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Chronic obstructive pulmonary disease (COPD) is a global public health issue and is defined as persistent airflow limitation. COPD is a major cause of morbidity and mortality worldwide. Long noncoding RNAs are involved in the course of pulmonary diseases. Here, we revealed that a long noncoding RNA called myocardial-infarction-associated transcript (MIAT) is upregulated in lung tissues of cigarette smoke (CS)-exposed mice. Knockdown of MIAT attenuated CS or CS-extract-induced inflammatory processes, epithelial-mesenchymal transition (EMT), and collagen deposition. Moreover, according to bioinformatic analyses and luciferase reporter assays, MIAT binds to microRNA-29c-3p (miR-29c-3p) and upregulates hypoxia-inducible factor 3 alpha (HIF3A), a target gene of miR-29c-3p. When the MIAT-specific short hairpin RNA and an miR-29c-3p inhibitor were cotransfected into cells, the inhibitor reversed the effects of MIAT knockdown on cell proliferation, apoptosis, inflammation, EMT, and collagen deposition. Overall, these results indicate that MIAT participates in CS-induced EMT and airway remodeling in COPD by upregulating miR-29c-3p-HIF3A axis output, thereby offering a novel promising biomarker for the assessment of COPD exacerbation induced by CS exposure.

Lung cancer in its occurrence and development of different stages exist different biological behavior changes. This paper studies the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 in benign and malignant lung lesions and its early diagnosis value of nonsmall-cell lung cancer (NSCLC), aiming to provide reference for the early diagnosis and therapy of NSCLC. Some lung surgery specimens are selected from January 2021 to March 2022. All cases received no radiotherapy and chemotherapy before surgery, including 90 sufferers with benign lung lesions as the contrast set. hnRNP A2/B1 expressions are measured for comparison. The experimental results show that for lung cancer sufferers, the positive expression of hnRNP A2/B1 in their malignant lesion tissue is notoriously higher than that in their benign lesion tissue, and hnRNP A2/B1 is differently expressed in different differentiation and in different stages.

To systematically evaluate the effect of hydrocortisone combined with vitamin C and vitamin B1 on the efficacy of patients with sepsis or septic shock.Databases including CNKI, Sino Med, VIP, Wanfang, PubMed, the Cochrane Library, and Embase were searched from inception to January 2021 for the randomized controlled trial (RCT) about hydrocortisone combined with vitamin C and vitamin B1 to treat sepsis or septic shock. The experimental group was given intravenous injection of hydrocortisone, vitamin B1 and vitamin C based on conventional treatment; the control group was given conventional treatment or placebo/hydrocortisone/hydrocortisone+vitamin B1 based on conventional treatment. Outcome indicators included sequential organ failure assessment (SOFA), mortality, the duration of vasoactive drugs, new acute kidney injury (AKI) patients, length of stay in intensive care unit (ICU) and in hospital. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.3 software was then used to perform Meta-analysis. Funnel plot was used to test publication bias.A total of 6 articles involving 816 patients were included, with 411 patients in the experimental group and 405 patients in the control group. The Meta-analysis results showed that the duration of vasoactive drugs in the experimental group was significantly shorter than that in the control group [mean difference (MD) = -24.02, 95% confidence interval (95%CI) was -32.36 to -15.68, P0.000 01]. However, there were no significant differences in SOFA, mortality, new AKI patients, the length of ICU stay and hospital stay between the two groups [SOFA: MD = -0.14, 95%CI was -1.15 to 0.87, P = 0.79; mortality: relative risk (RR) = 0.99, 95%CI was 0.81 to 1.21, P = 0.92; new AKI patients: RR = 1.10, 95%CI was 0.42 to 2.87, P = 0.84; length of ICU stay: MD = 1.33, 95%CI was -2.22 to 4.89, P = 0.46; length of hospital stay: MD = 1.02, 95%CI was -0.66 to 2.69, P = 0.23]. The funnel plot showed that most of the points were symmetrical and showed an inverted funnel shape, suggesting that the publication bias among the studies was small. There was no significant publication bias on this Meta-analysis.Hydrocortisone combined with vitamin C and vitamin B1 can shorten the duration of vasoactive drugs in patients with sepsis or septic shock, but it cannot effectively reduce the SOFA score, mortality, new AKI patients, length of stay in ICU and in hospital. Limited by the number and quality of the included studies, further large-scale, multi-center, blinded, RCT are still needed for verification.

