👤 B Monica Bowen

Age-related cognitive decline is a growing public health concern, yet early molecular indicators remain poorly defined. Since brain changes often precede behavioral symptoms, identifying early markers of vulnerability is critical. Here, we investigated whether dopamine regulation and synaptic or inflammatory signaling might provide early indicators of cognitive decline, prior to behavioral impairment. Method and Finding: Female hooded-Lister rats at 6 (young) and 12 (age-unimpaired) months of age were tested using the novel object recognition (NOR) task, with no observable cognitive deficits found in either group. Biochemical analyses revealed marked molecular differences in the prefrontal cortex (PFC) of aged-unimpaired rats. Synaptic proteins BDNF, PSD-95, and synaptophysin were significantly reduced, indicating synaptic destabilization. Concurrently, expression of COMT and NET, key regulators of dopamine catabolism and reuptake, was increased, suggesting reduced dopaminergic tone. Inflammatory signaling also shifted: Nfkb and Socs3 were increased at the transcriptional level in the PFC, while Il-6 and Cox2 remained stable. In contrast, the hippocampus showed relative resistance to these changes, with no significant alterations in most markers, although NF-κB activation was detected at the mRNA level, indicating posttranscriptional regulation. Our findings suggest that the PFC undergoes a latent vulnerability phase during midlife, marked by synaptic and dopaminergic dysregulation alongside low-grade inflammation, despite preserved cognitive performance. The hippocampus appears more resilient at this stage. Together, these early molecular changes may indicate later cognitive decline and offer a critical window for preventive intervention. Targeting these early shifts in the aging brain could hold transformative potential for delaying cognitive impairment. Show less

Short sleep duration, low physical activity (PA), and sedentary behavior (SB) are associated with negative health outcomes and highly prevalent in adolescents. This study examined changes in the amount and timing of PA and SB following a 1-week sleep extension manipulation in adolescents. Forty-three habitually short-sleeping (≤7 h/night on school days), habitually inactive (<3 hours of regular physical activity per week), and healthy-weight adolescents (16.0 ± 1.24 years, 69.8% female; 86% White) completed a randomized crossover procedure during the school year. Participants slept for 1 week on their typical school schedule (Typical Sleep, TS), and 1 week during which time in bed was extended by ≥1 hour each school night (Sleep Extension, EXT). Home-monitoring of sleep with wrist-worn actigraphy and activity with thigh-worn accelerometer was completed during both conditions. Relationships between sleep, SB, PA, and experimental manipulation were assessed with linear mixed models. SB and light PA (LPA) across the 24 days decreased significantly during EXT compared to TS by 72 minutes and 13.2 minutes, respectively (95% CI: -102, -42, p < .001; 95% CI: -26.4, 0.00, p = .048). SB decreased predominantly between the hours of 18:00-00:00 (-39 minute 95% CI: -54.6, -24, p < .001). There was no significant change in moderate-to-vigorous PA (MVPA) between conditions (p > .05). Increased sleep duration replaced time spent in SB primarily in the evening hours. While LPA decreased primarily in the morning hours, the amount of change was small and likely not clinically significant. Sleep extension did not impact MVPA. Show less

Multiplexed assays of variant effect (MAVEs) systematically measure variant function but have been limited to cancer cell lines rather than disease-relevant cell types. We developed saturation genome editing in human iPSCs (iPSC-SGE) to introduce variant libraries into a single allele of a target gene while programming the genetic background of the second allele, enabling variant assessment across differentiated cell types and genetic contexts at scale. We edited 1,137 variants into Show less

Abdominal aortic aneurysm (AAA), a dilatation of the infrarenal aorta, typically affects males >65 years. The pathobiological mechanisms of human AAA are poorly understood. The goal of this study was to identify novel pathways involved in the development of AAAs. A custom-designed 'AAA-chip' was used to assay 43 of the differentially expressed genes identified in a previously published microarray study between AAA (n = 15) and control (n = 15) infrarenal abdominal aorta. Protein analyses were performed on selected genes. Altogether 38 of the 43 genes on the 'AAA-chip' showed significantly different expression. Novel validated genes in AAA pathobiology included ADCY7, ARL4C, BLNK, FOSB, GATM, LYZ, MFGE8, PRUNE2, PTPRC, SMTN, TMODI and TPM2. These genes represent a wide range of biological functions, such as calcium signaling, development and differentiation, as well as cell adhesion not previously implicated in AAA pathobiology. Protein analyses for GATM, CD4, CXCR4, BLNK, PLEK, LYZ, FOSB, DUSP6, ITGA5 and PTPRC confirmed the mRNA findings. The results provide new directions for future research into AAA pathogenesis to study the role of novel genes confirmed here. New treatments and diagnostic tools for AAA could potentially be identified by studying these novel pathways. Show less

Genome wide association studies (GWAS), mostly in Europeans have identified several common variants as associated with key lipid traits. Replication of these genetic effects in South Asian populations is important since it would suggest wider relevance for these findings. Given the rising prevalence of metabolic disorders and heart disease in the Indian sub-continent, these studies could be of future clinical relevance. We studied seven common variants associated with a variety of lipid traits in previous GWASs. The study sample comprised of 3178 sib-pairs recruited as participants for the Indian Migration Study (IMS). Associations with various lipid parameters and quantitative traits were analyzed using the Fulker genetic association model. We replicated five of the 7 main effect associations with p-values ranging from 0.03 to 1.97x10(-7). We identified particularly strong association signals at rs662799 in APOA5 (beta=0.18 s.d, p=1.97 x 10(-7)), rs10503669 in LPL (beta =-0.18 s.d, p=1.0 x 10(-4)) and rs780094 in GCKR (beta=0.11 s.d, p=0.001) loci in relation to triglycerides. In addition, the GCKR variant was also associated with total cholesterol (beta=0.11 s.d, p=3.9x10(-4)). We also replicated the association of rs562338 in APOB (p=0.03) and rs4775041 in LIPC (p=0.007) with LDL-cholesterol and HDL-cholesterol respectively. We report associations of five loci with various lipid traits with the effect size consistent with the same reported in Europeans. These results indicate an overlap of genetic effects pertaining to lipid traits across the European and Indian populations. Show less

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome. Show less

A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent. Show less