SHP-1 Regulates CD8+ T Cell Effector Function but Plays a Subtle Role with SHP-2 in T Cell Exhaustion Due to a Stage-Specific Nonredundant Functional Relay.

SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.

Incidence and severity of SARS-CoV-2 reinfection, a multicenter cohort study in Shanghai, China.

During March 2022 to January 2023, two Omicron waves hit Shanghai and caused a massive number of reinfections. To better understand the incidence and clinical characteristics of SARS-CoV-2 reinfection in Shanghai, China, we conducted a multicenter cohort study. COVID-19 patients first infected with BA.2 (March 1, 2022-May 23, 2022) who were quarantined in Huashan Hospital, Renji Hospital, and Shanghai Jing'an Central Hospital were followed up for reinfection from June 1, 2022 to January 31, 2023. Of 897 primary infections, 148 (16.5%) experienced reinfection. Incidence rate of reinfection was 0.66 cases per 1000 person-days. Female gender (adjusted odds ratio [aOR]= 2.19, 95% confidence interval [CI]: 1.29-3.83) was a risk factor for reinfection. The four most common symptoms of reinfections during the circulation of BA.5 sublineages were cough (62.59%), sore throat (54.42%), fatigue (48.98%), and fever (42.57%). Having received a booster vaccination was not associated with reduced severity of reinfection in comparison with not having received booster vaccination. After matched 1:1 by age and sex, we found that reinfections with BA.5 sublineages had significantly lower occurrence and severity of fever, fatigue, sore throat, and cough, as compared to primary infections with BA.5 sublineages. SARS-CoV-2 Omicron reinfections were less severe than Omicron primary infections during the circulation of the same subvariant. Protection offered by both vaccination and previous infection was poor against SARS-CoV-2 reinfection.

Effects of exergaming on cognitive functions and loneliness of older adults with cognitive frailty.

OBJECTIVES: Cognitive frailty combines physical frailty and cognitive impairment in the absence of dementia. The prompt detection of cognitive frailty and early implementation of preventive interventions may reduce the incidence of dementia. However, intervention studies of exergaming in older adults with cognitive frailty are scant. Therefore, we aim to investigate the effectiveness of exergaming on cognitive functions and loneliness among older adults with cognitive frailty. DESIGN: Quasi-experimental design. METHODS: Participants were recruited from four community settings. The experimental group participated in two 40-min group exergaming sessions weekly for eight weeks; the control group received usual care. The outcome measures were the Montreal Cognitive Assessment (MoCA) and the Chinese Version of the Loneliness Scale. Analyses of covariance were conducted to analyze whether exergaming influenced participants' cognitive functions and loneliness. In addition, the effect size of the posttest of the experimental group relative to its baseline value was calculated to determine the effectiveness of the intervention. RESULT: 69 older adults with cognitive frailty were included, and 35 and 34 were assigned to the experimental and control groups, respectively. The exergaming effectively improved the cognitive function of older adults with cognitive frailty. CONCLUSIONS: Exergaming interventions can effectively improve the cognitive functions of older adults with cognitive frailty but do not positively affect loneliness. We provide evidence to healthcare workers to apply exergaming interventions for older adults with cognitive frailty to improve cognitive function.

A Chitosan-Based Flocculation Method for Efficient Recovery of High-Purity B-Phycoerythrin from a Low Concentration of Phycobilin in Wastewater.

Increasing the yield and purity of B-phycoerythrin (B-PE) can improve the economic state of microalgae industrial processing. One method of cost reduction involves the recovery of remaining B-PE from wastewater. In this study, we developed a chitosan (CS)-based flocculation technique for the efficient recovery of B-PE from a low concentration of phycobilin in wastewater. We investigated the effects of the molecular weight of chitosan, B-PE/CS mass ratio, and solution pH on the flocculation efficiency of CS and the effects of phosphate buffer concentration and pH on the recovery rate of B-PE. The maximum flocculation efficiency of CS, recovery rate, and purity index of B-PE were 97.19% ± 0.59%, 72.07% ± 1.37%, and 3.20 ± 0.025 (drug grade), respectively. The structural stability and activity of B-PE were maintained during the recovery process. Economic evaluation revealed that our CS-based flocculation method is more economical than the ammonium sulfate precipitation method is. Furthermore, the bridging effect and electrostatic interaction play important roles in B-PE/CS complex flocculation process. Hence, our study provides an efficient and economical method to recover high-purity B-PE from a low concentration of phycobilin in wastewater, which promoted the application of B-PE as a natural pigment protein in food and chemical applications.

