Discovery and characterization of small-molecule TGR5 ligands with agonistic activity.

The Takeda G protein-coupled receptor 5 (TGR5) is activated endogenously by primary and secondary bile acids. This receptor is considered a candidate target for addressing inflammatory and metabolic disorders. We have targeted TGR5 with structure-based methods for ligand finding using the recently solved experimental structures, as well as structures obtained from molecular dynamics simulations.

Synthesis and Macrodomain Binding of Gln-carba-ADPr-peptide.

Mono-ADP-ribosylation is a dynamic post-translational modification (PTM) with important roles in cell signalling. This modification occurs on a wide variety of amino acids, and one of the canonical modification sites within proteins is the side chain of glutamic acid. Given the transient nature of this modification (acylal linkage) and the high sensitivity of ADP-ribosylated glutamic acid, stabilized isosteres are required for structural and biochemical studies.

ICON 2020-International Scientific Tendinopathy Symposium Consensus: the development of a core outcome set for gluteal tendinopathy.

Gluteal tendinopathy (GT) is common and can be debilitating and challenging to manage. A lack of condition specific and appropriate outcome measures compromise evidence synthesis for treatment and limits clinical guideline development. Our objective was to develop a core outcome measurement set for GT (COS-GT).

Disordered protein regions partner up the cBAF remodeler for a chromatin dance.

Intrinsically disordered protein regions form condensates and mediate interactions with factors that regulate gene activity. Patil et al. decode how such regions within the chromatin remodeler cBAF choreograph self-condensation and non-self interactions with transcriptional regulators, potentially impacting disease.

Sex-Specific Implant Fixation Can Reduce Revision Rates in Total Hip Arthroplasty: Evidence From the Swiss National Joint Registry.

Background: Patient's sex is considered a risk factor for revision following primary total hip arthroplasty (THA), but sex-specific treatment guidelines are lacking. The purpose was to assess sex-specificity of risk factors for periprosthetic femoral fractures (PFFs) and aseptic stem loosening (ASL) in a nationwide register study.

Methods: All uncemented and hybrid THAs for hip osteoarthritis registered in the Swiss National Joint Registry were considered.

XPC-PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair.

Cells employ global genome nucleotide excision repair (GGR) to eliminate a broad spectrum of DNA lesions, including those induced by UV light. The lesion-recognition factor XPC initiates repair of helix-destabilizing DNA lesions, but binds poorly to lesions such as CPDs that do not destabilize DNA. How difficult-to-repair lesions are detected in chromatin is unknown.

Aseptic Revision of Total Hip Arthroplasty With a Single Modular Femoral Stem and a Modified Extended Trochanteric Osteotomy-Treatment Assessment With the Forgotten Joint Score-12.

Background: Aseptic loosening is among the most common reasons for revision total hip arthroplasty (RTHA). Modular revision stems implanted through an extended trochanteric osteotomy (ETO) promise good results, but patient-reported outcome measures (PROMs) are rarely conveyed. This study used the Forgotten Joint Score-12 (FJS-12) to assess patient-reported outcome in patients who had undergone RTHA for aseptic stem loosening using a modified ETO approach with a tapered, fluted modular stem.

Characterization of Constituents with Potential Anti-Inflammatory Activity in Chinese Lonicera Species by UHPLC-HRMS Based Metabolite Profiling.

This study centered on detecting potentially anti-inflammatory active constituents in ethanolic extracts of Chinese Lonicera species by taking an UHPLC-HRMS-based metabolite profiling approach. Extracts from eight different Lonicera species were subjected to both UHPLC-HRMS analysis and to pharmacological testing in three different cellular inflammation-related assays. Compounds exhibiting high correlations in orthogonal projections to latent structures discriminant analysis (OPLS-DA) of pharmacological and MS data served as potentially activity-related candidates.

Mid-term outcomes following transfemoral revision of total hip arthroplasty for Vancouver B2/B3 periprosthetic fractures.

Introduction: Periprosthetic femoral fractures (PFF) are often the reason for revising total hip arthroplasty (RTHA). Converting these fractures into modified extended trochanteric osteotomy (mETO) facilitates stem revision. Modular revision stems are a common choice with good results.

The histone chaperone FACT facilitates heterochromatin spreading by regulating histone turnover and H3K9 methylation states.

Heterochromatin formation requires three distinct steps: nucleation, self-propagation (spreading) along the chromosome, and faithful maintenance after each replication cycle. Impeding any of those steps induces heterochromatin defects and improper gene expression. The essential histone chaperone FACT (facilitates chromatin transcription) has been implicated in heterochromatin silencing, but the mechanisms by which FACT engages in this process remain opaque.

Chemical synthesis of linear ADP-ribose oligomers up to pentamer and their binding to the oncogenic helicase ALC1.

