The crystal structure of 4-(3-bromophenyl)pyrimidin-2-amine, C 10 H 8 BrN 3

C10H8BrN3, orthorhombic, Pbca (no. 61), a = 7.214(3) Å, b = 12.735(6) Å, c = 21.305(9) Å, V = 1957.3(15) Å3, Z = 8, R gt (F) = 0.0353, wR ref (F 2) = 0.0808, T = 293 K

Nonresonant powering of injectable nanoelectrodes enables wireless deep brain stimulation in freely moving mice

Devices that electrically modulate the deep brain have enabled important breakthroughs in the management of neurological and psychiatric disorders. Such devices are typically centimeter-scale, requiring surgical implantation and wired-in powering, which increases the risk of hemorrhage, infection, and damage during daily activity. Using smaller, remotely powered materials could lead to less invasive neuromodulation. Here, we present injectable, magnetoelectric nanoelectrodes that wirelessly transmit electrical signals to the brain in response to an external magnetic field. This mechanism of modulation requires no genetic modification of neural tissue, allows animals to freely move during stimulation, and uses nonresonant carrier frequencies. Using these nanoelectrodes, we demonstrate neuronal modulation in vitro and in deep brain targets in vivo. We also show that local subthalamic modulation promotes modulation in other regions connected via basal ganglia circuitry, leading to behavioral changes in mice. Magnetoelectric materials present a versatile platform technology for less invasive, deep brain neuromodulation

MERS-CoV Infection and Its Impact on the Expression of TSLP Cytokine and IgG Antibodies: An In Vivo and In Vitro Study

Ayman Mubarak,1 Mahfoudh Alqoufail,1 Saeedah Almutairi,1 Bahauddeen Alrfaei,2 Abdulaziz Almotairi,3 Ibrahim Aziz,1 Taghreed N Almanaa,1 Mostafa A Abdel-Maksoud,1 Mohamed A Farrag,1 Allolo D Aldreiwish,4 Maaweya E Awadalla,5 Bandar Alosaimi,5 Wael Alturaiki4 1Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia; 2Stem Cells Unit, Department of Cellular Therapy, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Science, MNGHA, Riyadh, Saudi Arabia; 3College of Medicine, Almaarefa University, Riyadh, Saudi Arabia; 4Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, 11952, Saudi Arabia; 5Research Center, King Fahad Medical City, Riyadh Second Health Cluster, Riyadh, Saudi ArabiaCorrespondence: Wael Alturaiki, Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, 11952, Saudi Arabia, Email [email protected]: Thymic stromal lymphopoietin (TSLP) is a proinflammatory cytokine produced by epithelial cells that is involved in the activation of allergic disorders. To date, no study has examined TSLP induction during Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Herein, we aimed to study the effects of the recombinant spike protein of MERS-CoV on TSLP production. Additionally, the effects of recombinant human TSLP (rhTSLP) on B cell survival and antibody production were investigated.Patients and Methods: B cells were separated using the Human B Cell Enrichment Kit, and B cell survival was measured using the WST-1 Assay Kit. Enzyme-linked immunosorbent assay (ELISA) was used to measure TSLP levels in the sera of both MERS-CoV-infected (n=4; median age, 53 years) and healthy individuals (n=5; median age, 35 years).Results: We showed that the group of infected patients had significantly higher levels of TSLP than healthy controls (37.6 pg/mL vs 19.8 pg/mL, &ast;p< 0.05). The levels of TSLP in A549 cells were remarkably increased after 48 h of stimulation with recombinant full-length spike protein (rSP) (32.2 pg/mL, p=0.01). B cell survival was greatly enhanced by rhTSLP alone or in combination with rSP (0.02 vs 0.046, and 0.045; &ast;&ast;p< 0.01, respectively). Our data also showed a significant synergistic effect of rhTSLP and rSP on the augmented response of IgG antibodies against the spike protein of MERS-CoV compared with unstimulated cells (0.156 vs 0.22; &ast;p< 0.05).Conclusion: TSLP production is induced in vivo after MERS-CoV infection and in vitro after treatment with the rSP of MERS-CoV, which has a significant effect on the survival of B cells. Our data suggest that TSLP can be used as a strong mucosal adjuvant for vaccine development against MERS-CoV infection. However, further investigation is required to study the functional role of TSLP in MERS-CoV infection.Keywords: MERS-CoV, TSLP, recombinants spike protein, B cell

Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals with 56 Distinct Heterozygous NFKB1 Mutations

Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.info:eu-repo/semantics/publishedVersio

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old

Current state of cloud computing risk assessment in Malaysian private sector

The potential benefits of cloud computing, such as flexibility and cost-effective, have attracted many companies to use it. Nevertheless, security issues are still prominent in cloud computing. Measuring the security of cloud computing can be effectively implemented by performing cloud computing risk assessments. Since the traditional risk assessment method is no longer applicable to cloud computing, the effective method in assessing cloud computing becomes the debated issues among scholars. This study reveals the current state of cloud computing risk assessment conducted in the private sector in Malaysia. We performed a semi-structured interview session with five private companies and highlighted the issues debated by the scholar

Clustering of diet, physical activity and sedentary behaviour and related physical and mental health outcomes: a systematic review

Abstract Background Physical activity (PA), sedentary behaviour (SB) and diet play an important role in the physical and mental health of young people. Understanding how these behaviours cluster, and the impact of clusters on health is important for the development of public health interventions. This review examines the prevalence of clusters of PA, sedentary time, and dietary behaviours, and how clusters relate to physical and mental health indicators among children, adolescents and young adults. Methods Electronic (PubMed, Web of Science and Scopus) and manual searches were conducted for articles that were (i) observational studies including children, adolescents and/or young adults aged 5–24 years, (ii) examined the 'patterning', ‘clustering’, or ‘co-existence’ of each of PA, dietary behaviour and SB, and (iii) published in English up to and including July 2022. In addition to information on clustering, data on physical and mental health outcomes were extracted where reported. Included studies were assessed using the Cochrane risk of bias for observational studies. A narrative synthesis was conducted due to high heterogeneity. This review was registered with PROSPERO (CRD42021230976). Results Forty-nine cross-sectional studies and four prospective cohort studies from eighteen countries reporting data from 778,415 individual participants were included. A broad range of clusters (n = 172) were found (healthy, unhealthy, and mixed). Mixed clusters were common (n = 98), and clusters of high diet quality, low PA and high SB were more prevalent in girls, while mixed clusters of high PA, high SB and low diet quality were more prevalent in boys. Unhealthy clusters comprising low moderate to vigorous PA, low consumption of fruits and vegetables, and high screen time were prevalent, particularly in those from lower socioeconomic status families. Compared to those with healthy behavioural clusters, those with unhealthy and mixed clusters had a higher adiposity, higher risk of cardiovascular disease, poorer mental health scores, and lower cardiorespiratory fitness. Conclusions PA, SB and diet cluster in healthy, unhealthy and mixed patterns in young people that differ across sociodemographic characteristics. Unhealthy clusters are associated with poorer health outcomes. Intervention strategies targeting un-clustering multiple unhealthy behaviours should be developed and evaluated for their impact on health outcomes