesia for women. The outcome was ERMF. Univariate and multivariate logistic regression models were utilized to explore the association between NLR level and ERMF. And the association was further investigated in subgroups of age, body mass index (BMI) before pregnancy, and parity of delivery. The results were presented as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Totally, 614 parturients, of whom 171 (27.85%) had ERMF. High NLR level was associated with higher incidence of ERMF (OR = 2.70, 95% CI: 1.58-4.69). Parturients with ERMF had higher proportion of postpartum hemorrhage, longer labor times, and other adverse outcomes in parturients. The association also observed in subgroups of age <35 years old (OR = 2.74, 95% CI: 1.55-4.29), BMI <24 kg/m2 before pregnancy (OR = 2.32, 95% CI: 1.32-4.13), BMI ≥24 kg/m2 before pregnancy (OR = 38.28, 95%CI: 3.67-854.66), primipara (OR = 2.26, 95% CI:1.27-4.04), and multipara (OR = 30.60, 95% CI: 3.73-734.03). CONCLUSION: High NLR levels were associated with ERMF in women. It indicated that physicians may measure NLR levels as a regular measurement, which may beneficial for pregnancy outcomes.

The mouse multi-organ proteome from infancy to adulthood.

The early-life organ development and maturation shape the fundamental blueprint for later-life phenotype. However, a multi-organ proteome atlas from infancy to adulthood is currently not available. Herein, we present a comprehensive proteomic analysis of ten mouse organs (brain, heart, lung, liver, kidney, spleen, stomach, intestine, muscle and skin) at three crucial developmental stages (1-, 4- and 8-weeks after birth) acquired using data-independent acquisition mass spectrometry. We detect and quantify 11,533 protein groups across the ten organs and obtain 115 age-related differentially expressed protein groups that are co-expressed in all organs from infancy to adulthood. We find that spliceosome proteins prevalently play crucial regulatory roles in the early-life development of multiple organs, and detect organ-specific expression patterns and sexual dimorphism. This multi-organ proteome atlas provides a fundamental resource for understanding the molecular mechanisms underlying early-life organ development and maturation.

Clinical Efficacy and Safety Meta-Analysis of Different Surgical Approaches for Female Stress Urinary Incontinence.

OBJECTIVE: Meta-analysis was conducted to compare and evaluate the efficacy and safety of tension-free vaginal tape (TVT), outside-in trans-obturator tape (TOT), inside-out tension-free vaginal tape-obturator (TVT-O) and transvaginal tension-free urethral sling surgery (TVT-S) in the treatment of female stress urinary incontinence (SUI). METHODS: A computer-based systematic search of the PubMed, The Cochrane Library, Medline, Embase, Web of Science and ScienceDirect databases for randomised controlled trials (RCTs) comparing TVT, TOT, TVT-O and TVT-S for the treatment of SUI was performed from the time of library construction to November 2023. Two investigators performed data extraction and quality evaluation of the included RCTs, extracting information including the follows: First author, time of publication, intervention, sample size, age, duration of follow-up and objective cure rate, subjective cure rate, dyspareunia, vaginal mucosal perforation, urinary tract infection, sling exposure and postoperative thigh pain/groin pain. Review Manager (RevMan) 5.4 was used for data processing. RESULTS: A total of 14 RCTs with 2665 patients were included. Meta-analysis showed no statistically significant differences in objective cure rate, urinary tract infection, sling exposure and postoperative thigh pain/groin pain. The subjective cure rate of TVT was higher than that of TOT (odds ratio (OR), 95% confidence interval (CI) = 1.37 (1.02, 1.84), p = 0.03); The incidence of TVT-O voiding difficulty was lower than that of TVT (OR, 95% CI = 2.94 (1.20, 7.20), p = 0.02); And the incidence of vaginal mucosal perforation of TOT was lower than that of TVT (OR, 95% CI = 0.11 (0.02, 0.61), p = 0.01). CONCLUSIONS: The four surgical procedures, TVT, TOT, TVT-O and TVT-S, were relatively similar in terms of SUI outcomes. TVT had a higher subjective cure rate than TOT and a higher incidence of postoperative dyspareunia and vaginal mucosal perforation.

[Vitamin D3 alleviates the gastritis that associated with Helicobacter pylori infection in mice with hypercholesterolemia by enhancing the activity of vitamin D receptors in the liver tissue and blocking the signaling pathway of JAK/STAT3].

