[Study of the methotrexate loaded extracellular vesicles in the treatment of experimental periodontitis in mice].

Objective: To investigate the therapeutic effect of methotrexate loaded vesicles on experimental periodontitis in mice. Methods: Extracellular vesicles (EVs) were isolated from human umbilical cord mesenchymal stem cells (hUC-MSC). Methotrexate loaded vesicles (MTX-EVs) were constructed, whose morphology and size were analyzed by using scanning electron microscopy and particle size analyzer. Western blotting was used to identify their surface specific proteins. C57BL/6J male mice of 4-5 weeks (provided by Experimental Animal Center of The Fourth Military Medical University) were selected, among which 8 were randomly selected by blind grasp method without treatment and fed normally as normal group, and others were induced to periodontitis models by local injection of lipopolysaccharide (LPS) into the periodontium. The LPS was injected once every day with a concentration of 2 g/L and a volume of 5 µl, lasting for two weeks. The mice with successfully induced periodontitis were randomly divided into 4 groups by blind grasping method, with 8 mice in each group. The LPS group was with no treatment, and the other three groups were treated with periodontal local injection of MTX, EVs or MTX-EVs, respectively. Two weeks later, enzyme-linked immunosorbent assay (ELISA) was used to detect the expressions of inflammatory cytokine interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α) in gingival tissue. The amount of alveolar bone resorption of four groups was detected by using micro-CT scanning and HE staining. The expression proportion of the inflammatory factor in gingival tissue was analyzed by using flow cytometry. Results: The scanning electron microscopy results showed that EVs and MTX-EVs were circular or elliptical in shape. Dynamic light scattering (DLS) particle size analysis showed that the particle size of EVs was around 200 nm, while that of MTX-EVs was around 300 nm. The ELISA results showed IL-1ß levels in the normal group, LPS group, LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were (28.86±2.76), (51.50±2.04), (35.26±2.40), (45.49±2.04) and (35.77±3.49) ng/L. That is, the IL-1ß concentrations in the LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were significantly lower than that in the LPS group (P<0.05); the mass concentration of IL-1ß in the LPS +MTX-EVs group was significantly lower than that in the LPS+EVs group (P<0.05). The concentrations of IL-6 in the normal group, LPS group, LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were (125.44±4.12), (221.64±10.59), (178.16±16.90), (181.09±18.22) and (170.15±9.04) ng/L, among which the concentration of IL-6 in the last three groups were significantly lower than that in the LPS group (P<0.05). The mass concentration of IL-6 in the LPS+MTX-EVs group was significantly lower than those in the LPS+MTX group and LPS+EVs group (P<0.05). The concentrations of TNF-α in the normal group, LPS group, LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were (320.27±38.68), (479.62±40.94), (342.18±25.89), (415.88±12.01) and (325.75±30.83) ng/L, among which the concentrations of last three groups were significantly lower than the LPS group (P<0.05); the mass concentration of TNF-α in the LPS+MTX-EVs group was significantly lower than those in the LPS+EVs group and LPS+MTX group (P<0.05). The micro-CT results showed that the distance of cement-enamel junction-alveolar bone crest (CEJ-ABC) of the first molar and root (M1R1) in the normal group, LPS group, LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group of mice were (0.11±0.03), (0.28±0.02), (0.23±0.03), (0.20±0.04), and (0.18±0.03) mm, respectively. Compared with the LPS group, the CEJ-ABC of the M1R1 in the LPS+MTX group, LPS+EVs group and LPS+MTX-EVs group were inhibited to varied degrees with statistically significant differences (P<0.05). Among them, LPS+MTX-EVs group had the best bone resorption inhibitioin effect compared to LPS+MTX group and LPS+EVs group, and the differences were statistically significant (P<0.05). The flow cytometry results indicated that the proportion of interferon-γ (IFN-γ) positive cells was (11.77±1.02)% in the LPS group, (6.87±0.65)% in the LPS+EVs group, and (4.15±0.92)% in the LPS+MTX-EVs group, respectively. The proportions of IFN-γ positive cells in the LPS+EVs group and LPS+MTX-EVs group were significantly lower than that in the LPS group (P<0.05), while the ratio of IFN-γ positive cells in the LPS+MTX-EVs group was found significantly lower than that in the LPS+EVs group (P<0.05). Conclusions: MTX-EVs can effectively alleviate the periodontal local inflammatory environment and reduce bone resorption of alveolar bone in periodontitis model mice.

