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This is the first study, to our knowledge, to examine myofiber hypertrophy from low-load resistance training with blood flow restriction (BFR) in females. Although this type of training did not result in myofiber hypertrophy, there were comparable increases in muscle cross-sectional area compared with high-load resistance training. These findings possibly highlight that males and females respond in a similar manner to high-load resistance training and low-load resistance training with BFR.

Herein, we determined if a multi-ingredient supplement (NAD3; 312 mg of combined Wasabia japonica extract, theacrine, and copper (I)niacin chelate) versus a placebo (CTL) affected peripheral blood mononuclear (PMBC) transcriptomic, DNA methylation, and sirtuin activity profiles in middle-aged adults after 12 weeks of supplementation. Several mRNAs demonstrated interactions (n = 148 at ±1.5-fold change, p < 0.01), and more stringent filtering indicated that 25 mRNAs were upregulated and 29 were downregulated in the NAD3 versus CTL group. Bioinformatics on these 64 mRNAs suggested that DNA conformational alterations may have been promoted with NAD3 supplementation, and this was corroborated with more CpG sites being hypermethylated (p < 0.001) in the CTL versus the NAD3 group when examining pre- to post-intervention changes (369 versus 35). PBMC SIRT activity decreased in CTL participants (p < 0.001), but not in NAD3 participants (p = 0.289), and values at 12 weeks trended higher in NAD3 participants (p = 0.057). Interestingly, the pre- to post- changes in SIRT activity values significantly correlated with changes in PBMC NAD+: NADH values obtained from a previous investigation in these participants (r = 0.534, p = 0.015). In conclusion, the current mRNA and DNA methylation data indirectly suggest that NAD3 supplementation may affect PBMC DNA conformation, while other direct assays suggest that NAD3 supplementation maintains SIRT activity through the potential maintenance of NAD+: NADH levels. However, these results are preliminary due to limited n-sizes and the study being performed in middle-aged adults.

Osteosarcoma is an aggressive malignancy characterized by high genomic complexity. Identification of few recurrent mutations in protein coding genes suggests that somatic copy-number aberrations (SCNA) are the genetic drivers of disease. Models around genomic instability conflict—it is unclear whether osteosarcomas result from pervasive ongoing clonal evolution with continuous optimization of the fitness landscape or an early catastrophic event followed by stable maintenance of an abnormal genome. We address this question by investigating SCNAs in >12,000 tumor cells obtained from human osteosarcomas using single-cell DNA sequencing, with a degree of precision and accuracy not possible when inferring single-cell states using bulk sequencing. Using the CHISEL algorithm, we inferred allele- and haplotype-specific SCNAs from this whole-genome single-cell DNA sequencing data. Surprisingly, despite extensive structural complexity, these tumors exhibit a high degree of cell-cell homogeneity with little subclonal diversification. Longitudinal analysis of patient samples obtained at distant therapeutic timepoints (diagnosis, relapse) demonstrated remarkable conservation of SCNA profiles over tumor evolution. Phylogenetic analysis suggests that the majority of SCNAs were acquired early in the oncogenic process, with relatively few structure-altering events arising in response to therapy or during adaptation to growth in metastatic tissues. These data further support the emerging hypothesis that early catastrophic events, rather than sustained genomic instability, give rise to structural complexity, which is then preserved over long periods of tumor developmental time. Significance: Chromosomally complex tumors are often described as genomically unstable. However, determining whether complexity arises from remote time-limited events that give rise to structural alterations or a progressive accumulation of structural events in persistently unstable tumors has implications for diagnosis, biomarker assessment, mechanisms of treatment resistance, and represents a conceptual advance in our understanding of intratumoral heterogeneity and tumor evolution.