Fucoxanthin Inactivates the PI3K/Akt Signaling Pathway to Mediate Malignant Biological Behaviors of Non-Small Cell Lung Cancer.

Although lung cancer treatment strategies have improved in recent years, the 5-year overall survival of non-small cell lung cancer (NSCLC) remains less than 15%. Chemotherapy is considered the most promising option in the comprehensive treatment of NSCLC. Fucoxanthin (FX) is a natural product derived from brown algae and has extensive applications in medicine. Previous studies reported that FX effectively inhibits the growth of NSCLC cells in vitro and in vivo. However, the mechanism underlying the anti-NSCLC effect of FX remains unknown. In this study, NSCLC cell lines and a xenograft nude mouse model were used to examine the anti-NSCLC activities of FX in vitro and in vivo. Network pharmacology analysis and inhibitors or activators of the PI3K/Akt signaling pathway were used to explore the anti-NSCLC mechanisms of FX. The results indicated that FX could inhibit proliferation, migration, and invasion, arrest cell cycle at the G0/G1 phase, and induce apoptosis of NSCLC cells in vitro. Additionally, FX suppressed tumor growth in vivo. The PI3K/Akt signaling pathway was found to be involved in the anti-NSCLC activity of FX. In conclusion, FX inhibits malignant biological behaviors of NSCLC by suppressing the phosphorylation of both PI3K and AKT, and subsequently inactivating PI3K/AKT signaling pathway.

Eliciting positive emotion through strategic responses to COVID-19 crisis: Evidence from the tourism sector.

While social media are effective means of communicating with adverse customer emotions during a crisis, it remains unclear how tourism organisations can respond to pandemic crisis on social media to prevent negative aftermaths. Using a set-theoretical approach, we investigate how COVID-19 response strategies and linguistic cues of responses are intertwined to evoke positive emotions among consumers. This study entails a qualitative content analysis of tourism organisations' COVID-19 announcements and a social media analytics approach that captures consumers' emotional reactions to these announcements via their Twitter replies. Our results extend some well-established findings in the tourism crisis literature by suggesting that combining innovative response strategy, argument quality, and assertive language can reinforce positive emotions during the COVID-19 crisis. Taking organisational characteristics into consideration, we suggest that young established hotels utilise innovative response strategies, whereas retrenchment response strategies for all types of restaurants should be avoided during the COVID-19 crisis.

Interleukin-16 aggravates ovalbumin-induced allergic inflammation by enhancing Th2 and Th17 cytokine production in a mouse model.

Asthma is a chronic inflammatory disease that involves a variety of cytokines and cells. Interleukin-16 (IL-16) is highly expressed during allergic airway inflammation and is involved in its development. However, its specific mechanism of action remains unclear. In the present study, we used an animal model of ovalbumin (OVA)-induced allergic asthma with mice harboring an IL-16 gene deletion to investigate the role of this cytokine in asthma, in addition to its underlying mechanism. Increased IL-16 expression was observed during OVA-induced asthma in C57BL/6J mice. However, when OVA was used to induce asthma in IL-16-/- mice, a diminished inflammatory reaction, decreased bronchoalveolar lavage fluid (BALF) eosinophil numbers, and the suppression of OVA-specific IgE levels in the serum and BALF were observed. The results also demonstrated decreased levels of T helper type 2 (Th2) and Th17 cytokines upon OVA-induced asthma in IL-16-/- mice. Hence, we confirmed that IL-16 enhances the lung allergic inflammatory response and suggest a mechanism possibly associated with the up-regulation of IgE and the promotion of Th2 and Th17 cytokine production. This work explored the mechanism underlying the regulation of IL-16 in asthma and provides a new target for the clinical treatment of asthma.