[Educational attainment increases the risk of developing allergic rhinitis and (or) eczema: a Mendelian randomization study based on genome-wide association studies in European patients].

Objective: To determine the causal relationship between educational attainment and the risk of allergic rhinitis and (or) eczema using Mendelian randomization (MR) analyses. Methods: This study was a secondary data analysis based on the summary data of genome-wide association studies (GWAS), which involved 293 723 participants (educational attainment) from the Social Science Genetics Association Consortium and 462 013 participants [allergic rhinitis and (or) eczema] from the UK Biobank. Genetic variants that were closely related to educational attainment were identified as instrumental variables. Two-sample MR analyses, including inverse-variance weighted (IVW), MR-Egger regression, weighted median method and weighted model-based estimation, were performed to investigate the causal relationship between educational attainment and the risk of allergic rhinitis and (or) eczema, in which the odds ratio (OR) values were used as indicators. Results: A total of 70 single-nucleotide polymorphisms (SNPs) were chosen as instrumental variables. The MR-Egger regression results suggested that the genetic pleiotropy was unlikely to bias our results (P=0.107). In the univariable MR analyses, IVW regression showed that the risk of allergic rhinitis and (or) eczema was OR=1.044 (95%CI: 1.020-1.069, P<0.001) and OR=1.170 (95%CI: 1.074-1.256, P<0.001), respectively, for the increase in the duration of education by one year or one standard deviation (SD) (3.71 years). In the reverse MR analysis, IVW regression showed little evidence that allergic rhinitis and (or) eczema affected educational attainment (OR=1.020, 95%CI: 0.927-1.023, P=0.683). The results of the weighted median method and weighted mode-based estimation were consistent with the results of IVW. Conclusion: This study suggests that there is a positive causal relationship between educational attainment and the risk of allergic rhinitis and (or) eczema, which means that educational attainment can increase the occurrence of allergic rhinitis and (or) eczema.

[Molecular characteristics and drug susceptibility analysis of Streptococcus agalactiae from respiratory specimen sources].

To study the carriage status of drug susceptibility, clonal complex groups, serotypes, surface proteins and virulence genes of Streptococcus agalactiae from respiratory specimen sources. A total of 35 strains of S.agalactiae meeting the criteria were collected from 3 hospitals in 2 locations, Tangshan and Jinan. The age span of the patients was 3 days-92 years, and the percentage of elderly patients≥60 years was 71.5%.The susceptibility to 9 antimicrobial drugs was measured and analyzed using the micro broth dilution method. The strains were 100.0% sensitive to penicillin, linezolid, vancomycin, and ceftriaxone; However, it exhibits high resistance rates to erythromycin, clindamycin and levofloxacin, at 97.1%, 85.7% and 82.9% respectively; and the resistance rates to tetracycline and chloramphenicol were 34.3% and 14.2%, respectively. Genome sequence determination and analysis showed that 16 resistance genes were detected in 35 strains, among which: macrolide and lincosamide resistance genes were mainly ermB, with a carrying rate of 74.2%; tetracycline resistance genes were mainly tetM, with a carrying rate of 25.7%; in addition, the mutation rates of the quinolone resistance determinants gyrA and parC were 88.5% and 85.7%, respectively. 35 strains belonged to 6 ST types and 4 clonal groups, with CC10/ST10 as the main one, accounting for 62.8%; they contained 4 serotypes of Ⅰb, Ⅱ, Ⅲ, and Ⅴ, as well as 1 untyped strain, with serotype Ⅰb as the main one, accounting for 65.7%. The strains carried three pilus types, PI1+PI2a, PI2a and PI2b types, respectively, and detected five surface proteins, alpha, alp1, rib, srr, and rdf_0594, and seven virulence factors, cba, cfb, cylE, fbsA, hylB, lmb, and pavA. Overall, S.agalactiae isolated from respiratory tract specimens is predominantly sourced from elderly patients, with CC10 strains being most prevalent. These strains harbor multiple drug-resistant and virulence genes, demonstrating elevated resistance rates to macrolides, lincosamides, and quinolones. This emphasizes the necessity for vigilant attention to the health threat posed by S. agalactiae from respiratory tract speciments of elderly patients.