Understanding the strong interaction dynamics that govern the emergence of hadron mass (EHM) represents a challenging open problem in the Standard Model. In this paper we describe new opportunities for gaining insight into EHM from results on nucleon resonance ($N^\ast$) electroexcitation amplitudes (i.e. $\gamma_vpN^\ast$ electrocouplings) in the mass range up to 1.8\,GeV for virtual photon four-momentum squared (i.e. photon virtualities $Q^2$) up to 7.5\,GeV$^2$ available from exclusive meson electroproduction data acquired during the 6-GeV era of experiments at Jefferson Laboratory (JLab). These results, combined with achievements in the use of continuum Schwinger function methods (CSMs), offer new opportunities for charting the momentum dependence of the dressed quark mass from results on the $Q^2$-evolution of the $\gamma_vpN^\ast$ electrocouplings. A successful description of the $\Delta(1232)3/2^+$ and $N(1440)1/2^+$ electrocouplings has been achieved using CSMs with, in both cases, common momentum-dependent mass functions for the dressed quarks, for the gluons, and the same momentum-dependent strong coupling. Parameter-free CSM predictions for the electrocouplings of the $\Delta(1600)3/2^+$ became available in 2019. The experimental results obtained in the first half of 2022 have confirmed the CSM predictions. We also discuss prospects for these studies during the 12-GeV era at JLab using the CLAS12 detector, with experiments that are currently in progress, and canvass the physics motivation for continued studies in this area with a possible increase of the JLab electron beam energy up to 22\,GeV., Comment: 23 pages, 11 figures, 2 tables

Introduction: As an essential component of service delivery, radiotherapy clinical trials were championed within the NHS England service specifications. A call for a 15% increase in research and clinical trial activity, alongside a demand for equity of access for patients with cancer subsequently ensued. National understanding of current radiotherapy clinical trials operational practices is absent, but essential to help establish the current provision required to support the development of a strategic plan for implementation of NHS England's specifications. Methods: A cross-sectional survey was developed by a multi-disciplinary team and distributed to therapeutic radiography clinical trial leads across the UK to ascertain the current provision of radiotherapy clinical trials only, including workforce resources and the trials management processes to establish a benchmark and identify potential barriers, enablers, and opportunities to increase access to clinical trials. Results: Thirty-two complete responses were obtained equating to 49% of the total UK NHS departments and 74% of those departments invited. Four key findings were identified: 1) research strategy and systems, 2) participation and activity in radiotherapy clinical trials, 3) access to clinical trials at alternative departments and 4) facilitators & barriers. Overarchingly a lack of radiotherapy clinical trials strategy or supported processes were apparent across the UK, aggravating existing barriers to trial activity. Conclusion: It is essential for radiotherapy clinical trials to be embedded in to departmental and Trust strategy, this will help to ensure the processes and resources required for trial delivery are not only in place, but also recognised as imperative and important for patients with cancer as radiotherapy treatment delivery. Implications for practice: Failure to address the barriers or build upon the facilitators may result in UK radiotherapy departments facing challenges in achieving the 15% increase in radiotherapy clinical trial activity.

This study continues to delineate muscle biology differences between lower and higher responders to resistance training and is unique in that a female population was interrogated. As has been reported in prior studies, increases in satellite cell numbers are related to positive responses to resistance training. Satellite cell responsivity, rather than changes in muscle ribosome content per milligrams of tissue, may be a more important factor in delineating resistance-training responses in women.

Although past studies have examined aspects of extracellular matrix remodeling in relation to mechanical overload or resistance training, this study serves to expand our knowledge on a multitude of extracellular matrix markers and whether these markers adapt to resistance training or are associated with differential hypertrophic responses.