Deoxyshikonin isolated from Arnebia euchroma inhibits colorectal cancer by down-regulating the PI3K/Akt/mTOR pathway.

Context: Shikonins, a series of natural occurring naphthoquinones extracted from Arnebia euchroma (Royle) Jonst. (Boraginaceae), have antitumor activities and low toxicity. Objective: To illuminate potential activity and mechanism of shikonins against colorectal cancer (CRC). Materials and methods: Five shikonins were isolated from A. euchroma, and elucidated by extensive spectroscopic analysis. Anti-proliferative activities of shikonins (0-100 µg/mL) on human colorectal cells were evaluated by MTT and CCK-8 for 24 or 48 h. Cell apoptosis and cycle distribution were examined by FCM analysis. The expression of PI3K/Akt/mTOR pathway mRNAs and proteins was analysed by RT-PCR and Western blot, respectively. Cell viability, cell apoptosis, cell cycle and protein expression were measured, when co-treated with PI3K/Akt/mTOR pathway inhibitors. The in vivo activity of deoxyshikonin was evaluated using xenograft tumour model. Results: Deoxyshikonin and another four shikonins were isolated and identified. Deoxyshikonin exhibited anti-proliferative activity with IC50 of 10.97 µM against HT29 cells. Moreover, the percentage of early apoptotic cells and G0/G1 cells increased from 1 to 29% and 44 to 67% with 0-50 µg/mL deoxyshikonin, respectively. Deoxyshikonin also down-regulated the expression of PI3K, p-PI3K, Akt, p-Akt308 and mTOR proteins in HT29 and DLD-1 cells. Moreover, LY294002, NVP-BEZ235 and MK-2206 can make deoxyshikonin more cell proliferation inhibited, cell cycle arrested at G0/G1 and apoptosis promoted. In vivo study, the weight of tumour tissues at deoxyshikonin groups was significantly reduced compared with the control group, and PI3K, p-PI3K, Akt, p-Akt308 and mTOR expression was decreased. Discussion and conclusions: We can conclude that deoxyshikonin isolated from Arnebia euchroma inhibited CRC through the PI3K/Akt/mTOR pathway.

[Effect of Shaoyao Tang on ulcerative colitis in rats via regulation of TLR4/NF-κB signal pathway].

The aim of this paper was to investigate the effect of Shaoyao Tang on ulcerative colitis(UC) in rats via regulation of TLR4/NF-κB signal pathway. A total of 56 Wistar rats were randomly divided into 6 groups: normal control group(double distilled water), model group(double distilled water), mesalazine group(10 mL·kg~(-1)), high dose, middle dose and low dose Shaoyao Tang groups(2.4, 1.2, and 0.6 g·mL~(-1)). After UC rat models were established by 2, 4-dinitrochlorobenzene(DNCB)/ethanol enema, the rats received double distilled water or corresponding drugs twice a day for 7 days. After the treatment cycle, the general performance and disease activity index(DAI) of rats were observed on the next day. Then the rats were sacrificed. The length of colon was measured. Macroscopic and histological score of colon were evaluated. Histopathological changes of colon were observed by HE staining. Ultraviolet spectrophotometry detection was used to detect the content of myeloperoxidase(MPO) in blood and colon tissues. The levels of P-selectin, macrophage migration inhibitory factor(MIF) and thromboxane B_2(TXB_2) in blood and colon tissues were determined by ELISA. Immunohistochemistry and Western blot analysis were performed to detect the protein expressions of TLR4 and NF-κB in colon tissues. The results showed that as compared with the model group, Shaoyao Tang of different doses improved the general performance of UC rats. Moreover, high-dose Shaoyao Tang group showed the most obvious effect in scoring of disease activity index(P<0.001); both medium and high doses of Shaoyao Tang significantly inhibited the colon shortening and pathological injury, with significantly decreased expression levels of MPO, P-selectin, MIF and TXB_(2 )in serum and colon tissues of UC rats(P<0.001). Immunohistochemistry and Western blot assay showed that the levels of TLR4 and NF-κB protein expression in the colon tissues of Shaoyao Tang high-dose group were remarkably lower than that in the model group(P<0.001). This study shows that Shaoyao Tang has protective and repairing effects on UC, and its possible mechanism is achieved probably by regulating the TLR4/NF-κB pathway and inhibiting the expressions of MPO, P-selectin, MIF and TXB_2.

