Transcription-wide mapping of dihydrouridine reveals that mRNA dihydrouridylation is required for meiotic chromosome segregation.

The epitranscriptome has emerged as a new fundamental layer of control of gene expression. Nevertheless, the determination of the transcriptome-wide occupancy and function of RNA modifications remains challenging. Here we have developed Rho-seq, an integrated pipeline detecting a range of modifications through differential modification-dependent rhodamine labeling. Using Rho-seq, we confirm that the reduction of uridine to dihydrouridine (D) by the Dus reductase enzymes targets tRNAs in E. coli and fission yeast. We find that the D modification is also present on fission yeast mRNAs, particularly those encoding cytoskeleton-related proteins, which is supported by large-scale proteome analyses and ribosome profiling. We show that the α-tubulin encoding mRNA nda2 undergoes Dus3-dependent dihydrouridylation, which affects its translation. The absence of the modification on nda2 mRNA strongly impacts meiotic chromosome segregation, resulting in low gamete viability. Applying Rho-seq to human cells revealed that tubulin mRNA dihydrouridylation is evolutionarily conserved.

Altered dNTP pools accelerate tumor formation in mice.

Alterations in deoxyribonucleoside triphosphate (dNTP) pools have been linked to increased mutation rates and genome instability in unicellular organisms and cell cultures. However, the role of dNTP pool changes in tumor development in mammals remains unclear. In this study, we present a mouse model with a point mutation at the allosteric specificity site of ribonucleotide reductase, RRM1-Y285A. This mutation reduced ribonucleotide reductase activity, impairing the synthesis of deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP). Heterozygous Rrm1+/Y285A mice exhibited distinct alterations in dNTP pools across various organs, shorter lifespans and earlier tumor onset compared with wild-type controls. Mutational spectrum analysis of tumors revealed two distinct signatures, one resembling a signature extracted from a human cancer harboring a mutation of the same amino acid residue in ribonucleotide reductase, RRM1Y285C. Our findings suggest that mutations in enzymes involved in dNTP metabolism can serve as drivers of cancer development.

Strand switching mechanism of Pif1 helicase induced by its collision with a G-quadruplex embedded in dsDNA.

G-rich sequences found at multiple sites throughout all genomes may form secondary structures called G-quadruplexes (G4), which act as roadblocks for molecular motors. Among the enzymes thought to process these structures, the Pif1 DNA helicase is considered as an archetypical G4-resolvase and its absence has been linked to G4-related genomic instabilities in yeast. Here we developed a single-molecule assay to observe Pif1 opening a DNA duplex and resolving the G4 in real time. In support of former enzymological studies, we show that the helicase reduces the lifetime of G4 from hours to seconds. However, we observe that in the presence of a G4, Pif1 exhibits a strong strand switching behavior, which can lead to Pif1 escaping G4 resolution, depending on the structural context surrounding the substrate. This behavior is also detected in the presence of other roadblocks (LNA or RNA). We propose that the efficiency of Pif1 to remove a roadblock (G4 or other) is affected by its strand switching behavior and depends on the context surrounding the obstacle. We discuss how this switching behavior may explain several aspects of Pif1 substrate preference and affect its activity as a G4 resolvase in vivo.

Folding and persistence times of intramolecular G-quadruplexes transiently embedded in a DNA duplex.

G-quadruplex (G4) DNA structures have emerged as important regulatory elements during DNA metabolic transactions. While many in vitro studies have focused on the kinetics of G4 formation within DNA single-strands, G4 are found in vivo in double-stranded DNA regions, where their formation is challenged by the complementary strand. Since the energy of hybridization of Watson-Crick structures dominates the energy of G4 folding, this competition should play a critical role on G4 persistence. To address this, we designed a single-molecule assay allowing to measure G4 folding and persistence times in the presence of the complementary strand. We quantified both folding and unfolding rates of biologically relevant G4 sequences, such as the cMYC and cKIT oncogene promoters, human telomeres and an avian replication origin. We confirmed that G4s are found much more stable in tested replication origin and promoters than in human telomere repeats. In addition, we characterized how G4 dynamics was affected by G4 ligands and showed that both folding rate and persistence time increased. Our assay opens new perspectives for the measurement of G4 dynamics in double-stranded DNA mimicking a replication fork, which is important to understand their role in DNA replication and gene regulation at a mechanistic level.

