The Energetics and Physiological Impact of Cohesin Extrusion.

Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.

Structures of telomerase at several steps of telomere repeat synthesis.

Telomerase is unique among the reverse transcriptases in containing a noncoding RNA (known as telomerase RNA (TER)) that includes a short template that is used for the processive synthesis of G-rich telomeric DNA repeats at the 3' ends of most eukaryotic chromosomes1. Telomerase maintains genomic integrity, and its activity or dysregulation are critical determinants of human longevity, stem cell renewal and cancer progression2,3. Previous cryo-electron microscopy structures have established the general architecture, protein components and stoichiometries of Tetrahymena and human telomerase, but our understandings of the details of DNA-protein and RNA-protein interactions and of the mechanisms and recruitment involved remain limited4-6. Here we report cryo-electron microscopy structures of active Tetrahymena telomerase with telomeric DNA at different steps of nucleotide addition. Interactions between telomerase reverse transcriptase (TERT), TER and DNA reveal the structural basis of the determination of the 5' and 3' template boundaries, handling of the template-DNA duplex and separation of the product strand during nucleotide addition. The structure and binding interface between TERT and telomerase protein p50 (a homologue of human TPP17,8) define conserved interactions that are required for telomerase activation and recruitment to telomeres. Telomerase La-related protein p65 remodels several regions of TER, bridging the 5' and 3' ends and the conserved pseudoknot to facilitate assembly of the TERT-TER catalytic core.

TNFα and IFNγ cooperate for efficient pro- to anti-inflammatory transition of macrophages during muscle regeneration.

IFNγ is traditionally known as a proinflammatory cytokine with diverse roles in antimicrobial and antitumor immunity. Yet, findings regarding its sources and functions during the regeneration process following a sterile injury are conflicting. Here, we show that natural killer (NK) cells are the main source of IFNγ in regenerating muscle. Beyond this cell population, IFNγ production is limited to a small population of T cells. We further show that NK cells do not play a major role in muscle regeneration following an acute injury or in dystrophic mice. Surprisingly, the absence of IFNγ per se also has no effect on muscle regeneration following an acute injury. However, the role of IFNγ is partially unmasked when TNFα is also neutralized, suggesting a compensatory mechanism. Using transgenic mice, we showed that conditional inhibition of IFNGR1 signaling in muscle stem cells or fibro-adipogenic progenitors does not play a major role in muscle regeneration. In contrast to common belief, we found that IFNγ is not present in the early inflammatory phase of the regeneration process but rather peaks when macrophages are acquiring an anti-inflammatory phenotype. Further transcriptomic analysis suggests that IFNγ cooperates with TNFα to regulate the transition of macrophages from pro- to anti-inflammatory states. The absence of the cooperative effect of these cytokines on macrophages, however, does not result in significant regeneration impairment likely due to the presence of other compensatory mechanisms. Our findings support the arising view of IFNγ as a pleiotropic inflammatory regulator rather than an inducer of the inflammatory response.

Residue coevolution and mutational landscape for OmpR and NarL response regulator subfamilies.

DNA-binding response regulators (DBRRs) are a broad class of proteins that operate in tandem with their partner kinase proteins to form two-component signal transduction systems in bacteria. Typical DBRRs are composed of two domains where the conserved N-terminal domain accepts transduced signals and the evolutionarily diverse C-terminal domain binds to DNA. These domains are assumed to be functionally independent, and hence recombination of the two domains should yield novel DBRRs of arbitrary input/output response, which can be used as biosensors. This idea has been proved to be successful in some cases; yet, the error rate is not trivial. Improvement of the success rate of this technique requires a deeper understanding of the linker-domain and inter-domain residue interactions, which have not yet been thoroughly examined. Here, we studied residue coevolution of DBRRs of the two main subfamilies (OmpR and NarL) using large collections of bacterial amino acid sequences to extensively investigate the evolutionary signatures of linker-domain and inter-domain residue interactions. Coevolutionary analysis uncovered evolutionarily selected linker-domain and inter-domain residue interactions of known experimental structures, as well as previously unknown inter-domain residue interactions. We examined the possibility of these inter-domain residue interactions as contacts that stabilize an inactive conformation of the DBRR where DNA binding is inhibited for both subfamilies. The newly gained insights on linker-domain/inter-domain residue interactions and shared inactivation mechanisms improve the understanding of the functional mechanism of DBRRs, providing clues to efficiently create functional DBRR-based biosensors. Additionally, we show the feasibility of applying coevolutionary landscape models to predict the functionality of domain-swapped DBRR proteins. The presented result demonstrates that sequence information can be used to filter out bioengineered DBRR proteins that are predicted to be nonfunctional due to a high negative predictive value.