Biological Mediators and Partial Regulatory Mechanisms on Neuropathic Pain Associated With Chemotherapeutic Agents.

One of the most common issues caused by antineoplastic agents is chemotherapy-induced peripheral neuropathy (CIPN). In patients, CIPN is a sensory neuropathy accompanied by various motor and autonomic changes. With a high prevalence of cancer patients, CIPN is becoming a major problem for both cancer patients and for their health care providers. Nonetheless, there are lacking effective interventions preventing CIPN and treating the CIPN symptoms. A number of studies have demonstrated the cellular and molecular signaling pathways leading to CIPN using experimental models and the beneficial effects of some interventions on the CIPN symptoms related to those potential mechanisms. This review will summarize results obtained from recent human and animal studies, which include the abnormalities in mechanical and temperature sensory responses following chemotherapy such as representative bortezomib, oxaliplatin and paclitaxel. The underlying mechanisms of CIPN at cellular and molecular levels will be also discussed for additional in-depth studies needed to be better explored. Overall, this paper reviews the basic picture of CIPN and the signaling mechanisms of the most common antineoplastic agents in the peripheral and central nerve systems. A better understanding of the risk factors and fundamental mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

[Comparison of clinical characteristics in intermittent exotropia patients with different visual perception and oculomotor control].

Objective: To explore the clinical characteristics of intermittent exotropia (IXT) patients with different visual perception and oculomotor control. Methods: A cross-sectional study was conducted. Minor IXT patients between March 2021 and May 2023 at Beijing Tongren Hospital were enrolled. Demographic characteristics were recorded, and visual perception and oculomotor control were evaluated. The patients were divided into simultaneous vision disappearing and existing groups, fusion disappearing and existing groups, distant stereoscopic vision disappearing and normal groups, and near stereoscopic vision injury and normal groups. Statistical description was performed by using M (Q1, Q3). Rank sum test was used to compare the Revised Newcastle Control Score (RNCS), near and far strabismus degree, duration of disease, and age of onset among different groups. The correlation between visual perception and oculomotor control and the correlation of duration of disease and age of onset with visual perception and oculomotor control were analyzed by Pearson correlation analysis. Results: A total of 381 patients were enrolled, including 189 males and 192 females, with a median age of 7 (6, 9) years. The incidence of normal visual perception was 19.4% (74/381). Compared with simultaneous vision and fusion existing groups and distant and near stereoscopic vision normal groups, the RNCS [7 (5, 9) vs 4 (3, 6), 6 (5, 8) vs 4 (3, 6), 5 (4, 7) vs 3 (3, 5), and 5 (3, 6) vs 4 (3, 6)], near strabismus degree [65Δ (60Δ, 80Δ) vs 40Δ (30Δ, 50Δ), 60Δ (45Δ, 65Δ) vs 40Δ (30Δ, 50Δ), 50Δ (40Δ, 60Δ) vs 35Δ (30Δ, 45Δ), and 45Δ (30Δ, 60Δ) vs 40Δ (30Δ, 50Δ)] and far strabismus degree [60Δ (50Δ, 75Δ) vs 35Δ (25Δ, 50Δ), 55Δ (41Δ, 65Δ) vs 35Δ (25Δ, 45Δ), 45Δ (30Δ, 60Δ) vs 35Δ (25Δ, 45Δ), and 40Δ (30Δ, 60Δ) vs 35Δ (25Δ, 45Δ)] increased significantly in disappearing simultaneous vision, fusion, and distant stereoscopic vision groups and injury near stereoscopic vision group (all P<0.05). Compared with simultaneous vision and fusion existing groups and distant stereoscopic vision normal group, duration of disease was significant longer in disappearing simultaneous vision, fusion, and distant stereoscopic vision groups [3 (1, 5) years vs 2 (1, 3) years, 2 (1, 4) years vs 1 (1, 3) years, 2 (1, 4) years vs 1 (1, 3) years, all P<0.05]. The age of onset in disappearing distant stereoscopic vision group was significantly lower than normal distant stereoscopic vision group [5 (3, 7) years vs 6 (4, 8) years, P=0.005]. Pearson correlation analysis showed that subjective angle and random dot stereogram (RDS) stereoacuity were positive correlation with RNCS, and the near and far strabismus degree (r=0.414, 0.516, and 0.559, all P<0.001; r=0.153, 0.142, and 0.173, all P<0.05). Subjective angle, RNCS, and the near and far strabismus degree were positive correlation with duration of disease (r=0.238, 0.195, 0.236, 0.239, all P<0.001) and negative correlation with age of onset (r=-0.184, -0.279, -0.112, -0.147, all P<0.05). Conclusions: Nearly 20% of IXT patients have normal visual perception. With the longer duration of disease or lower age of onset, the incidence of abnormal visual perception is higher and injury of visual perception and oculomotor control is more serious.

