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Sirt5 desuccinylates Cdc42 to mediate osteoclastogenesis and bone remodeling in mice

Zhang, Yuang; Wang, Jing; Luan, Jing; Liu, Chuanju; Cui, Yazhou; Han, Jinxiang
SCOPUS:85181829364
ISSN: 2352-4820
CID: 5628922

Sirt5 desuccinylates Cdc42 to mediate osteoclastogenesis and bone remodeling in mice

Zhang, Yuang; Wang, Jing; Luan, Jing; Liu, Chuanju; Cui, Yazhou; Han, Jinxiang
PMCID:10806281
PMID: 38274381
ISSN: 2352-3042
CID: 5625332

Academy of Orthopaedic Surgeons Technology Overview Summary: Concentrated Bone Marrow Aspirate for Knee Osteoarthritis

Dubin, Jonathan; Leucht, Philipp; Murray, Martha; Pezold, Ryan; ,
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.
PMID: 38295392
ISSN: 1940-5480
CID: 5627112

Chemosensory detection of polyamine metabolites guides C. elegans to nutritive microbes

Brissette, Benjamin; Ficaro, Lia; Li, Chenguang; Jones, Drew R; Ramanathan, Sharad; Ringstad, Niels
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.
PMCID:10959419
PMID: 38517971
ISSN: 2375-2548
CID: 5640842

Dietary pyruvate targets cytosolic phospholipase A2 to mitigate inflammation and obesity in mice

Hasan, Sadaf; Ghani, Nabil; Zhao, Xiangli; Good, Julia; Huang, Amanda; Wrona, Hailey Lynn; Liu, Jody; Liu, Chuan-Ju
Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity, but it also sheds light on the mechanism of its action. Pyruvate's prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.
PMID: 38512816
ISSN: 1674-8018
CID: 5640752

Persistence of backtracking by human RNA polymerase II

Yang, Kevin B; Rasouly, Aviram; Epshtein, Vitaly; Martinez, Criseyda; Nguyen, Thao; Shamovsky, Ilya; Nudler, Evgeny
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.
PMID: 38340716
ISSN: 1097-4164
CID: 5635502

Is Postoperative Splinting Advantageous After Upper Extremity Fracture Surgery? Results From the Arm Splint Pain Improvement Research Experiment

Sgaglione, Matthew W; Solasz, Sara J; Leucht, Philipp; Egol, Kenneth A
OBJECTIVES/OBJECTIVE:The authors report no conflict of interest.To determine if short-term immobilization with a rigid long arm plaster elbow splint after surgery of the arm, elbow, or forearm results in superior outcomes compared with a soft dressing with early motion. DESIGN/METHODS:Prospective Randomized Control Trial. SETTING/METHODS:Academic Medical Center. PATIENT SELECTION CRITERIA/UNASSIGNED:Patients undergoing operative treatment for a mid-diaphysis or distal humerus, elbow, or forearm fracture were consented and randomized according to the study protocol for postoperative application of a rigid elbow splint (10-14 days in a plaster Sugar Tong Splint for forearm fracture or a Long Arm plaster Splint for 10-14 for all others) or soft dressing and allowing immediate free range of elbow and wrist motion (range of motion [ROM]). OUTCOME MEASURES AND COMPARISONS/UNASSIGNED:Self-reported pain (visual analog score or VAS), Healthscale (0-100, 100 denoting excellent health), and physical function (EuroQol 5 Dimension or EQ-5D) surveyed on postoperative days 1-5 and 14 were compared between groups. Patient-reported pain score (0-10, 10 denoting highest satisfaction) at week 6, time to fracture union, ultimate disabilities of the arm, shoulder, and hand score, and elbow ROM were also collected for analysis. Incidence of complications were assessed. RESULTS:Hundred patients (38 men to 62 women with a mean age of 55.7 years) were included. Over the first 5 days and again at postop day 14, the splint cohort reported a higher "Healthscale" from 0 to 100 than the nonsplint group on all study days ( P = 0.041). There was no difference in reported pain between the 2 study groups over the same interval ( P = 0.161 and 0.338 for least and worst pain, respectively), and both groups reported similar rates of treatment satisfaction ( P = 0.30). Physical function ( P = 0.67) and rates of wound problems ( P = 0.27) were similar. Additionally, the mean time to fracture healing was similar for the splint and control groups (4.6 ± 2.8 vs. 4.0 ± 2.2 months, P = 0.34). Ultimate elbow ROM was similar between the study groups ( P = 0.48, P = 0.49, P = 0.61, and P = 0.51 for elbow extension, flexion, pronation, and supination, respectively). CONCLUSIONS:Free range of elbow motion without splinting produced similar results compared with elbow immobilization after surgical intervention for a fracture to the humerus, elbow, and forearm. There was no difference in patient-reported pain outcomes, wound problems, or elbow ROM. Immobilized patients reported slightly higher "healthscale" ratings than nonsplinted patients and, however, reported similar rates of satisfaction. Both treatment strategies are acceptable after upper extremity fracture surgery. LEVEL OF EVIDENCE/METHODS:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
PMID: 38117579
ISSN: 1531-2291
CID: 5633762