Objective: To evaluate the change in consumption of specific antibiotics in a neonatal intensive care unit after the implementation of an antimicrobial stewardship program (ASP). Design: Retrospective cohort study between January 1, 2010, and December 31,2019. Setting: The neonatal intensive care unit at British Columbia Women’s Hospital (Vancouver Canada), a tertiary-care center. Patients: Admitted neonates prescribed antibiotics. Methods: We implemented an ASP with an early implementation phase starting in January 2014 (period 2) and a later phase starting in January 2017 (period 3). Patient demographics were collected, including birth weight, gestational age, history of necrotizing enterocolitis (NEC), and surgical operations from existing databases. Interrupted time-series analysis was used, and comparison of antibiotic days of therapy (DOT) averages were conducted across the preimplementation period (period 1), period 2, and period 3 regarding total patients and subgroups. Results: We identified 4,512 infants. There was a significant decrease in DOT from 472 (95% confidence interval [CI], 431–517) in period 1 to 405 (95% CI, 367–446) in period 2 to 313 (95% CI, 280–350) in period 3. We detected a significant decrease in the use of ampicillin, aminoglycosides, cloxacillin, and linezolid but not in vancomycin or cefotaxime. Subgroup analyses of infants Conclusions: The implementation of an ASP was associated with a significant decrease in the overall DOT and use of certain antibiotics. This study presents important targets for ongoing ASP work.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is currently diagnosed using a combination of clinical features, imaging, electrocardiography, and genetic investigations. An abnormal signal-averaged electrocardiogram (SAECG) is defined as a minor diagnostic criterion by the 2010 Task Force Criteria, but doubts remain about the value of this investigation.We evaluated the utility of the SAECG in diagnosing ARVC using the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry, a population representative registry of probands with ARVC and relatives, less influenced by referral bias.Probands with ARVC and family members from the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry underwent phenotype review. SAECG parameters were compared individually and in combination between those with varying degrees of ARVC severity and healthy controls (family members of probands with ARVC and unexplained sudden death, free of evidence of cardiac disease).A total of 196 patients with ARVC and 205 controls were included (mean age 44 ± 15 years; 186 of 401 men [46%]). SAECG abnormalities were seen in 83 of 205 controls (40%), 33 of 68 patients with ARVC and mild disease (51%), and 31 of 42 with severe disease (74%). The SAECG associated strongly with imaging abnormalities (major: odds ratio 3.0, 95% confidence interval 1.3-6.9; minor: odds ratio 3.5, 95% confidence interval 0.7-16.5) but not with other aspects of phenotype. Patients carrying pathogenic variants but with minimal phenotype had similar SAECGs to healthy controls (filtered QRS duration 111.2 ± 11.2 ms vs 111 ± 7.6 ms, P = .93; duration of low amplitude signals40 μV 32.3 ± 8.9 ms vs 34.2 ± 7.2 ms, P = .32; root mean square of the terminal 40 ms of the filtered QRS complex 43.1 ± 25.2 ms vs 38.2 ± 20.2 ms, P = .38).The SAECG appears to be a surrogate marker for structural abnormalities seen on imaging in those with ARVC. Great caution is required in interpreting SAECG findings in those without other corroborating evidence of an ARVC phenotype.

Antibodies targeting insulin-like growth factor 1 receptor (IGF-1R) induce objective responses in only 5% to 15% of children with sarcoma. Understanding the mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R–targeted antibodies. Sensitivity to the IGF-1R–targeting antibody TZ-1 was determined in rhabdomyosarcoma and Ewing sarcoma cell lines. Acquired resistance to TZ-1 was developed and characterized in sensitive Rh41 cells. The BRD4 inhibitor, JQ1, was evaluated as an agent to prevent acquired TZ-1 resistance in Rh41 cells. The phosphorylation status of receptor tyrosine kinases (RTK) was assessed. Sensitivity to TZ-1 in vivo was determined in Rh41 parental and TZ-1–resistant xenografts. Of 20 sarcoma cell lines, only Rh41 was sensitive to TZ-1. Cells intrinsically resistant to TZ-1 expressed multiple (>10) activated RTKs or a relatively less complex set of activated RTKs (∼5). TZ-1 decreased the phosphorylation of IGF-1R but had little effect on other phosphorylated RTKs in all resistant lines. TZ-1 rapidly induced activation of RTKs in Rh41 that was partially abrogated by knockdown of SOX18 and JQ1. Rh41/TZ-1 cells selected for acquired resistance to TZ-1 constitutively expressed multiple activated RTKs. TZ-1 treatment caused complete regressions in Rh41 xenografts and was significantly less effective against the Rh41/TZ-1 xenograft. Intrinsic resistance is a consequence of redundant signaling in pediatric sarcoma cell lines. Acquired resistance in Rh41 cells is associated with rapid induction of multiple RTKs, indicating a dynamic response to IGF-1R blockade and rapid development of resistance. The TZ-1 antibody had greater antitumor activity against Rh41 xenografts compared with other IGF-1R–targeted antibodies tested against this model.

