A comparative analysis of alternative splicing patterns in Atlantic salmon (Salmo salar) in response to Moritella viscosa and sea lice (Lepeophtheirus salmonis) infection.

Moritella viscosa (M. viscosa) and sea lice (Lepeophtheirus salmonis) are severe pathogens that primarily infect the skin of Atlantic salmon (Salmo salar), which cause significant economic losses in the farming industry. However, the pathogenesis and molecular mechanisms underlying the host's immune defence at the post-transcriptional level remain unclear. Alternative splicing (AS) is an evolutionarily conserved post-transcriptional mechanism that can greatly increase the richness of the transcriptome and proteome. In this study, transcriptomic data derived from skin tissues of Atlantic salmon after M. viscosa and sea lice infections were used to examine the AS profiles and their differential expression patterns. In total, we identified 33,044 AS events (involving 13,718 genes) in the control (CON) group, 35,147 AS events (involving 14,340 genes) in the M. viscosa infection (MV) group, and 30,364 AS events (involving 13,142 genes) in the sea lice infection (LC) group, respectively. Among the five types of AS identified in our study (i.e., SE, A5SS, A3SS, MXE, and RI), SE was the most prevalent type in all three groups (i.e., CON, MV, and LC groups). Decreased percent-spliced-in (PSI) levels were observed in SE events under both MV- and LC-infected conditions, suggesting that MV or LC infection elevated exon-skipping isoforms and promoted the selection of shorter transcripts in numerous DAS genes. In addition, most of the differential AS genes were found to be associated with pathways related to mRNA regulation, epithelial or muscle development, and immune response. These findings provide novel insights into the role of AS in host-pathogen interactions and represent the first comparative analysis of AS in response to bacterial and parasitic infections in fish.

Impact of fellowship training for specialists on thyroidectomy outcomes of patients with thyroid cancer.

We aimed to evaluate the impact of fellowship training (FT) for thyroid specialists on the outcomes of patients with thyroid cancer. We reviewed surgeries performed for thyroid cancer before (non-FT group) and after (FT group) fellowship training and compared several variables, including length of stay of patients, tumor diameter, surgical method, lymph node dissection, parathyroid implantation, surgical duration, intraoperative blood loss, and postoperative complications. Compared with the non-FT group, the FT group had a shorter hospital stay, more adequate fine needle aspiration biopsy of the thyroid, less intraoperative blood loss, higher rate of parathyroid implantation, higher lymph node dissection rate, and lower nerve injury and hypoparathyroidism rates. When the surgical duration was < 200 min and/or only central lymph node dissection was performed, the FT group had a lower incidence of postoperative complications than the non-FT group. When, the incidence of postoperative complications, including postoperative nerve injury and hypoparathyroidism. In conclusion, FT for thyroid specialists is beneficial for patients with thyroid cancer and may allow a shorter hospital stay and reduced incidence of postoperative complication. Accordingly, FT may facilitate a more appropriate surgical approach with a preoperative pathological diagnosis.

Job burnout among primary healthcare workers during COVID-19 pandemic: cross-sectional study in China.

Objective: This study evaluated job burnout among primary healthcare workers (PHCWs) in China during the COVID-19 pandemic, explored its influencing factors, and examined PHCWs' preferences for reducing job burnout. Method: We conducted a multicenter cross-sectional study in Heilongjiang, Sichuan, Anhui, Gansu, and Shandong Provinces. An electronic questionnaire survey was conducted through convenience sampling in communities from May to July 2022. We collected sociodemographic characteristics, job burnout level, job satisfaction, and preferred ways to reduce job burnout among PHCWs. Results: The job burnout rate among PHCWs in China was 59.87% (937/1565). Scores for each dimension of job burnout were lower among PHCWs who had a better work environment (emotional exhaustion OR: 0.60; depersonalization OR: 0.73; personal accomplishment OR: 0.76) and higher professional pride (emotional exhaustion OR: 0.63; depersonalization OR: 0.70; personal accomplishment OR: 0.44). PHCWs with higher work intensity (emotional exhaustion OR: 2.37; depersonalization OR: 1.34; personal accomplishment OR: 1.19) had higher scores in all job burnout dimensions. Improving work environments and raising salaries were the preferred ways for PHCWs to reduce job burnout. Conclusion: Strategies should be developed to improve job satisfaction among PHCWs, enhance their professional identity, and alleviate burnout to ensure the effective operation of the healthcare system, especially during periods of overwork.