Preoperative Evaluation, Anesthetic Considerations, and Perioperative Oral and Parenteral Medications in Total Knee Arthroplasty.

Effective pain management protocol is critical to early mobilization, early discharge, and increasing patient satisfaction for hip and knee arthroplasty. Surgeons have tried to minimize dependence on opioids and opioid-related adverse events through multimodal protocols that use periarticular injections as well as oral and parenteral medications. The efficacy, cost, and adverse effects of each of these components need to be considered when formulating an evidence-based multimodal pain protocol. Recent advancements have changed understanding of the variability in metabolism of commonly given agents around the time of surgery. It is important to provide a systematic approach to the preoperative evaluation, anesthetic considerations, and the administration of oral and parenteral medications routinely used in total knee arthroplasty.

Robotic-assisted total knee arthroplasty is associated with the use of thinner polyethylene liners compared to navigation-guided and manual techniques.

PURPOSE: The purpose of this study was to examine the effects of intraoperative technology use on the rate of using polyethylene liners 15 mm or greater during primary total knee arthroplasty (TKA). METHODS: There were 103,295 implants from 16,386 primary unilateral TKAs performed on 14,253 patients at a single institution between 1 January 2018, and 30 June 2022, included in the current study. Robotic assistance and navigation guidance were used in 1274 (8%) and 8345 (51%) procedures, respectively. The remaining 6767 TKAs (41%) were performed manually. Polyethylene liners were manually identified and further subcategorised by implant thickness. Patients who underwent robotic-assisted TKA were younger (p < 0.001) and more likely to be male (p < 0.001) compared to patients who underwent navigation-guided or manual TKAs. RESULTS: Average polyethylene liner thickness was similar between groups (10.5 ± 1.5 mm for robotic-assisted TKAs, 10.9 ± 1.8 mm for navigation-guided TKAs and 10.8 ± 1.8 mm for manual TKAs). The proportions of polyethylene liners 15 mm or greater used were 4.9%, 3.8% and 1.9% for navigation-guided, manual and robotic-assisted procedures, respectively (p < 0.001). Multivariate regression analyses demonstrated that navigation-guided (odds ratio [OR]: 2.6, 95% confidence Interval [CI]: [1.75-4.07], p < 0.001) and manual (OR: 2.0, 95% CI: [1.34-3.20], p = 0.001) procedures were associated with an increased use of polyethylene liners 15 mm or greater. CONCLUSION: Robotic-assisted TKA was associated with a lower proportion of polyethylene liners 15 mm or greater used compared to navigation-guided and manual TKA. These findings suggest that robotic assistance can reduce human error via a more precise cutting system, limit over-resection of the tibia and flexion-extension gap mismatch and ultimately allow for more appropriately sized implants. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

An Artificial Intelligence Chatbot is an Accurate and Useful Online Patient Resource Prior to Total Knee Arthroplasty.

BACKGROUND: Online information is a useful resource for patients seeking advice on their orthopaedic care. While traditional websites provide responses to specific frequently asked questions (FAQs), sophisticated artificial intelligence tools may be able to provide the same information to patients in a more accessible manner. Chat Generative Pretrained Transformer (ChatGPT) is a powerful artificial intelligence chatbot that has been shown to effectively draw on its large reserves of information in a conversational context with a user. The purpose of this study was to assess the accuracy and reliability of ChatGPT-generated responses to FAQs regarding total knee arthroplasty. METHODS: We distributed a survey that challenged arthroplasty surgeons to identify which of the 2 responses to FAQs on our institution's website was human-written and which was generated by ChatGPT. All questions were total knee arthroplasty-related. The second portion of the survey investigated the potential to further leverage ChatGPT to assist with translation and accessibility as a means to better meet the needs of our diverse patient population. RESULTS: Surgeons correctly identified the ChatGPT-generated responses 4 out of 10 times on average (range: 0 to 7). No consensus was reached on any of the responses to the FAQs. Additionally, over 90% of our surgeons strongly encouraged the use of ChatGPT to more effectively accommodate the diverse patient populations that seek information from our hospital's online resources. CONCLUSIONS: ChatGPT provided accurate, reliable answers to our website's FAQs. Surgeons also agreed that ChatGPT's ability to provide targeted, language-specific responses to FAQs would be of benefit to our diverse patient population.