Hind limb ischemia (HLI) is the most severe form of peripheral arterial disease, associated with a substantial reduction of limb blood flow that impairs skeletal muscle homeostasis to promote functional disability. The molecular regulators of HLI-induced muscle perturbations remain poorly defined. This study investigated whether changes in the molecular catabolic-autophagy signaling network were linked to temporal remodeling of skeletal muscle in HLI. HLI was induced in mice via hindlimb ischemia (femoral artery ligation) and confirmed by Doppler echocardiography. Experiments were terminated at time points defined as early- (7 days; n = 5) or late- (28 days; n = 5) stage HLI. Ischemic and nonischemic (contralateral) limb muscles were compared. Ischemic versus nonischemic muscles demonstrated overt remodeling at early-HLI but normalized at late-HLI. Early-onset fiber atrophy was associated with excessive autophagy signaling in ischemic muscle; protein expression increased for Beclin-1, LC3, and p62 ( P < 0.05) but proteasome-dependent markers were reduced ( P < 0.05). Mitophagy signaling increased in early-stage HLI that aligned with an early and sustained loss of mitochondrial content ( P < 0.05). Upstream autophagy regulators, Sestrins, showed divergent responses during early-stage HLI (Sestrin2 increased while Sestrin1 decreased; P < 0.05) in parallel to increased AMP-activated protein kinase (AMPK) phosphorylation ( P < 0.05) and lower antioxidant enzyme expression. No changes were found in markers for mechanistic target of rapamycin complex 1 signaling. These data indicate that early activation of the sestrin-AMPK signaling axis may regulate autophagy to stimulate rapid and overt muscle atrophy in HLI, which is normalized within weeks and accompanied by recovery of muscle mass. A complex interplay between Sestrins to regulate autophagy signaling during early-to-late muscle remodeling in HLI is likely.

Retrotransposons are gene segments that proliferate in the genome, and the Long INterspersed Element 1 (LINE-1 or L1) retrotransposon is active in humans. Although older mammals show enhanced skeletal muscle L1 expression, exercise generally reverses this trend. We hypothesize skeletal muscle L1 expression influences muscle physiology, and additional innovative investigations are needed to confirm this hypothesis.

The enhanced observation period during the HIGHWAY field campaign in East Africa provided the opportunity to obtain continuous ground-based radar observations over the Lake Victoria basin. This provided insight into thunderstorm initiation processes and thunderstorm evolution. This insight is significant for it can lead to nowcasting thunderstorms over Lake Victoria, which is particularly important because of the >200 000 fishers using the lake daily and the extremely high number of drownings resulting from capsized boats caused by large waves and high winds from thunderstorms. Radar data from the south shoreline of Lake Victoria made it possible to observe thunderstorm activity over the entire lake. Unexpectedly the radar returns from high concentration of insects over the lake made it possible for the radar to observe boundary layer convergence lines. With this information a radar-trained forecaster could provide nowcasts of severe storm locations and by using extrapolation techniques provide nowcasts of their future location. In addition, rules for forecasting the timing and extent of nighttime thunderstorm activity over the lake based on radar monitoring of earlier activity along the northeast land/lake region are provided. While there are many obstacles to overcome, it is hoped that in the near future this possible life-saving information can be provided to Lake Victoria boaters. Significance Statement Radar data from the south shore of Lake Victoria has enabled new understanding of thunderstorm initiation and evolution over the lake. This understanding provides the potential to nowcast thunderstorms over Lake Victoria. This is particularly important because of the extremely high number of drownings that occur over the lake that result from capsized boats caused by large waves and high winds from thunderstorms. Radar-based rules are provided for forecasting and nowcasting the timing and severity of Lake Victoria thunderstorms.

