Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors.

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, and tolerance regulate similar "signature" inflammatory genes such as TNF, IL6, and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating JAK-STAT signaling and interferon-stimulated genes, also play a key role in regulating training, priming, and tolerance via chromatin-mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-γ-mediated priming, affects regulation of AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a "training-priming continuum" model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.

Covalent Organic Framework Catalyzed Amide Synthesis Directly from Alcohol Under Red Light Excitation.

The dehydrogenative coupling of alcohols and amines to form amide bonds is typically catalysed by homogeneous transition metal catalysts at high temperatures ranging from 130-140 °C. In our pursuit of an efficient and recyclable photocatalyst capable of conducting this transformation at room temperature, we report herein a COF-mediated dehydrogenative synthesis. The TTT-DHTD COF was strategically designed to incorporate a high density of functional units, specifically dithiophenedione, to trap photogenerated electrons and effectively facilitate hydrogen atom abstraction reactions. The photoactive TTT-DHTD COF, synthesized using solvothermal methods showed high crystallinity and moderate surface area, providing an ideal platform for heterogeneous amide synthesis.  Light absorption by the COF across the entire visible range, narrow band gap, and valence band position make it well-suited for the efficient generation of excitons necessary for targeted dehydrogenation. Utilizing red light irradiation and employing extremely low loading of the COF, we have successfully prepared a wide range of amides, including challenging secondary amides, in good to excellent yields. The substrate's functional group tolerance, very mild reaction conditions, and the catalyst's significant recyclability represent substantial advancements over prior methodologies.

A Thiazole-linked Covalent Organic Framework for Lithium-Sulphur Batteries.

Lithium-sulphur (Li-S) batteries are a promising alternative power source, as they can provide a higher energy density than current lithium-ion batteries. Porous materials are often used as cathode materials as they can act as a host for sulphur in such batteries. Recently, covalent organic frameworks (COFs) have also been used, however they typically suffer from stability issues, resulting in limited and thus insufficient durability under practical conditions and applications. Herein, we report the synthesis of a crystalline and porous imine-linked triazine-based dimethoxybenzo-dithiophene functionalized COF (TTT-DMTD) incorporating high-density redox sites. The imine linkages were further post-synthetically transformed to yield a robust thiazole-linked COF (THZ-DMTD) by utilizing a sulphur-assisted chemical conversion method, while maintaining the crystallinity. As a synergistic effect of its high crystallinity, porosity and the presence of redox-active moieties, the thiazole-linked THZ-DMTD exhibited a high capacity and long-term stability (642 mAh g-1 at 1.0 C; 78.9 % capacity retention after 200 cycles) when applied as a cathode material in a Li-S battery.

Potential Biomarkers Associated with Multiple Sclerosis Pathology.

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves an intricate and aberrant interaction of immune cells leading to inflammation, demyelination, and neurodegeneration. Due to the heterogeneity of clinical subtypes, their diagnosis becomes challenging and the best treatment cannot be easily provided to patients. Biomarkers have been used to simplify the diagnosis and prognosis of MS, as well as to evaluate the results of clinical treatments. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and promptly measured, their specificity, and their reproducibility. Biomarkers are classified into several categories depending on whether they address personal or predictive susceptibility, diagnosis, prognosis, disease activity, or response to treatment in different clinical courses of MS. The identified members indicate a variety of pathological processes of MS, such as neuroaxonal damage, gliosis, demyelination, progression of disability, and remyelination, among others. The present review analyzes biomarkers in cerebrospinal fluid (CSF) and blood serum, the most promising imaging biomarkers used in clinical practice. Furthermore, it aims to shed light on the criteria and challenges that a biomarker must face to be considered as a standard in daily clinical practice.

Locus folding mechanisms determine modes of antigen receptor gene assembly.

The dynamic folding of genomes regulates numerous biological processes, including antigen receptor (AgR) gene assembly. We show that, unlike other AgR loci, homotypic chromatin interactions and bidirectional chromosome looping both contribute to structuring Tcrb for efficient long-range V(D)J recombination. Inactivation of the CTCF binding element (CBE) or promoter at the most 5'Vß segment (Trbv1) impaired loop extrusion originating locally and extending to DßJß CBEs at the opposite end of Tcrb. Promoter or CBE mutation nearly eliminated Trbv1 contacts and decreased RAG endonuclease-mediated Trbv1 recombination. Importantly, Trbv1 rearrangement can proceed independent of substrate orientation, ruling out scanning by DßJß-bound RAG as the sole mechanism of Vß recombination, distinguishing it from Igh. Our data indicate that CBE-dependent generation of loops cooperates with promoter-mediated activation of chromatin to juxtapose Vß and DßJß segments for recombination through diffusion-based synapsis. Thus, the mechanisms that fold a genomic region can influence molecular processes occurring in that space, which may include recombination, repair, and transcriptional programming.

Staphyloccocus aureus biofilm, in absence of planktonic bacteria, produces factors that activate counterbalancing inflammatory and immune-suppressive genes in human monocytes.