[Study of isobutyrylshikonin inhibiting proliferation of colon carcinoma cells through PI3K/Akt/m-TOR pathway].

To investigate the inhibitory effect of isobutyrylshikonin on the growth of human colon carcinoma cells in vitro and its effect on the PI3K/Akt/m-TOR pathway. MTT assay was used to detect the inhibitory effect of different concentrations (0, 6.25, 12.5, 25, 50, 100 mg·L⁻¹) of isobutyrylshikonin on the proliferation of human colon carcinoma cell HT29 at 24, 48 h. CCK-8 method was used to detect the inhibitory effect of isobutyrylshikonin on HT29, HCT116, DLD-1 and Caco-2 at 48 h. AnnexinV/propidium iodide staining was applied in detecting the apoptoticrate of HT29 cells treated with different concentrations of isobutyrylshikonin at 24 h and 48 h. Cycletest plus DNA was employed to analyze HT29 apoptosis and cell cycle after 48 h treatment with isobutyrylshikonin at different concentrations. Western blot and RT-PCR assay were used to examine the protein and mRNA expressions of PI3K, p-PI3K, Akt, p-Akt and m-TOR. The results showed that isobutyrylshikonin inhibited the proliferation of different human colon carcinoma cells, and the inhibition rate was in a dose-dependent manner. Isobutyrylshikonin induced apoptosis mainly in the early stage and blocked cells in the G0/G1 or G2/M phase. Isobutyrylshikonin reduced the protein expressions of PI3K, p-PI3K, Akt, p-Akt, m-TOR and the mRNA expressions of PI3K, Akt, m-TOR in a dose-dependent manner. Isobutyrylshikonin can significantly inhibit the proliferation, induce the early apoptosis and change the cycle distribution in colon carcinoma cells.This biological effect may be correlated with the inhibition of PI3K/AKT/m-TOR pathway.

Disequilibrium in the CD8+CD28+/CD8+CD28- T Lymphocyte Balance Is Related to Prognosis in Rats with Trinitrobenzenesulfonic Acid-Induced Colitis.

PURPOSE: The CD8+CD28+/CD8+CD28- T lymphocyte balance is vital for human ulcerative colitis (UC) but has not been defined in experimental colitis. This investigation will try to identify the changes that occur in the CD8+CD28+/CD8+CD28- T lymphocyte balance during the progression of trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. METHODS: The frequencies of blood CD8+CD28+ and CD8+CD28- T lymphocytes were detected in the rats belonging to the normal, model, and treated groups on five days using flow cytometry. The treated rats were administered with mesalazine and were euthanized after a 14-day treatment, as were the normal and model rats. The sensitivity and specificity of the CD8+CD28+/CD8+CD28- T lymphocyte balance in diagnosing early colitis were analyzed by receiver operating characteristics (ROC) curves. The frequencies of CD8+CD28+ and CD8+CD28- T lymphocytes in the colon tissue were tested via immunofluorescence. ELISA was used to measure the levels of the cytokines. Immunohistochemistry and Western blotting were used to detect the colonic expression of JAK3, STAT6, NFATc2, and GATA3. RESULTS: We found that the ratio of CD8+CD28+/CD8+CD28- T lymphocytes decreased, as did the level of interleukin-7, but not IL-12p40, IL-13, or IL-15, in the blood; however, the ratio increased along with JAK3, STAT6, NFATc2, and GATA3 in the colon of the rats with colitis. The changes were effectively reversed through the administration of mesalazine for 13 days. Surprisingly, the balance in the blood could sensitively distinguish rats with early colitis from normal rats. CONCLUSION: These data show that increase in CD8+CD28+ T cells in blood and decrease in CD8+CD28- T cells in colon are associated with experimental colitis.