Summary Regulatory T cells (Tregs) are specialized in immune suppression and play a dominant role in peripheral immune tolerance. Treg cell lineage development and function maintenance is determined by the forkhead box protein 3 (FoxP3) transcriptional factor, whose activity is fine‐tuned by its post‐translational modifications (PTMs) and interaction partners. In this review, we summarize current studies in the crystal structures, the PTMs and interaction partners of FoxP3 protein, and discuss how these insights may provide a roadmap for new approaches to modulate Treg suppression, and new therapies to enhance immune tolerance in autoimmune diseases., FOXP3 is the master transcription factor in regulating Treg cell development and function. The forkhead domain of FOXP3 forms a domain‐swapped dimer which can bridge two long‐range FOXP3‐targeted genes (a). The zinc‐finger and leucine‐zipper domain forms oligomerization through the hydrophobic coiled‐coil surface (b). Acetylation of K250 and K252 located in the coiled‐coil region changes the conformation of FOXP3, which implies a structure‐based regulation of the conformation and activity of FOXP3 by integration of posttranslational modifications may modulate Treg function. Understanding the molecular and structural features of Foxp3 helps to design rational therapeutic strategies against autoimmune diseases.

Scintillators are widely used for nondestructive testing, nuclear medicine imaging, space exploration and security inspection. Recently, lead halide perovskite scintillation crystals have been brought into focus due to their effective atomic number, fast scintillation decay time, strong luminous efficiency, and tunable band gap. However, their application is limited by lead toxicity. Here we report that Ce-doping can increase sensitivity in lead-free double perovskite crystals (Cs2 NaTbCl6 ) for X-ray detection and imaging. The introduction of Ce ions as sensitizer can be used to improve the radioluminescence of the crystals. The light output of Ce : Cs2 NaTbCl6 crystals is about 52153 ph/MeV, which is 25 % higher than that of un-doped crystal. The X-ray sensitivity is significantly enhanced. Based on our scintillation film X-ray detector the detection limit is 30 nGy ⋅ s-1 , which is about 1/183 of the typical medical imaging dose. Our scintillating film has excellent imaging ability with spatial resolution of up to 10 lp/mm. This research shows that Ce : Cs2 NaTbCl6 perovskite crystal scintillators are promising materials for X-ray imaging application.

The FOXP3 transcription factor acts as a master regulator in the development and function of regulatory T cells (Tregs). Insufficient expression or mutation of FOXP3 gene impairs Treg abundancy and function and causes fatal autoimmune lymphoproliferative diseases in mice and humans. The available crystal structures of FOXP3 protein fragments provide insights into understanding details of the FOXP3 work mechanism in Tregs. This chapter consists of four sections. First, we introduce some features of Treg cells indispensable for the establishment of immune tolerance; second, we describe the critical roles of FOXP3 in Treg development and function; third, we summarize the current available crystal structures of FOXP3 functional domains and related pathogenic mutations in autoimmune diseases; finally, we discuss the potential functional and pathological relevance of FOXP3 protein structure modulation, partner interaction, and posttranslation modification based on the clinical significance in IPEX disease. The information presented in this chapter will help to consider therapeutic strategies to enhance FOXP3 activity and Treg function in the settings of autoimmune disease. Targeting Treg suppression based on FOXP3 structure and interactions hold great promises for the therapy of autoimmune diseases.

The FOXP3 transcription factor acts as a master regulator in the development and function of regulatory T cells (Tregs). Insufficient expression or mutation of FOXP3 gene impairs Treg abundancy and function and causes fatal autoimmune lymphoproliferative diseases in mice and humans. The available crystal structures of FOXP3 protein fragments provide insights into understanding details of the FOXP3 work mechanism in Tregs. This chapter consists of four sections. First, we introduce some features of Treg cells indispensable for the establishment of immune tolerance; second, we describe the critical roles of FOXP3 in Treg development and function; third, we summarize the current available crystal structures of FOXP3 functional domains and related pathogenic mutations in autoimmune diseases; finally, we discuss the potential functional and pathological relevance of FOXP3 protein structure modulation, partner interaction, and posttranslation modification based on the clinical significance in IPEX disease. The information presented in this chapter will help to consider therapeutic strategies to enhance FOXP3 activity and Treg function in the settings of autoimmune disease. Targeting Treg suppression based on FOXP3 structure and interactions hold great promises for the therapy of autoimmune diseases.