Prevalence of diagnosable depression in patients awaiting orthopaedic specialist consultation: a cross-sectional analysis.

BACKGROUND: Musculoskeletal conditions, including osteoarthritis (OA), are a leading cause of disability and chronic pain, and are associated with high rates of comorbid depression. However, signs of depression are often masked by pain. The aim of this study was to determine the prevalence and severity of depression and pain in individuals awaiting specialist orthopaedic consultation. A secondary objective was to determine the relationship between pain and depression, irrespective of demographic factors and clinical diagnosis. METHODS: Cross-sectional analysis of individuals awaiting orthopaedic consultation at a public hospital in Melbourne, Australia. Relevant data were extracted from medical records and questionnaires. Descriptive statistics were used to summarise participant characteristics. The patient health questionnaire (PHQ-9) was used to assess depression and a numerical rating scale (NRS) was used to assess pain severity. Multiple linear regression analyses were used to establish the relationship between pain and depression. RESULTS: Nine hundred and eighty-six adults (mean ± standard deviation, age = 54.1 ± 15.7 years, 53.2% women) participated in the study. OA was present in 56% of the population and 34% of the entire population had moderate depression or greater, 19% of which met the criteria for major depressive disorder. Moderate-to-severe pain was present in 79% of individuals with OA and 55% of individuals with other musculoskeletal complaints. Pain was significantly associated with depression scores (ß = 0.84, adjusted R2 = 0.13, P < 0.001), and this relationship remained significant after accounting for gender, age, education and employment status, OA status, number of joints affected and waiting time (ß = 0.91, adjusted R2 = 0.19, P < 0.001). CONCLUSIONS: Depression affects one-third of individuals on an orthopaedic waitlist. A strong link between pain and depression in patients awaiting specialist orthopaedic consultation exists, indicating a need for an integrated approach in addressing pain management and depression to manage this complex and comorbid presentation.

Elimination of rNMPs from mitochondrial DNA has no effect on its stability.

Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to genome stability and can result in DNA strand breaks when not removed in a timely manner. However, the presence of a certain level of rNMPs is tolerated in mitochondrial DNA (mtDNA) although aberrant mtDNA rNMP content has been identified in disease models. We investigated the effect of incorporated rNMPs on mtDNA stability over the mouse life span and found that the mtDNA rNMP content increased during early life. The rNMP content of mtDNA varied greatly across different tissues and was defined by the rNTP/dNTP ratio of the tissue. Accordingly, mtDNA rNMPs were nearly absent in SAMHD1-/- mice that have increased dNTP pools. The near absence of rNMPs did not, however, appreciably affect mtDNA copy number or the levels of mtDNA molecules with deletions or strand breaks in aged animals near the end of their life span. The physiological rNMP load therefore does not contribute to the progressive loss of mtDNA quality that occurs as mice age.

Do Certain Patient Cohorts Benefit From Different Surgical Approaches in Total Hip Arthroplasty?

BACKGROUND: Unfortunately, an important minority of total hip arthroplasty (THA) patients report unsatisfactory outcomes. We aimed to compare the patient-reported outcome measures (PROMs) for three main THA approaches and evaluate the effect of sex and body mass index (BMI) on PROMs over a 10-year period. METHODS: A total of 906 patients (535 women, mean BMI 30.7 [range, 15 to 58]; 371 men, mean BMI 31.2 [range, 17 to 56]) who underwent primary THA by an anterior (AA) (312), lateral (LA) (211), or posterior (383) approach between 2009 and 2020 at a single institution were evaluated using the Oxford Hip Score (OHS). PROMs were prospectively collected before surgery and routinely at 6 weeks, 6 months, and 1, 2, 5, and 10 years after surgery. RESULTS: All three approaches resulted in significant postoperative OHS improvement. Overall, women experienced significantly lower OHS than men (P < .01). A significant negative relationship between BMI and OHS was identified and this relationship was exacerbated with an AA (P < .01). Women who had a BMI ≤ 25 reported OHS with a difference more than 5 points in favor of the AA, while women who had a BMI ≥ 42 reported an OHS with a difference more than 5 in favor of the LA. The BMI ranges were wider when comparing the anterior and posterior approaches, 22 to 46 for women and > 50 for men. For men, an OHS difference more than 5 was only seen with BMI ≥ 45 in favor of the LA. CONCLUSION: This study demonstrated that no single THA approach is superior to another but rather that certain patient cohorts may benefit more from specific approaches. We suggest that women who have a BMI ≤ 25 should consider undergoing an anterior approach for THA, while for women who have a BMI ≥ 42, a lateral approach or for a BMI ≥ 46, a posterior approach is advised.

