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Vertical-axis wind turbines (VAWTs) have received renewed research interest in the offshore environment due to a number of design synergies that have the potential to decrease the cost of energy for offshore wind. Many studies have been completed on the rotor design for straight-bladed rotors (H-rotors); however, there is sparse information on the effect of blade inclination angle on VAWT aerodynamic performance and the optimal blade design of VAWTs with inclined blades (V-rotors) for maximum power capture. This paper presents a systematic study into the effect of blade inclination angle and chord distribution on VAWT performance for different aspect ratios using a 3D implementation of the 2D actuator cylinder model which has been previously validated against higher-fidelity methods. A systematic approach based on a grid search is used to allow the wider design space to be studied and trends identified. In the case of fixed-chord-length blades, it is found that significant power gains are available through blade inclination, between 12 % and 71 % depending on blade length. This is driven by the increase in rotor swept area. Further investigation indicates that despite this, under maximum blade stress limitations the most economical solution for fixed-chord-length blades is H-rotors. Optimal chord distributions, which maximise the rotor power coefficient, are then obtained, and a natural blade taper is observed. For rotors with optimal chord distributions, similar power gains are observed through blade inclination, again between 12 % and 71 % depending on blade length. However, rotor configurations with the largest power gains are found to have significantly increased blade mass. For a given power rating, whilst satisfying limitations on maximum blade root bending stress, it is found that blade volume, a proxy for the blade mass, can be reduced between 16 % and 42 % dependent on blade length, and rotor torque can be reduced between 4 % and 9 %. This indicates the potential of V-rotors to reduce the cost of energy compared to H-rotors in traditional VAWT designs. Additionally, inclined blades are shown to increase the operational tip-speed ratio, demonstrating their applicability to turbines using secondary rotors, such as the X-rotor, where high tip-speed ratios are required for efficient power conversion between primary and secondary rotors.

Abstract Background Children’s active travel to school is associated with physical activity and thus health. Safe Routes to School (SR2S) programs identify ‘safe routes’ to promote children’s active travel to school. No field audit tool exists specifically to assess the microscale built environment of these ‘safe routes’ within Australia. This study describes the reliability assessment of the Field Audit for Children’s Active Transport to School (FACTS) tool. Methods The FACTS tool was developed using a multi-step process, including a literature search, expert opinion, and pilot testing. For the reliability assessment, two trained auditors collected data at eight schools over three weeks in April 2021. For inter-rater reliability, auditors conducted audits on the ‘safe routes’ for the same six schools. For intra-rater reliability, auditors conducted repeat measures on the ‘safe routes’ for four schools each (eight schools total), including three different schools each from the six used for inter-rater reliability and one additional school. Item-by-item reliability was assessed using Cohen’s Kappa, Cohen’s Weighted Kappa, and percentage agreement. The reliability of calculated domain scores was assessed using intraclass correlation coefficients. Results For inter-rater reliability, 31 of the 45 (68.9%) items had moderate to almost perfect agreement, seven items (15.6%) had below moderate agreement, and a Kappa statistic could not be calculated for seven items (15.6%) due to constant values. For intra-rater reliability, 37 of the 45 (82.2%) items had moderate to almost perfect agreement, two items (4.4%) had below moderate agreement, and a Kappa statistic could not be calculated for six items (13.3%) due to constant values. For inter- and intra-rater reliability of the segment domain scores, three of the four domains had substantial to almost perfect agreement. For inter- and intra-rater reliability of the crossing domain scores, all four domains had moderate to almost perfect agreement. For inter- and intra-rater reliability of the segment, crossing, route, and school scores, all had substantial to perfect agreement. Conclusions The FACTS tool can reliably characterise the microscale built environment of promoted ‘safe routes’ for their use within SR2S programs, and should be considered for use in future SR2S programs within the suburban Australian context.