What is the central question of this study? Do changes in myofibre cross-sectional area, pennation angle and fascicle length predict vastus lateralis whole-muscle cross-sectional area changes following resistance training? What is the main finding and its importance? Changes in vastus lateralis mean myofibre cross-sectional area, fascicle length and pennation angle following a period of resistance training did not collectively predict changes in whole-muscle cross-sectional area. Despite the limited sample size in this study, these data reiterate that it remains difficult to generalize the morphological adaptations that predominantly drive tissue-level vastus lateralis muscle hypertrophy.Myofibre hypertrophy during resistance training (RT) poorly associates with tissue-level surrogates of hypertrophy. However, it is underappreciated that, in pennate muscle, changes in myofibre cross-sectional area (fCSA), fascicle length (L

This is the first study to comprehensively examine how different midthigh muscle imaging techniques and histology compare with one another in participants that performed 10 weeks of resistance training. Our study suggests that histology results show poor agreement with results yielded from other common muscle imaging techniques, and researchers should be aware of this limitation.

Accurate ocean initial conditions are beneficial to coupled ocean - atmosphere forecasts in several ways depending on context. On short time scale (days), some extreme, societally high-impacting meteorological events such as tropical cyclones are associated with exceptionally intense air-sea exchanges, thus requiring good knowledge of the initial state of the upper ocean layers. As the forecast evaluation time scale gets longer (seasonal, decadal), the information contained within the atmospheric initial conditions becomes virtually ineffective to the advantage of that contained within the ocean’s.In phase one of the Destination Earth (DestinE) initiative of the European Union, ECMWF is responsible for delivering the first two digital twins, on weather extremes and climate change adaptation. These will rely on the fusion of observations and cutting-edge, high-resolution versions of Earth system models. Developing a cheap, affordable method for generating realistic high-resolution ocean initial conditions is particularly critical to both these forthcoming digital twins developed in DestinE. In this presentation, we thus introduce a new ocean initial condition generation method built to meet these specific needs.This method consists in running preliminary nudged ocean-standalone experiments, using the NEMO ocean model, which is part of the ECMWF’s Integrated Forecasting System. Its main technical novelty is the adaptation of a former sea-ice nudging scheme to NEMO’s multicategory SI3 sea-ice model, and it can be significantly cheaper than relying on ocean data assimilation, particularly at high resolutions. However, this method touches on several matters related to the ability of ocean models to be diverted from their natural equilibrium by being constrained towards increasingly realistic states. We investigate the criteria for obtaining realistic ocean initial condition using distinct combinations of model and nudging dataset resolutions, and evaluate the resulting skill of coupled ocean - atmosphere forecasts.

BackgroundThe role of multidisciplinary clinics for psychosocial care is increasingly recognized for those living with inherited cardiac conditions (ICC). In Canada, access to healthcare providers differ between clinics. Little is known about the relationship between access to specialty care and a patient's ability to cope with, and manage their condition.MethodsWe leveraged the Hearts in Rhythm Organization (HiRO) to conduct a cross-sectional, community-based survey of individuals with ICC and their family members. We aimed to describe access to services, and explore the relationships between participants’ characteristics, cardiac history and self-reported health status and self-efficacy (GSE: General Self-Efficacy Scale) and empowerment (GCOS-24: Genetic Counseling Outcome Scale).ResultsWe collected 235 responses from Canadian participants in 10 provinces and territories. Overall, 63% of participants reported involvement of a genetic counsellor in their care. Access to genetic testing was associated with greater empowerment [mean GCOS-24: 121.14 (SD = 20.53) vs. 105.68 (SD = 21.69); p = 0.004]. Uncertain genetic test results were associated with lower perceived self-efficacy (mean GSE: uncertain = 28.85 vs. positive = 33.16, negative = 34.13; p = 0.01). Low global mental health scores correlated with both lower perceived self-efficacy and empowerment scores, with only 11% of affected participants reporting involvement of psychology services in their care.ConclusionDifferences in resource accessibility, clinical history and self-reported health status impact the perceived self-efficacy and empowerment of patients with ICC. Future research evaluating interventions to improve patient outcomes is recommended.

