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TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer’s disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.

Genome-wide association studies (GWAS) have identified many modifiers of Alzheimer disease (AD) risk enriched in microglia. Two of these modifiers are common variants in theMS4Alocus (rs1582763: protective and rs6591561: risk) and serve as major regulators of CSF sTREM2 levels. To understand their functional impact on AD, we used single nucleus transcriptomics to profile brains from carriers of these variants. We discovered a “chemokine” microglial subpopulation that is altered inMS4Avariant carriers and for whichMS4A4Ais the major regulator. The protective variant increasesMS4A4Aexpression and shifts the chemokine microglia subpopulation to an interferon state, while the risk variant suppressesMS4A4Aexpression and reduces this subpopulation of microglia. Our findings provide a mechanistic explanation for the AD variants in theMS4Alocus. Further, they pave the way for future mechanistic studies of AD variants and potential therapeutic strategies for enhancing microglia resilience in AD pathogenesis.

Facial motoneuron (FMN) survival is mediated by CD4+ T cells in an interleukin-10 (IL-10)-dependent manner after facial nerve axotomy (FNA), but CD4+ T cells themselves are not the source of this neuroprotective IL-10. The aims of this study were to (1) identify the temporal and cell-specific induction of IL-10 expression in the facial motor nucleus and (2) elucidate the neuroprotective capacity of this expression after axotomy. Immunohistochemistry revealed that FMN constitutively produced IL-10, whereas astrocytes were induced to make IL-10 after FNA. Il10 mRNA co-localized with microglia before and after axotomy, but microglial production of IL-10 protein was not detected. To determine whether any single source of IL-10 was critical for FMN survival, Cre/Lox mouse strains were utilized to selectively knock out IL-10 in neurons, astrocytes, and microglia. In agreement with the localization data reflecting concerted IL-10 production by multiple cell types, no single cellular source of IL-10 alone could provide neuroprotection after FNA. These findings suggest that coordinated neuronal and astrocytic IL-10 production is necessary for FMN survival and has roles in neuronal homeostasis, as well as neuroprotective trophism after axotomy.

More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau. To do this, we analyzed genes differentially expressed in induced pluripotent stem cell (iPSC)–derived neurons that represent the three major categories of MAPT mutations: splicing (IVS10+16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. Here, we identified 275 genes that were commonly differentially expressed in MAPT IVS10+16, p.P301L, and p.R406W neurons. These genes were enriched in synaptic and endolysosomal pathways and neuronal development and were also altered in the presence of tau aggregation in a mouse model of tauopathy. The MAPT mutations commonly led to changes in genes and pathways sensitive to disruptions in calcium homeostasis. One of these genes, CALB1, plays a role in calcium dysregulation and is targeted by several FDA- approved drugs used to treat neurological symptoms. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from progressive supranuclear palsy patients, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-derived neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and endolysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. AD is also the result of complex genetic architecture that can be leveraged to understand pathways central to disease processes. We have previously identified coding variants in the phospholipase D3 (PLD3) gene that double the late-onset AD risk. However, the mechanism by which PLD3 impacts AD risk is unknown. One AD risk variant, PLD3 p.A442A, disrupts a splicing enhancer-binding site and reduces PLD3 splicing in human brains. Using differentiated induced pluripotent stem cells from a PLD3 p.A442A carrier and CRISPR-reverted, isogenic control, we show that PLD3 p.A442A cortical neurons exhibit a PLD3 splicing defect and a significant increase in Aβ42 and Aβ40, both of which are corrected upon reversion of the risk allele in isogenic control neurons. Thus, PLD3 p.A442A is sufficient to alter PLD3 splicing and Aβ metabolism. While the normal function of PLD3 is poorly understood, PLD3 is highly expressed in neurons and brain regions most susceptible to amyloid pathology. PLD3 expression is significantly lower in AD brains than controls, suggesting that PLD3 may play a role in sporadic AD. Thus, we sought to determine whether PLD3 contributes to Aβ accumulation in AD. In a mouse model of amyloid accumulation, loss of Pld3 increases interstitial fluid (ISF) Aβ and reduces Aβ turnover. AAV-mediated overexpression of PLD3 in the hippocampus decreased ISF Aβ levels and accelerated Aβ turnover. To determine whether PLD3-mediated reduction of ISF Aβ impacts amyloid accumulation, we measured amyloid plaque abundance and size after significant Aβ deposition. We found that in the absence of Pld3, amyloid plaques were less compact and more diffuse. Additionally, we observed reduced recruitment of microglia to amyloid plaques in the absence of Pld3. PLD3 may impact amyloid accumulation and AD risk through disrupted microglia function as PLD3 is enriched in disease associated microglia in human brains. Together, our findings demonstrate that PLD3 regulates Aβ clearance through cell-autonomous and non-cell-autonomous pathways in a manner that likely contributes to AD risk.