[Mechanisms by which Mettl3 regulates pericyte-myofibroblast transdifferentiation through PI3K/AKT signaling pathway].

Objective: To investigate the role and underlying mechanisms of methyltransferase (Mettl) 3 in the process of angiotensin Ⅱ (Ang Ⅱ)-induced pericyte-to-myofibroblast transdifferentiation and renal fibrosis. Methods: C57BL/6J mice were used, in cell experiments, mouse renal pericytes were isolated and cultured using magnetic bead sorting. These pericytes were then induced to transdifferentiate into myofibroblasts with 1×106 mmol/L Ang Ⅱ, which was the Ang Ⅱ group, while pericytes cultured in normal conditions served as the control group. Successful transdifferentiation was verified by immunofluorescence staining, Western blotting, and real-time reverse transcription PCR (RT-qPCR) for α-smooth muscle actin (α-SMA). The levels of m6A modifications and related enzymes (Mettl3, Mettl14), Wilms tumor 1-associated protein (WTAP), fat mass and obesity protein (FTO), ALKBH5, YTHDF1, YTHDF2, YTHDC1, YTHDC2, YTHDC3 were assessed by Dot blot, RT-qPCR and Western blot. Mettl3 expression was inhibited in cells using lentivirus-mediated Mettl3-shRNA transfection, creating sh-Mettl3 and Ang Ⅱ+sh-Mettl3 groups, while lentivirus empty vector transfection served as the negative control (Ang Ⅱ+sh-NC group). The impact of Ang Ⅱ on pericyte transdifferentiation was observed, and the expression of downstream phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway proteins, including PI3K, AKT, phosphorylated AKT at serine 473 (p-AKT (S473)), and phosphorylated AKT at threonine 308 (p-AKT (T308)), were examined. PI3K gene transcription was inhibited by co-culturing cells with actinomycin D, and the half-life of PI3K mRNA was calculated by measuring residual PI3K mRNA expression over different co-culture time. The reversibility of Mettl3 inhibition on Ang Ⅱ-induced pericyte-to-myofibroblast transdifferentiation was assessed by adding the AKT activator SC79 to the Ang Ⅱ+sh-Mettl3 group. In animal experiments, mice were divided into these groups: sham group (administered 0.9% sterile saline), Ang Ⅱ group (infused with Ang Ⅱ solution), sh-Mettl3 group (injected with Mettl3 shRNA lentivirus solution), Ang Ⅱ+sh-Mettl3 group (infused with Ang Ⅱ solution and injected with Mettl3 shRNA lentivirus solution), and Ang Ⅱ+sh-Mettl3+SC79 group (administered Ang Ⅱ solution and Mettl3 shRNA lentivirus, with an additional injection of SC79). Each group consisted of six subject mice. Blood pressure was measured using the tail-cuff method before and after surgery, and serum creatinine, urea, and urinary albumin levels were determined 4 weeks post-surgery. Kidney tissues were collected at 28 days and stained using hematoxylin-eosin (HE) and Masson's trichrome to assess the extent of renal fibrosis. Results: Primary renal pericytes were successfully obtained by magnetic bead sorting, and intervened with 1×106 mmol/L Ang Ⅱ for 48 hours to induce pericyte-to-myofibroblast transdifferentiation. Dot blot results indicated higher m6A modification levels in the Ang Ⅱ group compared to the control group (P<0.05). RT-qPCR and Western blot results showed upregulation of Mettl3 mRNA and protein levels in the Ang Ⅱ group compared to the control group (both P<0.05). In the Ang Ⅱ+sh-Mettl3 group, Mettl3 protein expression was lower than that in the Ang Ⅱ group, with reduced expression levels of α-SMA, vimentin, desmin, fibroblast agonist protein (FAPa) and type Ⅰ collagen (all P<0.05). Compared to the control group, PI3K mRNA expression level was elevated in the Ang Ⅱ group, along with increased p-AKT (S473) and p-AKT (T308) expressions. In the Ang Ⅱ+sh-Mettl3 group, PI3K mRNA expression and p-AKT (S473) and p-AKT (T308) levels were decreased (all P<0.05). The half-life of PI3K mRNA was shorter in the Ang Ⅱ+sh-Mettl3 group than that in the Ang Ⅱ+sh-NC group (2.34 h vs. 3.42 h). The ameliorative effect of Mettl3 inhibition on Ang Ⅱ-induced pericyte-to-myofibroblast transdifferentiation was reversible by SC79. Animal experiments showed higher blood pressure, serum creatinine, urea, and 24-hour urinary protein levels, and a larger fibrosis area in the Ang Ⅱ group compared to the sham group (all P<0.05). The fibrosis area was smaller in the Ang Ⅱ+sh-Mettl3 group than that in the Ang Ⅱ group (P<0.05), but increased again upon addition of SC79. Conclusion: Mettl3-mediated RNA m6A epigenetic regulation is involved in Ang Ⅱ-induced pericyte-to-myofibroblast transdifferentiation and renal fibrosis, potentially by affecting PI3K stability and regulating the PI3K/AKT signaling pathway.

