Faculty Bibliography

Centrosomes break symmetry in the C. elegans one-cell embryo, triggering its anterior-posterior polarization and initiating segregation of somatic and germline cell lineages. In this issue of Developmental Cell, De Henau et al. show that mitochondria also contribute to symmetry breaking by producing hydrogen peroxide at the egg's future posterior pole.

Gram-negative bacteria are surrounded by an outer membrane composed of phospholipids and lipopolysaccharide, which acts as a barrier and contributes to antibiotic resistance. The systems that mediate phospholipid trafficking across the periplasm, such as MCE (Mammalian Cell Entry) transporters, have not been well characterized. Our ~3.5 Å cryo-EM structure of the E. coli MCE protein LetB reveals an ~0.6 megadalton complex that consists of seven stacked rings, with a central hydrophobic tunnel sufficiently long to span the periplasm. Lipids bind inside the tunnel, suggesting that it functions as a pathway for lipid transport. Cryo-EM structures in the open and closed states reveal a dynamic tunnel lining, with implications for gating or substrate translocation. Our results support a model in which LetB establishes a physical link between the two membranes and creates a hydrophobic pathway for the translocation of lipids across the periplasm.

Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSCs). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine crosstalk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporter(s) to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer.

The H2A.Z histone variant, a genome-wide hallmark of permissive chromatin, is enriched near transcription start sites in all eukaryotes. H2A.Z is deposited by the SWR1 chromatin remodeler and evicted by unclear mechanisms. We tracked H2A.Z in living yeast at single-molecule resolution, and found that H2A.Z eviction is dependent on RNA Polymerase II (Pol II) and the Kin28/Cdk7 kinase, which phosphorylates Serine 5 of heptapeptide repeats on the carboxy-terminal domain of the largest Pol II subunit Rpb1. These findings link H2A.Z eviction to transcription initiation, promoter escape and early elongation activities of Pol II. Because passage of Pol II through +1 nucleosomes genome-wide would obligate H2A.Z turnover, we propose that global transcription at yeast promoters is responsible for eviction of H2A.Z. Such usage of yeast Pol II suggests a general mechanism coupling eukaryotic transcription to erasure of the H2A.Z epigenetic signal.

Trichorhinophalangeal syndrome type 1 (TRPS1; Online Mendelian Inheritance in Man #190350) is an autosomal dominant disorder caused by mutations in TRPS1. We report a Thai male with TRPS1 who carried a c.1842C>T (p.Arg615Ter) mutation. He had 15 supernumerary teeth, double mental foramina, hypoplastic mandibular condyles with slender condylar necks and unique ultrastructural hair findings. Body hair was absent. The hair in the area of a congenital melanocytic nevus had a greater number of hair cuticles than normal. Occipital hair had abnormal hair follicles and cuticles. The scale edges of the hair cuticles were detached and rolled up. Hypoplastic mandibular condyles with slender condylar necks, double mental foramina and the rolled up edges of hair cuticles have not been reported in patients with TRPS1.

The COVID-19 pandemic poses a major challenge in delivering care to wound patients. Due to multiple comorbidities, wound patients are at an increased risk for the most extreme complications of COVID-19 and providers must focus on reducing their exposure risk. The Federal, State, and local governments, as well as payers, have urged hospitals and providers to reduce utilization of nonessential health services, but they also have given more flexibility to shift the site of necessary care to lower risk environments. Providers must be prepared for disruption from this pandemic mode of health care for the next 18 months, at minimum. The wound provider must accept the new normal during the pandemic by adapting their care to meet the safety needs of the patient and the public. The Wound Center Without Walls is a strategy to untether wound care from a physical location and aggressively triage and provide care to patients with wounds across the spectrum of the health system utilizing technology and community-centered care.

OBJECTIVE: CONCLUSIONS:

Rationale: Regression of atherosclerosis is an important clinical goal, however the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, yet the numbers of these immunosuppressive cells decrease with disease progression, and whether they contribute to atherosclerosis regression is not known. Objective: We investigated the roles of Tregs in the resolution of atherosclerotic inflammation, tissue remodeling and plaque contraction during atherosclerosis regression. Methods and Results: Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. Single cell RNA-sequencing of plaque immune cells from revealed that Tregs from regressing plaques shared some similarity with splenic Tregs, but were distinct from skin and colon Tregs supporting recent findings of tissue-dependent Treg heterogeneity. Unlike Tregs from progressing plaques that expressed markers of natural Tregs derived from the thymus, Tregs in regressing plaques lacked Nrp1 and Helios expression, suggesting that they are induced in the periphery during lipid lowering therapy. To test whether Tregs are required for resolution of atherosclerotic inflammation and plaque regression, Tregs were depleted using CD25 monoclonal antibody in atherosclerotic mice during apolipoprotein B anti-sense oligonucleotide-mediated lipid lowering. Morphometric analyses revealed that Treg depletion blocked plaque remodeling and contraction, and impaired hallmarks of inflammation resolution including dampening of the Th1 response, alternative activation of macrophages, efferocytosis, and upregulation of specialized pro-resolving lipid mediators. Conclusions: Our data establish essential roles for Tregs in resolving atherosclerotic cardiovascular disease and provide mechanistic insight into the pathways governing plaque remodeling and regression of disease.