Transcriptome analysis revealed immune responses in the kidney of Atlantic salmon (Salmo salar) co-infected with sea lice (Lepeophtheirus salmonis) and infectious salmon anemia virus.

Sea lice (Lepeophtheirus salmonis) and infectious salmon anemia virus (ISAv) are two of the most important pathogens in Atlantic salmon (Salmo salar) farming and typically cause substantial economic losses to the industry. However, the immune interactions between hosts and these pathogens are still unclear, especially in the scenario of co-infection. In this study, we artificially infected Atlantic salmon with sea lice and ISAv, and investigated the gene expression patterns of Atlantic salmon head kidneys in response to both lice only and co-infection with lice and ISAv by transcriptomic analysis. The challenge experiment indicated that co-infection resulted in a cumulative mortality rate of 47.8 %, while no mortality was observed in the lice alone infection. We identified 240 differentially expressed genes (DEGs) under the lice alone infection, of which 185 were down-regulated and 55 were up-regulated, while a total of 994 DEGs were identified in the co-infection, of which 206 were down-regulated and 788 were significantly up-regulated. The pathway enrichment analysis revealed that single-infection significantly suppressed the innate immune system (e.g., the complement system), whereas co-infection induced a strong immune response, leading to the activation of immune-related signaling pathways such as Toll-like receptors and NOD-like receptors pathways, as well as significant upregulation of genes related to the activation of interferon and MH class I protein complex. Our results provide the first global transcriptomic study of gene expression in the Atlantic salmon head kidney in response to co-infection with sea lice and ISAv, and provided the baseline knowledge for understanding the immune responses during co-infection.

A Case-Control Study on Factors of HPV Vaccination for Mother and Daughter in China.

(1) Background: To explore the influencing factors of human papillomavirus (HPV) vaccination among mothers and daughters so as to provide evidence and strategies for improving the HPV vaccination rate of 9-18-years-old girls. (2) A questionnaire survey was conducted among the mothers of 9-18-year-old girls from June to August 2022. The participants were divided into the mother and daughter vaccinated group (M1D1), the mother-only vaccinated group (M1D0), and the unvaccinated group (M0D0). Univariate tests, the logistic regression model, and the Health Belief Model (HBM) were employed to explore the influencing factors. (3) Results: A total of 3004 valid questionnaires were collected. According to the regions, Totally 102, 204, and 408 mothers and daughters were selected from the M1D1, M1D0, and M0D0 groups, respectively. The mother having given her daughter sex education (OR = 3.64; 95%CI 1.70, 7.80), the mother's high perception of disease severity (OR = 1.79; 95%CI 1.02, 3.17), and the mother's high level of trust in formal information (OR = 2.18; 95%CI 1.26, 3.78) were all protective factors for both the mother and her daughter's vaccination. The mother's rural residence (OR = 0.51; 95%CI 0.28, 0.92) was a risk factor for vaccination of both mother and daughter. The mother's education of high school or above (OR = 2.12; 95%CI 1.06, 4.22), the mother's high level of HPV and HPV vaccine knowledge (OR = 1.72; 95%CI 1.14, 2.58), and the mother's high level of trust in formal information (OR = 1.72; 95%CI 1.15, 2.57) were protective factors of mother-only vaccination. The older the mother (OR = 0.95; 95%CI 0.91, 0.99) was classed as a risk factor for mother-only vaccination. "Waiting until the daughters are older to receive the 9-valent vaccine" is the main reason why the daughters of M1D0 and M0D0 are not vaccinated". (4) Chinese mothers had a high willingness to vaccinate their daughters with the HPV vaccine. The higher education level of the mother, giving sex education to the daughter, the older ages of mothers and daughters, the mother's high level of HPV and HPV vaccine knowledge, a high level of perception of the disease severity, and a high level of trust in formal information were promoting factors of HPV vaccination for mother and daughter, and rural residence was a risk factor to vaccination. To promote HPV vaccination in girls from 9-18 years old, communities could provide health education to rural mothers with low education levels; the government could advocate for HPV vaccination through issuing policy documents; and doctors and the CDC could popularize the optimal age for HPV vaccination to encourage mothers to vaccinate their daughters at the age of 9-14 years old.