Staphyloccocus aureus (S. aureus) is a major bacterial pathogen in orthopedic periprosthetic joint infection (PJI). S. aureus forms biofilms that promote persistent infection by shielding bacteria from immune cells and inducing an antibiotic-tolerant metabolic state. We developed an in vitro system to study S. aureus biofilm interactions with primary human monocytes in the absence of planktonic bacteria. In line with previous in vivo data, S. aureus biofilm induced expression of inflammatory genes such as TNF and IL1B, and their anti-inflammatory counter-regulator IL10. S. aureus biofilm also activated expression of PD-1 ligands, and IL-1RA, molecules that have the potential to suppress T cell function or differentiation of protective Th17 cells. Gene induction did not require monocyte:biofilm contact and was mediated by a soluble factor(s) produced by biofilm-encased bacteria that was heat resistant and >3 kD in size. Activation of suppressive genes by biofilm was sensitive to suppression by Jak kinase inhibition. These results support an evolving paradigm that biofilm plays an active role in modulating immune responses, and suggest this occurs via production of a soluble vita-pathogen-associated molecular pattern, a molecule that signals microbial viability. Induction of T cell suppressive genes by S. aureus biofilm provides insights into mechanisms that can suppress T cell immunity in PJI.

Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis.

Besides its mitochondria-based anti-apoptotic role, Bcl-xL also travels to the nucleus to promote cancer metastasis by upregulating global histone H3 trimethyl Lys4 (H3K4me3) and TGFß transcription. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates H3K4me3 modification are not understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced cell migration and metastasis in mouse models. Furthermore, knockout of CtBP2 suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFß mRNA upregulation as well as cell invasion. Moreover, cleavage under targets and release using nuclease (CUT&RUN) coupled with next generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor region of genes encoding TGFß and its signaling pathway in the cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1.

Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8+ T cells4,5. Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8+ T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8+ T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8+ T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

Dynamic link between bilateral FDI, the quality of environment and institutions: evidence from G20 countries.

The sustenance of a clean, natural, and relatively less tampered environment is one of the most important apprehensions of contemporary households, firms, and governments in the globalized world. Both developing and developed countries rely heavily on foreign direct investments (FDI) and institutional arrangements for economic prosperity and have feedback repercussions about environmental quality. Thus, the current paper attempts to explore such a triplex integrated linkage among bilateral FDI, institutional quality, and environmental quality proxied by CO2 emissions intensity on each other for 19 selected G20 countries during 2009-2017. The empirical estimation of this paper takes into account three equations that jointly address the endogeneity problem by employing both static (such as seemingly unrelated regression and three-stage least square) and dynamic simultaneous econometric techniques (such as the system generalized method of moments) with a panel dataset considering host and source countries with 342-panel pairs for the selected sample time. The empirical results confirm that bilateral FDI reduces CO2 emission intensity and strengthens the institutional quality of G20. It also supports the idea that institutional quality has a favorable and considerable impact on bilateral FDI. This paper confirms a positive and considerable feedback between environmental and institutional quality. Further, this study establishes a triplex relationship between these three factors. This study argues that governments should use incentives like tax cuts and additional subsidies to promote greener FDI in G20 nations. This is because it facilitates the employment of more modern technology and clean energy-efficient technologies to minimize emissions and spur economic growth.

Ayurvedic Herbal Therapies: A Review of Treatment and Management of Dementia.

Dementia has been characterized by atypical neurological syndromes and several cognitive deficits, such as extended memory loss, strange behavior, unusual thinking, impaired judgment, impotence, and difficulty with daily living activities. Dementia is not a disease, but it is caused by several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Lewy's bodies. Several drugs and remedies are indicated for alleviating unusual cognitive decline, but no effective pharmacological treatment regimens are available without side effects. Herbal drugs or traditional medicines like Ayurveda have been known for facilitating and corroborating the balance between mind, brain, body, and environment. Ayurvedic therapy comprises 600 herbal formulas, 250 single plant remedies, and natural and holistic health-giving treatments that relieve dementia in patients and increase vitality. Ayurvedic Rasayana herbs [rejuvenating elements] strengthen the brain cells, enhance memory, and decrease stress. The current medicine scenario in the treatment of dementia has prompted the shift in exploring the efficacy of ayurvedic medicine, its safety, and its efficiency. This review presents the literature on several herbal treatments for improving dementia symptomatology and patients' quality of life.

Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses.

Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I-stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.

Role of polymorphisms in dopamine synthesis and metabolism genes and association of DBH haplotypes with Parkinson's disease among North Indians.