Ginsenoside Rh2 alleviates dextran sulfate sodium-induced colitis via augmenting TGFß signaling.

Ginsenoside Rh2 (GRh2) has been reported to have therapeutic effects on various diseases. However, whether it may also affect the recovery from ulcerative colitis remains unknown. Here we induced colitis in mice by dextran sulfate sodium (DSS) administration, and then treated the mice with GRh2. We found that GRh2-treated mice showed significant alleviation of the DSS-induced colitis. Moreover, significant increase in the activity of TGFß signaling was detected in the GRh2-treated colon that had received DSS. To investigate whether there is a causative link among GRh2 treatment, TGFß signaling augment and the cure of colitis, we gave the DSS-treated mice a combination of GRh2 and a specific TGFß receptor I inhibitor, SB431542. SB431542 significantly decreased the activation of TGFß signaling in the colon from the GRh2-administrated mice, and consequently attenuated the therapeutic effect of GRh2. Our data thus demonstrate that GRh2 may alleviate DSS-induced colitis via augmenting TGFß signaling.

Self-assembled gel microneedle formed by MS deep eutectic solvent as a transdermal delivery system for hyperpigmentation treatment.

Hyperpigmentation (HP) is an unfavorable skin disease that typically caused by injury, inflammation, or photoaging and leads to numerous physical and psychological issues in patients. Recently, development and application of natural whitening substances, particularly compound curcumin (CUR), is one of the most prevalent treatments for HP. However, it is still a formidable challenge to improve the percutaneous delivery of CUR due to its inadequate solubility in water and excellent barrier function of skin. To overcome the limitations of conventional delivery and increase the percutaneous absorption of CUR, the efficient delivery of CUR is urgently required. Herein, we developed a new malic acid-sorbitol deep eutectic solvent (MS/DES) gel microneedle loaded with CUR as a transdermal delivery system for HP treatment. The MS/DES gel produces three-dimensional (3D) network structure by self-assembly of hydrogen bond interactions, which conferred the CUR-MS/DES-GMN with sufficient mechanical properties to successfully penetrate skin tissue while also helping to enhance the drug's release rate. The CUR-MS/DES-GMN exhibit high biocompatibility and mechanical property in vivo of mice. The zebrafish experiments also show that CUR-MS/DES gel has significant effect of anti-pigmentation. Therefore, the designed CUR-MS/DES-GMN system provides a novel strategy for HP treatment based on self-assembly of naturally molecules.

Analysis of bone metabolic alterations linked with osteoporosis progression in type 2 diabetic db/db mice.

Type 2 diabetes (T2D) is a common chronic disease, characterized by persistent hyperglycemia and insulin resistance. This disorder is associated with decreased bone quality and an elevated risk of bone fractures. However, evidence on the relationship between systemic metabolic change and the development of type 2 diabetic osteoporosis (T2DOP) remains elusive. Herein, we investigate the changes of bone metabolites with bone loss in db/db mice (an animal model of T2DOP exhibited bone loss with age progression), and explore the potential metabolic mechanism underlying type 2 diabetes and osteoporosis. C57BKS male mice were distributed in four groups, consisting six mice in each group: 8w m/m, 24w m/m, 8w db/db and 24w db/db. Bone morphometric and biomechanical parameters of db/db mice were analyzed by micro-CT and materials tester, it was found that 24w db/db mice showed severe bone loss and decreased bone tissue hardness compared with misty/misty littermates. The tibia of misty/misty mice (8 weeks, 24 weeks) and db/db mice (8 weeks, 24 weeks) were screened for differential metabolites by UPLC-Orbitrap MS. Ninety-eight metabolites were identified (35 and 63 metabolites are associated with early staged and late staged, respectively), consisting of amino acids, fatty acyls, and nucleotides. Notably, fatty acyls (such as 18-HEPE, 16(17)-EpDPE, arachidonic acid) and glycerophospholipids (such as phosphocholines (PC) (O-10:1(9E)/0:0), PC (O-16:1(9E)/0:0) [U] and phosphatidylethanolamines (PE) (P-16:0/0:0)) were significantly increased, and metabolites of amino acid pathway (such as l-glutamine, proline, phenylalanine) showed a downregulation trend. Dysregulation of lipid and glutathione pathways is the major contributor to progression of T2DOP in C57BKS mice.