The clinical relevance and prediction efficacy from therapy of tumor microenvironment related signature score in colorectal cancer.

Introduction: As the top 3 cancer in terms of incidence and mortality, the first-line treatment for CRC includes FOLFOX, FOLFIRI, Cetuximab or immunotherapy. However, the drug sensitivity of patients to regimens is different. There has been increasing evidence that immune components of TME can affect the sensitivity of patients to drugs. Therefore, it is necessary to define novo molecular subtypes of CRC based on TME immune components, and screen patients who are sensitive to the treatments, to make personalized therapy possible. Methods: We analyzed the expression profiles and 197 TME-related signatures of 1775 patients using ssGSEA, univariate Cox proportional risk model and LASSO-Cox regression model, and defined a novo molecular subtype (TMERSS) of CRC. Simultaneously, we compared the clinicopathological factors, antitumor immune activity, immune cell abundance and differences of cell states in different TMERSS subtypes. In addition, patients sensitive to the therapy were screened out by correlation analysis between TMERSS subtypes and drug responses. Results: Compared with low TMERSS subtype, high TMERSS subtype has a better outcome, which may be associated to higher abundance of antitumor immune cell in high TMERSS subtype. Our findings suggested that the high TMERSS subtype may have a higher proportion of respondents to Cetuximab agent and immunotherapy, while the low TMERSS subtype may be more suitable for treatment with FOLFOX and FOLFIRI regimens. Discussion: In conclusion, the TMERSS model may provide a partial reference for the prognosis evaluation of patients, the prediction of drug sensitivity, and the implementation of clinical decision-making.

Identification of a prognostic risk-scoring model and risk signatures based on glycosylation-associated cluster in breast cancer.

Breast cancer is a heterogeneous disease whose subtypes represent different histological origins, prognoses, and therapeutic sensitivity. But there remains a strong need for more specific biomarkers and broader alternatives for personalized treatment. Our study classified breast cancer samples from The Cancer Genome Atlas (TCGA) into three groups based on glycosylation-associated genes and then identified differentially expressed genes under different glycosylation patterns to construct a prognostic model. The final prognostic model containing 23 key molecules achieved exciting performance both in the TCGA training set and testing set GSE42568 and GSE58812. The risk score also showed a significant difference in predicting overall clinical survival and immune infiltration analysis. This work helped us to understand the heterogeneity of breast cancer from another perspective and indicated that the identification of risk scores based on glycosylation patterns has potential clinical implications and immune-related value for breast cancer.

Malignant granular cell tumor in the thoracic wall: A case report.

Granulosa cell tumor (GCT) is a rare tumor that originates from neural/Schwann cells. GCTs can occur at any age and at any site in the body. The most common site is the tongue, followed by the mammary gland, upper respiratory tract ( throat and bronchus), and gastrointestinal tract (esophagus, large intestine and perianal area, stomach, small intestine, and bile duct). Malignant GCTs account for less than 1%-2% of all GCTs. Fewer than five GCTs in the thoracic wall have been reported, almost all of these benign. Here, we report a new case of malignant GCT of the thoracic wall, with rib invasion and pleural metastasis, in an Asian male. Microscopic examination revealed round, granular cells with eosinophilic cytoplasm and without prominent atypia. Despite these findings the disease showed rapid clinical progression. In summary, the tumor, although histologically 'benign', was clinically 'malignant'.

Distributed model-free formation control of networked fully-actuated autonomous surface vehicles.