Effects of feed conditioning temperature on pellet quality, growth performance, intestinal development and blood parameters of geese from 1 to 28 d of age.

A 28-d experiment was conducted to investigate the effects of feed-conditioning temperature on the pellet quality, growth performance, intestinal development, and blood parameters of geese. A total of 180 one-day-old White Yuzhou goslings were randomly allotted to 5 treatment groups, with 6 replicates containing 6 birds each. Five diets were conditioned at 65, 70, 75, 80, and 85°C. Body weight and feed intake per pen basis were recorded from the arrival to the end of the trial. Blood and small intestine samples were collected on d 28 for analysis. The results showed that the pellet durability index (PDI), pellet hardness, and gelatinisation degree of starch (GDS) increased with increasing conditioning temperature (P < 0.05). The final body weight (FBW), average daily gain (ADG) and average daily feed intake (ADFI) of goslings significantly increased when conditioning temperature increased from 65 or 70°C to 80 or 85°C (P < 0.05), accompanied by unaffected feed conversion ratio (FCR) (P > 0.05). The villus height to crypt depth ratio (VH/CD) in the duodenum and ileum improved with increasing conditioning temperature (P < 0.05). Additionally, trypsin and amylase activity were enhanced when the conditioning temperature increased from 65 to 85°C (P < 0.05). No significant differences in the carcass traits and blood parameters of goslings were observed among the groups (P > 0.05). Overall, under the present experimental conditions, increasing the steam-conditioning temperature of pelleted feed improved pellet quality, growth performance, intestinal morphology, and digestive enzyme activity in goslings. Based on broken-line regression analysis, the lower critical conditioning temperature for ADG in geese from 1 to 28 d of age was 80.95°C.