ADP-ribosylation is a pivotal post-translational modification that mediates various important cellular processes producing negatively charged biopolymer, poly (ADP-ribose), the functions of which need further elucidation. Toward this end, the availability of well-defined ADP-ribose (ADPr) oligomers in sufficient quantities is a necessity. In this work, we demonstrate the chemical synthesis of linear ADPr oligomers of defined, increasing length using a modified solid phase synthesis method.

Different outcomes after proximal femoral replacement in oncologic and failed revision arthroplasty patients - a retrospective cohort study.

Background: Proximal femoral replacement (PFR) is a technically demanding procedure commonly performed to restore extensive, oncological or non-oncological bone defects in a severely debilitated patient collective. Depending on different indications, a varying outcome has been reported. The aim of the study was to assess the functional outcomes and complication rates of PFR with the modular Munich-Luebeck (MML) femoral megaprosthesis (ESKA/Orthodynamics, Luebeck, Germany), and to highlight outcome differences in patients treated for failed revision total hip arthroplasty (THA) or malignant bone disease.

The Effects of 3D Immersion Technology (3Scape) on Mental Health in Outpatients From a Short-Term Assessment, Rehabilitation, and Treatment Program: Feasibility Protocol for a Randomized Controlled Trial.

Background: Mental health conditions are prevalent among Canadians and are a leading cause of disability. Each year, 1 in 5 Canadians experiences a mental health issue. A total of 5% of people aged ≥65 years perceive their mental health as fair or poor, and 6.

Crosstalk between Drp1 phosphorylation sites during mitochondrial remodeling and their impact on metabolic adaptation.

Mitochondria constantly undergo fusion and fission events, referred as mitochondrial dynamics, which determine mitochondrial architecture and bioenergetics. Cultured cell studies demonstrate that mitochondrial dynamics are acutely regulated by phosphorylation of the mitochondrial fission orchestrator dynamin-related protein 1 (Drp1) at S579 or S600. However, the physiological impact and crosstalk of these phosphorylation sites is poorly understood.

Tibial joint line orientation has no effect on joint awareness after mechanically aligned total knee arthroplasty.

Purpose: Joint line orientation (JLO) plays an important role in total knee arthroplasty (TKA), but its influence on patient-reported outcomes (PROs) is unclear. The purpose of this study was to examine JLO impact as measured by the forgotten joint score (FJS-12). The hypothesis was that restoring the joint line (JL) parallel to the floor would influence joint awareness favorably, i.

Nucleolar release of rDNA repeats for repair involves SUMO-mediated untethering by the Cdc48/p97 segregase.

Ribosomal RNA genes (rDNA) are highly unstable and susceptible to rearrangement due to their repetitive nature and active transcriptional status. Sequestration of rDNA in the nucleolus suppresses uncontrolled recombination. However, broken repeats must be first released to the nucleoplasm to allow repair by homologous recombination.

Treatment of Gluteal Tendinopathy: A Systematic Review and Stage-Adjusted Treatment Recommendation.

Background: Gluteal tendinopathy is the most common lower limb tendinopathy. It presents with varying severity but may cause debilitating lateral hip pain.

Purpose: To review the therapeutic options for different stages of gluteal tendinopathy, to highlight gaps within the existing evidence, and to provide guidelines for a stage-adjusted therapy for gluteal tendinopathy.

Direct anterior approach improves in-hospital mobility following hemiarthroplasty for femoral neck fracture treatment.

Introduction: In elderly patients, an established treatment for femoral neck fractures is hip hemiarthroplasty (HHA) using the anterolateral approach (ALA). Early postoperative mobilization is crucial to reduce perioperative complications. The direct anterior approach (DAA) has been reported to facilitate early recovery of ambulation and is increasingly popular in elective hip surgery but rarely used in femoral neck fractures.

ADP-ribosyltransferases, an update on function and nomenclature.

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases.

Higher body mass index is associated with larger postoperative improvement in patient-reported outcomes following total knee arthroplasty.

Background: Total knee arthroplasty is known to successfully alleviate pain and improve function in endstage knee osteoarthritis. However, there is some controversy with regard to the influence of obesity on clinical benefits after TKA. The aim of this study was to investigate the impact of body mass index (BMI) on improvement in pain, function and general health status following total knee arthroplasty (TKA).

Information and Communication Technologies for Managing Frailty: A Systematic Literature Review.

Frailty is a prevalent condition among Canadians; over one million are diagnosed as medically frail, and in the next ten years this number will double. Information and telecommunication technologies can provide a low-cost method for managing frailty more proactively. This study aims to examine the range and extent of information and telecommunication technologies for managing frailty in older adults, their technology readiness level, the evidence, and the associated outcomes.