Alpha2beta1 Integrin (VLA-2) Protects Activated Human Effector T Cells From Methotrexate-Induced Apoptosis

β1 integrins are critical for T cell migration, survival and costimulation. The integrin α2β1, which is a receptor for collagen, also named VLA-2, is a major costimulatory pathway of effector T cells and has been implicated in arthritis pathogenesis. Herein, we have examined its ability to promote methotrexate (MTX) resistance by enhancing effector T cells survival. Our results show that attachment of anti-CD3-activated human polarized Th17 cells to collagen but not to fibronectin or laminin led to a significant reduction of MTX-induced apoptosis. The anti-CD3+collagen-rescued cells still produce significant amounts of IL-17 and IFNγ upon their reactivation indicating that their inflammatory nature is preserved. Mechanistically, we found that the prosurvival role of anti-CD3+collagen involves activation of the MTX transporter ABCC1 (ATP Binding Cassette subfamily C Member 1). Finally, the protective effect of collagen/α2β1 integrin on MTX-induced apoptosis also occurs in memory CD4+ T cells isolated from rheumatoid arthritis (RA) patients suggesting its clinical relevance. Together these results show that α2β1 integrin promotes MTX resistance of effector T cells, and suggest that it could contribute to the development of MTX resistance that is seen in RA

Uses of quinazolin-2-[(β-propionoyl)isothiocyanate]-4-one as a building block in synthesis of some heterocyclic compounds of expected biological activity

1153-115

Supercoherent States, Super K\"ahler Geometry and Geometric Quantization

Generalized coherent states provide a means of connecting square integrable representations of a semi-simple Lie group with the symplectic geometry of some of its homogeneous spaces. In the first part of the present work this point of view is extended to the supersymmetric context, through the study of the OSp(2/2) coherent states. These are explicitly constructed starting from the known abstract typical and atypical representations of osp(2/2). Their underlying geometries turn out to be those of supersymplectic OSp(2/2) homogeneous spaces. Moment maps identifying the latter with coadjoint orbits of OSp(2/2) are exhibited via Berezin's symbols. When considered within Rothstein's general paradigm, these results lead to a natural general definition of a super K\"ahler supermanifold, the supergeometry of which is determined in terms of the usual geometry of holomorphic Hermitian vector bundles over K\"ahler manifolds. In particular, the supergeometry of the above orbits is interpreted in terms of the geometry of Einstein-Hermitian vector bundles. In the second part, an extension of the full geometric quantization procedure is applied to the same coadjoint orbits. Thanks to the super K\"ahler character of the latter, this procedure leads to explicit super unitary irreducible representations of OSp(2/2) in super Hilbert spaces of $L^2$ superholomorphic sections of prequantum bundles of the Kostant type. This work lays the foundations of a program aimed at classifying Lie supergroups' coadjoint orbits and their associated irreducible representations, ultimately leading to harmonic superanalysis. For this purpose a set of consistent conventions is exhibited.Comment: 53 pages, AMS-LaTeX (or LaTeX+AMSfonts

A diabetes risk score for Qatar utilizing a novel mathematical modeling approach to identify individuals at high risk for diabetes

We developed a diabetes risk score using a novel analytical approach and tested its diagnostic performance to detect individuals at high risk of diabetes, by applying it to the Qatari population. A representative random sample of 5,000 Qataris selected at different time points was simulated using a diabetes mathematical model. Logistic regression was used to derive the score using age, sex, obesity, smoking, and physical inactivity as predictive variables. Performance diagnostics, validity, and potential yields of a diabetes testing program were evaluated. In 2020, the area under the curve (AUC) was 0.79 and sensitivity and specificity were 79.0% and 66.8%, respectively. Positive and negative predictive values (PPV and NPV) were 36.1% and 93.0%, with 42.0% of Qataris being at high diabetes risk. In 2030, projected AUC was 0.78 and sensitivity and specificity were 77.5% and 65.8%. PPV and NPV were 36.8% and 92.0%, with 43.0% of Qataris being at high diabetes risk. In 2050, AUC was 0.76 and sensitivity and specificity were 74.4% and 64.5%. PPV and NPV were 40.4% and 88.7%, with 45.0% of Qataris being at high diabetes risk. This model-based score demonstrated comparable performance to a data-derived score. The derived self-complete risk score provides an effective tool for initial diabetes screening, and for targeted lifestyle counselling and prevention programs.Peer reviewe

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC

Privacy preserving in indoor fingerprint localization and radio map expansion

People spend most of their life time in indoor environments and in all of these environments, Location Service Providers (LSPs) improve users’ navigation. Preserving privacy in Location Based Services (LBSs) is vital for indoor LBSs and fingerprinting based indoor localization method is an emerging technique in indoor localization. In such systems, LSP may be curious and untrusted. Therefore, it is preferred that user estimates its location by using a Partial Radio Map (PRM) which is achieved by LSP, anonymously. In this paper, a privacy preserving method that uses Bloom filter for preserving anonymity and creating PRM during localization process, is proposed. In this method, LSP cannot recognize user identity, which is anonymized by the anonymizer. The proposed method has lower computational complexity compared with methods that use encryption or clustering concepts. The proposed method also has higher accuracy in localization compared with those that use Bloom filter with one random selected AP. Then, in order to decrease the complexity and to increase the accuracy at the same time, we introduce a method that expands the radio map by authenticated users, without compromising their privacy. We also enhance the performance of this method, using Hilbert curve for preserving the ambiguity of users’ location. After verifying the user’s data, LSP sends a certificate to the authenticated users. This certificate can increase the priority of users in LBS requests. Simulation results and measurements show that the proposed method on average improves the localization accuracy up to 16% compared with existing location privacy methods