[Coenzyme Q10 alleviates depression-like behaviors in mice with chronic restraint stress by down-regulating the pyroptosis signaling pathway].

OBJECTIVE: To explore the neuroprotective effect of coenzyme Q10 and its possible mechanism in mice with chronic restraint stress (CRS). METHODS: Mouse models of CRS were treated with intraperitoneal injections of coenzyme Q10 at low, moderate and high doses (50, 100 and 200 mg/kg, respectively, n=8), VX765 (a caspase-1 specific inhibitor, 50 mg/kg, n=8), or fluoxetine (10 mg/kg, n=8) on a daily basis for 4 weeks, and the changes in depression-like behaviors of the mice were assessed by sugar water preference test, forced swimming test and tail suspension test. The expression of glial fibrillary acidic protein (GFAP) in the hippocampus of the mice was detected using immunohistochemistry, and the number of synaptic spines was determined with Golgi staining. Western blotting was performed to detect the changes in the expressions of GFAP and pyroptosis-related proteins in the hippocampus, and the colocalization of neurons and caspase-1 p10 was examined with immunofluorescence assay. RESULTS: Compared with the normal control mice, the mouse models of CRS showed significantly reduced sugar water preference and increased immobility time in forced swimming and tail suspension tests (P < 0.05), and these depression-like behaviors were obviously improved by treatment with coenzyme Q10, VX765 or FLX. The mouse models showed a significantly decreased positive rate of GFAP and lowered GFAP protein expression in the hippocampus with obviously decreased synaptic spines, enhanced expressions of GSDMD-N, caspase-1 and IL-1ß, and increased colocalization of neurons and caspase-1 p10 (all P < 0.05). All these changes were significantly ameliorated in the mouse models after treatment with Q10. CONCLUSION: Coenzyme Q10 can alleviate depression-like behaviors in mice with CRS by down-regulating the pyroptosis signaling pathway.

[Discussion on the prevention and control strategies of chronic hepatitis B: experience from AIDS prevention and control in China].

Hepatitis B is a major infectious disease that seriously endangers the health of the people of China. Patients with hepatitis B have a large base in our country, and the core indicators such as detection and antiviral treatment ratio are far from the real goal of eliminating the public health threat of uiral hepatitis.Notably, the chronic hepatitis B prevention and control system lacks a wide targeted strategies. This paper systematically analyzes our country's main successful experience with AIDS prevention and control and, on that basis, proposes the ideas and strategic paths for the construction of a chronic hepatitis B prevention and control system, analyzes and discusses the current difficulties and problems in prevention and control, and looks forward to future prevention and control efforts.

Illustrated State-of-the-Art Capsules of the ISTH 2024 Congress.

Here, we present a series of illustrated capsules from the State of the Art (SOA) speakers at the 2024 International Society on Thrombosis and Haemostasis Congress in Bangkok, Thailand. This year's Congress marks the first time that the International Society on Thrombosis and Haemostasis has held its flagship scientific meeting in Southeast Asia and is the first to be organized by an international Planning Committee. The Bangkok program will feature innovative science and clinical updates from around the world, reflecting the diversity and multidisciplinary growth of our field. In these illustrated SOA capsules, you will find an exploration of novel models of thrombosis and bleeding and biomaterial discoveries that can trigger or block coagulation. Thromboinflammation is now understood to drive many disease states, and the SOA speakers cover cellular and coagulation responses to COVID-19 and other infections. The theme of crosstalk between coagulation and inflammation expands with capsules on protein S signaling, complement, and fibrinolytic inhibitors. Novel agents for hemophilia and thrombosis prevention are introduced. Challenging clinical conditions are also covered, such as inherited platelet disorders and antiphospholipid antibody syndrome. The scientific program in Bangkok will also showcase the work of clinicians and scientists from all parts of the world and chronicle real-world challenges. For example, 2 SOA capsules address the diagnosis and management of von Willebrand disease in low-income settings. Take some time to browse through these short illustrated reviews; we're sure that you'll be entertained, educated, and inspired to further explore the world of thrombosis and hemostasis.