Objective To provide the best clinical practice guidance for surfactant use in preterm neonates with respiratory distress syndrome (RDS). The RDS-Neonatal Expert Taskforce (RDS-NExT) initiative was intended to add to existing evidence and clinical guidelines, where evidence is lacking, with input from an expert panel. Study design An expert panel of healthcare providers specializing in neonatal intensive care was convened and administered a survey questionnaire, followed by 3 virtual workshops. A modified Delphi method was used to obtain consensus around topics in surfactant use in neonatal RDS. Result Statements focused on establishing RDS diagnosis and indicators for surfactant administration, surfactant administration methods and techniques, and other considerations. After discussion and voting, consensus was achieved on 20 statements. Conclusion These consensus statements provide practical guidance for surfactant administration in preterm neonates with RDS, with a goal to contribute to improving the care of neonates and providing a stimulus for further investigation to bridge existing knowledge gaps.

The becoming of, and being, an early-career academic is a dynamic journey, marked by movement through learning, adapting, and adopting new skills and capacities, being ‘thrown in the deep end’ of academic responsibilities, and beginning to develop an academic identity. We explored how early-career women academics within Australian universities conceptualise their academic identities, and the subject positions (i.e., identities/ways of being) made available through their discourse. Seventeen participants were interviewed, aged between 27 and 62 years, with transcripts of interviews analyzed using Foucauldian Discourse Analysis. Three subject positions were identified—The Compliant Woman (who follows the rules and meets the expectations of the institution); The Strategic Woman (who balances complying and safely challenging the traditional academic ways of being); and The Rebellious Woman (who outrightly challenges the conditions of academia). Discourse surrounding compliance, tolerance, obedience, the patriarchy, and survival, created subjectivities suggesting that the early-career women academics felt unsafe and insecure in academia, as well as having to work harder to prove themselves in a setting that works to exclude them. The key message was that no matter their approach, the early-career women academics felt damned in their navigation of academia.

Skeletal muscle integrates many of the systemic signals, which contribute to the adaptive remodeling, and beneficial effects of exercise. One mechanism through which muscle mediates the systemic effects of exercise is through muscle-derived hormones known as myokines. We identified the metabolite β-aminoisobutyric acid (BAIBA) as an exercise-mediated small molecule myokine. BAIBA is secreted from muscle in response to increased expression of the transcriptional co-regulator PGC-1α, a master regulator of the muscle adaptive response to exercise. However, how BAIBA functions to regulate the adaptive responses of skeletal muscle to exercise remains poorly understood. We show that BAIBA improves muscle metabolism, exercise efficiency and performance in mice. Oxygen consumption (VO2) and energy expenditure are increased in BAIBA-treated mice. Furthermore, BAIBA increased soleus in situ muscle contractile force, fatigue resistance, mitochondrial number and function. We found that BAIBA drives muscle fiber-type switching to an oxidative phenotype in vivo. BAIBA regulates specific fiber-type gene expression in human myocytes through PPARΔ. Our findings demonstrate that BAIBA is a key paracrine myokine, which, in part, regulates the effects of exercise to improve muscle function with resultant effects on exercise performance. H.N.D. acknowledges the support of the Biotechnology and Biological Sciences Research Council (BB/T004231/1). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC. P.J. is supported by the Daniel Bravo Foundation grant and Spanish Society of Cardiology Magda Heras mobility grant, A.G. by the Wilton W. Webster Fellow of Heart Rhythm Society, The Johns Hopkins ARVD/C Programme by the Leonie-Wild Foundation, Leyla Erkan Family Fund for ARVD Research, The Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center, Dr Francis P. Chiramonte Private Foundation, Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, Bogle Foundation, Campanella Family, Patrick J. Harrison Family, Peter French Memorial Foundation, and Wilmerding Endowments, H.K.J. by grants from Novo Nordisk Foundation, Denmark (NNF18OC0031258 and NNF20OC0065151), S.A.L. by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007, R.T. by the Canada Research Chairs programme, J.C.T. by the Philippa and Marvin Carsley Cardiology Research Chair. S.G.P. receives support from Ricerca Corrente funding scheme of the Italian Ministry of Health and Italian Ministry of Research and University Dipartimenti di Eccellenza 2018 to 2022 grant to the Molecular Medicine Department (University of Pavia). Sí