[Protective effect of baicalin against LPS-induced intestinal injury].

OBJECTIVE: To investigate the protective effect of baicalin on the intestinal mucosal injury caused by endotoxin-lipopolysaccharide (LPS) and the anti-oxidative injury in colonic and ileal mucosa of rats with septicopyemia. METHOD: Fifty healthy male BALB/c mice were randomly divided into 5 groups: the normal control group, the model group, and baicalin high-dose, medium-dose and low-dose groups. They were orally administered with double distilled water, 100 mg x kg(-1) of baicalin, 50 mg x kg(-1) of baicalin, and 25 mg x kg(-1) of baicalin respectively for three days, once a day. 1 h after the oral administration on 3 d, they were intraperitoneally injected with normal saline or LPS (17 mg x kg(-1)). At 20 h after the injection of LPS, all of the mice were sacrificed, and their colonic and ileal tissues were collected. The mental status, life state and death rate of mice in each group were observed, and the lengths of colonic were measured. Chiu's scoring method was used to assess the intestinal mucosal injury. Histopathological changes of intestinal tissues were tested by HE staining. The ultraviolet spectrophotometry was used to detect total antioxidant capacity (T-AOC), superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-PX) of intestinal homogenate. The immunohistochemical method was used to analyze the expression of PCNA in intestinal tissues of each group. RESULT: The death of mice was observed after the intraperitoneal injection of LPS. The death rates of baicalin groups were remarkably lower than the death rate of the model group. The colons in the medium-dose baicalin group were much longer than that in the model group (P < 0.05), with a much lower intestinal mucosa injury degree than the model group. Colonic and ileal injuries in the high-dose baicalin group significantly (P < 0.05). Colonic and ileal injuries in the medium-dose baicalin group and the low-dose baicalin group significantly reduced compare with the model group (P < 0.000 1). The medium-dose baicalin group showed no significant increase in homogenate's T-AOC, T-SOD and GSH-PX compare with the model group (P < 0.05). There was no significant difference between baicalin groups and the model group in PCNA. CONCLUSION: Baicalin can protect intestinal epithelial cells suffering from injury from oxygen radicals, and relieve the intestinal injury caused by LPS by improving the intestinal mucosa structure and functions.

DRCNN: decomposing residual convolutional neural networks for time series forecasting.

Recent studies have shown great performance of Transformer-based models in long-term time series forecasting due to their ability in capturing long-term dependencies. However, Transformers have their limitations when training on small datasets because of their lack in necessary inductive bias for time series forecasting, and do not show significant benefits in short-time step forecasting as well as that in long-time step as the continuity of sequence is not focused on. In this paper, efficient designs in Transformers are reviewed and a design of decomposing residual convolution neural networks or DRCNN is proposed. The DRCNN method allows to utilize the continuity between data by decomposing data into residual and trend terms which are processed by a designed convolution block or DR-Block. DR-Block has its strength in extracting features by following the structural design of Transformers. In addition, by imitating the multi-head in Transformers, a Multi-head Sequence method is proposed such that the network is enabled to receive longer inputs and more accurate forecasts are obtained. The state-of-the-art performance of the presented model are demonstrated on several datasets.

Interleukin-35 -producing B cells rescues inflammatory bowel disease in a mouse model via STAT3 phosphorylation and intestinal microbiota modification.

Interleukin-35 (IL-35)-producing B cells (IL-35+B cells) play an important role in diseases, and the expansion of IL-35+ immune cells have been observed in inflammatory bowel disease (IBD). However, how IL-35+B cells function and the manner in which they perform their roles remain unclear. In this study, human samples and animal models were used to confirm the expansion of IL-35+B cells during IBD. In addition, by using il12a-/- and ebi3-/- mice, we demonstrated that the regulatory role of B cells in IBD depends on IL-35. Mechanically, IL-35+B cells can promote its own expansion through endocrine actions and depend on the transcription factor signal transducer and activator of transcription 3. Interestingly, we found that the diversity of intestinal microbes and expression of microbial metabolites decreased during IBD. IL-35+B cells promote the high expression of indoleacetic acid (IAA), and exogenous metabolite supplementation with IAA can further promote the expansion of IL-35+B cells and rescues the disease. This study provides a new concept for the regulatory model of B cells and a new approach for the treatment of IBD.