This paper presents a distributed constant bearing guidance and model-free disturbance rejection control method for formation tracking of autonomous surface vehicles subject to fully unknown kinetic model. First, a distributed constant bearing guidance law is designed at the kinematic level to achieve a consensus task. Then, by using an adaptive extended state observer (AESO) to estimate the total uncertainties and unknown input coefficients, a simplified model-free kinetic controller is designed based on a dynamic surface control (DSC) design. It is proven that the closed-loop system is input-to-state stable The stability of the closed-loop system is established. A salient feature of the proposed method is that a cooperative behavior can be achieved without knowing any priori information. An application to formation control of autonomous surface vehicles is given to show the efficacy of the proposed integrated distributed constant bearing guidance and model-free disturbance rejection control.

Jiedutongluotiaogan formula restores pancreatic function by suppressing excessive autophagy and endoplasmic reticulum stress.

CONTEXT: Jiedutongluotiaogan formula (JTTF), a traditional Chinese medicine (TCM), could promote islet function. However, the potential effect of JTTF on endoplasmic reticulum stress (ERS) and autophagy have not been reported. OBJECTIVE: This study explores the potential effect of JTTF on ERS and autophagy in the pancreas. MATERIALS AND METHODS: The Zucker diabetic fatty (ZDF) rats were randomised into five groups, control, model, JTTF (1, 3, 5 g/kg/day for 12 weeks). LPS induced pancreatic ß-cells were treated with JTTF (50, 100, 200 µg/mL). LPS was used to induce pancreatic ß-cell injury, with cell viability and insulin secretion evaluated using MTT, glucose-stimulated insulin secretion (GSIS) assays, and PCR. Intracellular Ca2+ concentration was measured using flow cytometry, while ERS and autophagy levels were monitored via Western blotting and/or immunostaining. RESULTS: Compared with the model group, body weight, FGB, HbA1c, IPGTT, FINs, and HOMA-IR in JTTF treatment groups were significantly reduced. In islets cells treated with JTTF, the pancreatic islet cells in the JTTF group were increased, lipid droplets were reduced, and there was a decrease in Ca2+ (16.67%). After JTTF intervention, PERK, p-PERK, IRE1α, p- IRE1α, ATF6, eIF2α, GRP78, p-ULK1, LC3 and p62 expression decreased, whereas Beclin1and p-mTOR expression increased. In addition, the expression of proteins related to apoptosis in the JTTF groups were lower than those in the control group. DISCUSSION AND CONCLUSIONS: JTTF may alleviate pancreatic ß-cell injury by inhibiting ER stress and excessive autophagy in diabetic rats. This provides a new direction for treating diabetes and restoring pancreatic dysfunction by TCM.

Effects of dietary lysolecithin on growth performance, serum biochemical indexes, antioxidant capacity, lipid metabolism and inflammation-related genes expression of juvenile large yellow croaker (Larimichthys crocea).

A 70-day feeding trial was conducted to investigate effects of dietary lysolecithin on growth performance, serum biochemical indexes, antioxidant capacity, lipid metabolism and inflammation-related genes expression of juvenile large yellow croaker (Larimichthys crocea) with initial weight of 6.04 ± 0.08 g. A formulated diet containing approximately 42% crude protein and 12.5% crude lipid was used as the control diet (CON). The other three experimental diets were formulated with supplementation of 0.2%, 0.4% and 0.6% lysolecithin based on the control diet, respectively. Results showed that weight gain rate (WGR) and specific growth rate (SGR) significantly increased in fish fed diets with lysolecithin compared with those in the control diet (P < 0.05). Fish fed diets with 0.4% and 0.6% lysolecithin had notably higher lipid content in muscle than that in the control diet (P < 0.05). When fish were fed diets with lysolecithin, serum high-density lipoprotein cholesterol (HDL-c) content was notably higher than that in the control diet (P < 0.05), while fish fed the diet with 0.6% lysolecithin had a significant lower serum low-density lipoprotein cholesterol (LDL-c) content than that in the control diet (P < 0.05). Meanwhile, serum aspartate transaminase (AST) and alanine transaminase (ALT) activities in fish fed diets with lysolecithin were remarkably lower than those in the control diet (P < 0.05). With the increase of dietary lysolecithin from 0.2% to 0.6%, mRNA expression of stearoyl-coenzyme A desaturase 1 (scd1), diacylglycerol acyltransferase 2 (dgat2) and sterol-regulatory element binding protein 1 (srebp1) showed decreasing trends. Furthermore, mRNA expression of carnitine palmitoyl transferase 1 (cpt1) and lipoprotein lipase (lpl) among each dietary lysolecithin treatment were significantly higher than those in the control diet (P < 0.05). In terms of inflammation, mRNA expression of tumor necrosis factor α (tnf-α) and interleukin-1 ß (il-1ß) were significantly down-regulated in fish fed diets with lysolecithin compared with those in the control diet (P < 0.05), while the mRNA expression of interleukin-10 (il-10) was significantly higher than that in the control diet (P < 0.05). In conclusion, dietary lysolecithin could promote the growth performance, improve hepatic lipid metabolism and regulate inflammation response in juvenile large yellow croaker, and the optimal supplement level of lysolecithin was approximately 0.4% in this study.