Estimation of the genetic parameters of sheep growth traits based on machine vision acquisition.

In the realm of animal phenotyping, manual measurements are frequently utilised. While machine-generated data show potential for enhancing high-throughput breeding, additional research and validation are imperative before incorporating them into genetic evaluation processes. This research presents a method for managing meat sheep and collecting data, utilising the Sheep Data Recorder system for data input and the Sheep Body Size Collector system for image capture. The study aimed to investigate the genetic parameter changes of growth traits in Ujumqin sheep by comparing machine-generated measurements with manual measurements. The dataset consisted of 552 data points from the offspring of 75 breeding rams and 399 breeding ewes. Six distinct random regression models were assessed to pinpoint the most suitable model for estimating genetic parameters linked to growth traits. These models were distinguished based on the inclusion or exclusion of maternal genetic effects, maternal permanent environmental effects, and covariance between maternal and direct genetic effects. Fixed factors such as individual age, individual sex, and ewe age were taken into account in the analysis. The genetic parameters for the yearling growth traits of Ujumqin sheep were calculated using ASReml software. The Akaike information criterion, the Bayesian information criterion, and fivefold cross-validation were employed to identify the optimal model. Research findings indicate that the most accurate models for manually measured data revealed heritability estimates of 0.12 ± 0.15 for BW, 0.05 ± 0.07 for body slanting length, 0.03 ± 0.07 for withers height, 0.15 ± 0.12 for hip height, 0.11 ± 0.11 for chest depth, 0.13 ± 0.13 for shoulder width, and 0.53 ± 0.15 for chest circumference. The optimal models for machine-predicted data showed heritability estimates of 0.1 ± 0.09 for body slanting length, 0.14 ± 0.12 for withers height, 0.55 ± 0.15 for hip height, 0.34 ± 0.15 for chest depth, 0.26 ± 0.15 for shoulder width, and 0.47 ± 0.16 for chest circumference. In manually measured data, genetic correlations ranged from 0.35 to 0.99, while phenotypic correlations ranged from 0.07 to 0.90. In machine data, genetic correlations ranged from -0.05 to 0.99, while phenotypic correlations ranged from 0.03 to 0.84. The results suggest that machine-based estimations may lead to an overestimation of heritability, but this discrepancy does not impact the selection of breeding models.

Effects of particulate matter exposure on the risk of type 2 diabetes: a Mendelian randomization study.

OBJECTIVE: The impact of particulate matter (PM) on the risk of type 2 diabetes (T2D) remains inconclusive. The purpose of this study was to assess the causal relationship between PM and T2D using Mendelian randomization (MR) analysis. MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs) for PM2.5, PM10, and T2D were obtained from the UK Biobank and FinnGen datasets. Inverse variance weighted, MR-Egger, and weighted median were utilized to examine the causal relationship between exposure and outcome. MR-Egger intercept analysis, Cochran's Q test, and leave-one-out sensitivity analysis were used to assess horizontal pleiotropy, heterogeneity, and robustness of the results, respectively. RESULTS: The MR analysis revealed a significant association between PM2.5 and increased risk of T2D (OR: 1.159, 95% CI: 1.003 to 1.339, p = 0.045), while no significant association was found between PM10 and T2D risk (OR: 1.031, 95% CI: 0.788 to 1.350, p = 0.822). MR-Egger intercept analysis and Cochran's Q test indicated no evidence of horizontal pleiotropy or heterogeneity in these results. Sensitivity analysis demonstrated the robustness of the results. CONCLUSIONS: This MR analysis suggests that PM2.5, rather than PM10, is associated with an increased risk of T2D. The use of air purifiers and anti-smog masks may potentially help reduce the risk of T2D. Further research is needed to elucidate the specific effects and underlying mechanisms of PM2.5 and PM10 on T2D.

[The clinicopathological features of adult thyroid tumors with DICER1 mutation].