Nedd4 family E3 ubiquitin ligases have been shown to restrict T-cell function and impact T-cell differentiation. We show here that Ndfip1 and Ndfip2, activators of Nedd4 family ligases, together limit accumulation and function of effector CD4+ T cells. Using a three-part proteomics approach in primary T cells, we identify stabilization of Jak1 in Ndfip1/2-deficient T cells stimulated through the TCR. Jak1 degradation is aborted in activated T cells that lack Ndfips. In wild-type cells, Jak1 degradation lessens CD4+ cell sensitivity to cytokines during TCR stimulation, while in Ndfip-deficient cells cytokine responsiveness persists, promoting increased expansion and survival of pathogenic effector T cells. Thus, Ndfip1/Ndfip2 regulate the cross talk between the T-cell receptor and cytokine signalling pathways to limit inappropriate T-cell responses., Ndfip1 is an activator of Itch E3 ubiquitin ligase that limits T cell activation. Here the authors identify Jak1 in a proteomic screen for Ndfip dependent substrates, and show that Ndfip1/2 double-deficient T cells have reduced degradation of Jak1 and as a result are hyper-responsive to cytokine stimulation.

Overcoming acquired adaptive immune resistance to anti-PD-1 therapy is imperative for enhancing the efficacy of immune checkpoint blockade (ICB) in solid tumors. Regulatory T cells (Tregs) play a prominent role in the suppressive tumor microenvironment (TME) and are major contributors to adaptive immune resistance. Tregs limit CD8+ T cell reinvigoration and are a promising target for combination therapy. While the clinical efficacy of anti-CTLA4 may be partially explained by restriction of Tregs, its co-administration with anti-PD1 causes significant toxicity. Thus, safer approaches to limit Treg activity are needed. To elucidate the dynamic changes in immuno-regulatory circuits within the TME during ICB, we performed deep immune profiling of peripheral blood and tumors from patients with advanced melanoma prior to (n=7) and after 1 cycle of anti-PD-1 therapy with pembrolizumab (n=9). Tregs were abundant in the TME and retained their immunosuppressive phenotype and functionality following anti-PD-1. Epigenetic, transcriptomic, and proteomic analysis of Tregs after ICB identified tumor necrosis factor receptor 2 (TNFR2) signaling as a possible driver of CD8+ T cell suppression. TNFR2 was preferentially expressed by Tregs in the TME (mean 18.03 %, SD +/− 10.13 %) relative to CD8+ T cells (mean 0.64 %, SD +/− 0.82 %) and peripheral Tregs (mean 3.16 %, SD +/− 3.21 %), suggesting it might be a safe and effective target for combination therapy. Indeed, dual blockade of TNFR2 and PD-1 led to potent CD8+ T cell expansion in two mouse tumor models, and restored sensitivity to ICB in a resistant murine model of melanoma. Our data suggest that anti-TNFR2 might synergize with current ICB by countering the development of adaptive immune resistance.

Tumor cells evolve multiple sophisticated mechanisms to escape immune surveillance, one of which is to establish tolerogenic microenvironment by recruiting certain immune suppressive cells such as regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs). Tregs are subpopulation of CD4+ T cells, which specialize in suppressing immune responses and preventing autoimmune damage to collateral tissue. Emerging evidence suggests that Treg cell number increases in various types of cancer, which correlates with tumor grade and poor patient prognosis. This review will focus on discussion of the origins and features of tumor-infiltrating Treg cells. Ultimately, these features may provide insight into potential therapeutic intervention by targeting Treg cells to invigorate immune response against tumor.

Foxp3+ T regulatory (Treg) cells suppress immune cell activation and establish normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient Treg cells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts Treg cell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient Treg cells. Thus, Ndfip1 preserves Treg lineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active Treg cells and by preventing pathological secretion of IL-4 from Treg cells., T regulatory (Treg) cells are essential for maintaining immune homeostasis, but how the stability of their lineage and function is regulated is unclear. Here the authors show that Ndfip1 is essential for suppressing Treg cell IL-4 production and metabolic alteration to preserve Treg lineage and function.