Data-driven model-free resilient speed control of an autonomous surface vehicle in the presence of actuator anomalies.

This paper is concerned with the resilient speed control of an autonomous surface vehicle (ASV) in the presence of actuator anomalies. A data-driven model-free resilient speed control method is presented based on available input and output data only with pulse-width-modulation inputs. Specifically, a data-driven neural predictor is designed to learn the unknown system dynamics of the speed control system of the ASV. Then, a resilient speed control law is designed based on the learned dynamics obtained from the neural network predictor, where a cost function is designed for selecting the optimal duty cycle for the motor. The stability of the data-driven neural predictor is analyzed by using input-state stability (ISS) theory. The advantage of the developed data-driven model-free resilient control method is that the optimal speed control performance can be achieved in the presence of actuator anomalies without any modeling process. Simulation results show the learning ability of the data-driven neural predictor and the effectiveness of the proposed data-driven model-free resilient speed control method for the ASV subject to actuator anomalies.

Docosahexaenoic Acid Alleviates Palmitic Acid-Induced Inflammation of Macrophages via TLR22-MAPK-PPARγ/Nrf2 Pathway in Large Yellow Croaker (Larimichthys crocea).

Palmitic acid (PA) is a saturated fatty acid (SFA) that can cause an inflammatory response, while docosahexaenoic acid (DHA) is always used as a nutritional modulator due to its anti-inflammatory properties. However, the potential molecular mechanism is still not completely elucidated in fish. Herein, the PA treatment induced an inflammatory response in macrophages of large yellow croaker (Larimichthys crocea). Meanwhile, the mRNA expression of Toll-like receptor (TLR)-related genes, especially tlr22, and the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway were significantly upregulated by PA. Further investigation found that the PA-induced inflammatory response was suppressed by tlr22 knockdown and MAPK inhibitors. Moreover, the results of the peroxisome proliferator-activated receptor γ (PPARγ) agonist and inhibitor treatment proved that PPARγ was involved in the PA-induced inflammation. PA treatment decreased the protein expression of PPARγ, while tlr22 knockdown and MAPK inhibitors recovered the decreased expression. Besides, the PA-induced activation of Nrf2 was regulated by p38 MAPK. Furthermore, DHA-executed anti-inflammatory effects by regulating the phosphorylation of the MAPK pathway and expressions of PPARγ and Nrf2. Overall, the present study revealed that DHA alleviated PA-induced inflammation in macrophages via the TLR22-MAPK-PPARγ/Nrf2 pathway. These results could advance the understanding of the molecular mechanism of the SFA-induced inflammatory response and provide nutritional mitigative strategies.

Interleukin-22 attenuates allergic airway inflammation in ovalbumin-induced asthma mouse model.