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor overall survival. This tumor is absolutely dependent on the continued expression and activity of its defining molecular lesion, the EWS–WT1 transcription factor. Unfortunately, the therapeutic targeting of transcription factors is challenging, and there is a critical need to identify compounds that inhibit EWS–WT1. Here we show that the compound lurbinectedin inhibits EWS–WT1 by redistributing the protein within the nucleus to the nucleolus. This nucleolar redistribution interferes with the activity of EWS–WT1 to reverse the expression of over 70% of the transcriptome. In addition, the compound blocks the expression of the EWS–WT1 fusion protein to inhibit cell proliferation at the lowest GI50 ever reported for this compound in any cell type. The effects occur at concentrations that are easily achievable in the clinic and translate to the in vivo setting to cause tumor regressions in multiple mice in a xenograft and PDX model of DSRCT. Importantly, this mechanism of nucleolar redistribution is also seen with wild-type EWSR1 and the related fusion protein EWS–FLI1. This provides evidence for a “class effect” for the more than 18 tumors driven by EWSR1 fusion proteins. More importantly, the data establish lurbinectedin as a promising clinical candidate for DSRCT.

To adapt an existing virtual family-based mental health intervention learning platform (I-InTERACT-North), using participatory action research design, to meet the needs of parents and children with congenital, neonatal, and neurodevelopmental conditions that impact development. A purposive sample of parent knowledge users recruited from a large pediatric hospital (n = 21) and clinician stakeholders (n = 16) participated in one interview. An iterative process was adopted to implement feedback in the adaption of the learning platform. Qualitative thematic analysis was used to examine themes across participant feedback. Initial satisfaction with the adapted website was high. Qualitative results revealed four themes: acceptability, usability, recommendations, and dissatisfaction. Addressed with iterations, technical difficulties, wanting more information on content, resources, and intended audience were areas of dissatisfaction. This study reflects the importance of participatory action research methods in informing virtual mental health interventions. Future directions to improve the learning platform are discussed.

Purpose of Review “I can’t breathe” were the last words spoken by Eric Garner (July 17, 2014), Javier Ambler (March 28, 2019), Elijah McClain (August 30, 2019), Manuel Ellis (March 3, 2020), and George Floyd (May 25, 2020). These were all African American men who died at the hands of police in the United States. Recently, police brutality has gained critical and overdue attention as one clear manifestation of systemic racism. However, historical and current policies related to a wide range of environmental hazards have exposed Black, Indigenous, and People of Color (BIPOC) to disproportionately high levels of physical, mental, social, emotional, and cultural toxicities, thus creating unbreathable and unlivable communities. Recent Findings This paper traces the roots of systemic anti-Black racism in America from its origins in the 1400s, through systems of scientific racism that pathologized Blackness in order to justify slavery, and through evolving policies and structures that have shifted over time but consistently exposed many African American communities to unsafe and unhealthy environments. Summary We conclude with calls for bold solutions to move through and past this oppressive history and toward true environmental justice the enables all communities to thrive together.

