MASTR-seq: Multiplexed Analysis of Short Tandem Repeats with sequencing.

Unlabelled: More than 60 human disorders have been linked to unstable expansion of short tandem repeat (STR) tracts. STR length and the extent of DNA methylation is linked to disease pathology and can be mosaic in a cell type-specific manner in several repeat expansion disorders. Mosaic phenomenon have been difficult to study to date due to technical bias intrinsic to repeat sequences and the need for multi-modal measurements at single-allele resolution.

A multi-looping chromatin signature predicts dysregulated gene expression in neurons with familial Alzheimer's disease mutations.

Mammalian genomes fold into tens of thousands of long-range loops, but their functional role and physiologic relevance remain poorly understood. Here, using human post-mitotic neurons with rare familial Alzheimer's disease (FAD) mutations, we identify hundreds of reproducibly dysregulated genes and thousands of miswired loops prior to amyloid accumulation and tau phosphorylation. Single loops do not predict expression changes; however, the severity and direction of change in mRNA levels and single-cell burst frequency strongly correlate with the number of FAD-gained or -lost promoter-enhancer loops.

Psychological and emotional experiences of participants in a medical school, early assurance admissions program targeting students from groups underrepresented in medicine.

Background: There are growing number of pathway programs, with an early assurance of admission, that target undergraduate students from groups underrepresented in medicine (URiM) to enable their competitiveness for and matriculation to medical school, including the Penn Access Summer Scholars (PASS) program. The psychological and emotional experiences of students in these programs, however, have not been previously described.

Methods: Students from the summer 2021 cohort of the PASS program were interviewed using a structured set of questions that explored four specific areas: (i) the application process; (ii) the benefits and value of being in the PASS program; (iii) the emotional and psychological challenges and stresses of being in the PASS program; (iv) feelings and emotions about not taking the MCAT or having to interview at multiple schools.

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome.

Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion.

Periosteal progenitors contribute to load-induced bone formation in adult mice and require primary cilia to sense mechanical stimulation.

Background: The fully developed adult skeleton adapts to mechanical forces by generating more bone, usually at the periosteal surface. Progenitor cells in the periosteum are believed to differentiate into bone-forming osteoblasts that contribute to load-induced adult bone formation, but in vivo evidence does not yet exist. Furthermore, the mechanism by which periosteal progenitors might sense physical loading and trigger differentiation is unknown.

Adenylyl cyclases and TRPV4 mediate Ca/cAMP dynamics to enhance fluid flow-induced osteogenesis in osteocytes.

Bone adapts to physical forces and this process is dependent on osteocyte mechanotransduction. One way osteocytes sense mechanical stimulation is through the primary cilium, a sensory organelle that triggers intracellular signaling cascades in response to fluid shear. Our lab previously determined that flow-induced ciliary Ca influx and changes in cytosolic cAMP levels are critical for osteogenesis.