BACKGROUND: Allergic asthma is a chronic airway inflammatory disease with a number of cytokines participating in its pathogenesis and progress. Interleukin (IL)-22, which is derived from lymphocytes, acts on epithelial cells and play a role in the chronic airway inflammation. However, the actual role of IL-22 in allergic asthma is still unclear. Therefore, we explored the effect of IL-22 on allergic airway inflammation and airway hyperresponsiveness (AHR) in an ovalbumin (OVA)-induced asthma mouse model. METHODS: To evaluate the effect of IL-22 in an allergic asthma model, BALB/c mice were sensitized and challenged with OVA; then the recombinant mouse IL-22 was administered intranasally 24 h prior to each challenge. The IL-22 levels in lung homogenates and bronchoalveolar lavage fluid (BALF) were measured by enzyme linked immunosorbent assay, respectively. AHR was evaluated through indicators including airways resistance (Rrs), elastance (Ers) and compliance (Crs); the inflammatory cell infiltration was assessed by quantification of differential cells counts in BALF and lung tissues stained by hematoxylin and eosin (H&E); IL-22 specific receptors were determined by immunohistochemistry staining. RESULTS: The concentration of IL-22 was significantly elevated in the OVA-induced mice compared with the control mice in lung homogenates and BALF. In the OVA-induced mouse model, IL-22 administration could significantly attenuate AHR, including Rrs, Ers and Crs, decrease the proportion of eosinophils in BALF and reduce inflammatory cell infiltration around bronchi and their concomitant vessels, compared with the OVA-induced group. In addition, the expression of IL-22RA1 and IL-10RB in the lung tissues of OVA-induced mice was significantly increased compared with the control mice, while it was dramatically decreased after the treatment with IL-22, but not completely attenuated in the IL-22-treated mice when compared with the control mice. CONCLUSION: Interleukin-22 could play a protective role in an OVA-induced asthma model, by suppressing the inflammatory cell infiltration around bronchi and their concomitant vessels and airway hyperresponsiveness, which might associate with the expression of its heterodimer receptors. Thus, IL-22 administration might be an effective strategy to attenuate allergic airway inflammation.

Decoding the chemical composition and pharmacological mechanisms of Jiedu Tongluo Tiaogan Formula using high-performance liquid chromatography coupled with network pharmacology-based investigation.

Type 2 diabetes mellitus (T2DM), a chronic low-grade inflammatory disease with high morbidity and mortality, is a serious threat to public health. Previously we demonstrated that a traditional Chinese medicine formulation, Jiedu Tongluo Tiaogan Formula (JDTL), exerted a favorable hypoglycemic effect due to unknown molecular mechanisms involving interactions among JDTL compounds and various cellular components. This study aimed to explore JDTL mechanisms for alleviating hyperglycemia using an integrated strategy incorporating system pharmacology, bioinformatics analysis, and experimental verification. This strategy entailed initial elucidation of JDTL chemical composition using fingerprint analysis via high performance liquid chromatography (HPLC). Next, functions of putative shared target genes and associated pathways were deduced using GO and KEGG pathway enrichment and molecular docking analyses. Ultimately, targets associated with JTDL anti-T2DM effects were found to be functionally associated with biological functions related to lipopolysaccharide and cytokine receptor binding. These results implicated PI3K-Akt signaling pathway involvement in JDTL anti-T2DM effects, as this pathway had been previously shown to play significant roles in glucose and lipid metabolism-related diseases. Furthermore, addition of JDTL to INS-1 and HepG2 cell cultures stimulated cellular mRNA-level and protein-level expression leading to enhanced production of IRS1, Akt, and PI3K. In summary, here JDTL bioactive ingredients, potential targets, and molecular mechanisms underlying JDTL anti-T2DM effects were identified using a multi-component, multi-target, and multi-channel analytical approach, thus providing an important scientific foundation to facilitate development of new drugs mechanistic strategies for preventing and treating T2DM.

Variability of Type 2 inflammatory markers guiding biologic therapy of severe asthma: A 5-year retrospective study from a single tertiary hospital.