This paper is primarily focused on E-commerce fraud detection using machine learning techniques. There are many different ways to detect E-commerce fraud using machine learning approach. In this work, comparison study is conducted between various available machine learning algorithms to detect the online frauds. During the comparative study, focus is underlined on comparison of all the algorithms to identify the fraud transactions. When compared to other algorithms, such as support vector machine, Decision Tree, K-nearest neighbour and Random Forest, it has been observed that Logistic regression gives better result among all machine learning algorithms.

An imbalance in gut homeostasis results in local and systemic pathogenesis. It is still not well-understood how the immune system interacts with the gut microbiome and maintains a delicate balance. Here, we utilized a mouse model in which STAT3 expression is deleted in CD11c+ (i.e., dendritic) cells (STAT3 cKO); these mice developed an ulcerative colitis-like disease, colon carcinoma and myelodysplastic syndrome-like disease. Circulating IgE levels in STAT3 cKO mice were significantly elevated. The gut microbiome was indispensable for the observed pathogenesis, as treatment with broad-spectrum antibiotics or cross-fostering STAT3 cKO pups with mothers harboring a different microbiome prevented disease development. Gut microbiome analyses suggested that decreased commensal bacteria and increased pathogenic bacteria most likely contributed to disease. Our data suggest that STAT3 controls the manifestation of inflammation in the gut caused by the microbiome. Therefore, we conclude that a deficiency of STAT3 in DCs is sufficient to trigger uncontrolled inflammation and the development of inflammatory bowel disease.

Background After peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA). Methods Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the facial motor nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets. Results CD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro. Conclusions These findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA.

Invariant natural killer T (iNKT) cells play critical roles in autoimmune, anti-tumor, and anti-microbial immune responses, and are activated by glycolipids presented by the MHC class I-like molecule, CD1d. How the activation of signaling pathways impacts antigen (Ag)-dependent iNKT cell activation is not well-known. In the current study, we found that the MAPK JNK2 not only negatively regulates CD1d-mediated Ag presentation in APCs, but also contributes to CD1d-independent iNKT cell activation. A deficiency in the JNK2 (but not JNK1) isoform enhanced Ag presentation by CD1d. Using a vaccinia virus (VV) infection model known to cause a loss in iNKT cells in a CD1d-independent, but IL-12-dependent manner, we found the virus-induced loss of iNKT cells in JNK2 KO mice was substantially lower than that observed in JNK1 KO or wild-type (WT) mice. Importantly, compared to WT mice, JNK2 KO mouse iNKT cells were found to express less surface IL-12 receptors. As with a VV infection, an IL-12 injection also resulted in a smaller decrease in JNK2 KO iNKT cells as compared to WT mice. Overall, our work strongly suggests JNK2 is a negative regulator of CD1d-mediated Ag presentation and contributes to IL-12-induced iNKT cell activation and loss during viral infections.

Recently vehicle tracking system is getting vast popularity because of the rising number of the stolen vehicles .Vehicle theft can happen mainly in areas which lacks in security. People have started to use the theft control systems installed in their vehicles. The commercially available antitheft vehicular systems are very expensive. And this project is developed as low cost vehicle theft control scheme using a microcontroller and with usage of GPS and GSM technology along with lock keypad. The system contains ARDUINO board which is the main part . Using this system we can control the vehicle ignition and get the location of the vehicle by sending message to the GSM module. We can also lock and unlock the vehicle by sending a message. If the vehicle seems to be stolen, the owner can stop the vehicle ignition and lock the vehicle by sending message. It is exceptionally straightforward method which provides more security for vehicles with robbery assurance. The simplicity of this work makes it unique.