Smartphone Technology to Remotely Measure Postural Sway during Double- and Single-Leg Squats in Adults with Femoroacetabular Impingement and Those with No Hip Pain.

BACKGROUND: The COVID-19 pandemic has accelerated the demand for utilising telehealth as a major mode of healthcare delivery, with increasing interest in the use of tele-platforms for remote patient assessment. In this context, the use of smartphone technology to measure squat performance in people with and without femoroacetabular impingement (FAI) syndrome has not been reported yet. We developed a novel smartphone application, the TelePhysio app, which allows the clinician to remotely connect to the patient's device and measure their squat performance in real time using the smartphone inertial sensors. The aim of this study was to investigate the association and test-retest reliability of the TelePhysio app in measuring postural sway performance during a double-leg (DLS) and single-leg (SLS) squat task. In addition, the study investigated the ability of TelePhysio to detect differences in DLS and SLS performance between people with FAI and without hip pain. METHODS: A total of 30 healthy (nfemales = 12) young adults and 10 adults (nfemales = 2) with diagnosed FAI syndrome participated in the study. Healthy participants performed DLS and SLS on force plates in our laboratory, and remotely in their homes using the TelePhysio smartphone application. Sway measurements were compared using the centre of pressure (CoP) and smartphone inertial sensor data. A total of 10 participants with FAI (nfemales = 2) performed the squat assessments remotely. Four sway measurements in each axis (x, y, and z) were computed from the TelePhysio inertial sensors: (1) average acceleration magnitude from the mean (aam), (2) root-mean-square acceleration (rms), (3) range acceleration (r), and (4) approximate entropy (apen), with lower values indicating that the movement is more regular, repetitive, and predictable. Differences in TelePhysio squat sway data were compared between DLS and SLS, and between healthy and FAI adults, using analysis of variance with significance set at 0.05. RESULTS: The TelePhysio aam measurements on the x- and y-axes had significant large correlations with the CoP measurements (r = 0.56 and r = 0.71, respectively). The TelePhysio aam measurements demonstrated moderate to substantial between-session reliability values of 0.73 (95% CI 0.62-0.81), 0.85 (95% CI 0.79-0.91), and 0.73 (95% CI 0.62-0.82) for aamx, aamy, and aamz, respectively. The DLS of the FAI participants showed significantly lower aam and apen values in the medio-lateral direction compared to the healthy DLS, healthy SLS, and FAI SLS groups (aam = 0.13, 0.19, 0.29, and 0.29, respectively; and apen = 0.33, 0.45, 0.52, and 0.48, respectively). In the anterior-posterior direction, healthy DLS showed significantly greater aam values compared to the healthy SLS, FAI DLS, and FAI SLS groups (1.26, 0.61, 0.68, and 0.35, respectively). CONCLUSIONS: The TelePhysio app is a valid and reliable method of measuring postural control during DLS and SLS tasks. The application is capable of distinguishing performance levels between DLS and SLS tasks, and between healthy and FAI young adults. The DLS task is sufficient to distinguish the level of performance between healthy and FAI adults. This study validates the use of smartphone technology as a tele-assessment clinical tool for remote squat assessment.

Water-Splitting Artificial Leaf Based on a Triple-Junction Silicon Solar Cell: One-Step Fabrication through Photoinduced Deposition of Catalysts and Electrochemical Operando Monitoring.