BACKGROUND: Currently, biotherapy is mainly administered to treat patients with severe asthma with the Type 2 (T2) inflammation phenotype. The variability of T2 inflammatory markers remains poorly understood. OBJECTIVE: We aimed to describe the individual distributions of different biomarkers at varying thresholds and their variation patterns in participants with severe asthma. METHODS: We retrospectively reviewed the data of participants who had completed 2 or more fraction of exhaled nitric oxide (FeNO) and peripheral blood eosinophil counts in our centre within 5 years. The individual distribution of biomarkers (blood or sputum eosinophils, FeNO, and serum total IgE) with repeated measurements at different thresholds was analysed. The varied patterns of biomarkers were analysed by cluster analysis. RESULTS: A total of 241 eligible participants were screened. Through long-term longitudinal multiple measurements, we found that approximately 50% of severe asthmatics had blood eosinophil levels fluctuating around the threshold defined by biological agents. FeNO persisted at levels >19.5 ppb or 25 ppb in more than half of patients; about 30% of participants crossed this threshold. In our centre, 47.4% of participants consistently exceeded sputum eosinophils >3%, and 47.4% of patients crossed this threshold. Approximately 66.7% of participants had more than 50% alterations of serum total IgE, and 98.1% of participants continued to have IgE levels greater than 30 IU/mL. We used cluster analysis to classify variability and levels of FeNO and blood eosinophils and identified 4 patient clusters. Cluster 1 can be summarised as T2 severe asthma with low blood eosinophil levels and stability. Cluster 2 can be summarised as asthma with continuous increase and small fluctuations in various T2 inflammatory markers. Cluster 3 can be summarised as a non/low-T2 inflammatory phenotype. Cluster 4 can be summarised as a stable, moderate T2 inflammatory phenotype. CONCLUSION: We identified the distributions and variable patterns of the T2 inflammatory markers currently used to guide asthma biotherapy in clinical practice. The longitudinal comprehensive multiple assessments of T2 inflammatory markers provide support for initiating biologic therapy patients with severe asthma whose biomarker levels vary.

Cytokine antibody array-based analysis of IL-37 treatment effects in asthma.

Asthma is driven by group 2 innate lymphoid cells, antigen-specific CD4+ T helper type 2 cells and their cytokines such as interleukin (IL)-4, IL-5, IL-13. IL-37 is decreased in asthma and negatively related to Th2 cytokines and other pro-inflammatory cytokines. Our study showed that IL-37 level in asthmatic peripheral blood mononuclear cells was lower than in healthy. Further, IL-37 was negatively correlated with exhaled nitric oxide, asthma control test score, atopy and rhinitis history in asthmatics. Then an OVA-induced asthma mice model treated with rhIL-37 was established. An antibody array was employed to uncover altered cytokines induced by IL-37 in mice lung tissue. 20 proteins differentially expressed after rhIL-37 treatment and five of them were validated in asthmatic peripheral blood mononuclear cells. Consistent with cytokine antibody array, CCL3, CCL4, CCL5 decreased after IL-37 administration. While CXCL9 and CXCL13 were no change. We concluded that IL-37 reduce asthmatic symptoms by inhibit pro-inflammatory cytokine such as CCL3, CCL4, CCL5.

High Fat Activates O-GlcNAcylation and Affects AMPK/ACC Pathway to Regulate Lipid Metabolism.

A high-fat diet often leads to excessive fat deposition and adversely affects the organism. However, the mechanism of liver fat deposition induced by high fat is still unclear. Therefore, this study aimed at acetyl-CoA carboxylase (ACC) to explore the mechanism of excessive liver deposition induced by high fat. In the present study, the ORF of ACC1 and ACC2 were cloned and characterized. Meanwhile, the mRNA and protein of ACC1 and ACC2 were increased in liver fed with a high-fat diet (HFD) or in hepatocytes incubated with oleic acid (OA). The phosphorylation of ACC was also decreased in hepatocytes incubated with OA. Moreover, AICAR dramatically improved the phosphorylation of ACC, and OA significantly inhibited the phosphorylation of the AMPK/ACC pathway. Further experiments showed that OA increased global O-GlcNAcylation and agonist of O-GlcNAcylation significantly inhibited the phosphorylation of AMPK and ACC. Importantly, the disorder of lipid metabolism caused by HFD or OA could be rescued by treating CP-640186, the dual inhibitor of ACC1 and ACC2. These observations suggested that high fat may activate O-GlcNAcylation and affect the AMPK/ACC pathway to regulate lipid synthesis, and also emphasized the importance of the role of ACC in lipid homeostasis.