Introduction Learning disabilities cannot be cured but they can be treated successfully and children with learning disabilities can go to live happy and successful lives. Learning disability is a classification including several disorders in which a person has difficulty learning in a typical manner usually caused by an unknown factor or factors .The unknown factor is the disorder that affects the brains ability to receive and process information .This disorder can make it problematic for a person to learn as quickly or in the same way as someone who isnt affected by a learning disability .Learning disability have trouble performing specific types of skills or completing task if left to figure things out by themselves or if taught in conventional ways.Objectives 1. To assess the existing level of knowledge of parents regarding the learning disability of autistic children in selected special school Bangalore.2. To assess the post-test knowledge level of parents regarding the learning disabilities of autism children in selected special school Bangalore.3.To assess the effectiveness of information booklet on knowledge of parents regarding learning disabilities of autism children.4.To find out the association between pre and post-test knowledge score with selected score of the parents in a selected demographic variables.Design Quasi - experimental one group pre-test and post-test design was selected for the study. 30 parents in Navachethana trust was recruited by non probability purposive sampling method. Necessary administrative permission was obtained from concerned authority. Structured interview schedule was used to elicit the baseline data and structured questionnaire were used to elicit the knowledge of parents.Setting The study was conducted in Navachethana trust situated in Banashankari Bangalore.Result The study revealed that among10 33 parents had moderately adequate knowledge 20 parents 67 parents had adequate knowledge in the post-test score on learning disabilities. There was no inadequate knowledge found in the post-test. The mean pre-test knowledge score of parents in the special school was 18.5 whereas the mean post-test knowledge score was 24.56. The obtainedlsquotrsquo value for knowledge was 18.37 lsquoprsquo value was 3.92.Conclusion The study concluded that the information booklet on learning disabilities carried out in the study was found to be effective in improving the knowledge of parents as evidenced by the significant change between pre-test and post-test knowledge score.

Cytokines that regulate the immune response signal through the Janus kinase / signal transducer and activation of transcription (JAK/STAT) pathway, but whether this pathway can regulate CD1d-mediated lipid antigen presentation to natural killer T (NKT) cells is unknown. Here, we found that STAT3 promotes antigen presentation by CD1d. Antigen-presenting cells (APCs) in which STAT3 expression was inhibited exhibited markedly reduced endogenous lipid antigen presentation to NKT cells without an impact on exogenous lipid antigen presentation by CD1d. Consistent with this observation, in APCs where STAT3 was knocked down, dramatically decreased levels of UDP glucose ceramide glucosyltransferase (UGCG), an enzyme involved in the first step of glycosphingolipid biosynthesis, were observed. Impaired lipid antigen presentation was reversed by ectopic expression of UGCG in STAT3-silenced CD1d(+) APCs. Hence, by controlling a fundamental step in CD1d-mediated lipid antigen presentation, STAT3 signalling promotes innate immune responses driven by CD1d.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS.

Summary CD1d-mediated lipid antigen presentation activates a subset of innate immune lymphocytes called invariant natural killer T (NKT) cells that, by virtue of their potent cytokine production, bridge the innate and adaptive immune systems. Transforming growth factor (TGF-β) is a known immune modulator that can activate the mitogen-activated protein kinase p38; we have previously shown that p38 is a negative regulator of CD1d-mediated antigen presentation. Several studies implicate a role for TGF-β in the activation of p38. Therefore, we hypothesized that TGF-β would impair antigen presentation by CD1d. Indeed, a dose-dependent decrease in CD1d-mediated antigen presentation and impairment of lipid antigen processing was observed in response to TGF-β treatment. However, it was found that this inhibition was not through p38 activation. Instead, Smads 2, 3 and 4, downstream elements of the TGF-β canonical signalling pathway, contributed to the observed effects. In marked contrast to that observed with CD1d, TGF-β was found to enhance MHC class II-mediated antigen presentation. Overall, these results suggest that the canonical TGF-β/Smad pathway negatively regulates an important arm of the host's innate immune responses – CD1d-mediated lipid antigen presentation to NKT cells.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive disorder characterized by the selective degeneration of motor neurons (MN). The impact of peripheral immune status on disease progression and MN survival is becoming increasingly recognized in the ALS research field. In this review, we briefly discuss findings from mouse models of peripheral nerve injury and immunodeficiency to understand how the immune system regulates MN survival. We extend these observations to similar studies in the widely used superoxide dismutase 1 (SOD1) mouse model of ALS. Last, we present future hypotheses to identify potential causative factors that lead to immune dysregulation in ALS. The lessons from preceding work in this area offer new exciting directions to bridge the gap in our current understanding of immune-mediated neuroprotection in ALS.