Purpose: Shoulder arthroscopy and arthroplasty are increasingly common procedures used to address shoulder pathologies. This study sought to evaluate the incidence of hand-related pathologies, including carpal tunnel syndrome (CTS), cubital tunnel syndrome (CuTS), trigger finger (TF), de Quervain tenosynovitis, and Dupuytren disease following shoulder arthroscopy and arthroplasty procedures. We hypothesized that patients undergoing shoulder surgery would have a higher incidence of hand-related pathologies within 1 year of surgery compared to controls. Methods: This was a retrospective analysis of 12,179 patients who underwent shoulder arthroscopy or arthroplasty surgery that were subsequently diagnosed with CTS, CuTS, TF, de Quervain tenosynovitis, or Dupuytren disease within 1 year after surgery. Relative risk of having associated hand pathologies following shoulder surgery was compared to controls. Results: In total, 10,285 patients underwent shoulder arthroscopy procedures during this period, of whom 815 (7.9%) had an associated hand pathology within 1 year from their shoulder procedure. Arthroscopic surgery was associated with an increased likelihood of having a hand pathology (RR 1.65, 95% CI 1.54–1.76), CTS (RR 1.57, 95% CI 1.42–1.73), CuTS (RR 2.25, 95% CI 1.94–2.61), TF (RR 1.76, 95% CI 1.53–2.03), and Dupuytren disease (RR 2.02, 95% CI 1.54–2.65), but was not associated with a higher likelihood of having de Quervain tenosynovitis. In total, 1,894 patients underwent shoulder arthroplasty procedures during this period, of whom 188 (9.9%) had an associated hand pathology within 1 year. Shoulder arthroplasty was associated with an increased likelihood of having a hand pathology (RR 2.04, 95% CI 1.78–2.34), CTS (RR 2.10, 95% CI 1.72–2.57), CuTS (RR 3.29, 95% CI 2.48–4.39), and TF (RR 1.99, 95% CI 1.47–2.70), but was not associated with an increased likelihood of having de Quervain tenosynovitis or Dupuytren disease. Conclusions: Shoulder arthroscopy and arthroplasty procedures were associated with an increased likelihood of having a CTS, CuTS, or a TF diagnosis made within 1 year of surgery. Only shoulder arthroscopy procedures were associated with a higher likelihood of having Dupuytren disease. Neither shoulder arthroscopy nor arthroplasty procedures were associated with an increased likelihood of a diagnosis of de Quervain tenosynovitis. These associations, however, do not necessarily imply causation, and further investigation is warranted to delineate this relationship. Type of study/level of evidence: Differential Diagnosis/Symptom Prevalence Study Level 3.

The NOAA Chemical Sciences Laboratory (CSL) conducted the Southwest Urban NOx and VOCs Experiment (SUNVEx) to study emissions and the role of boundary layer (BL) dynamics and sea-breeze (SB) transitions in the evolution of coastal air quality. The study presented utilizes remote sensing and in situ observations in Pasadena, California. Separate analyses are conducted on the synoptic conditions during ozone (O3) exceedance (>70 ppb) and non-exceedance ( ppb) days, as well as the fine-structure variability of in situ chemistry measurements during BL growth and SB transitions. Diurnal analyses spanning August 2021 revealed a markedly different wind direction during evenings preceding O3 exceedance (northerly) versus non-exceedance (easterly) days. Increased O3 occurred simultaneously with warmer and drier conditions, a reduction in winds, and an increase in volatile organic compounds (VOCs) and fine particulate matter (PM2.5). While the average BL height was lower and surface pressure was higher, the day-to-day variability of these quantities led to an overall weak statistical relationship. Investigations focused on the fine-structure variability of in situ chemistry measurements superimposed on background trends were conducted using a novel multivariate spectral coherence mapping (MSCM) technique that combined the spectral structure of two or more independent measurements through a wavelet analysis as reported by maximum-normalized scaleograms. A case study was chosen to illustrate the MSCM technique, where the dominant peaks in scaleograms were identified and compared to BL height during the growth phase. The temporal widths of peaks (τmax) derived from VOC and nitrogen oxide (NOx) scaleograms, as well as scaleograms combining VOCs, NOx, and variations in BL height, indicated a broadening with respect to time as the BL increased in depth. A separate section focused on comparisons between τmax and BL height during August 2021 revealed uncorrelated or weakly correlated scatter, except in the case of VOCs when really large τmax and relatively deep BL heights were ignored. Instances of large τmax and relatively deep BL heights occurred near sunrise and as onshore flow entered Pasadena, respectively. Wind transitions likely influenced both the dynamical evolution of the BL and tracer advection and thus offer additional challenges when separating factors contributing to the fine structure. Other insights gained from this work include observations of descending wind jets from the San Gabriel Mountains that were not resolved by the High-Resolution Rapid Refresh (HRRR) model and the derivation of intrinsic properties of oscillations observed in NOx and O3 during the interaction between an SB and enhanced winds above the BL that flowed in opposition to the SB.