Real-world Effectiveness of Mepolizumab in Severe Eosinophilic Asthma: A Systematic Review and Meta-analysis.

PURPOSE: Mepolizumab is a human monoclonal antibody against interleukin 5 (IL-5) used to treat severe eosinophilic asthma. Several studies have evaluated the effectiveness of mepolizumab in the real world. We conducted a systematic review and meta-analysis in the context of heterogeneity among patients, clinicians, and treatment regimens to study the effectiveness of mepolizumab in the real world. METHODS: We searched the PubMed and Embase databases for real-world studies on severe asthma treatment with mepolizumab as of June 30, 2020. Exacerbations, asthma-related hospitalizations, forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire (ACQ) or Asthma Control Test (ACT), corticosteroid use, peripheral blood eosinophil counts, and the fraction of exhaled nitric oxide were selected as indicators to evaluate the effectiveness. Standardized mean differences by the Cohen method and mean differences were chosen as indicators of effect size. Cohen d values of 0.2, 0.5, and 0.8 are considered as small, medium, and large effects, respectively. We used the Dersimonian-Laird random-effect model to quantify pooled effectiveness estimates. FINDINGS: A total of 1457 patients from 13 studies were included in this review. At all time points, mepolizumab was associated with reductions in exacerbations (2.92 and 2.73 events per patient per year fewer at 6 and 12 months, respectively) and hospitalizations (0.36 events per patient per year fewer at 12 months); improvements in asthma control (ACQ scores reductions of 1.32 and 1.03 at 6 and 12 months, respectively; ACT scores increase of 6.52 at 6-12 months); slight improvements in pulmonary function (FEV1 increase of 0.23 L at 1-3 months and 6-12 months, respectively); reductions in oral corticosteroid use (9.02- and 7.68-mg decrease at 6 and 12 months, respectively); and reductions in peripheral blood eosinophil counts (decreases of 559.11 cells/µL and 599.17 cells/µL at 1-3 months and 6-12 months, respectively) and fraction of exhaled nitric oxide (13-ppb reduction at 6-12 months). IMPLICATIONS: Our study suggests that mepolizumab is associated with improvements in several clinically meaningful real-world outcomes. This study is a supplement to and extension of the efficacy of randomized controlled trials of mepolizumab.

Early Life Intervention Using Probiotic Clostridium butyricum Improves Intestinal Development, Immune Response, and Gut Microbiota in Large Yellow Croaker (Larimichthys crocea) Larvae.

Marine fish larvae are vulnerable during the early life period. The early intervention using probiotics may be a promising method to improve growth of fish larvae. In this study, a 30-day feeding trial was conducted to evaluate the effects of early life intervention using probiotic Clostridium butyricum (CB) on growth performance, intestinal development, immune response and gut microbiota of large yellow croaker (Larimichthys crocea) larvae. Four isonitrogenous and isolipidic diets were formulated with the supplementation of four different levels of CB (5 × 109 CFU g-1), 0.00% (Control), 0.10% (CB1), 0.20% (CB2), and 0.40% (CB3). Results showed that larvae fed diets with CB had significant higher final length than the control group. Meanwhile, larvae fed the diet with 0.10% CB had significant higher final weight and specific growth rate (SGR) than the control group. However, no significant difference in survival rate was observed among dietary treatments. CB supplementation significantly increased the height of intestinal villus and the length of intestinal enterocyte. Similarly, CB supplementation significantly increased the expression of tight zonula occludens-2 (zo-2) and ornithine decarboxylase (odc) than the control group. Larvae fed the diet with 0.20% CB had significant higher lipase and leucine-aminopeptidase (LAP) activity than the control group. Moreover, CB supplementation significantly improved immune enzyme activities than the control group. Sequencing of bacterial 16S rRNA V4-5 region indicated that dietary CB altered intestinal microbiota profile and decreased intestinal microbial diversities of larvae. CB supplementation could effectively increase the abundance of CB, and decrease the abundance of some potential pathogenic bacteria in larval gut. These results revealed that early life intervention using 0.10-0.20% CB could promote growth of large yellow croaker larvae probably through promoting intestinal development, improving immune enzyme activities and modulating gut microbiota.