To Stage or Not to Stage? Comparison of Patient-Reported Outcomes, Complications, and Discharge Disposition After Staged and Simultaneous Bilateral Posterior Total Hip Arthroplasty.

BACKGROUND: Patients who have bilateral hip arthritis can be treated with bilateral total hip arthroplasty (bTHA) in either a staged or simultaneous fashion. The goal of this study was to determine whether staged and simultaneous posterior bTHA patients differ in regard to (1) patient-reported outcome measures, (2) 90-day complication rates, and (3) discharge dispositions and cumulative lengths of stay. METHODS: Patients who (1) underwent simultaneous bTHA or staged bTHA (within 12 months) using the posterior approach, and (2) completed preoperative and 1-year postoperative Hip dysfunction and Osteoarthritis Outcome Score for Joint Replacement surveys were included in the study. A total of 266 patients (87 simultaneous bTHA and 179 staged bTHA) were included. Chart review was performed to collect patient-level variables, postoperative complications, discharge dispositions, and lengths of stay. RESULTS: Staged bTHA patients had higher Hip dysfunction and Osteoarthritis Outcome Score for Joint Replacement, Lower Extremity Activity Scale, and Veterans RAND 12-Item Health Survey physical component scores compared to simultaneous bTHA patients at 6 weeks after surgery (P = .019, .006, and .008, respectively), but these differences did not meet the minimal clinically important difference threshold for any questionnaire. Simultaneous bTHA was associated with higher rate of periprosthetic fractures (P = .034) and discharge to a location other than home (P < .001). CONCLUSIONS: There were statistically significant, but likely not clinically meaningful differences in patient-reported outcomes for staged and simultaneous bTHA patients at 6 weeks after surgery. Surgeons should be aware of the higher periprosthetic fracture risk and greater likelihood of discharge to a rehabilitation facility associated with simultaneous bTHA. Further research should aim to understand which patients may benefit most from simultaneous bTHA.

Contemporary Isolated Bearing Exchange for the Management of Hip Instability Following Primary Total Hip Arthroplasty.

BACKGROUND: Isolated ball and liner exchanges (IBLEs) can be performed to increase hip joint stability, but historical results have been mixed due to a lack of head size options or dual mobility articulations. The purpose of this study was to evaluate the contemporary results of IBLEs in patients who have instability following primary total hip arthroplasty (THA). METHODS: We retrospectively reviewed 65 primary THAs from 2016 to 2020 with hip instability undergoing IBLE or conversion to dual mobility articulation. There were 31 men and 34 women who had an average age of 70 years (range, 26 to 92). The mean time to revision from primary was 40.1 months (range, 1 to 120). In 52 cases, IBLE was performed using conventional bearings, while 13 hips were converted to dual mobility. Radiographic factors, including acetabular component orientation, reproduction of hip joint offset, leg lengths, and outcomes such as recurrent instability requiring subsequent revision and patient-reported outcome measure, were recorded and compared. RESULTS: There were 12 (18.4%) hips that experienced subsequent instability and required another revision (17.3% ball and liner exchange versus 23.1% dual mobility articulation, P = .615). The mean time to rerevision for instability was 17.1 months. There were no significant differences in either acetabular component anteversion (P = .25) or restoration of hip joint offset (P = .87) in patients who required another revision for instability compared to those who did not, respectively. At 1 year, patients undergoing conventional bearing exchange reported higher Hip Dysfunction Osteoarthritis Outcome Score for Joint Replacements (P = .002) and Veterans Rand physical component (P = .023) scores compared to those who underwent a conversion to dual mobility articulation. Only age > 75 years at the time of surgery was associated with increased risk for dislocation (odds ratio 7.2, confidence interval 1.2 to 43.7, P = .032). CONCLUSIONS: Isolated bearing exchanges for instability following THA remained at high risk for subsequent instability. Conversion to dual mobility articulations did not reduce the risk of reoperation.

Clinical Outcomes of Isolated Polyethylene Exchange Versus Full Component Revision for the Management of Instability Following Total Knee Arthroplasty.