Objective To investigate whether vitamin D3 (VD3) can alleviate Helicobacter pylori (Hp) infection by reducing blood lipids and inhibiting the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Methods High-cholesterol mouse model and Hp infected mouse model were established. Each was treated with VD3 via oral administration for 8 weeks. Real-time quantitative PCR was used to detect the expression of vitamin D receptor (VDR), insulin-induced gene 2 (Insig-2), and gastrin mRNA. Western blot analysis was used to examine the expression of JAK, STAT3, and cyclooxygenase-2 (COX2) proteins in gastric tissues. Biochemical analyses were performed to measure serum cholesterol levels, and ELISA was utilized to evaluate serum gastrin, interleukin 6 (IL-6), and IL-8 levels, along with histopathological examination of liver and gastric tissues using HE staining. Results After oral administration of VD3, the levels of VDR and Insig-2 in mouse liver tissue significantly increased in the high cholesterol group and the high cholesterol combined with Hp infection group. And the expression of serum gastrin decreased. The expression of JAK, STAT3 in gastric tissues reduced, as did the expression of COX2. Serum cholesterol levels decreased, with no significant changes in IL-6 levels, but a reduction in IL-8 levels. Compared to the control group, the high cholesterol combined with Hp infection group showed reduced hepatic ballooning degeneration and alleviated gastric tissue inflammation. In addition, inflammation in gastric tissue was also reduced in the cholesterol group and the Hp infection group. Conclusion VD3 alleviates gastritis by enhancing the activity of VDR in liver tissues, blocking the JAK/STAT3 signaling pathway, and inhibiting the expression of inflammatory factors.

Doctor simulator: Delta-Age-Sex-AdaIn enhancing bone age assessment through AdaIn style transfer.

BACKGROUND: Bone age assessment assists physicians in evaluating the growth and development of children. However, deep learning methods for bone age estimation do not currently incorporate differential features obtained through comparisons with other bone atlases. OBJECTIVE: To propose a more accurate method, Delta-Age-Sex-AdaIn (DASA-net), for bone age assessment, this paper combines age and sex distribution through adaptive instance normalization (AdaIN) and style transfer, simulating the process of visually comparing hand images with a standard bone atlas to determine bone age. MATERIALS AND METHODS: The proposed Delta-Age-Sex-AdaIn (DASA-net) consists of four modules: BoneEncoder, Binary code distribution, Delta-Age-Sex-AdaIn, and AgeDecoder. It is compared with state-of-the-art methods on both a public Radiological Society of North America (RSNA) pediatric bone age prediction dataset (14,236 hand radiographs, ranging from 1 to 228 months) and a private bone age prediction dataset from Zigong Fourth People's Hospital (474 hand radiographs, ranging from 12 to 218 months, 268 male). Ablation experiments were designed to demonstrate the necessity of incorporating age distribution and sex distribution. RESULTS: The DASA-net model achieved a lower mean absolute deviation (MAD) of 3.52 months on the RSNA dataset, outperforming other methods such as BoneXpert, Deeplasia, BoNet, and other deep learning based methods. On the private dataset, the DASA-net model obtained a MAD of 3.82 months, which is also superior to other methods. CONCLUSION: The proposed DASA-net model aided the model's learning of the distinctive characteristics of hand bones of various ages and both sexes by integrating age and sex distribution into style transfer.

Loss of Tet hydroxymethylase activity causes mouse embryonic stem cell differentiation bias and developmental defects.

The TET family is well known for active DNA demethylation and plays important roles in regulating transcription, the epigenome and development. Nevertheless, previous studies using knockdown (KD) or knockout (KO) models to investigate the function of TET have faced challenges in distinguishing its enzymatic and nonenzymatic roles, as well as compensatory effects among TET family members, which has made the understanding of the enzymatic role of TET not accurate enough. To solve this problem, we successfully generated mice catalytically inactive for specific Tet members (Tetm/m). We observed that, compared with the reported KO mice, mutant mice exhibited distinct developmental defects, including growth retardation, sex imbalance, infertility, and perinatal lethality. Notably, Tetm/m mouse embryonic stem cells (mESCs) were successfully established but entered an impaired developmental program, demonstrating extended pluripotency and defects in ectodermal differentiation caused by abnormal DNA methylation. Intriguingly, Tet3, traditionally considered less critical for mESCs due to its lower expression level, had a significant impact on the global hydroxymethylation, gene expression, and differentiation potential of mESCs. Notably, there were common regulatory regions between Tet1 and Tet3 in pluripotency regulation. In summary, our study provides a more accurate reference for the functional mechanism of Tet hydroxymethylase activity in mouse development and ESC pluripotency regulation.

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

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

Mesoporous manganese nanocarrier target delivery metformin for the co-activation STING pathway to overcome immunotherapy resistance.

Targeting the stimulator of interferon genes (STING) pathway is a promising strategy to overcome primary resistance to immune checkpoint inhibitors in non-small cell lung cancer with the STK11 mutation. We previously found metformin enhances the STING pathway and thus promotes immune response. However, its low concentration in tumors limits its clinical use. Here, we constructed high-mesoporous Mn-based nanocarrier loading metformin nanoparticles (Mn-MSN@Met-M NPs) that actively target tumors and respond to release higher concentration of Mn2+ ions and metformin. The NPs significantly enhanced the T cells to kill lung cancer cells with the STK11 mutant. The mechanism shows that enhanced STING pathway activation promotes STING, TBKI, and IRF3 phosphorylation through Mn2+ ions and metformin release from NPs, thus boosting type I interferon production. In vivo, NPs in combination with a PD-1 inhibitor effectively decreased tumor growth. Collectively, we developed a Mn-MSN@Met-M nanoactivator to intensify immune activation for potential cancer immunotherapy.