INVESTIGATION OF QUASI BI-SLANT RIEMANNIAN MAPS

Riemannian maps are generalization of well-known notions of isometric immersions and Riemannian submersions. In this paper, we defne and study a natural generalization of previously defned quasi bi-slant submersions [18] in the case of Riemannian maps. We mainly investigate fundamental results on quasi bi-slant Riemannian maps from almost Hermitian manifolds to Riemannian manifolds: the integrability of distributions, geometry of foliations, the condition for such maps to be totally geodesic, etc. At the end of the article, we give proper non-trivial examples for this notion

Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ.

Phosphoinositide 3-kinase δ (PI3Kδ), a lipid kinase consisting of a catalytic (p110δ, encoded by PIK3CD) and a regulatory subunit (p85, encoded by PIK3R1), generates the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in the plasma membrane of leukocytes downstream of antigen and cytokine receptors.1 Signaling via PDK1, AKT, mTOR and downstream targets such as FOXO1, contributes to the metabolic and transcriptional changes required for the expansion, differentiation and effector function of lymphocytes. Activating germline mutations in PIK3CD cause the immune dysregulatory disease activated PI3Kδ syndrome (APDS), usually presenting with recurrent sinopulmonary infections in childhood, herpesvirus infections and CD4+ lymphopenia, underscoring the important role of balanced p110δ activity in human adaptive immunity. Ablation of p110δ in mice leads to aberrant T cell responses and intestinal inflammation. In humans, immune dysregulation including severe colitis is present in many cancer patients who are treated with the p110δ-specific inhibitor Idelalisib. Recently, one patient with autosomal recessive deficiency of p85α and two patients with loss-of function mutations in p110δ have been described who developed humoral immunodeficiency and colitis

A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu

Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism

Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1. We performed mass cytometry, proteomic and transcriptomic analyses to investigate peripheral blood cells and serum of HPS-1 patients. Using spatial transcriptomics, granuloma-associated signatures in the tissue of an HPS-1 patient with granulomatous colitis were dissected. In vitro studies were conducted to investigate anti-microbial responses of HPS-1 patient macrophages and cell lines. Monocytes of HPS-1 patients exhibit an inflammatory phenotype associated with dysregulated TNF, IL-1α, OSM in serum, and monocyte-derived macrophages. Inflammatory macrophages accumulate in the intestine and granuloma-associated macrophages in HPS-1 show transcriptional signatures suggestive of a lipid storage and metabolic defect. We show that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. Rab32-mediated mTOR signaling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation

Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease

OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS: Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS: NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex

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

QDB: A new database of plasma chemistries and reactions

One of the most challenging and recurring problems when modeling plasmas is the lack of data on the key atomic and molecular reactions that drive plasma processes. Even when there are data for some reactions, complete and validated datasets of chemistries are rarely available. This hinders research on plasma processes and curbs development of industrial applications. The QDB project aims to address this problem by providing a platform for provision, exchange, and validation of chemistry datasets. A new data model developed for QDB is presented. QDB collates published data on both electron scattering and heavy-particle reactions. These data are formed into reaction sets, which are then validated against experimental data where possible. This process produces both complete chemistry sets and identifies key reactions that are currently unreported in the literature. Gaps in the datasets can be filled using established theoretical methods. Initial validated chemistry sets for SF 6 /CF 4 /O 2 and SF 6 /CF 4 /N 2 /H 2 are presented as examples

Modeling of growth and prediction of properties of electronic nanomaterials: Silicon thin films and compound semiconductor quantum dots

The enhanced functionality and tunability of electronic nanomaterials enables the development of next-generation photovoltaic, optoelectronic, and electronic devices, as well as biomolecular tags. Design and efficient synthesis of such semiconductor nanomaterials require a fundamental understanding of the underlying process-structure/composition-property-function relationships. To this end, this thesis focuses on a systematic, comprehensive analysis of the physical and chemical phenomena that determine the composition and properties of semiconductor nanomaterials. Through synergistic combination of computational modeling and experimental studies, the thesis addresses the thermodynamics and kinetics that are relevant during synthesis and processing and their resulting impact on the properties of silicon thin films and ternary quantum dots (TQDs) of compound semiconductors. The thesis presents a computational study of the growth mechanisms of plasma deposited a-Si:H thin films based on kinetic Monte Carlo (KMC) simulations according to a transition probability database constructed by first-principles density functional theory (DFT) calculations. Based on the results, a comprehensive model is proposed for a-Si:H thin-film growth by plasma deposition under conditions that make the silyl (SiH3) radical the dominant deposition precursor. It is found that the relative roles of surface coordination defects are crucial in determining the surface composition of plasma deposited a-Si:H films and should be properly accounted for. The KMC predictions for the temperature dependence (over the range from 300 K to 700 K) of the surface concentration of SiHx(s) (x = 1,2,3) surface hydride species, the surface hydrogen content, and the surface dangling-bond coverage are in agreement with experimental measurements. In addition, the thesis details a systematic analysis of equilibrium compositional distribution in TQDs and their effects on the electronic and optoelectronic properties. Formation of hetero-nanostructures, such as core/shell-like structures, through atomic-scale assembly driven by equilibrium surface segregation is studied as a function of nanocrystal size, composition, and temperatures for TQD morphologies that include faceted equilibrium nanocrystal shapes for ZnSe1-xTex and InxGa1-xAs TQDs; the results are based on coupled compositional, structural, and volume relaxation of the nanocrystals according to Monte Carlo and conjugate-gradient methods employing a DFT-parameterized description of interatomic interactions. A phenomenological species transport theory also is developed that explains the concentration profiles due to surface-segregation-induced ordering of constituent and dopant atoms in the dilute limit. The nm-scale diffusion lengths in nanocrystals introduce an interesting interplay between the kinetic and thermodynamic stability of interfaces. The thermodynamic stability of such interfaces in ZnSe 1-xSx TQDs are investigated based on DFT calculations combined with X-ray photoelectron spectroscopy (XPS) and photoluminescence (PL) spectra of TQDs that are synthesized and annealed using colloidal methods. The results demonstrate the possibility of compositional redistribution that causes degradation over time of core/shell TQD electronic properties, with far reaching implications for the use of such nanostructures in devices. Electronic structure calculations of ZnSe1-xSx (type-I) and ZnSe1-xTe x (type-II) TQDs elucidate the impact of composition and compositional distribution on the electron density distribution, density of states, and band gap of the TQDs. The resulting relationships with respect to the distributions in the TQDs of constituent/dopant/impurity atoms (core/shell vs. alloyed TQDs) provide an interpretation for the key features observed in the PL spectra, as well as useful guidelines for improving the design and device performance of TQDs

On the growth mechanism of plasma deposited amorphous silicon thin films

We propose a comprehensive mechanism of amorphous silicon thin film growth by plasma deposition based on results of kinetic Monte Carlo simulations according to a database constructed by first-principles density functional theory calculations. The growth mechanism consists of various surface kinetic events including radical-surface and adsorbed radical-radical interactions, radical-surface diffusion, and surface hydride dissociation reactions. Of particular importance is the radical dissociative adsorption mediated by Si over-coordination defects along the reaction pathway. The proposed mechanism explains fully the experimentally measured surface composition of plasma deposited films under conditions that make the silyl radical the dominant deposition precursor