Abstract The acute phase of ischemic stroke presents a critical window for therapeutic intervention, where novel approaches such as hyper-acute cerebral flow augmentation offer promising avenues for neuroprotection. In this study, we investigated the effects of two such therapies, NEH (a combination of norepinephrine and hydralazine) and Sanguinate (pegylated bovine carboxyhemoglobin), on resting-state functional connectivity, global mean signal (GMS), and blood oxygen level-dependent (BOLD) time lag in a pre-clinical canine model of stroke via permanent occlusion of the middle cerebral artery (total of n = 40 IACUC-approved mongrel canines randomly split into control/natural history and two treatment groups). Utilizing group independent component analysis (ICA), we identified and examined the integrity of sensorimotor and visual networks both pre- and post-occlusion, across treatment and control groups. Our results demonstrated that while the control group exhibited significant disruptions in these networks following stroke, the treatment groups showed remarkable preservation of network integrity. Voxel-wise functional connectivity analysis revealed less pronounced alterations in the treatment groups, suggesting maintained neural connections. Notably, the treatments stabilized GMS, with only minimal reductions observed post-occlusion compared to significant decreases in the control group. Furthermore, BOLD time-lag unity plots indicated that NEH and Sanguinate maintained consistent hemodynamic response timing, as evidenced by tighter clustering around the line of unity, suggesting a potential neuroprotective effect. These findings were underscored by robust statistical analyses, including paired T-tests and Mann–Whitney U tests, which confirmed the significance of the connectivity changes observed. The correlation of BOLD time-lag variations with neuroimaging functional biomarkers highlighted the impact of stroke and the efficacy of early therapeutic interventions. Our study supports the further study of flow augmentation therapies such as NEH and Sanguinate in stroke treatment protocols and suggests flow augmentation therapies should be further explored in an effort to improve patient outcomes.

Abstract Background The Collaborative Care Model (CoCM) is an evidence-based mental health treatment in primary care. A greater understanding of the determinants of successful CoCM implementation, particularly the characteristics of multi-level implementers, is needed. Methods This study was a process evaluation of the Collaborative Behavioral Health Program (CBHP) study (NCT04321876) in which CoCM was implemented in 11 primary care practices. CBHP implementation included screening for depression and anxiety, referral to CBHP, and treatment with behavioral care managers (BCMs). Interviews were conducted 4- and 15-months post-implementation with BCMs, practice managers, and practice champions (primary care clinicians). We used framework-guided rapid qualitative analysis with the Consolidated Framework for Implementation Research, Version 2.0, focused on the Individuals domain, to analyze response data. These data represented the roles of Mid-Level Leaders (practice managers), Implementation Team Members (clinicians, support staff), Innovation Deliverers (BCMs), and Innovation Recipients (primary care/CBHP patients) and their characteristics (i.e., Need, Capability, Opportunity, Motivation). Results Mid-level leaders (practice managers) were enthusiastic about CBHP (Motivation), appreciated integrating mental health services into primary care (Need), and had time to assist clinicians (Opportunity). Although CBHP lessened the burden for implementation team members (clinicians, staff; Need), some were hesitant to reallocate patient care (Motivation). Innovation deliverers (BCMs) were eager to deliver CBHP (Motivation) and confident in assisting patients (Capability); their opportunity to deliver CBHP could be limited by clinician referrals (Opportunity). Although CBHP alleviated barriers for innovation recipients (patients; Need), it was difficult to secure services for those with severe conditions (Capability) and certain insurance types (Opportunity). Conclusions Overall, respondents favored sustaining CoCM and highlighted the positive impacts on the practice, health care team, and patients. Participants emphasized the benefits of integrating mental health services into primary care and how CBHP lessened the burden on clinicians while providing patients with comprehensive care. Barriers to CBHP implementation included ensuring appropriate patient referrals, providing treatment for patients with higher-level needs, and incentivizing clinician engagement. Future CoCM implementation should include strategies focused on education and training, encouraging clinician buy-in, and preparing referral paths for patients with more severe conditions or diverse needs. Trial registration ClinicalTrials.gov(NCT04321876). Registered: March 25,2020. Retrospectively registered.

