Two-directional simultaneous inference for high-dimensional models

This paper proposes a general two directional simultaneous inference (TOSI) framework for high-dimensional models with a manifest variable or latent variable structure, for example, high-dimensional mean models, high-dimensional sparse regression models, and high-dimensional latent factors models. TOSI performs simultaneous inference on a set of parameters from two directions, one to test whether the assumed zero parameters indeed are zeros and one to test whether exist zeros in the parameter set of nonzeros. As a result, we can exactly identify whether the parameters are zeros, thereby keeping the data structure fully and parsimoniously expressed. We theoretically prove that the proposed TOSI method asymptotically controls the Type I error at the prespecified significance level and that the testing power converges to one. Simulations are conducted to examine the performance of the proposed method in finite sample situations and two real datasets are analyzed. The results show that the TOSI method is more predictive and has more interpretable estimators than existing methods

The Construction of a Community Long-term Care Model for Home-based Elderly Individuals

With rapidly aging populations, family care functions can become weakened, and community health services often lack unified standards. A standardized and professional community home-based long-term care model (CHLCM) for the elderly is urgently needed in many regions of China and in other countries. Here, we explored the indicators of the need for a CHLCM among elderly individuals, and we constructed a CHLCM. We created and distributed a questionnaire regarding the requirement of long-term care services, based on a literature review. The two-rounds Delphi method was used, involving 20 experts who were randomly selected from among the medical universities, community health service centers, and nursing homes in Nanning, Guangxi, China. The experts’ enthusiasm rates in the questionnaire’s two rounds were 95% and 100%, respectively. The authentic coefficient of the experts’ consulting was 0.857, and that of the experts’ academic level was 0.835; the judgement coefficient was 0.880 and the familiar coefficient was 0.855. The CHLCM includes service content and an evaluation. The coordination coefficients for the two primary, eight secondary, and 29 tertiary indicators were 0.200, 0.386, and 0.184, respectively (p<0.05). The experts’ enthusiasm and authority were high. The coordination of the experts’ agreement was sufficient, and the analysis results were reliable. The CHLCM includes 29 items that provide a foundation and references for the formulation of concrete indicators and subsequent research

Shikonin Prolongs Allograft Survival via Induction of CD4+FoxP3+ Regulatory T Cells

A transplanted organ is usually rejected without any major immunosuppressive treatment because of vigorous alloimmune responsiveness. However, continuous global immunosuppression may cause severe side effects, including nephrotoxicity, tumors, and infections. Therefore, it is necessary to seek novel immunosuppressive agents, especially natural ingredients that may provide sufficient efficacy in immunosuppression with minimal side effects. Shikonin is a bioactive naphthoquinone pigment, an ingredient originally extracted from the root of Lithospermum erythrorhizon. Previous studies have shown that shikonin regulates immunity and exerts anti-inflammatory effects. In particular, it can ameliorate arthritis in animal models. However, it is unclear whether shikonin inhibits alloimmunity or allograft rejection. In this study and for the first time, we demonstrated that shikonin significantly prolonged the survival of skin allografts in wild-type mice. Shikonin increased the frequencies of CD4+Foxp3+ regulatory T cells (Tregs) post-transplantation and induced CD4+Foxp3+ Tregs in vitro as well. Importantly, depleting the Tregs abrogated the extension of skin allograft survival induced by shikonin. It also decreased the frequencies of CD8+CD44highCD62Llow effector T cells and CD11c+CD80+/CD11c+CD86+ mature DCs after transplantation. Moreover, we found that shikonin inhibited the proliferation of T cells in vitro and suppressed their mTOR signaling. It also reduced the gene expression of pro-inflammatory cytokines, including IFNγ, IL-6, TNFα, and IL-17A, while increasing the gene expression of anti-inflammatory mediators IL-10, TGF-β1, and indoleamine-2, 3-dioxygenase (IDO) in skin allografts. Further, shikonin downregulated IDO protein expression in skin allografts and DCs in vitro. Taken together, shikonin inhibits allograft rejection via upregulating CD4+Foxp3+ Tregs. Thus, shikonin is a novel immunosuppressant that could be potentially used in clinical transplantation

Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance

Cellular therapies with polyclonal regulatory T-cells (Tregs) in transplantation and autoimmune diseases have been carried out in both animal models and clinical trials. However, The use of large numbers of polyclonal Tregs with unknown antigen specificities has led to unwanted effects, such as systemic immunosuppression, which can be avoided via utilization of antigen-specific Tregs. Antigen-specific Tregs are also more potent in suppression than polyclonal ones. Although antigen-specific Tregs can be induced in vitro, these iTregs are usually contaminated with effector T cells during in vitro expansion. Fortunately, Tregs can be efficiently engineered with a predetermined antigen-specificity via transfection of viral vectors encoding specific T cell receptors (TCRs) or chimeric antigen receptors (CARs). Compared to Tregs engineered with TCRs (TCR-Tregs), CAR-modified Tregs (CAR-Tregs) engineered in a non-MHC restricted manner have the advantage of widespread applications, especially in transplantation and autoimmunity. CAR-Tregs also are less dependent on IL-2 than are TCR-Tregs. CAR-Tregs are promising given that they maintain stable phenotypes and functions, preferentially migrate to target sites, and exert more potent and specific immunosuppression than do polyclonal Tregs. However, there are some major hurdles that must be overcome before CAR-Tregs can be used in clinic. It is known that treatments with anti-tumor CAR-T cells cause side effects due to cytokine “storm” and neuronal cytotoxicity. It is unclear whether CAR-Tregs would also induce these adverse reactions. Moreover, antibodies specific for self- or allo-antigens must be characterized to construct antigen-specific CAR-Tregs. Selection of antigens targeted by CARs and development of specific antibodies are difficult in some disease models. Finally, CAR-Treg exhaustion may limit their efficacy in immunosuppression. Recently, innovative CAR-Treg therapies in animal models of transplantation and autoimmune diseases have been reported. In this mini-review, we have summarized recent progress of CAR-Tregs and discussed their potential applications for induction of immunological tolerance

Interactions between CNS and immune cells in tuberculous meningitis

The central nervous system (CNS) harbors its own special immune system composed of microglia in the parenchyma, CNS-associated macrophages (CAMs), dendritic cells, monocytes, and the barrier systems within the brain. Recently, advances in the immune cells in the CNS provided new insights to understand the development of tuberculous meningitis (TBM), which is the predominant form of Mycobacterium tuberculosis (M.tb) infection in the CNS and accompanied with high mortality and disability. The development of the CNS requires the protection of immune cells, including macrophages and microglia, during embryogenesis to ensure the accurate development of the CNS and immune response following pathogenic invasion. In this review, we summarize the current understanding on the CNS immune cells during the initiation and development of the TBM. We also explore the interactions of immune cells with the CNS in TBM. In the future, the combination of modern techniques should be applied to explore the role of immune cells of CNS in TBM

Dual‐templating surface gel into thin SSZ‐13 zeolite membrane for fast selective hydrogen separation

Abstract: Highly permeable zeolite membranes are desirable for fast gas separation in the industry. Reducing the membrane's thickness is deemed to be an optimal solution for permeability improvement. Herein, we report the synthesis route of thin SSZ‐13 zeolite membranes via the conversion of template‐contained surface gels. The synthesis gel is fully crystallized into crack‐free SSZ‐13 membranes assisted with dual templates of N, N, N‐trimethyl‐1‐adamantammonium hydroxide (TMAdaOH) and tetraethylammonium hydroxide (TEAOH). The specific functions of TMAdaOH for structure directing and TEAOH for crystallization regulating are well discussed. Thin surface gel layer is impregnated onto porous alumina with subsequent crystallization into a 500 nm thick membrane. This submicron‐thick membrane exhibits high H2 permeance with 50 × 10−8 mol s−1 m−2 Pa−1 during hydrogen separation. Meanwhile, the separation factors are retained around 23.0 and 31.5 for H2/C2H6 and H2/C3H8, respectively. This approach offers a possibility for obtaining high‐quality zeolite membranes for efficient hydrogen separation

Screen printing directed synthesis of covalent organic framework membranes with water sieving property