BACKGROUND: Instability following total knee arthroplasty (TKA) is a common cause for revision. Isolated polyethylene exchange (IPE) can be performed to increase knee joint stability, but results have been mixed. The purpose of this study was to compare the survivorship and patient-reported outcomes of patients undergoing revision TKA for instability with IPE versus full component revision. METHODS: We reviewed 280 primary TKAs undergoing revision TKA for instability. There were 181 knees that underwent revision with IPE, compared to 99 knees treated with full component revision. The mean follow-up was 32.8 months (range, 24.8 to 82.5). Patient demographics, radiographic parameters, prosthesis constraints, reoperations for instability, and patient-reported outcomes were compared. RESULTS: The survivorship for instability was significantly higher at 2 years (99 versus 92%, P = .024) and 5 years (94 versus 84%, P = .024) for patients undergoing full component revision. Although there was no difference in Knee Injury and Osteoarthritis Outcome Score for Joint Replacements and Veterans RAND 12 physical component scores between the 2 groups at 6 weeks, 1 year, and 2 years after surgery, full revision patients reported greater pain relief (P = .006) and greater improvements in Veterans RAND 12 physical component scores (P = .027) at 1 year and Knee Injury and Osteoarthritis Outcome Score for Joint Replacements scores at 2 years (P = .017) compared to IPE patients. Men were associated with an increased risk for recurrent instability following IPE (hazard ratio 3.3, 95% confidence interval: [1.0 to 10.6]). CONCLUSIONS: Isolated polyethylene exchange was not as reliable or durable compared to full component revision for the management of postoperative instability. These procedures should only be reserved in cases with competent collaterals and when component position, offset, and rotation are optimized.

Claw bed inverted squamous papilloma associated with canine papillomavirus type 2 in a dog.

A claw bed inverted squamous papilloma (ISP) presented clinically as a swollen digit in a dog. Canine papillomavirus (CPV) type 2 was amplified by PCR and localised to the papilloma's epidermis using in situ hybridisation. This is the first report demonstrating a claw bed ISP caused by CPV.

Un papillome squameux inversé de la matrice unguéale est décrit cliniquement comme un gonflement du doigt chez un chien. Le papillomavirus canin (CPV) de type 2 a été amplifié par PCR et localisé dans l'épiderme du papillome par hybridation in situ. Il s'agit du premier rapport faisant état d'un papillome squameux inversé de la matrice unguéale par le CPV.

Um caso de papiloma escamoso invertido no leito ungueal em um cão apresentando aumento de volume em um dígito. O vírus do papiloma canino (CVP) Tipo 2 foi amplificado por PCR e localizado na epiderme do papiloma utilizando hibridização in situ. Este foi o primeiro relato demonstrando um papiloma escamoso invertido causado por CPV.

Un papiloma escamoso invertido del lecho ungueal se presentó clínicamente como un dedo hinchado en un perro. Se amplificó mediante PCR genoma del virus papiloma canino tipo 2 (CPV) y se localizó en la epidermis el papiloma mediante hibridación in situ. Este es el primer reporte de caso que demuestra la existencia de un papiloma escamoso invertido del lecho ungueal causado por CPV.

Changes in Body Composition and Athletic Performance in National Collegiate Athletic Association Division I Female Field Hockey Athletes Throughout a Competitive Season.

ABSTRACT: Summer, LC, Cheng, R, Moran, JT, Lee, M, Belanger, AJ, TaylorIV, WL, and Gardner, EC. Changes in body composition and athletic performance in National Collegiate Athletic Association Division I female field hockey athletes throughout a competitive season. J Strength Cond Res 38(1): 146-152, 2024-The purposes of this study were (a) to analyze the changes in total and regional body composition measurements in a National Collegiate Athletic Association (NCAA) Division I female field hockey team throughout a 17-game competitive season using dual X-ray absorptiometry (DXA); (b) to examine improvements, if any, in athletic performance measures after a season; and (c) to report on the relationship between these body composition changes and changes in athletic performance. Preseason and postseason dual-energy DXA and performance data from the 2019-2020 season were retrospectively identified for 20 field players (forwards, midfielders, and defenders). Body composition data included total and regional fat mass, lean mass, and body fat percentage, whereas athletic performance measures included the vertical jump, 10-yard dash, and pro-agility (5-10-5) shuttle run. All variables were quantitative and analyzed using paired t -tests or its nonparametric equivalent and an alpha level of p < 0.05 was used to determine significance. After a competitive season, athletes had significant decreases in fat mass and increases in lean mass in their arms, legs, trunks, gynoids, and total body measurements. Android fat mass and body fat percentage also decreased. Athletes performed significantly better on the pro-agility shuttle run at the end of the season, but no significant differences were observed in other performance metrics. Moderate correlations were observed between changes in body composition (total fat mass and total lean mass) and changes in athletic performance. Our study provides a novel, longitudinal assessment of body composition and athletic performance for elite female field hockey athletes that will help trainers and coaches better understand how these variables change throughout a season and allow them to better prepare their players for competitive success.

