Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer’s disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYKtSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools

CD4/CD8 Ratio and Cancer Risk among Adults with HIV

Background: Independent of CD4 cell count, a low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the United States and Canada. Methods: We examined all cancer-free PWH with 1 or more CD4/CD8 values from North American AIDS Cohort Collaboration on Research and Design observational cohorts with validated cancer diagnoses between 1998 and 2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines. Models were adjusted for age, sex, race and ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness. Results: Among 83 893 PWH, there were 5628 incident cancers, including lung cancer (n = 755), Kaposi sarcoma (n = 501), non-Hodgkin lymphoma (n = 497), and anal cancer (n = 439). The median age at cohort entry was 43 years. The overall median 6-month lagged CD4/CD8 ratio was 0.52 (interquartile range = 0.30-0.82). Compared with a 6-month lagged CD4/CD8 of 0.80, a CD4/CD8 of 0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval = 1.14 to 1.35]). The CD4/CD8 ratio was also inversely associated with non-Hodgkin lymphoma, Kaposi sarcoma, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all 2-sided P <. 05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values. Conclusions: A low CD4/CD8 ratio up to 24 months before cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker

TIC 172900988: A transiting circumbinary planet detected in one sector of TESS data

We report the first discovery of a transiting circumbinary planet detected from a single sector of Transiting Exoplanet Survey Satellite (TESS) data. During Sector 21, the planet TIC 172900988b transited the primary star and then five days later it transited the secondary star. The binary is itself eclipsing, with a period P ≈ 19.7 days and an eccentricity e ≈ 0.45. Archival data from ASAS-SN, Evryscope, KELT, and SuperWASP reveal a prominent apsidal motion of the binary orbit, caused by the dynamical interactions between the binary and the planet. A comprehensive photodynamical analysis of the TESS, archival and follow-up data yields stellar masses and radii of M1 = 1.2384 ± 0.0007 Me and R1 = 1.3827 ± 0.0016 Re for the primary and M2 = 1.2019 ± 0.0007 Me and R2 = 1.3124 ± 0.0012 Re for the secondary. The radius of the planet is R3 = 11.25 ± 0.44 R (1.004 ± 0.039RJup). The planet's mass and orbital properties are not uniquely determined-there are six solutions with nearly equal likelihood. Specifically, we find that the planet's mass is in the range of 824 M3 981 M (2.65 M3 3.09MJup), its orbital period could be 188.8, 190.4, 194.0, 199.0, 200.4, or 204.1 days, and the eccentricity is between 0.02 and 0.09. At V = 10.141 mag, the system is accessible for high-resolution spectroscopic observations, e.g., the Rossiter-McLaughlin effect and transit spectroscopy

UNITY : a low-field magnetic resonance neuroimaging initiative to characterize neurodevelopment in low and middle-income settings

DATA AVAILABILITY : Data collected as part of the UNITY network will be made available to researchers from the academic communities at varying levels of granularity depending on site-specific IRB approvals. For some sites, full access to individual raw and processed data will be provided, whilst for others, owing to national policies (e.g., those located in India) may only be able to provide de-identified composite values (e.g., regional volumes, mean relaxometry measures, etc.). The Bill & Melinda Gates Foundation is committed to open access and broad data availability as permitted.Measures of physical growth, such as weight and height have long been the predominant outcomes for monitoring child health and evaluating interventional outcomes in public health studies, including those that may impact neurodevelopment. While physical growth generally reflects overall health and nutritional status, it lacks sensitivity and specificity to brain growth and developing cognitive skills and abilities. Psychometric tools, e.g., the Bayley Scales of Infant and Toddler Development, may afford more direct assessment of cognitive development but they require language translation, cultural adaptation, and population norming. Further, they are not always reliable predictors of future outcomes when assessed within the first 12–18 months of a child’s life. Neuroimaging may provide more objective, sensitive, and predictive measures of neurodevelopment but tools such as magnetic resonance (MR) imaging are not readily available in many low and middle-income countries (LMICs). MRI systems that operate at lower magnetic fields (< 100mT) may offer increased accessibility, but their use for global health studies remains nascent. The UNITY project is envisaged as a global partnership to advance neuroimaging in global health studies. Here we describe the UNITY project, its goals, methods, operating procedures, and expected outcomes in characterizing neurodevelopment in sub-Saharan Africa and South Asia.The Bill & Melinda Gates Foundation, the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, and through a Wellcome Trust Investigator Award and a Wellcome Trust Strategic Award.https://www.elsevier.com/locate/dcnhj2024Biochemistry, Genetics and Microbiology (BGM)ImmunologyPaediatrics and Child HealthRadiologySDG-03:Good heatlh and well-beingSDG-17:Partnerships for the goal

Annealing studies of amorphous alloys

Amorphous films of the alloys Ni-Nb, Ni-Mo, Mo-Si, and W-Si were sputter deposited on single-crystal semiconductor substrates. One-hour crystallization temperatures of the films were determined to within +-25/sup 0/C by annealing and x-ray diffraction measurements. Interdiffusion between Au or Cu overlayers and the amorphous films were studied by annealing combined with Auger Electron Spectroscopy (AES) profiling, and by Rutherford Backscatter (RBS) analysis. Supplementary measurements used to study structural relaxation and crystallization included resistivity as a function of temperature; DTA and DSC; and electron microscopy