Solar hydrogen generation via water splitting using a monolithic photoelectrochemical cell, also called artificial leaf, could be a powerful technology to accelerate the transition from fossil to sustainable energy sources. Identification of scalable methods for the fabrication of monolithic devices and gaining insights into their operating mode to identify solutions to improve performance and stability represent great challenges. Herein, we report on the one-step fabrication of a CoWO|ITO|3jn-a-Si|Steel|CoWS monolithic device via the simple photoinduced deposition of CoWO and CoWS as oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) catalyst layers, respectively, onto an illuminated ITO|3jn-a-Si|Steel solar cell using a single-deposition bath containing the [Co(WS4)2]2- complex. In a pH 7 phosphate buffer solution, the best device achieved a solar-to-hydrogen conversion yield of 1.9%. Evolution of the catalyst layers and that of the 3jn-a-Si light-harvesting core during the operation of the monolithic device are examined by conventional tools such as scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and inductively coupled plasma optical emission spectroscopy (ICP-OES) together with a bipotentiostat measurement. We demonstrate that the device performance degrades due to the partial dissolution of the catalyst. Still, this degradation is healable by simply adding [Co(WS4)2]2- to the operating solution. However, modifications on the protecting indium-doped tin oxide (ITO) layer are shown to initiate irreversible degradation of the 3jn-a-Si light-harvesting core, resulting in a 10-fold decrease of the performances of the monolithic device.

Kinesin-14 family proteins and microtubule dynamics define S. pombe mitotic and meiotic spindle assembly, and elongation.

To segregate the chromosomes faithfully during cell division, cells assemble a spindle that captures the kinetochores and pulls them towards opposite poles. Proper spindle function requires correct interplay between microtubule motors and non-motor proteins. Defects in spindle assembly or changes in spindle dynamics are associated with diseases, such as cancer or developmental disorders. Here, we compared mitotic and meiotic spindles in fission yeast. We show that, even though mitotic and meiotic spindles underwent the typical three phases of spindle elongation, they have distinct features. We found that the relative concentration of the kinesin-14 family protein Pkl1 is decreased in meiosis I compared to mitosis, while the concentration of the kinesin-5 family protein Cut7 remains constant. We identified the second kinesin-14 family protein Klp2 and microtubule dynamics as factors necessary for proper meiotic spindle assembly. This work defines the differences between mitotic and meiotic spindles in fission yeast Schizosaccharomyces pombe, and provides prospect for future comparative studies.This article has an associated First Person interview with the first author of the paper.

Crystallization Pathways and Evolution of Morphologies and Structural Defects of α-MnO2 under Air Annealing.

Manganese dioxide nanomaterials have wide applications in many areas from catalysis and Li-ion batteries to gas sensing. Understanding the crystallization pathways, morphologies, and formation of defects in their structure is particularly important but still a challenging issue. Herein, we employed an arsenal of X-ray diffraction (XRD), scanning electron microscopy (SEM), neutron diffraction, positron annihilation spectroscopies, and ab initio calculations to investigate the evolution of the morphology and structure of α-MnO2 nanomaterials prepared via reduction of KMnO4 solution with C2H5OH prior to being annealed in air at 200-600 °C. We explored a novel evolution that α-MnO2 nucleation can be formed even at room temperature and gradually developed to α-MnO2 nanorods at above 500 °C. We also found the existence of H+ or K+ ions in the [1 × 1] tunnels of α-MnO2 and observed the simultaneous presence of Mn and O vacancies in α-MnO2 crystals at low temperatures. Increasing the temperature removed these O vacancies, leaving only the Mn vacancies in the samples.

Can a Hip Brace Improve Short-Term Hip-Related Quality of Life for People With Femoroacetabular Impingement and Acetabular Labral Tears: An Exploratory Randomized Trial.