Structural reorganization and relaxation dynamics of axially stressed chromosomes.

Chromosomes endure mechanical stresses throughout the cell cycle; for example, resulting from the pulling of chromosomes by spindle fibers during mitosis or deformation of the nucleus during cell migration. The response to physical stress is closely related to chromosome structure and function. Micromechanical studies of mitotic chromosomes have revealed them to be remarkably extensible objects and informed early models of mitotic chromosome organization. We use a data-driven, coarse-grained polymer modeling approach to explore the relationship between the spatial organization of individual chromosomes and their emergent mechanical properties. In particular, we investigate the mechanical properties of our model chromosomes by axially stretching them. Simulated stretching led to a linear force-extension curve for small strain, with mitotic chromosomes behaving about 10-fold stiffer than interphase chromosomes. Studying their relaxation dynamics, we found that chromosomes are viscoelastic solids with a highly liquid-like, viscous behavior in interphase that becomes solid-like in mitosis. This emergent mechanical stiffness originates from lengthwise compaction, an effective potential capturing the activity of loop-extruding SMC complexes. Chromosomes denature under large strains via unraveling, which is characterized by opening of large-scale folding patterns. By quantifying the effect of mechanical perturbations on the chromosome's structural features, our model provides a nuanced understanding of in vivo mechanics of chromosomes.

The Nucleome Data Bank: web-based resources to simulate and analyze the three-dimensional genome.

We introduce the Nucleome Data Bank (NDB), a web-based platform to simulate and analyze the three-dimensional (3D) organization of genomes. The NDB enables physics-based simulation of chromosomal structural dynamics through the MEGABASE + MiChroM computational pipeline. The input of the pipeline consists of epigenetic information sourced from the Encode database; the output consists of the trajectories of chromosomal motions that accurately predict Hi-C and fluorescence insitu hybridization data, as well as multiple observations of chromosomal dynamics in vivo. As an intermediate step, users can also generate chromosomal sub-compartment annotations directly from the same epigenetic input, without the use of any DNA-DNA proximity ligation data. Additionally, the NDB freely hosts both experimental and computational structural genomics data. Besides being able to perform their own genome simulations and download the hosted data, users can also analyze and visualize the same data through custom-designed web-based tools. In particular, the one-dimensional genetic and epigenetic data can be overlaid onto accurate 3D structures of chromosomes, to study the spatial distribution of genetic and epigenetic features. The NDB aims to be a shared resource to biologists, biophysicists and all genome scientists. The NDB is available at https://ndb.rice.edu.

Update of pediatric bone tumors: osteogenic tumors and osteoclastic giant cell-rich tumors.

There are numerous bone tumors in the pediatric population, with imaging playing an essential role in diagnosis and management. Our understanding of certain bone tumors has rapidly evolved over the past decade with advancements in next-generation genetic sequencing techniques. This increased level of understanding has altered the nomenclature, management approach, and prognosis of certain lesions. We provide a detailed update of bone tumors that occur in the pediatric population with emphasis on the recently released nomenclature provided in the 5th edition of the World Health Organization Classification of Soft Tissue and Bone Tumours.

Update of pediatric bone tumors-notochordal tumors, chondrogenic tumors, and vascular tumors of the bone.

There are numerous bone tumors in the pediatric population, with imaging playing an essential role in diagnosis and management. Our understanding of certain bone tumors has rapidly evolved over the past decade with advancements in next-generation genetic sequencing techniques. This increased level of understanding has altered the nomenclature, management approach, and prognosis of certain lesions. We provide a detailed update of bone tumors that occur in the pediatric population with emphasis on the recently released nomenclature provided in the 5th edition of the World Health Organization Classification of Soft Tissue and Bone Tumours. In the current manuscript, we address notochordal tumors, chondrogenic tumors, and vascular tumors of the bone.

High degree of alignment precision associated with total knee arthroplasty performed using a surgical robot or handheld navigation.

