Faculty Bibliography

BACKGROUND:Ten percent of the female population suffers from congenital abnormalities of the vagina, uterus, or oviducts, with severe consequences for reproductive and psychological health. Yet, the underlying causes of most of these malformations remain largely unknown. ADGRA3 (GPR125) is involved in WNT signaling and planar cell polarity, mechanisms vital to female reproductive tract development. Although ADGRA3 is a well-established spermatogonial stem cell marker, its role within the female urogenital system remains unclear. RESULTS:females with a closed vagina. CONCLUSIONS:Our collective results shed new insights into the complex mechanisms by which the adhesion receptor ADGRA3 regulates distal vaginal tissue remodeling during vaginal canalization via altered sex hormone responsiveness and balance in apoptotic regulators. This highlights the potential of ADGRA3 as a target in diagnostic screening and/or therapy for obstructive vaginal malformations in humans.

Glycolysis is a fundamental cellular process, yet its regulatory mechanisms remain incompletely understood. Here, we show that a subset of glucose transporter 1 (GLUT1/SLC2A1) co-endocytoses with platelet-derived growth factor (PDGF) receptor (PDGFR) upon PDGF-stimulation. Furthermore, multiple glycolytic enzymes localize to these endocytosed PDGFR/GLUT1-containing vesicles adjacent to mitochondria. Contrary to current models, which emphasize the importance of glucose transporters on the cell surface, we find that PDGF-stimulated glucose uptake depends on receptor/transporter endocytosis. Our results suggest that growth factors generate glucose-loaded endocytic vesicles that deliver glucose to the glycolytic machinery in proximity to mitochondria, and argue for a new layer of regulation for glycolytic control governed by cellular membrane dynamics.

The Platelet-Rich Plasma (PRP) for Knee Osteoarthritis Technology Overview is based on a systematic review of current scientific and clinical research. Through analysis of the current best evidence, this technology overview seeks to evaluate the efficacy of PRP for patients with knee osteoarthritis. The systematic literature review resulted in 54 articles: 36 high-quality and 18 moderate-quality. The findings of these studies were summarized to present findings on PRP versus control/placebo, acetaminophen, non-steroidal anti-inflammatory drugs, corticosteroids, exercise, prolotherapy, autologous conditioned serum, bone marrow aspirate concentrate, hyaluronic acid, and ozone therapy. In addition, the work group highlighted areas that needed additional research when evidence proved lacking on the topic and carefully noted the potential harms associated with an intervention, required resource utilization, acceptability, and feasibility.

C. pyrenoidosa, a species of microalgae, has been recognized as a viable protein source for human consumption. The primary challenges in this context are the development of an efficient extraction process and the valorization of the resultant waste streams. This study, situated within the paradigm of circular economy, presents an innovative extraction approach that achieved a protein extraction efficiency of 62 %. The extracted protein exhibited remarkable oil-water emulsifying performances, such as uniform morphology with high creaming stability, suggesting a sustainable alternative to conventional emulsifiers. Additionally, hydrothermal liquefaction technique was employed for converting the residual biomass and waste solution from the extraction process into biocrude. A biocrude yield exceeding 40 wt%, characterized by a carbon content of 73 % and a higher heating value of 36 MJ/kg, were obtained. These findings demonstrate the promising potential of microalgae biorefinery, which is significant for paving toward circular economy and zero-waste society.

Progranulin (PGRN), encoded by the GRN gene in humans, was originally isolated as a secreted growth factor that implicates in a multitude of processes ranging from regulation of tumorigenesis, inflammation to neural proliferation. Compelling evidence indicating that GRN mutation can lead to various common neuronal degenerative diseases and rare lysosomal storage diseases. These findings have unveiled a critical role for PGRN as a lysosomal protein in maintaining lysosomal function. The phenotypic spectrum of PGRN imbalance has expanded to encompass a broad spectrum of diseases, including autoimmune diseases, metabolic, musculoskeletal and cardiovascular diseases. These diseases collectively referred to as Progranulinopathy- a term encompasses the wide spectrum of disorders influenced by PGRN imbalance. Unlike its known extracellular function as a growth factor-like molecule associated with multiple membrane receptors, PGRN also serves as an intracellular co-chaperone engaged in the folding and traffic of its associated proteins, particularly the lysosomal hydrolases. This chaperone activity is required for PGRN to exert its diverse functions across a broad range of diseases, encompassing both the central nervous system and peripheral systems. In this comprehensive review, we present an update of the emerging role of PGRN in Progranulinopathy, with special focus on elucidating the intricate interplay between PGRN and a diverse array of proteins at various levels, ranging from extracellular fluids and intracellular components, as well as various pathophysiological processes involved. This review seeks to offer a comprehensive grasp of PGRN's diverse functions, aiming to unveil intricate mechanisms behind Progranulinopathy and open doors for future research endeavors.

The integrated stress response (ISR) refers to signaling pathways initiated by stress-activated eIF2α kinases. Distinct eIF2α kinases respond to different stress signals, including amino acid deprivation and mitochondrial stress. Such stress-induced eIF2α phosphorylation attenuates general mRNA translation and, at the same time, stimulates the preferential translation of specific downstream factors to orchestrate an adaptive gene expression program. In recent years, there have been significant new advances in our understanding of ISR during metabolic stress adaptation. Here, I discuss those advances, reviewing among others the ISR activation mechanisms in response to amino acid deprivation and mitochondrial stress. In addition, I review how ISR regulates the amino acid metabolic pathways and how changes in the ISR impact the physiology and pathology of various disease models.

