👤 Sonya Reid

White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition, whereas increased metabolism in atypical WM (AWM; corona radiata) was linked to worse cognition, indicating a compensatory mechanism. EWM metabolism declined with aging, Alzheimer's disease (AD) progression (amyloid-β and APOE-ε4 carrier), and white matter hyperintensities, while AWM metabolism increased with aging and vascular risk but was partially weakened by AD neuropathology. Longitudinally, higher EWM and lower AWM metabolism predicted slower cognitive decline. Divergent WM metabolic patterns shed light on the dynamic role of WM in maintaining cognitive function. This study emphasizes the complementary information provided by WM metabolism for predicting future cognitive decline and identifying cognitive resilience. Show less

The association of germline pathogenic and likely pathogenic variants (GPVs) in hereditary breast cancer genes with underlying tumor biology and clinical outcomes remain incompletely understood. This study characterized differences in somatic alterations and intrinsic subtypes between sporadic and hereditary breast cancers associated with GPVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2. This retrospective cohort study included women with breast cancer and an ATM, BRCA1, BRCA2, CHEK2, or PALB2 GPV who underwent tumor sequencing and whole transcriptome RNA expression analysis. Clinicopathologic features, intrinsic subtypes, somatic alterations, and survival were compared by GPV status and immunohistochemistry-defined subtype, and to sporadic cases. All significance tests were 2-sided. 4,988 women with breast cancer included 98 BRCA1, 126 BRCA2, 74 PALB2, 54 ATM, and 83 CHEK2 GPVs. Compared to sporadic cases, HR+/HER2- tumors in BRCA1 GPVs were significantly enriched for basal subtype (45.5% vs 11.4%, p < 0.001), while CHEK2 carriers had a higher prevalence of luminal A subtype (80.4% vs 60.3%, p = 0.006). In HR+/HER2- breast cancers, BRCA1 GPVs were enriched for TP53 alterations (84.6% vs 29.8%, q < 0.001), ATM GPVs with FGFR1 alterations (35.4% vs 12.7%, q = 0.04), and BRCA2 GPVs with APC alterations (10.1% vs 1.5%, q = 0.004). Conversely, BRCA2 GPVs were inversely associated with PIK3CA alterations (13.0% vs 34.1%, q = 0.005), and CHEK2 GPVs with TP53 alterations (8.0% vs 29.8%, q = 0.02). GPVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2 are associated with distinct intrinsic breast cancer subtypes and somatic genomic alterations. These findings may enhance precision in risk stratification and guide personalized treatment strategies. Show less

Hypertrophic cardiomyopathy (HCM) affects approximately 600,000 people in the United States. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM, with the majority of mutations resulting in haploinsufficiency. To restore cardiac MYBPC3, we use an adeno-associated virus (AAV9) vector and engineer an optimized expression cassette with a minimal promoter and cis-regulatory elements (TN-201) to enhance packaging efficiency and cardiomyocyte expression. Rather than simply preventing cardiac dysfunction preclinically, we demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve diastolic dysfunction, and prolong survival. Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. These findings suggest that TN-201 may offer therapeutic benefits in MYBPC3-associated cardiomyopathy, pending further validation in clinical settings. Show less

Pathogenic variants in PI3K-AKT-mTOR pathway and GATOR1 complex genes resulting in hyperactivation of mechanistic target of rapamycin (mTOR) complex 1 are a major cause of drug-resistant epilepsy and focal cortical malformations (FCM). Resective neurosurgery is often required to achieve seizure control in patients with mTORopathies due to lack of effectiveness of nonsurgical therapies, including antiseizure medication and mTOR inhibitors. Elevated hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4) has been proposed as a key marker in some mTOR-related brain malformations. This study aimed to investigate HCN4 as a biomarker in the brain across the genetic spectrum of mTORopathies in humans. Our study investigated the relative steady-state levels and cellular localization of HCN4 in resected human brain tissue from 18 individuals with mTORopathies (3 individuals with tuberous sclerosis complex (TSC) due to Elevated HCN4 was observed to be highly restricted to abnormal cell types (dysmorphic neurons and balloon cells) in brain tissue from all mTORopathy tissues ( HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy. Show less

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors ( Show less

UVR and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells promote cSCC carcinogenesis, and in other solid tumors, infiltrating regulatory T cells and CD8 Show less

Autologous bone grafts used for surgical reconstruction are limited by infection or insufficient supply of host material. Experimental agents that promote differentiation of stem cells into mature bone are currently being studied for future use in the repair of bone defects. The authors hypothesized that imiquimod, a synthetic immune response modifier, increases Notch pathway gene expression and acts synergistically with bone morphogenetic protein (BMP) 9 to induce differentiation of mesenchymal stem cells toward an osteogenic phenotype. Alkaline phosphatase activity was used to assess the osteogenic potential of cultured mouse immortalized multipotent adipose-derived cells (iMADs) treated with 0, 4, 6, and 8 μg/ml of imiquimod with and without BMP9. Adenoviral vectors expressing human BMP9 and a dominant-negative mutant of mouse Notch1 were used to assess BMP9 and Notch blockade on osteogenic activity, respectively. Expression of Notch signaling mediators and osteogenic markers were assayed by quantitative polymerase chain reaction. Alizarin red staining was used to assess the synergism between BMP9 and imiquimod. Imiquimod exposure enhanced osteogenic differentiation of iMADs by 2.8-fold (p < 0.001) and potentiated BMP9-induced osteogenic differentiation of iMADs by 1.6-fold (p < 0.001), shown by increased alkaline phosphatase activity and augmented matrix mineralization. Quantitative-real time polymerase chain reaction analysis demonstrated that imiquimod induced the expression of downstream genes (p < 0.01) of the Notch signaling pathway Hey1, Hey2, and Hes1, by increases of 9.7-, 22-, and 2.7-fold, respectively. These findings identify a novel role for imiquimod to shift mesenchymal stem cells toward an osteogenic phenotype. Imiquimod may be useful clinically when scaffolds are applied to treat bone defects. Show less

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 Show less

Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity. Show less

Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor. Show less