COVID‐19 effect on patients with noncommunicable diseases: a narrative review

Background and Aims: On March 11, 2020, the WHO has declared COVID‐19 a global pandemic, affecting our day‐to‐day lives. Physical distancing and lockdown made significant obstacles to populations, particularly healthcare systems. Most healthcare workers were reallocated to COVID‐19 facilities. Noncommunicable disease patients were given low priority and are at a higher risk of severe COVID‐19 infection, which disrupted the treatment and disease management of these patients. This review aimed to assess the effect of COVID‐19 on different types of noncommunicable diseases and the severity it may cause to patients. Methods: We have conducted a review of the literature on COVID‐19 and noncommunicable diseases from December 2019 until January 2022. The search was done in PubMed and Cochrane for relevant articles using variety of searching terms. Data for study variables were extracted. At the end of the selection process, 46 papers were selected for inclusion in the literature review. Result: The result from this review found that the COVID‐19 pandemic has affected the efficiency of the patient's treatment indirectly by either delaying or canceling sessions, which solidified the need to rely more on telemedicine, virtual visits, and in‐home visits to improve patient education and minimize the risk of exposure to the patients. The major and most common types of noncommunicable diseases are known to be related to the severe outcomes of COVID‐19 infection. It is strongly recommended to prioritize these patients for vaccinations against COVID‐19 to provide them with the protection that will neutralize the risk imposed by their comorbidities. Conclusion: We recommend conducting more studies with larger population samples to further understand the role of noncommunicable diseases (NCDs) in this pandemic. However, this pandemic has also affected the efficiency of NCDs treatment indirectly by delaying or canceling sessions and others

Free-Standing Hierarchically Sandwich-Type Tungsten Disulfide Nanotubes/Graphene Anode for Lithium-Ion Batteries

Transition metal dichalcogenides (TMD), analogue of graphene, could form various dimensionalities. Similar to carbon, one dimensional (1D) nanotube of TMD materials has wide application in hydrogen storage，Li-ion batteries and supercapacitors due to their unique structure and properties. Here we demonstrate the feasibility of tungsten disulfide nanotubes (WS2-NTs)/graphene (GS) sandwich-type architecture as anode for lithium-ion batteries for the first time. The graphene based hierarchical architecture plays vital roles in achieving fast electron/ion transfer, thus leading to good electrochemical performance. When evaluated as anode, WS2-NTs /GS hybrid could maintain a capacity of 318.6 mA/g over 500 cycles at a current density of 1A/g. Besides, the hybrid anode does not require any additional polymetric binder, conductive additives or a separate metal current-collector. The relatively high density of this hybrid is beneficial for high capacity per unit volume. Those characteristics make it a potential anode material for light and high performance lithium-ion batteries

Diabetes Alters Intracellular Calcium Transients in Cardiac Endothelial Cells

Diabetic cardiomyopathy (DCM) is a diabetic complication, which results in myocardial dysfunction independent of other etiological factors. Abnormal intracellular calcium ([Ca2+]i) homeostasis has been implicated in DCM and may precede clinical manifestation. Studies in cardiomyocytes have shown that diabetes results in impaired [Ca2+]i homeostasis due to altered sarcoplasmic reticulum Ca2+ ATPase (SERCA) and sodium-calcium exchanger (NCX) activity. Importantly, altered calcium homeostasis may also be involved in diabetes-associated endothelial dysfunction, including impaired endothelium-dependent relaxation and a diminished capacity to generate nitric oxide (NO), elevated cell adhesion molecules, and decreased angiogenic growth factors. However, the effect of diabetes on Ca2+ regulatory mechanisms in cardiac endothelial cells (CECs) remains unknown. The objective of this study was to determine the effect of diabetes on [Ca2+]i homeostasis in CECs in the rat model (streptozotocin-induced) of DCM. DCM-associated cardiac fibrosis was confirmed using picrosirius red staining of the myocardium. CECs isolated from the myocardium of diabetic and wild-type rats were loaded with Fura-2, and UTP-evoked [Ca2+]i transients were compared under various combinations of SERCA, sarcoplasmic reticulum Ca2+ ATPase (PMCA) and NCX inhibitors. Diabetes resulted in significant alterations in SERCA and NCX activities in CECs during [Ca2+]i sequestration and efflux, respectively, while no difference in PMCA activity between diabetic and wild-type cells was observed. These results improve our understanding of how diabetes affects calcium regulation in CECs, and may contribute to the development of new therapies for DCM treatment