BACKGROUND/UNASSIGNED:Significant heterogeneity in the classification and treatment of zone 3 proximal fifth metatarsal base fractures ("true Jones fractures") exists. This study compared time to clinical and radiographic healing between patients treated operatively and nonoperatively. We hypothesized that patients treated nonoperatively may demonstrate a greater time to clinical healing. METHODS/UNASSIGNED:This was a retrospective cohort study of patients presenting to a large, urban, academic medical center with "Jones" fractures between December 2012 and April 2022. Jones fractures were defined as fifth metatarsal base fractures occurring in the proximal metadiaphyseal region, distal to the articulation of the fourth and fifth metatarsals on the oblique radiographic view. Clinical healing was the time point at which the patient had returned to their baseline ambulatory status with no tenderness to palpation. Radiographic healing was the presence of bridging callus across at least 3 cortices. RESULTS/UNASSIGNED: = .331). Overall healing rate was 96% for the nonoperative group compared with 96.2% for the operative group. CONCLUSION/UNASSIGNED:In this study, nonoperative and operative treatment of true Jones fractures were associated with equivalent clinical and radiographic healing. The rate of delayed union in true Jones fractures was lower than previously described, and there was no difference in delayed union rate between nonoperative and operative management. LEVEL OF EVIDENCE/UNASSIGNED:Level III, retrospective cohort study.

Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm Caenorhabditis elegans is a microbivore that must distinguish nutritive microbes from pathogens. We characterized a neural circuit used by C. elegans to rapidly discriminate between nutritive bacteria and pathogens. Distinct sensory neuron populations responded to chemical cues from nutritive Escherichia coli and pathogenic Enterococcus faecalis, and these neural signals are decoded by downstream AIB interneurons. The polyamine metabolites cadaverine, putrescine, and spermidine produced by E. coli activate this neural circuit and elicit positive chemotaxis. Our study shows how polyamine odorants can be sensed by animals as proxies for microbe identity and suggests that, hence, polyamines might have widespread roles brokering host-microbe interactions.

RNA polymerase II (RNA Pol II) can backtrack during transcription elongation, exposing the 3' end of nascent RNA. Nascent RNA sequencing can approximate the location of backtracking events that are quickly resolved; however, the extent and genome-wide distribution of more persistent backtracking are unknown. Consequently, we developed a method to directly sequence the extruded, "backtracked" 3' RNA. Our data show that RNA Pol II slides backward more than 20 nt in human cells and can persist in this backtracked state. Persistent backtracking mainly occurs where RNA Pol II pauses near promoters and intron-exon junctions and is enriched in genes involved in translation, replication, and development, where gene expression is decreased if these events are unresolved. Histone genes are highly prone to persistent backtracking, and the resolution of such events is likely required for timely expression during cell division. These results demonstrate that persistent backtracking can potentially affect diverse gene expression programs.

IMPORTANCE/UNASSIGNED:Current measures of alopecia areata (AA) severity, such as the Severity of Alopecia Tool score, do not adequately capture overall disease impact. OBJECTIVE/UNASSIGNED:To explore factors associated with AA severity beyond scalp hair loss, and to support the development of the Alopecia Areata Severity and Morbidity Index (ASAMI). EVIDENCE REVIEW/UNASSIGNED:A total of 74 hair and scalp disorder specialists from multiple continents were invited to participate in an eDelphi project consisting of 3 survey rounds. The first 2 sessions took place via a text-based web application following the Delphi study design. The final round took place virtually among participants via video conferencing software on April 30, 2022. FINDINGS/UNASSIGNED:Of all invited experts, 64 completed the first survey round (global representation: Africa [4.7%], Asia [9.4%], Australia [14.1%], Europe [43.8%], North America [23.4%], and South America [4.7%]; health care setting: public [20.3%], private [28.1%], and both [51.6%]). A total of 58 specialists completed the second round, and 42 participated in the final video conference meeting. Overall, consensus was achieved in 96 of 107 questions. Several factors, independent of the Severity of Alopecia Tool score, were identified as potentially worsening AA severity outcomes. These factors included a disease duration of 12 months or more, 3 or more relapses, inadequate response to topical or systemic treatments, rapid disease progression, difficulty in cosmetically concealing hair loss, facial hair involvement (eyebrows, eyelashes, and/or beard), nail involvement, impaired quality of life, and a history of anxiety, depression, or suicidal ideation due to or exacerbated by AA. Consensus was reached that the Alopecia Areata Investigator Global Assessment scale adequately classified the severity of scalp hair loss. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This eDelphi survey study, with consensus among global experts, identified various determinants of AA severity, encompassing not only scalp hair loss but also other outcomes. These findings are expected to facilitate the development of a multicomponent severity tool that endeavors to competently measure various disease impact. The findings are also anticipated to aid in identifying candidates for current and emerging systemic treatments. Future research must incorporate the perspectives of patients and the public to assign weight to the domains recognized in this project as associated with AA severity.