Previous reports have suggested that human CD4(+) CD25(hi)FOXP3(+) T regulatory cells (Tregs) have functional plasticity and may differentiate into effector T cells under inflammation. The molecular mechanisms underlying these findings remain unclear. Here we identified the residue serine 422 of human FOXP3 as a phosphorylation site that regulates its function, which is not present in murine Foxp3. PIM1 kinase, which is highly expressed in human Tregs, was found to be able to interact with and to phosphorylate human FOXP3 at serine 422. T cell receptor (TCR) signaling inhibits PIM1 induction, whereas IL-6 promotes PIM1 expression in in vitro expanded human Tregs. PIM1 negatively regulates FOXP3 chromatin binding activity by specifically phosphorylating FOXP3 at Ser(422). Our data also suggest that phosphorylation of FOXP3 at the Ser(418) site could prevent FOXP3 phosphorylation at Ser(422) mediated by PIM1. Knockdown of PIM1 in in vitro expanded human Tregs promoted FOXP3-induced target gene expression, including CD25, CTLA4, and glucocorticoid-induced tumor necrosis factor receptor (GITR), or weakened FOXP3-suppressed IL-2 gene expression and enhanced the immunosuppressive activity of Tregs. Furthermore, PIM1-specific inhibitor boosted FOXP3 DNA binding activity in in vitro expanded primary Tregs and also enhanced their suppressive activity toward the proliferation of T effector cells. Taken together, our findings suggest that PIM1 could be a new potential therapeutic target in the prevention and treatment of human-specific autoimmune diseases because of its ability to modulate the immunosuppressive activity of human Tregs.

Regulatory T (Treg) cells are essential in preventing the host from developing certain autoimmune diseases and limiting excessive immune responses against pathogens. The normal function of most Treg cells requires sustained expression of functional FOXP3, a member of the FOXP family transcription factors. FOXP3 is distinct from other subfamily members because of its unique proline rich amino (N)-terminal domain. Mutations in this region are occasionally identified in certain patients with X-linked autoimmunity-allergic dysregulation syndrome (XLAAD) and similar mutations also increase susceptibility of autoimmune diseases in rodent models. Previous analyses of the FOXP3 N-terminal domain revealed a role in nuclear import, interaction with other transcription factors, and as sites of specific post-translational modifications of FOXP3 that contribute to FOXP3 stability.

Hemidiscoidal phycobilisomes (PBS), the major light harvesting complexes of photosynthesis in most cyanobacteria, are composed of rods and cores, which are linked by the linker CpcG1 (L-RC). Another type of PBS, CpcG2-PBS exits and their function in energy transfer has not been fully under-stood. We measured growth rates, absorption cross-sections and quantum efficiency of photosystem I in mutant strains of Synechococcus PCC sp. 7002 lacking the linker CpcG2. Our results showed that energy transfer from CpcG2-PBS to PSI in the absence of state transitions could be significant under PBS-absorbing light and energy transfer from two types of PBS is independent to each other. Evidence also suggested that CpcG2 anchors the CpcG2-PBS to thylakoid membranes. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Regulation of the extent of immune responses is a requirement to maintain self-tolerance and limit inflammatory processes. CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells play a role in regulation. The Foxp3 transcription factor is considered a dominant regulator for Treg cell development and function. Foxp3 function itself is directly regulated by multiple posttranslational modifications that occur in response to various external stimuli. The Foxp3 protein is a component of several dynamic macromolecular regulatory complexes. The complexes change constituents over time and through different signals to regulate the development and function of regulatory T cells. Here we identified a mechanism regulating Foxp3 level and activity that operates through discrete phosphorylation. The Pim-2 kinase can phosphorylate Foxp3, leading to decreased suppressive functions of Treg cells. The amino-terminal domain of Foxp3 is modified at several sites by Pim-2 kinase. This modification leads to altered expression of proteins related to Treg cell functions and increased Treg cell lineage stability. Treg cell suppressive function can be up-regulated by either pharmacologically inhibiting Pim-2 kinase activity or by genetically knocking out Pim-2 in rodent Treg cells. Deficiency of Pim-2 activity increases murine host resistance to dextran sodium sulfate-induced colitis in vivo, and a Pim-2 small molecule kinase inhibitor also modified Treg cell functions. Our studies define a pathway for limiting the regulation of Foxp3 function because the Pim-2 kinase represents a potential therapeutic target for modulating the Treg cell suppressive activities in controlling immune responses.