OBJECTIVES: To examine whether a hip brace can improve hip health quality-of-life (QoL) and is well-tolerated in people with femoroacetabular impingement syndrome (FAIS) or symptomatic labral tears after 6 weeks of wear. DESIGN: Parallel, two-arm, exploratory randomized trial. SETTING: Hospital and private clinics of orthopaedic surgeons. PARTICIPANTS: Individuals >18 years with FAIS or labral tears. INTERVENTIONS: Usual conservative care versus usual conservative care plus a hip brace. MAIN OUTCOMES: Patient-reported outcomes were assessed with the International Hip Outcome Tool (iHOT-33), and Copenhagen Hip and Groin Outcome Scores (HAGOS). Brace acceptability was measured using the Quebec User Evaluation of Satisfaction with Assistive Technology survey. Independent t-tests assessed between-group differences. RESULTS: Thirty-eight participants were recruited, 19 each group, 60% women, mean age 39.3 ± 11.8 years, body mass index 25.3 ± 4.4 kg/m2, iHOT-33 36.6 ± 24.8. Three participants dropped out (one usual care, 2 braced). The mean between-group difference for iHOT-33 was 19.4 (95% confidence interval [CI] 1.68-37.06, P = 0.03) favoring the brace. There were improvements in most HAGOS subscale scores favoring the brace. Issues with brace tolerability for some participants were perceived comfort and effectiveness. Three brace-related adverse events were reported. CONCLUSION: Between-group differences favored the braced group for hip health QoL, pain, symptoms, and function. Although these were promising results, the CIs for the estimates were wide, the small sample size likely a contributing factor. Our results suggest that further investigation of the brace is warranted, we calculated sample sizes and made recommendations for the design of a future trial.

Validity and Reliability of a Novel Smartphone Tele-Assessment Solution for Quantifying Hip Range of Motion.

BACKGROUND: Tele-health has become a major mode of delivery in patient care, with increasing interest in the use of tele-platforms for remote patient assessment. The use of smartphone technology to measure hip range of motion has been reported previously, with good to excellent validity and reliability. However, these smartphone applications did not provide real-time tele-assessment functionality. We developed a novel smartphone application, the TelePhysio app, which allows the clinician to remotely connect to the patient's device and measure their hip range of motion in real time. The aim of this study was to investigate the concurrent validity and between-sessions reliability of the TelePhysio app. In addition, the study investigated the concurrent validity, between-sessions, and inter-rater reliability of a second tele-assessment approach using video analysis. METHODS: Fifteen participants (nfemales = 6) were assessed in our laboratory (session 1) and at their home (session 2). We assessed maximum voluntary active hip flexion in supine and hip internal and external rotation, in both prone and sitting positions. TelePhysio and video analysis were validated against the laboratory's 3-dimensional motion capture system in session 1, and evaluated for between-sessions reliability in session 2. Video analysis inter-rater reliability was assessed by comparing the analysis of two raters in session 2. RESULTS: The TelePhysio app demonstrated high concurrent validity against the 3D motion capture system (ICCs 0.63-0.83) for all hip movements in all positions, with the exception of hip internal rotation in prone (ICC = 0.48, p = 0.99). The video analysis demonstrated almost perfect concurrent validity against the 3D motion capture system (ICCs 0.85-0.94) for all hip movements in all positions, with the exception of hip internal rotation in prone (ICC = 0.44, p = 0.01). The TelePhysio and video analysis demonstrated good between-sessions reliability for hip external rotation and hip flexion, ICC 0.64 and 0.62, respectively. The between-sessions reliability of hip internal and external rotation for both TelePhysio and video analysis was fair (ICCs 0.36-0.63). Inter-rater reliability ICCs for the video analysis were 0.59 for hip flexion and 0.87-0.95 for the hip rotation range. CONCLUSIONS: Both tele-assessment approaches, using either a smartphone application or video analysis, demonstrate good to excellent concurrent validity, and moderate to substantial between-sessions reliability in measuring hip rotation and flexion range of motion, but less in internal hip rotation in the prone position. Thus, it is recommended that the seated position be used when assessing hip internal rotation. The use of a smartphone to remotely assess hip range of motion is an appropriate, effective, and low-cost alternative to the face-to-face assessments. This method provides a simple, cost effective, and accessible patient assessment tool with no additional cost. This study validates the use of smartphone technology as a tele-assessment tool for remote hip range of motion assessment.

Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial.