Determining offshore wind energy operational expenditures relies on acquiring reliability data, particularly as turbine power ratings increase. The uncertainty surrounding operational costs and optimal drivetrain configurations for larger turbines persists. While previous research has addressed reliability data for 3 MW offshore wind turbines, this study reviews and collates updated failure data for 15 MW turbines, comparing direct-drive and medium-speed configurations. It employs an operation and maintenance (O&M) modelling tool to calculate total operational costs. The study concurs with existing literature, showing that direct-drive turbines have lower operational costs than medium-speed turbines in three case studies. However, the cost and availability differences between configurations are smaller than previously suggested. For 15 MW turbines, the analysis reveals that the cost disparity between direct-drive and medium-speed turbines is significantly smaller than for smaller-rated turbines, with percentages of 1.59 %, 1.58 %, and 5.78 % for the three ScotWind sites selected. Previously, the absolute percentage difference in cost between direct-drive and medium-speed turbines was estimated to be 29.79 %. Sensitivity analyses explore the influence of three factors – failure rates, accessibility limits, and major replacement times – on total operational costs. These analyses demonstrate that medium-speed configurations exhibit more significant cost fluctuations, and the cost gap between configurations is reduced if failure rates are lowered at the same rate for each configuration, accessibility increases, or the major replacement time is reduced for the larger wind turbine components.

IntroductionLong-acting injectable (LAI) antipsychotic medications and clozapine are effective yet underutilized medical therapies in early intervention services. The purpose of this study was to conduct a pre-implementation evaluation of contextual determinants of early intervention programs to implement innovations optimizing LAI antipsychotic and clozapine use within a shared decision-making model.MethodsSemi-structured interviews explored barriers and facilitators to implementing LAI antipsychotics and clozapine in early intervention services. Participants were: prescribers (n = 2), non-prescribing clinicians (n = 5), administrators (n = 3), clients (n = 3), and caregivers (n = 3). Interviews were structured and analyzed using the Consolidated Framework for Implementation Research (CFIR 2.0).ResultsParticipants were supportive of using LAI antipsychotics, despite barriers (e.g., transportation, insurance coverage), while most were unfamiliar with clozapine (Innovation). Critical incidents (e.g., COVID-19) did not interfere with implementation, while barriers included lack of performance measures; stigma affecting willingness to take medication; and clozapine considered to be a “last resort” (Outer Setting). Treatment culture was described as client-centered and collaborative, and most participants indicated LAI antipsychotic use was compatible with clinic workflows, but some were in need of resources (e.g., individuals trained to administer LAI antipsychotics; Inner Setting). Participants on the healthcare team expressed confidence in their roles. Family education and collaborative decision-making were recommended to improve client/family engagement (Individuals). Participants related the importance of tracking medication compliance, addressing client concerns, and providing prescribers with updated guidelines on evidence-based treatment (Implementation Process).DiscussionResults may guide implementation strategy selection for future programs seeking to optimize the use of LAI antipsychotics and clozapine for early-phase schizophrenia, when appropriate.