Early Weight-bearing Following Surgical Treatment of Ankle Fractures Without Trans-syndesmotic Fixation Is Safe and Improves Short-term Outcomes

Herbosa, Christopher G; Saleh, Hesham; Kadiyala, Manasa L; Solasz, Sara; McLaurin, Toni M; Leucht, Philipp; Egol, Kenneth A; Tejwani, Nirmal C
OBJECTIVES/OBJECTIVE:The objective of this study was to ascertain outcome differences after fixation of unstable rotational ankle fractures allowed to weight-bear 2 weeks postoperatively compared with 6 weeks. DESIGN/METHODS:Prospective case-control study. SETTING/METHODS:Academic medical center; Level 1 trauma center. PATIENT SELECTION CRITERIA/UNASSIGNED:Patients with unstable ankle fractures (OTA/AO:44A-C) undergoing open reduction internal fixation (ORIF) were enrolled. Patients requiring trans-syndesmotic fixation were excluded. Two surgeons allowed weight-bearing at 2 weeks postoperatively (early weight-bearing [EWB] cohort). Two other surgeons instructed standard non-weight-bearing until 6 weeks postoperatively (non-weight-bearing cohort). OUTCOME MEASURES AND COMPARISONS/UNASSIGNED:The main outcome measures included the Olerud-Molander questionnaire, the SF-36 questionnaire, and visual analog scale at 6 weeks, 3 months, 6 months, and 12 months postoperatively and complications, return to work, range of ankle motion, and reoperations at 12 months were compared between the 2 cohorts. RESULTS:One hundred seven patients were included. The 2 cohorts did not differ in demographics or preinjury scores ( P > 0.05). Six weeks postoperatively, EWB patients had improved functional outcomes as measured by the Olerud-Molander and SF-36 questionnaires. Early weight-bearing patients also had better visual analog scale scores (standardized mean difference -0.98, 95% confidence interval [CI] -1.27 to -0.70, P < 0.05) and a greater proportion returning to full capacity work at 6 weeks (odds ratio = 3.42, 95% CI, 1.08-13.07, P < 0.05). One year postoperatively, EWB patients had improved pain measured by SF-36 (standardized mean difference 6.25, 95% CI, 5.59-6.92, P < 0.01) and visual analog scale scores (standardized mean difference -0.05, 95% CI, -0.32 to 0.23, P < 0.01). There were no differences in complications or reoperation at 12 months ( P > 0.05). CONCLUSIONS:EWB patients had improved early function, final pain scores, and earlier return to work, without an increased complication rate compared with those kept non-weight-bearing for 6 weeks. LEVEL OF EVIDENCE/METHODS:Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
PMID: 38117568
ISSN: 1531-2291
CID: 5633752

The Alopecia Areata Severity and Morbidity Index (ASAMI) Study: Results From a Global Expert Consensus Exercise on Determinants of Alopecia Areata Severity