Importance: There remains a lack of randomized trials investigating aspirin monotherapy for symptomatic venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA) or total knee arthroplasty (TKA). Objective: To determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE after THA or TKA. Design, Setting, and Participants: Cluster-randomized, crossover, registry-nested trial across 31 hospitals in Australia. Clusters were hospitals performing greater than 250 THA or TKA procedures annually. Patients (aged ≥18 years) undergoing hip or knee arthroplasty procedures were enrolled at each hospital. Patients receiving preoperative anticoagulation or who had a medical contraindication to either study drug were excluded. A total of 9711 eligible patients were enrolled (5675 in the aspirin group and 4036 in the enoxaparin group) between April 20, 2019, and December 18, 2020. Final follow-up occurred on August 14, 2021. Interventions: Hospitals were randomized to administer aspirin (100 mg/d) or enoxaparin (40 mg/d) for 35 days after THA and for 14 days after TKA. Crossover occurred after the patient enrollment target had been met for the first group. All 31 hospitals were initially randomized and 16 crossed over prior to trial cessation. Main Outcomes and Measures: The primary outcome was symptomatic VTE within 90 days, including pulmonary embolism and deep venous thrombosis (DVT) (above or below the knee). The noninferiority margin was 1%. Six secondary outcomes are reported, including death and major bleeding within 90 days. Analyses were performed by randomization group. Results: Enrollment was stopped after an interim analysis determined the stopping rule was met, with 9711 patients (median age, 68 years; 56.8% female) of the prespecified 15 562 enrolled (62%). Of these, 9203 (95%) completed the trial. Within 90 days of surgery, symptomatic VTE occurred in 256 patients, including pulmonary embolism (79 cases), above-knee DVT (18 cases), and below-knee DVT (174 cases). The symptomatic VTE rate in the aspirin group was 3.45% and in the enoxaparin group was 1.82% (estimated difference, 1.97%; 95% CI, 0.54%-3.41%). This failed to meet the criterion for noninferiority for aspirin and was significantly superior for enoxaparin (P = .007). Of 6 secondary outcomes, none were significantly better in the enoxaparin group compared with the aspirin group. Conclusions and Relevance: Among patients undergoing hip or knee arthroplasty for osteoarthritis, aspirin compared with enoxaparin resulted in a significantly higher rate of symptomatic VTE within 90 days, defined as below- or above-knee DVT or pulmonary embolism. These findings may be informed by a cost-effectiveness analysis. Trial Registration: ANZCTR Identifier: ACTRN12618001879257.

Recumbent cycling to improve outcomes in people with hip fracture: a feasibility randomized trial.

BACKGROUND: Early mobilization after surgery is a key recommendation for people with hip fracture, however this is achieved by only 50% of people. Recumbent bike riding has been used in other populations with limited mobility and has potential to allow early exercise in people post hip fracture. The primary aim of this pilot trial was to demonstrate the feasibility of a trial protocol designed to determine the effect of early post-operative cycling in bed on outcomes in people with hip fracture. METHODS: Single-blinded, multi-site randomized controlled pilot trial. Fifty-one people with hip fracture were recruited within 4 days of surgery from two sites in Victoria. Participants were randomly allocated to receive either usual care (n = 25) or usual care plus active cycling in bed (n = 26). The cycling intervention was delivered on weekdays until the participant could walk 15 m with assistance of one person. The primary outcomes were trial feasibility and safety. Clinical outcomes, including mobility (Modified Iowa Level of Assistance Scale) and delirium were measured at day seven post-operatively and at hospital discharge by an assessor blinded to group. Additional outcomes at discharge included gait speed, cognition and quality of life. RESULTS: The intervention was safe, feasible and acceptable to patients and staff. Delivery of the intervention was ceased on (median) day 9.5 (IQR 7, 12); 73% of scheduled sessions were delivered; (median) 4 sessions (IQR 2.0, 5.5) were delivered per participant with (median) 9 min 34 s (IQR 04:39, 17:34) of active cycling per session. The trial protocol was feasible, however at day seven 75% of participants had not met the criterion (able to walk 15 m with assistance of one person) to cease the cycling intervention.. CONCLUSION: In bed cycling is feasible post-operatively following hip fracture, however seven days post-operatively is too early to evaluate the impact of the cycling intervention as many participants were still receiving the intervention. A fully powered RCT to explore the effectiveness and cost efficiency of this novel intervention is warranted. TRIAL REGISTRATION: The trial was prospectively registered (25/09/2017) with the Australian New Zealand Clinical Trials Registry ACTR N12617001345370 .

Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial.

BACKGROUND: Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. METHODS: Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. RESULTS: Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI - 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003). CONCLUSION: The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. TRIAL REGISTRATION DETAILS: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015.

De novo dNTP production is essential for normal postnatal murine heart development.

The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in WT postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in WT hearts.

Gold nanorod/molybdenum sulfide core-shell nanostructures synthesized by a photo-induced reduction process.

Coupling of plasmonic nanostructures and semiconductors gives promising hybrid nanostructures that can be used in different applications such as photosensing and energy conversion. In this report, we describe an approach for fabricating a new hybrid material by coupling a gold nanorod (Au NR) core and amorphous molybdenum sulfide (MoSx) shell. The Au NR/MoSx core-shell structure is achieved by exploiting the hot electrons generated in the plasmonic excitation of Au NRs to drive the reduction of [MoS4]2-, which is pre-adsorbed on the Au NR surface, producing a thin MoSx layer. This approach allows us to control the thickness of the MoSx coating layer on the Au NR surface. The resultant Au NR/MoSx hybrid is characterized by absorption spectroscopy, scanning electron microscopy, transmission electron microscopy, energy-dispersive x-ray spectroscopy elemental mapping, x-ray diffraction and x-ray photoelectron spectroscopy.

Insights into the Electrochemical Polymerization of [Mo3 S13 ]2- Generating Amorphous Molybdenum Sulfide.

Amorphous molybdenum sulfide is an attractive electrode material for Li/Mg batteries and an efficient Pt-free catalyst for the hydrogen evolution reaction in water. By using the electrochemical quartz crystal microbalance (EQCM) analysis, new insights were gained into the electrochemical polymerization of the [Mo3 S13 ]2- cluster, which generates amorphous molybdenum sulfide thin films. In this work, it is shown that, at the anodic potential, a two-electron oxidative elimination of the terminal disulfide ligand within the [Mo3 S13 ]2- cluster induces the polymerization. A reductive elimination of the terminal disulfide ligand also occurs at the cathodic potential, inducing the polymerization. However, in sharp contrast to the anodic polymerization, according to which the film growth is rapid, the cathodic polymerization competes with the electrochemical reductive corrosion of the readily grown film, therefore occurring at a significant lower growth rate.

Yeast DNA polymerase ζ maintains consistent activity and mutagenicity across a wide range of physiological dNTP concentrations.

In yeast, dNTP pools expand drastically during DNA damage response. We show that similar dNTP elevation occurs in strains, in which intrinsic replisome defects promote the participation of error-prone DNA polymerase ζ (Polζ) in replication of undamaged DNA. To understand the significance of dNTP pools increase for Polζ function, we studied the activity and fidelity of four-subunit Polζ (Polζ4) and Polζ4-Rev1 (Polζ5) complexes in vitro at 'normal S-phase' and 'damage-response' dNTP concentrations. The presence of Rev1 inhibited the activity of Polζ and greatly increased the rate of all three 'X-dCTP' mispairs, which Polζ4 alone made extremely inefficiently. Both Polζ4 and Polζ5 were most promiscuous at G nucleotides and frequently generated multiple closely spaced sequence changes. Surprisingly, the shift from 'S-phase' to 'damage-response' dNTP levels only minimally affected the activity, fidelity and error specificity of Polζ complexes. Moreover, Polζ-dependent mutagenesis triggered by replisome defects or UV irradiation in vivo was not decreased when dNTP synthesis was suppressed by hydroxyurea, indicating that Polζ function does not require high dNTP levels. The results support a model wherein dNTP elevation is needed to facilitate non-mutagenic tolerance pathways, while Polζ synthesis represents a unique mechanism of rescuing stalled replication when dNTP supply is low.