Summary: Background: In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions. Methods: In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7 mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906. Findings: Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)], −5.3 [5.2] versus −6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI): −2.5, 3.0]; p = 0.88) and Pain VAS (mean [SD], −19.5 [26.9] versus −32.2 [38.5]; least squares mean difference, 11.5 [96% CI: −4.8, 27.8]; p = 0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group. Interpretation: In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group. Funding: Funded by Sanifit, a CSL Vifor company.

Inferior quality of concrete surface layers can lead to significant deterioration of concrete infrastructure due to the infiltration of fluids and deleterious substances from the surrounding environment. Concrete structures such as foundations, abutments, flatwork, and underground tanks in agricultural and mining zones, as well as slabs in factories producing ammonium-based fertilizers, are highly susceptible to ammonium sulfate attack, which is known as the most aggressive sulfate deterioration driven by acid-sulfate reactions. Coatings are an effective strategy for protecting such concrete structures to restore its performance and prolong its service life. Therefore, this study aimed at investigating the performance of nano-based coatings as superficial treatments for concrete elements exposed to aggravated exposures of ammonium sulfate. Silane (hydrophobic agent) and vinyl ester (membrane-forming polymer) were used as base resins, in which nano-clay and nano-calcium carbonate particulates were dispersed at different dosages (0, 2.5, and 5 %). In addition, a colloidal silica solution was used as a surface treatment. The durability of coated concrete specimens was evaluated under two ammonium sulfate exposures: full immersion and combined with cyclic environmental conditions (freezing-thawing and wetting-drying cycles). Degradation of concrete specimens was monitored by visual assessment and quantified in terms of mass and length changes over time. In addition, the deterioration mechanisms and coatings’ performance were studied by thermal, mineralogical, and microstructural tests. The results showed that colloidal silica could not adequately protect concrete specimens from these exposures. Conversely, silane nanocomposites improved the durability of concrete under both exposures and superior performance was generally observed for concrete specimens coated with vinyl ester nanocomposites.

Introduction: An unpredictable illicit drug supply is driving high levels of overdose death in North America. Prior research has demonstrated the importance of involving people who use drugs in harm reduction intervention design and implementation. The inclusion of people who supply drugs in these efforts has been scant. We explore this possibility by interviewing persons targeted by a harm reduction educational program designed specifically for people who supply drugs. Methods: In-person interviews with people who use drugs were conducted in 2022 in Indianapolis, Indiana. We conducted a thematic analysis of data from six interviews with people who were either primarily or secondarily trained through this harm reduction training for people who supply drugs, Results: Participants described a diverse array of harm reduction strategies, some gained through the targeted education program, which they regularly practiced as they consumed and/or supplied drugs to others. People who supply drugs were regularly identified as key actors capable of widely reducing risk across drug networks. Participants described being motivated by a moral imperative to protect community members, tying the previous loss of friends and loved ones to overdose to their commitments to the safety of others. Conclusion: This article contributes to the scholarship on the role of people who supply drugs in implementing harm reduction interventions and reducing overdose risk. Better enabling grassroots harm reduction organizations to provide people who supply drugs with harm reduction training and access to harm reduction resources may help to reduce drug-related harms.

Abstract Extraction of nucleic acids (NAs) is critical for many methods in molecular biology and bioanalytical chemistry. NA extraction has been extensively studied and optimized for a wide range of applications and its importance to society has significantly increased. The COVID-19 pandemic highlighted the importance of early and efficient NA testing, for which NA extraction is a critical analytical step prior to the detection by methods like polymerase chain reaction. This study explores simple, new approaches to extraction using engineered smart nanomaterials, namely NA-binding, intrinsically disordered proteins (IDPs), that undergo triggered liquid–liquid phase separation (LLPS). Two types of NA-binding IDPs are studied, both based on genetically engineered elastin-like polypeptides (ELPs), model IDPs that exhibit a lower critical solution temperature in water and can be designed to exhibit LLPS at desired temperatures in a variety of biological solutions. We show that ELP fusion proteins with natural NA-binding domains can be used to extract DNA and RNA from physiologically relevant solutions. We further show that LLPS of pH responsive ELPs that incorporate histidine in their sequences can be used for both binding, extraction and release of NAs from biological solutions, and can be used to detect SARS-CoV-2 RNA in samples from COVID-positive patients.