,; Moussa, Anthony; Bennett, Michaela; Wall, Dmitri; Meah, Nekma; York, Katherine; Bokhari, Laita; Asfour, Leila; Rees, Huw; Abraham, Leonardo Spagnol; Asz-Sigall, Daniel; Basmanav, Fitnat Buket; Bergfeld, Wilma; Betz, Regina C; Bhoyrul, Bevin; Blume-Peytavi, Ulrike; Callender, Valerie; Chitreddy, Vijaya; Combalia, Andrea; Cotsarelis, George; Craiglow, Brittany; Dhurat, Rachita; Donovan, Jeff; Doroshkevich, Andrei; Eisman, Samantha; Farrant, Paul; Ferrando, Juan; Gadzhigoroeva, Aida; Green, Jack; Grimalt, Ramon; Harries, Matthew; Hordinsky, Maria; Irvine, Alan; Jolliffe, Victoria; Kaiumov, Spartak; King, Brett; Lee, Joyce; Lee, Won-Soo; Li, Jane; Lortkipanidze, Nino; McMichael, Amy; Mesinkovska, Natasha Atanaskova; Messenger, Andrew; Mirmirani, Paradi; Olsen, Elise; Orlow, Seth J; Ovcharenko, Yuliya; Piraccini, Bianca Maria; Pirmez, Rodrigo; Rakowska, Adriana; Reygagne, Pascal; Rudnicka, Lidia; Corralo, David Saceda; Senna, Maryanne; Shapiro, Jerry; Sharma, Pooja; Siliuk, Tatiana; Starace, Michela; Suchonwanit, Poonkiat; Takwale, Anita; Tosti, Antonella; Vañó-Galván, Sergio; Visser, Willem I; Vogt, Annika; Wade, Martin; Yip, Leona; Zhou, Cheng; Sinclair, Rodney
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.
PMID: 38324292
ISSN: 2168-6084
CID: 5632682

Proteomic profiling of interferon-responsive reactive astrocytes in rodent and human

Prakash, Priya; Erdjument-Bromage, Hediye; O'Dea, Michael R; Munson, Christy N; Labib, David; Fossati, Valentina; Neubert, Thomas A; Liddelow, Shane A
Astrocytes are a heterogeneous population of central nervous system glial cells that respond to pathological insults and injury by undergoing a transformation called "reactivity." Reactive astrocytes exhibit distinct and context-dependent cellular, molecular, and functional state changes that can either support or disturb tissue homeostasis. We recently identified a reactive astrocyte sub-state defined by interferon-responsive genes like Igtp, Ifit3, Mx1, and others, called interferon-responsive reactive astrocytes (IRRAs). To further this transcriptomic definition of IRRAs, we wanted to define the proteomic changes that occur in this reactive sub-state. We induced IRRAs in immunopanned rodent astrocytes and human iPSC-differentiated astrocytes using TNF, IL1α, C1Q, and IFNβ and characterized their proteomic profile (both cellular and secreted) using unbiased quantitative proteomics. We identified 2335 unique cellular proteins, including IFIT2/3, IFITM3, OASL1/2, MX1/2/3, and STAT1. We also report that rodent and human IRRAs secrete PAI1, a serine protease inhibitor which may influence reactive states and functions of nearby cells. Finally, we evaluated how IRRAs are distinct from neurotoxic reactive astrocytes (NRAs). While NRAs are described by expression of the complement protein C3, it was not upregulated in IRRAs. Instead, we found ~90 proteins unique to IRRAs not identified in NRAs, including OAS1A, IFIT3, and MX1. Interferon signaling in astrocytes is critical for the antiviral immune response and for regulating synaptic plasticity and glutamate transport mechanisms. How IRRAs contribute to these functions is unknown. This study provides the basis for future experiments to define the functional roles of IRRAs in the context of neurodegenerative disorders.
PMID: 38031883
ISSN: 1098-1136
CID: 5616902