Themis suppresses the effector function of CD8+ T cells in acute viral infection.

CD8+ T cells play a central role in antiviral immune responses. Upon infection, naive CD8+ T cells differentiate into effector cells to eliminate virus-infected cells, and some of these effector cells further differentiate into memory cells to provide long-term protection after infection is resolved. Although extensively investigated, the underlying mechanisms of CD8+ T-cell differentiation remain incompletely understood. Themis is a T-cell-specific protein that plays critical roles in T-cell development. Recent studies using Themis T-cell conditional knockout mice also demonstrated that Themis is required to promote mature CD8+ T-cell homeostasis, cytokine responsiveness, and antibacterial responses. In this study, we used LCMV Armstrong infection as a probe to explore the role of Themis in viral infection. We found that preexisting CD8+ T-cell homeostasis defects and cytokine hyporesponsiveness do not impair viral clearance in Themis T-cell conditional knockout mice. Further analyses showed that in the primary immune response, Themis deficiency promoted the differentiation of CD8+ effector cells and increased their TNF and IFNγ production. Moreover, Themis deficiency impaired memory precursor cell (MPEC) differentiation but promoted short-lived effector cell (SLEC) differentiation. Themis deficiency also enhanced effector cytokine production in memory CD8+ T cells while impairing central memory CD8+ T-cell formation. Mechanistically, we found that Themis mediates PD-1 expression and its signaling in effector CD8+ T cells, which explains the elevated cytokine production in these cells when Themis is disrupted.

CD19(+)CD1d(+)CD5(+) B cell frequencies are increased in patients with tuberculosis and suppress Th17 responses.

Although the importance of B cells in the host immune response upon Mycobacterium tuberculosis infection has been recognized, a conclusive role for B cells has yet to be determined. In the present study, we found that primary CD19(+) B cells isolated from patients with tuberculosis significantly inhibited Th17, but not Th1, cell activation. Moreover, the suppressive activity was mediated by a CD19(+)CD1d(+)CD5(+) B cell population. Notably, patients with tuberculosis were found to have significantly higher frequencies of CD19(+)CD1d(+)CD5(+) B cells with stronger suppressive activity than such cells from healthy donors. Furthermore, the frequency of CD19(+)CD1d(+)CD5(+) B cells in peripheral blood was inversely correlated with that of Th17 cells in patients with tuberculosis. This finding that B cells negatively regulate Th17 responses provides a novel mechanism in the regulation of CD4(+) T cell responses-aside from regulatory T cells-during M. tuberculosis infection, which may impact the clinical outcome of tuberculosis.

Structural characterization of a mannoglucan polysaccharide from Dendrobium huoshanense and evaluation of its osteogenesis promotion activities.

Dendrobium huoshanense, a valuable traditional Chinese herb, is widely used to prolong life in China. Our study aims to characterize the structure and osteogenesis-promotion effects of a heteropolysaccharide component isolated from Dendrobium huoshanense (DHPW1). The structure of DHPW1 was characterized using gas chromatography-mass spectrometry and nuclear magnetic resonance, while its osteogenic activity was evaluated using MG-63 cells and zebrafish skulls. The results showed that the molecular weight of DHPW1 was 230 kDa and it was mainly composed of mannose and glucose. In addition, the DHPW1 backbone consisted of (1 â†’ 4)-linked-ß-D-Mannopyranosyl and (1 â†’ 4)-linked-ß-d-Glucopyranosyl. Furthermore, DHPW1 significantly increased ALP activity and mineralized nodule formation in MG-63 cells. DHPW1 in zebrafish skull models significantly enhanced the relative fluorescence intensity of bone mass and increased the degree of bone mineralization. These results suggested that the DHPW1 component in D. huoshanense has potential to promote osteogenesis.