Abstract Background Post-overdose outreach programs engage overdose survivors and their families soon after an overdose event. Staff implementing these programs are routinely exposed to others’ trauma, which makes them vulnerable to secondary traumatic stress (STS) and compassion fatigue. The purpose of this study was to explore experiences of STS and associated upstream and downstream risk and protective factors among program staff. Methods We conducted a post-hoc analysis of semi-structured interviews with post-overdose outreach program staff in Massachusetts. Transcripts were analyzed using a multi-step hybrid inductive-deductive approach to explore approaches and responses to outreach work, factors that might give rise to STS, and compassion fatigue resilience. Findings were organized according to the three main constructs within Ludick and Figley’s compassion fatigue resilience model (empathy, secondary traumatic stress, and compassion fatigue resilience). Results Thirty-eight interviews were conducted with staff from 11 post-overdose outreach programs in Massachusetts. Within the empathy construct, concern for others’ well-being emerged as a motivator to engage in post-overdose outreach work – with staff trying to understand others’ perspectives and using this connection to deliver respectful and compassionate services. Within the secondary traumatic stress construct, interviewees described regular and repeated exposure to others’ trauma – made more difficult when exposures overlapped with staff members’ personal social spheres. Within the compassion fatigue resilience construct, interviewees described the presence and absence of self-care practices and routines, social supports, and workplace supports. Job satisfaction and emotional detachment from work experiences also arose as potential protective factors. Interviewees reported inconsistent presence and utilization of formal support for STS and compassion fatigue within their post-overdose outreach teams. Conclusion Post-overdose outreach program staff may experience secondary traumatic stress and may develop compassion fatigue, particularly in the absence of resilience and coping strategies and support. Compassion fatigue resilience approaches for post-overdose outreach staff warrant further development and study.

Abstract Organic forms of phosphorus (P) prevail in soils and their quantification is vital to better understand global biogeochemical cycles. P speciation in soil is commonly assessed by 31P NMR spectroscopy of sodium hydroxide‐EDTA (NaOH‐EDTA) extracts. A liquid chromatography‐inductively coupled plasma‐mass spectrometry (LC‐ICP‐MS) method that employs NaOH‐EDTA is described. Comparison with 31P NMR shows that LC‐ICP‐MS is up to three orders of magnitude more sensitive. It allows measurement in samples as small as 1 mg. We reveal variation of inositol phosphate distribution in Swedish boreal forest soil and identify myo‐ and scyllo‐inositol hexakisphosphates and other isomers including scyllo‐inositol pentakisphosphate. Speciation of the major inositol phosphates was not altered by long‐term nitrogen fertilization.

Abstract Currently 1677 species are listed under the U.S. Endangered Species Act (ESA), yet only a small percentage have been delisted due to recovery. In the fall of 2021, the U.S. Fish and Wildlife Service proposed delisting 23 species due to extinction. Tracking changes in species ‘recovery status over time is critical to understanding species’ statuses, informing adaptive management strategies, and assessing the performance of the ESA to prevent further species loss. In this paper, we describe four key obstacles in tracking species recovery status under the ESA. First, ESA 5‐year reviews lack a standardized format and clear documentation. Second, despite having been listed for decades, many species still suffer major data gaps in their biology and threats, rendering it difficult if not impossible to track progress towards recovery. Third, many species have continued declining after listing, yet given the above (1 & 2), understanding potential causes (proximate and/or ultimate) can be difficult. Fourth, many species currently have no path to clear recovery, which represents a potential failing of the process. We conclude with a discussion of potential policy responses that could be addressed to enhance the efficacy of the ESA.