Screen printing is introduced to direct the synthesis of crack-free and thickness-tunable TpPa(OH)2 covalent organic framework membranes. A smooth precursor layer is firstly screen printed and then fully crystallised into TpPa(OH)2 membrane. Molecular-scale pores endow the membrane fast water-sieving property, which is promising in water desalination

Mangiferin Attenuates Murine Lupus Nephritis by Inducing CD4+Foxp3+ Regulatory T Cells via Suppression of mTOR Signaling

Background/Aims: Lupus nephritis (LN) is an autoimmune glomerulonephritis that frequently develops secondary to systemic lupus erythematosus. Patients with LN require extensive treatments with global immunosuppressive agents. However, long-term treatment with conventional immunosuppressants may cause various side effects. Therefore, it’s important to seek alternative drugs for treating LN. Here we aimed to investigate the immunoregulatory effects of mangiferin (MG), an ingredient that was originally extracted from natural herbs, including Mangifera Indica Linn. and Rhizoma Anemarrhenae. Methods: FasL-deficient B6/ gld mice were used as a spontaneous LN model. The serum anti-dsDNA Ab and creatinine levels were analyzed via ELISA. Renal histology and immunopathology were determined using H&#38;E and PAS staining, immunofluorescence (IgG and C3), and IHC staining (CD3 and a-SMA). Cytokine gene expression was measured by RT-PCR assays while effector T cells and Tregs were enumerated by flow analysis. Finally, the proliferation and apoptosis of T cells were measured by CFSE staining and flow analysis while their mTOR signaling was detected through Western blotting. Results: We found that administration of MG ameliorated LN in lupus-prone B6/gld mice by reducing the urinary protein and serum creatinine levels, diminishing T cell infiltration in kidneys and improving renal immunopathology. MG also significantly lowered the percentages of CD44highCD62Llow effector T cells in B6/gld mice. Importantly, treatments with MG augmented CD4+FoxP3+ Treg frequencies in spleens, lymph nodes and kidneys of B6/gld mice. It also induced CD4+FoxP3+ Tregs from CD3+ T cells in vitro and promoted Treg proliferation. Furthermore, it inhibited CD3+ T cell proliferation in vitro and suppressed their phosphorylation of mTOR and its downstream P70S6K. However, MG did not promote T cell apoptosis, implying that it is not cytotoxic. Depletion of CD4+CD25+FoxP3+ Tregs in B6/gld mice abrogated its therapeutic effects on LN. Conclusion: MG exerts a novel therapeutic effect on murine LN via upregulating CD4+FoxP3+ Tregs, downregulating mTOR/p70S6K pathway and improving renal immunopathology. It may be useful for treating LN in clinic

Study on rheological, adsorption and hydration properties of cement slurries incorporated with EPEG-based polycarboxylate superplasticizers

A series of polycarboxylate superplasticizers (PCEs) with different side-chain densities, main chain polymerization degrees, and side-chain lengths were designed and synthesized using a novel highly active ethylene glycol mono vinyl ether polyethylene glycol as the ether monomer. The influence of polycarboxylate ether on the rheological properties, interface adsorption, and hydration characteristics in cement paste was investigated through characterization of charge density, rheological properties, adsorption behavior, and hydration heat. The results indicate that the adsorption process of PCE on cement particles is spontaneous physical adsorption, and the hydration kinetics fitting reveals that the geometric crystal growth exponent n is in the range of 1–2, with needle-like and lamellar hydration products formed. With a decrease in side-chain density, the broadening of molecular weight distribution and the increase of charge density accelerate the flow of slurry, reduces saturation adsorption, and delays cement hydration. A decrease in main chain polymerization degree results in a downward trend in molecular weight and charge density, leading to larger molecular conformations, reduced slurry flow, decreased saturation adsorption, and delayed cement hydration. As the side-chain length of PCE (molecular weight) increases, the charge density decreases, and the molecular conformation exhibits a compact structure with reduced slurry flow, decreased saturation adsorption, and delayed cement hydration. In cases of low side-chain density, short side chains, and low molecular weight, enhanced adsorption capacity and faster adsorption rates are observed, resulting in the lower viscosity and a delay in the cement hydration process