PURPOSE: The purpose of this study was to compare the precision of bony resections during total knee arthroplasty (TKA) performed using different computer-assisted technologies. METHODS: Patients who underwent a primary TKA using an imageless accelerometer-based handheld navigation system (KneeAlign2®, OrthAlign Inc.) or computed tomography-based large-console surgical robot (Mako®, Stryker Corp.) from 2017 to 2020 were retrospectively reviewed. Templated alignment targets and demographic data were collected. Coronal plane alignment of the femoral and tibial components and tibial slope were measured on postoperative radiographs. Patients with excessive flexion or rotation preventing accurate measurement were excluded. RESULTS: A total of 240 patients who underwent TKA using either a handheld (n = 120) or robotic (n = 120) system were included. There were no statistically significant differences in age, sex, and BMI between groups. A small but statistically significant difference in the precision of the distal femoral resection was observed between the handheld and robotic cohorts (1.5° vs. 1.1° difference between templated and measured alignments, p = 0.024), though this is likely clinically insignificant. There were no significant differences in the precision of the tibial resection between the handheld and robotic groups (coronal plane 0.9° vs. 1.0°, n.s.; sagittal plane 1.2° vs. 1.1°, n.s.). There were no significant differences in the rate of overall precision between cohorts (n.s.). CONCLUSIONS: A high degree of component alignment precision was observed for both imageless handheld navigation and CT-based robotic cohorts. Surgeons considering options for computer-assisted TKA should take other important factors, including surgical principles, templating software, ligament balancing, intraoperative adjustability, equipment logistics, and cost, into account. LEVEL OF EVIDENCE: III.

Survivorship and Clinical Outcomes of Primary Total Knee Arthroplasty Performed in Patients 35 Years of Age and Younger.

BACKGROUND: Total knee arthroplasties (TKAs) for patients aged ≤35 years are rare but necessary for patients who have diseases such as juvenile idiopathic arthritis, osteonecrosis, osteoarthritis, and rheumatoid arthritis. Few studies have examined the 10-year and 20-year survivorship and clinical outcomes of TKAs for young patients. METHODS: A retrospective registry review identified 185 TKAs in 119 patients aged ≤ 35 years performed between 1985 and 2010 at a single institution. The primary outcome was implant survivorship free of revision. Patient-reported outcomes were assessed at 2 time points: 2011 to 2012 and 2018 to 2019. The average age was 26 years (range, 12 to 35). Mean follow-up was 17 years (range, 8 to 33). RESULTS: Survivorship decreased from 84% (95% confidence interval [CI]: 79 to 90) at 5 years to 70% (95% CI: 64 to 77) at 10 years and to 37% (95% CI: 29 to 45) at 20 years. The most common reasons for revision were aseptic loosening (6%) and infection (4%). Risk factors for revision included increasing age at time of surgery (Hazards Ratio [HR] 1.3, P = .01) and use of constrained (HR 1.7, P = .05) or hinged prostheses (HR 4.3, P = .02). There were 86% of patients reporting that their surgery resulted in "a great improvement" or better. CONCLUSION: Survivorship of TKAs in young patients is less favorable than expected. However, for the patients who responded to our surveys, TKA demonstrated substantial pain relief and improvement in function at 17-year follow-up. Revision risk increased with older age and higher levels of constraint.

Structure of S. pombe telomerase protein Pof8 C-terminal domain is an xRRM conserved among LARP7 proteins.

La-related proteins 7 (LARP7) are a class of RNA chaperones that bind the 3' ends of RNA and are constitutively associated with their specific target RNAs. In metazoa, Larp7 binds to the long non-coding 7SK RNA as a core component of the 7SK RNP, a major regulator of eukaryotic transcription. In the ciliate Tetrahymena the LARP7 protein p65 is a component of telomerase, an essential ribonucleoprotein complex that maintains the telomeric DNA at eukaryotic chromosome ends. p65 is important for the ordered assembly of telomerase RNA (TER) with telomerase reverse transcriptase. Unexpectedly, Schizosaccharomyces pombe Pof8 was recently identified as a LARP7 protein and a core component of fission yeast telomerase essential for biogenesis. LARP7 proteins have a conserved N-terminal La motif and RRM1 (La module) and C-terminal RRM2 with specific RNA substrate recognition attributed to RRM2, first structurally characterized in p65 as an atypical RRM named xRRM. Here we present the X-ray crystal structure and NMR studies of S. pombe Pof8 RRM2. Sequence and structure comparison of Pof8 RRM2 to p65 and human Larp7 xRRMs reveals conserved features for RNA binding with the main variability in the length of the non-canonical helix α3. This study shows that Pof8 has conserved xRRM features, providing insight into TER recognition and the defining characteristics of the xRRM.