Regulatory T cells (Tregs) are key immune cells for enforcing peripheral tolerance against self. Supporting this, in humans and in mice, a defect in Treg number or function results in severe autoimmune disease. Tregs limit autoimmunity by restraining the activation and cytokine production of conventional T cells (among other mechanisms). Our data reveal how two E3 ubiquitin ligase-activating proteins, Ndfip1 and Ndfip2, regulate Treg fate and function. Ndfip (Nedd4 family interacting proteins) 1 and 2 are known to activate several members of the Nedd4-family of E3 ligases, such as Itch, that have known roles in T cells. We generated mice that constitutively lack Ndfip2 and conditionally lack Ndfip1 in Foxp3+ cells (Treg cDKO mice). These Treg cDKO mice, display severe spleen and lung pathology marked by pulmonary arterial fibrosis, and ectopic lymphoid follicles. Additionally, Treg cDKO mice have higher circulating antibody levels. Since Foxp3 is an X-linked gene, we expect female DKO Treg mice to have both normal and Ndfip-deficient Tregs. Surprisingly, we find that even these female mice are characterized by splenomegaly, pulmonary arterial fibrosis, and these mice show circulating autoantibodies by 16 weeks of age. We will present data explaining why both male and female Treg cDKO mice get sick and discuss the roles of Ndfip-proteins in Treg activation, Treg cytokine production, PD-1 expression, and FoxP3 stability.

Ubiquitylation tunes signaling pathways in stimulated T cells to regulate activation and function. We have found that, in vitro, Nedd4-family interacting protein 1 (Ndfip1) and Ndfip2 activate Nedd4-family catalytic E3 ligases with known roles in T cells. Ndfip1 negatively regulates T cell activation and Th2 polarization, but the in vivo role of Ndfip2 is unknown. We generated Ndfip2-/- mice and found that Ndfip2 is not a prominent negative regulator of T cell activation or Th2 polarization. However, loss of Ndfip2 exacerbates the inflammatory Ndfip1-/- phenotype, suggesting that Ndfip2 dampens inflammation. We generated mixed fetal liver chimeras and found that Ndfip1/Ndfip2 deficiency leads to T cell intrinsic hyperactivity. To identify signaling pathways affected by loss of Ndfips, we used semiquantitative proteomics to compare stimulated control and knockout CD4+ T cells. Pathway analysis revealed increased MEK1 activity in knockout cells, which was confirmed by observing increased ERK phosphorylation in stimulated Ndfip1/Ndfip2 deficient CD4+ T cells. To identify aberrant ubqiuitylation of proteins upstream of ERK, we have taken a quantitative proteomic approach, using Tandem Ubiquitin Binding Entities (TUBEs) to enrich for polyubiquitylated proteins in isotope labeled control and Ndfip deficient CD4+ T cells. This approach has yielded several potential targets of Ndfip-dependent ubiquitylation in CD4+ T cells that are currently under investigation.

The negative electrode (NE) for lithium‐ion batteries is conventionally made by casting a mixture of various carbon materials with polyvinylidene difluoride (PVDF) onto copper foil. Differential scanning calorimetry and accelerating rate calorimetry were used to evaluate the thermal stability of several lithiated NE materials: synthetic graphite (SFG-44), mesocarbon microbeads (MCMB), lignin‐based hard carbon (HC), and mixtures of these materials. The exothermic heat generation of lithiated NEs, in the absence of the electrolyte, is attributed to the reaction of PVDF with lithiated carbon . For all samples here, the total exothermic heat generation increases with an increase in lithiation content. The onset temperature for the thermal reaction of PVDF with SFG-44 or MCMB does not depend on the lithiation content. However, this onset temperature decreases as lithiation increases in HC electrodes. These differences are attributed to structural differences between highly graphitic SFG-44 and MCMB compared with the far less graphitic HC. Total heat generation increases with PVDF binder content. An alternative resin‐based binder, phenolformaldehyde phenolic‐resin , is proposed. Full or partial substitution of this material for PVDF lowers the exothermic heat of reaction of the binder agent with lithiated NE materials. © 2000 The Electrochemical Society. All rights reserved.