IL-15 sustains IL-7R-independent ILC2 and ILC3 development

The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra(−/−) mice. Il7ra(−/−) ILC2 primarily express an ST2(−) phenotype, but are not inflammatory ILC2. CCR6(+) ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra(−/−) siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra(−/−) ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling

Modernisasi Fungsi Security Bagi Peserta Pendidikan Dasar Satpam PT. Javas Anugerah Perkasa

This Community Service (PKM) aims to provide knowledge and insight to security guards who are carrying out Diksar (basic education) about public services, the rule of law, information technology, and the use of the Indonesian language that is good and right. The benefits of PKM activities are aimed at security guards (security) so that they can provide an understanding of public services, as law enforcers and comply with applicable laws or regulations, understand currently developing information technology and be able to use good and correct Indonesian according to situations and conditions . The results and conclusions of this PKM are that this PKM activity has educated and provided in-depth knowledge about the important role in terms of service and knowledge of security guards as law enforcers and obedient to rules, security guards can understand and apply information technology that is currently developing, and provide an understanding of the proper use of the Indonesian language according to the situation and conditions

Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription

Group 3 innate lymphoid cells (ILC3s) are RORγ

The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4 eosinophils unique to the small intestine

C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α− conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4− eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile

STING gain-of-function disrupts lymph node organogenesis and innate lymphoid cell development in mice

STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer\u27s patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β

Genome-wide DNA methylation analysis in cohesin mutant human cell lines

The cohesin complex has recently been shown to be a key regulator of eukaryotic gene expression, although the mechanisms by which it exerts its effects are poorly understood. We have undertaken a genome-wide analysis of DNA methylation in cohesin-deficient cell lines from probands with Cornelia de Lange syndrome (CdLS). Heterozygous mutations in NIPBL, SMC1A and SMC3 genes account for ∼65% of individuals with CdLS. SMC1A and SMC3 are subunits of the cohesin complex that controls sister chromatid cohesion, whereas NIPBL facilitates cohesin loading and unloading. We have examined the methylation status of 27 578 CpG dinucleotides in 72 CdLS and control samples. We have documented the DNA methylation pattern in human lymphoblastoid cell lines (LCLs) as well as identified specific differential DNA methylation in CdLS. Subgroups of CdLS probands and controls can be classified using selected CpG loci. The X chromosome was also found to have a unique DNA methylation pattern in CdLS. Cohesin preferentially binds to hypo-methylated DNA in control LCLs, whereas the differential DNA methylation alters cohesin binding in CdLS. Our results suggest that in addition to DNA methylation multiple mechanisms may be involved in transcriptional regulation in human cells and in the resultant gene misexpression in CdLS

P-Type ATPase TAT-2 Negatively Regulates Monomethyl Branched-Chain Fatty Acid Mediated Function in Post-Embryonic Growth and Development in C. elegans

Monomethyl branched-chain fatty acids (mmBCFAs) are essential for Caenorhabditis elegans growth and development. To identify factors acting downstream of mmBCFAs for their function in growth regulation, we conducted a genetic screen for suppressors of the L1 arrest that occurs in animals depleted of the 17-carbon mmBCFA C17ISO. Three of the suppressor mutations defined an unexpected player, the P-type ATPase TAT-2, which belongs to the flippase family of proteins that are implicated in mediating phospholipid bilayer asymmetry. We provide evidence that TAT-2, but not other TAT genes, has a specific role in antagonizing the regulatory activity of mmBCFAs in intestinal cells. Interestingly, we found that mutations in tat-2 also suppress the lethality caused by inhibition of the first step in sphingolipid biosynthesis. We further showed that the fatty acid side-chains of glycosylceramides contain 20%–30% mmBCFAs and that this fraction is greatly diminished in the absence of mmBCFA biosynthesis. These results suggest a model in which a C17ISO-containing sphingolipid may mediate the regulatory functions of mmBCFAs and is negatively regulated by TAT-2 in intestinal cells. This work indicates a novel connection between a P-type ATPase and the critical regulatory function of a specific fatty acid

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Arginase-I expression by innate lymphoid cells during fetal development, adult homeostasis, and inflammation

Innate lymphoid cells (ILCs) are a family of immune cells involved in development, homeostasis, and the host response to pathogens. In order to identify subsets of these cells in situ and genetically target them, additional markers for ILCs need to be established. Here, I demonstrate that arginase-I (Arg1), a urea cycle enzyme induced in alternatively activated macrophages, is expressed by multiple ILC lineages in the fetal and adult mouse. In the adult lung, group 2 ILCs (ILC2s) express Arg1 at rest and during type 2 inflammation induced by the parasitic helminth Nippostrongylus brasiliensis. While macrophages induce Arg1 through STAT6 activation, ILC2s express Arg1 in a STAT6-independent manner. Total numbers of Arg1+ cells in the lung are regulated by IL-33, which elevates ILC2 numbers and indirectly induces Arg1 expression in macrophages through activation of STAT6. Arg1 expression in ILC2s may provide a way to target these cells without altering T cell responses.In fetal development, specialized members of group 3 ILCs (ILC3s), lymphoid tissue inducer (LTi) cells, are required for lymph node and Peyer's patch organogenesis, but how LTi cells develop at these sites remains unclear. Here, we identify an Arg1+, Id2+ ILC population in the fetal intestine that can differentiate into IL-7Rα+NK1.1+T-bet+ group 1 ILCs (ILC1s), GATA3hi ILC2s, and RORγt+ group ILC3s in vitro. Based on transcription factor expression, ILC precursors in the fetal intestine represent an intermediate developmental stage between T-bet RORγt- ILC precursors and differentiated ILC lineages. These ILC precursors outnumber other innate lymphoid populations in the intestine at embryonic day (E) 13.5. At E16.5, after the initiation of Peyer's patch organogenesis, intestinal ILC precursors accumulate at the Peyer's patch anlage in a manner that is dependent on lymphotoxin-α (LTα). Thus, during development, ILC precursors accumulate in the intestine, where they aggregate at sites of lymphoid tissue organogenesis and differentiate into mature ILC lineages

Agency responses to a system-driven implementation of multiple evidence-based practices in children’s mental health services

Abstract Background Large mental health systems are increasingly using fiscal policies to encourage the implementation of multiple evidence-based practices (EBPs). Although many implementation strategies have been identified, little is known about the types and impacts of strategies that are used by organizations within implementation as usual. This study examined organizational-level responses to a fiscally-driven, rapid, and large scale EBP implementation in children’s mental health within the Los Angeles County Department of Mental Health. Methods Qualitative methods using the principles of grounded theory were used to characterize the responses of 83 community-based agencies to the implementation effort using documentation from site visits conducted 2 years post reform. Results Findings indicated that agencies perceived the rapid system-driven implementation to have both positive and negative organizational impacts. Identified challenges were primarily related to system implementation requirements rather than to characteristics of specific EBPs. Agencies employed a variety of implementation strategies in response to the system-driven implementation, with agency size associated with implementation strategies used. Moderate- and large-sized agencies were more likely than small agencies to have employed systematic strategies at multiple levels (i.e., organization, therapist, client) to support implementation. Conclusions These findings are among the first to characterize organizational variability in response to system-driven implementation and suggest ways that implementation interventions might be tailored by organizational characteristics