To examine attention, executive control, and performance variability in healthy varsity athletes and identify unique resting-state functional connectivity (rsFC) patterns associated with measures of speed, stability, and attention. A sample of 29 female university varsity athletes completed cognitive testing using the Attention Network Test- Interactions (ANT-I) and underwent resting-state functional MRI (rsfMRI) scans. Performance was characterized by examining mean reaction time (RT), variability in performance (ISD), and attention network scores on the ANT-I. RsfMRI data were analyzed using an independent component analysis (ICA) in the frontoparietal (FPN), dorsal attention (DAN), default mode, (DMN), salience (SN), and sensorimotor (SMN) networks. Group-level analyses using the performance variables of interest were conducted. Athletes' performance on the ANT-I revealed a main effect of orienting and executive control (ps0.001; partial η

Up to 1,000 drowning deaths occur every year on Lake Victoria in East Africa. Nocturnal thunderstorms are one of the main culprits for the high winds and waves that cause fishing boats to capsize. The High Impact Weather Lake System (HIGHWAY) project was established to develop an Early Warning System for Lake Victoria. Prior to HIGHWAY, weather forecasts for the lake were overly general and not trusted. Under the HIGHWAY project, forecasters from weather service offices in East Africa worked with leaders of fishing communities and Beach Management Units to develop marine forecasts and hazardous-weather warnings that were meaningful to fishermen and other stakeholders. Forecasters used high-resolution satellite, radar, and lightning observations collected during a HIGHWAY field campaign, along with guidance from numerical weather prediction models and a 4.4-km resolution Tropical Africa model, to produce specific forecasts and warnings for 10 zones over the lake. Forecasts were communicated to thousands of people by radio broadcasters, local intermediaries, and via smartphones using the WhatsApp application. Fishermen, ferry-boat operators, and lakeside communities used the new marine forecasts to plan their daytime and nighttime activities on the lake. A socioeconomic benefits study conducted by HIGHWAY found that ∼75% of the people are now using the forecasts to decide if and when to travel on the lake. Significantly, a 30% reduction in drowning fatalities on the lake is likely to have occurred, which, when combined with the reduction in other weather-related losses, generates estimated socioeconomic benefits of $44 million per year due to the HIGHWAY project activities; the new marine forecasts and warnings are helping to save lives and property.

Bacterial spot is an economically significant disease in tomato and pepper-producing countries globally. We report the whole genome sequence of 11 Xanthomonas strains associated with bacterial spot disease on pepper, tomato, and eggplant in the Southeastern Anatolia Region, Turkey. This genomic information can be used as a reference to study the genetic diversity of these species and contribute to illuminating pathogen evolution with respect to host specificity.

Background Tumors are complex tissues containing collections of phenotypically diverse malignant and nonmalignant cells. We know little of the mechanisms that govern heterogeneity of tumor cells nor of the role heterogeneity plays in overcoming stresses, such as adaptation to different microenvironments. Osteosarcoma is an ideal model for studying these mechanisms—it exhibits widespread inter- and intra-tumoral heterogeneity, predictable patterns of metastasis, and a lack of clear targetable driver mutations. Understanding the processes that facilitate adaptation to primary and metastatic microenvironments could inform the development of therapeutic targeting strategies. Results We investigated single-cell RNA-sequencing profiles of 47,977 cells obtained from cell line and patient-derived xenograft models as cells adapted to growth within primary bone and metastatic lung environments. Tumor cells maintained phenotypic heterogeneity as they responded to the selective pressures imposed during bone and lung colonization. Heterogenous subsets of cells defined by distinct transcriptional profiles were maintained within bone- and lung-colonizing tumors, despite high-level selection. One prominent heterogenous feature involving glucose metabolism was clearly validated using immunofluorescence staining. Finally, using concurrent lineage tracing and single-cell transcriptomics, we found that lung colonization enriches for multiple clones with distinct transcriptional profiles that are preserved across cellular generations. Conclusions Response to environmental stressors occurs through complex and dynamic phenotypic adaptations. Heterogeneity is maintained, even in conditions that enforce clonal selection. These findings likely reflect the influences of developmental processes promoting diversification of tumor cell subpopulations, which are retained, even in the face of selective pressures.

Characteristics of patient samples used in this study