OBJECTIVES: Genetic and non-genetic components are believed to govern the etiology of common complex traits such as Parkinson's disease (PD). In view of the biochemical evidence of depleted dopamine levels in the affected brains and also the most common and effective therapeutic modality of administration of levodopa in PD, genes from the dopaminergic pathway emerge as major determinants. We have earlier shown the role of DRD4-120 bp duplication marker in PD susceptibility. In this study, contribution of six genes involved in dopamine synthesis and metabolism to PD susceptibility and disease severity was assessed in a North Indian PD cohort. METHODS: 339 patients diagnosed using UKPD brain bank criteria and 344 matched controls were recruited and disease severity was assessed using the Hoehn and Yahr scale and Unified Parkinson Disease Rating Scale III scores. Allelic, genotypic and haplotypic associations with PD were computed; severity was compared among the genotypic categories of markers; gene-gene interactions were assessed using multiple logistic regression. RESULTS: A highly significant association of dopamine beta-hydroxylase (DBH) haplotypes (rs1611115T>C - rs1108580A>G - rs5320A>G - rs129882C>T) with PD was observed; haplotypes C-A-G-C [P=0.000005, Odds ratio (95% confidence interval): OR (95% CI)=1.76 (1.38-2.25)] and C-A-G-T [P=0.000001, OR (95% CI)=0.49 (0.37-0.65)] retaining significance after Bonferroni correction. rs129882, a 3'UTR SNP in DBH showed significant association with disease severity [Hoehn and Yahr (P=0.005) and Unified Parkinson Disease Rating Scale (P=0.006)]. CONCLUSION: Observed association of DBH SNP/SNP haplotypes with PD susceptibility and its role in modulating disease severity reiterates the importance of dopamine pathway in sporadic PD etiology in general and potential therapeutic implications of DBH in particular.

Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

BACKGROUND: Because excessive reduction in activities after back injury may impair recovery, it is important to understand and address the factors contributing to the variability in motor responses to pain. The current dominant theory is the "fear-avoidance model", in which the some patients' heightened fears of further injury cause them to avoid movement. We propose that in addition to psychological factors, neurochemical variants in the circuits controlling movement and their modification by pain may contribute to this variability. A systematic search of the motor research literature and genetic databases yielded a prioritized list of polymorphic motor control candidate genes. We demonstrate an analytic method that we applied to 14 of these genes in 290 patients with acute sciatica, whose reduction in movement was estimated by items from the Roland-Morris Disability Questionnaire. RESULTS: We genotyped a total of 121 single nucleotide polymorphisms (SNPs) in 14 of these genes, which code for the dopamine D2 receptor, GTP cyclohydrolase I, glycine receptor alpha1 subunit, GABA-A receptor alpha2 subunit, GABA-A receptor beta1 subunit, alpha-adrenergic 1C, 2A, and 2C receptors, serotonin 1A and 2A receptors, cannabinoid CB-1 receptor, M1 muscarinic receptor, and the tyrosine hydroxylase, and tachykinin precursor-1 molecules. No SNP showed a significant association with the movement score after a Bonferroni correction for the 14 genes tested. Haplotype analysis of one of the blocks in the GABA-A receptor beta1 subunit showed that a haplotype of 11% frequency was associated with less limitation of movement at a nominal significance level value (p = 0.0025) almost strong enough to correct for testing 22 haplotype blocks. CONCLUSION: If confirmed, the current results may suggest that a common haplotype in the GABA-A beta1 subunit acts like an "endogenous muscle relaxant" in an individual with subacute sciatica. Similar methods might be applied a larger set of genes in animal models and human laboratory and clinical studies to understand the causes and prevention of pain-related reduction in movement.

Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms.

BACKGROUND: A haplotype in the GTP cyclohydrolase 1 (dopa-responsive dystonia) gene (GCH1) is associated with decreased persistent pain. The aim of the present study was to develop a screening method for the pain-protective haplotype. METHODS: Complete genetic information for all 15 GCH1 DNA positions constituting the pain-protective GCH1 haplotype was available from 278 patients. In silico analyses, including discriminant analysis of the most frequent haplotypes, identified distinctive DNA positions that allow detection of the pain-protective haplotype at high sensitivity and specificity with the smallest possible number of DNA positions. Pyrosequencing(trade mark) assays were subsequently developed for these DNA positions, established with 662 DNA samples from healthy volunteers, and prospectively validated with a random selection of DNA samples genotyped for all 15 DNA positions. RESULTS: Diagnosis of the pain-protective GCH1 haplotype was possible with 100% sensitivity and specificity by screening for just 3 GCH1 genetic variants that span the entire DNA range of the haplotype: c.-9610G>A (dbSNP rs8007267G>A) in the 5' untranslated region, c.343 + 8900A>T (dbSNP rs3783641A>T) in intron 1, and c.*4279 (dbSNP rs10483639C>G) in the 3' untranslated region. Test sensitivity and specificity were still >95% with 2 or even just 1 of these GCH1 DNA positions. CONCLUSIONS: In silico analysis of complex GCH1 gene haplotypes reduced the requisite number of tested DNA positions from 15 to 3 while maintaining the reliability, specificity, and sensitivity of the genetic diagnosis. This screening method could reduce laboratory diagnostic efforts and facilitate investigations of the pain-protective GCH1 haplotype.