A total of 37 cases of thyroid tumors with pathological features suggestive of DICER1 gene mutation were selected to detect the DICER1 gene and BRAF gene using Sanger sequencing. A total of 10 patients (27.0%) exhibited DICER1 gene mutation all of whom were female with an age of [M(Q1, Q3)] 38.0 (30.5, 47.5) years. All patients had wild-type BRAFV600E gene. The ultrasound examination showed high-low echogenic well-demarcated intra-thyroidal nodules with abundant peripheral and internal blood flow signals in the DICER1 mutated thyroid tumor. The tumor was confined within the thyroid gland, with a diameter of (3.68±1.31) cm. The pathological features are as follows: the majority of tumors are encapsulated, which mainly composed of large follicles rich in colloid and some are small and micro follicles. The nucleus is round and deeply stained or slightly light stained, small to medium-sized, with occasional nuclear grooves and a lack of nuclear pseudoinclusion bodies within the nucleus. Immunohistochemical staining shows that Ki67 proliferation index of approximately 2%-10%. All cases were followed up for 11 to 18 months, and there was no recurrences or distant metastase. This study confirmed that the DICER1 gene mutation is mutually exclusive with the BRAFV600E gene mutation. The thyroid tumor with DICER1 mutation are in big size and are more common in young females with a good prognosis. Cases with the wild-type DICER1 gene may exhibit similar morphological features, and molecular testing is recommended. If somatic DICER1 mutation is confirmed, patients should undergo germline mutation testing to rule out DICER1 syndrome in order to define whether genetic counseling is necessary.

[The 506th case: fever of unknown origin, negative PET-CT and hemoperitoneum].

A 48-year-old male was admitted to Peking Union Medical College Hospital presented with intermittent fever for two years. The maximum body temperature was 39 ℃, and could spontaneously relieve. The efficacy of antibacterial treatment was poor. He had no other symptoms and positive signs. He had a significant weight loss, and the serum lactate dehydrogenase increased significantly. It was highly alert to be lymphoma, but bone marrow smear and pathology, and PET-CT had not shown obvious abnormalities. Considering high inflammatory indicators, increased ferritin and large spleen, the patient had high inflammatory status, and was treated with methylprednisolone. Then the patient's body temperature was normal, but the platelet decreased to 33×109/L. During hospitalization, he had suddenly hemoperitoneum and hemorrhagic shock. He was found spontaneous spleen rupture without obvious triggers, and underwent emergency splenectomy. The pathological diagnosis of spleen was diffuse large B-cell lymphoma.

METTL3 Modulates Ctsk+ Lineage Supporting Cranial Osteogenesis via Hedgehog.

N6-methyladenosine (m6A) modification, a eukaryotic messenger RNA modification catalyzed by methyltransferase-like 3 (METTL3), plays a pivotal role in stem cell fate determination. Calvarial bone development and maintenance are orchestrated by the cranial sutures. Cathepsin K (CTSK)-positive calvarial stem cells (CSCs) contribute to mice calvarial ossification. However, the role of m6A modification in regulating Ctsk+ lineage cells during calvarial development remains elusive. Here, we showed that METTL3 was colocalized with cranial nonosteoclastic Ctsk+ lineage cells, which were also associated with GLI1 expression. During neonatal development, depletion of Mettl3 in the Ctsk+ lineage cells delayed suture formation and decreased mineralization. During adulthood maintenance, loss of Mettl3 in the Ctsk+ lineage cells impaired calvarial bone formation, which was featured by the increased bone porosity, enhanced bone marrow cavity, and decreased number of osteocytes with the less-developed cellular outline. The analysis of methylated RNA immunoprecipitation sequencing and RNA sequencing data indicated that loss of METTL3 reduced Hedgehog (Hh) signaling pathway. Restoration of Hh signaling pathway by crossing Sufufl/+ alleles or by local administration of SAG21 partially rescued the abnormity. Our data indicate that METTL3 modulates Ctsk+ lineage cells supporting calvarial bone formation by regulating the Hh signaling pathway, providing new insights for clinical treatment of skull vault osseous diseases.