Summary: Mitochondrial ribosomes (mitoribosomes) have undergone substantial evolutionary structural remodeling accompanied by loss of ribosomal RNA, while acquiring unique protein subunits located on the periphery. We generated CRISPR-mediated knockouts of all 14 unique (mitochondria-specific/supernumerary) human mitoribosomal proteins (snMRPs) in the small subunit to study the effect on mitoribosome assembly and protein synthesis, each leading to a unique mitoribosome assembly defect with variable impact on mitochondrial protein synthesis. Surprisingly, the stability of mS37 was reduced in all our snMRP knockouts of the small and large ribosomal subunits and patient-derived lines with mitoribosome assembly defects. A redox-regulated CX9C motif in mS37 was essential for protein stability, suggesting a potential mechanism to regulate mitochondrial protein synthesis. Together, our findings support a modular assembly of the human mitochondrial small ribosomal subunit mediated by essential supernumerary subunits and identify a redox regulatory role involving mS37 in mitochondrial protein synthesis in health and disease.

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children’s Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.

Abstract Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1R189W demonstrated longer thin filaments than GFP-TMOD1wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1R189W showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant’s effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.

Abstract Fungal pathogens that impact perennial plants or natural ecosystems require management strategies beyond fungicides and breeding for resistance. Rust fungi, some of the most economically and environmentally important plant pathogens, have shown amenability to double-stranded RNA (dsRNA) mediated control. To date, dsRNA treatments have been applied prior to infection or together with the inoculum. Here we show that a dsRNA spray can effectively prevent and cure infection by Austropuccinia psidii (cause of myrtle rust) at different stages of the disease cycle. Significant reductions in disease coverage were observed in plants treated with dsRNA targeting essential fungal genes 48 h pre-infection through to 14 days post-infection. For curative treatments, improvements in plant health and photosynthetic capacity were seen 2–6 weeks post-infection. Two-photon microscopy suggests inhibitory activity of dsRNA on intercellular hyphae or haustoria. Our results show that dsRNA acts both preventively and curatively against myrtle rust disease, with treated plants recovering from severe infection. These findings have immediate potential in the management of the more than 10-year epidemic of myrtle rust in Australia.

The critical mechanism to restart zygote metabolism and prevent polyspermy during fertilization is the intracellular Ca2+ increase. All of the signaling molecules leading to the Ca2+ rise are not fully known in any species. In the sea star Patiria miniata, SFK1, SFK3, and PLCγ participate in this fertilization Ca2+ increase. These proteins share common regulatory features, including signaling via tyrosine phosphorylation and their SH2 domains. In this study, we explore two different bioinformatic strategies to identify transcripts in the Patiria miniata mature egg transcriptome (Accession PRJNA398668) that code for proteins possessing an SH2 domain. The first identified the longest open reading frame for each transcript and then utilized similarity searching tools to provide identities for each transcript. The second, novel, method involved a six-frame translation of the entire transcriptome to identify SH2 domain-containing proteins. The identified transcripts were aligned against the NCBI non-redundant database and the SwissProt database. Eighty-two transcripts that encoded SH2 domains were identified. Of these, 33 were only found using the novel method. This work furthers research into egg activation by providing possible target proteins for future experiments and a novel method for identifying specific proteins of interest within a de novo transcriptome.

We simulate the dynamics of Rydberg atoms resonantly exchanging energy via two-, three-, and four-body dipole-dipole interactions in a one-dimensional array. Using simplified models of a realistic experimental system, we study the initial-state survival probability, mean level spacing, spread of entanglement, and properties of the energy eigenstates. By exploring a range of disorders and interaction strengths, we find regions in parameter space where the three- and four-body dynamics either fail to thermalize or do so slowly. The interplay between the stronger hopping and weaker field-tuned interactions gives rise to quantum many-body scar states, which play a critical role in slowing the dynamics of the three- and four-body interactions.