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Abstract Multinucleated skeletal muscle cells need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal muscle biology has been the reason underlying this need for new nuclei in cells that already harbor hundreds of nuclei. Here we utilize nuclear RNA-sequencing approaches and develop a lineage tracing strategy capable of defining the transcriptional state of recently fused nuclei and distinguishing this state from that of pre-existing nuclei. Our findings reveal the presence of conserved markers of newly fused nuclei both during development and after a hypertrophic stimulus in the adult. However, newly fused nuclei also exhibit divergent gene expression that is determined by the myogenic environment to which they fuse. Moreover, accrual of new nuclei through fusion is required for nuclei already resident in adult myofibers to mount a normal transcriptional response to a load-inducing stimulus. We propose a model of mutual regulation in the control of skeletal muscle development and adaptations, where newly fused and pre-existing myonuclear populations influence each other to maintain optimal functional growth.

Abstract Bird colonies on islands sustain elevated productivity and biomass on adjacent reefs, through nutrient subsidies. However, the implications of this localized enhancement on higher and often more mobile trophic levels (such as sharks and rays) are unclear, as spatial trends in mobile fauna are often poorly captured by traditional underwater visual surveys. Here, we explore whether the presence of seabird colonies is associated with enhanced abundances of sharks and rays on adjacent coral reefs. We used a novel long‐range water‐landing fixed‐wing unoccupied aerial vehicle (UAV) to survey the distribution and density of sharks, rays and any additional megafauna, on and around tropical coral islands (n = 14) in the Chagos Archipelago Marine Protected Area. We developed a computer‐vision algorithm to distinguish greenery (trees and shrubs), sand and sea glitter from visible ocean to yield accurate marine megafauna density estimation. We detected elevated seabird densities over rat‐free islands, with the commonest species, sooty tern, reaching densities of 932 ± 199 per km−2 while none were observed over former coconut plantation islands. Elasmobranch density around rat‐free islands with seabird colonies was 6.7 times higher than around islands without seabird colonies (1.3 ± 0.63 vs. 0.2 ± SE 0.1 per km2). Our results are evidence that shark and ray distribution is sensitive to natural and localized nutrient subsidies. Correcting for non‐sampled regions of images increased estimated elasmobranch density by 14%, and our openly accessible computer vision algorithm makes this correction easy to implement to generate shark and ray and other wildlife densities from any aerial imagery. The water‐landing fixed‐wing long‐range UAV technology used in this study may provide cost effective monitoring opportunities in remote ocean locations.

Intertidal flats and salt marshes in channel–shoal environments are at severe risk of drowning under sea level rise (SLR) ultimately ceasing their function of coastal defense. Earlier studies indicated that these environments can be resilient against moderate SLR as their mean height is believed to correlate with tidal amplitude and mean sea level. Recent morphological analyses in the German Wadden Sea on the northwestern European continental shelf contradicted this assumption as mean tidal flat accretion surpassed relative SLR, indicating that nonlinear feedback between SLR, coastal morphodynamics, and tidal dynamics played a role. We explored this relationship in the German Wadden Sea's channel–shoal environment by revisiting the sensitivity of tidal dynamics to observed SLR and coastal bathymetry evolution over one nodal cycle (1997 to 2015) with a numerical model. We found a proportional response of tidal high and low water to SLR when the bathymetry was kept constant. In contrast, coastal bathymetry evolution caused a spatially varying hydrodynamic reaction with both increases and decreases in patterns of tidal characteristics within a few kilometers. An explorative assessment of potential mechanisms suggested that energy dissipation declined near the coast, which we related to a decreasing tidal prism and declining tidal energy import. Our study stresses the fact that an accurate representation of coastal morphology in hindcasts, nowcasts, and ensembles for bathymetry evolution to assess the impact of SLR is needed when using numerical models.

Abstract Background Perinatal substance use can have significant adverse effects on maternal and child health and family stability. Few interventions are specifically designed to address this significant public health problem. The Parent–Child Assistance Program (PCAP) is a 3-year case management and home-visiting intervention that seeks to help birthing persons with at-risk substance use during pregnancy to achieve and maintain substance use disorder recovery and avoid exposing future children to substances prenatally. At-risk refers to a level of substance use that creates problems in the individuals’ lives or puts them or their children at risk of harm either prenatally or postnatally. Although the program has consistently shown substantial pre- to post-intervention improvements in its participants, PCAP remains to be tested with a rigorous randomized controlled trial (RCT). This study protocol describes a randomized controlled trial that aims to examine the effectiveness of the intervention compared to services as usual in affecting primary outcomes related to substance use and family planning. Secondary outcomes will concern connection to recovery support services and family preservation. Methods Using an intent-to-treat design, the study will recruit from two metro areas in Oklahoma and enroll 200 birthing individuals who are pregnant or up to 24 months postpartum with at-risk substance use during their current or most recent pregnancy. Participants will be randomly assigned, stratified by location, to receive either PCAP or services as usual for 3 years. Participants in the PCAP condition will meet with their case manager approximately biweekly over the course of the intervention period, in their local communities or in their own homes whenever possible. Case managers will assist with goal setting and provide practical assistance in support of participants’ goals. Primary and secondary outcomes will be assessed at baseline and 12, 24, and 36 months post-baseline using the Addiction Severity Index interview and a self-administered survey. Discussion Results from this trial will help to gauge the effectiveness of PCAP in improving parent and child well-being. Results will be reviewed by federal clearinghouses on home-visiting and foster care prevention to determine the strength of evidence of effectiveness with implications for federal financing of this program model at the state level. Trial registration ClinicalTrials.gov NCT05534568. Registered on 6/8/2022.

Summary: Adult stem cells play a critical role in tissue repair and maintenance. In tissues with slow turnover, including skeletal muscle, these cells are maintained in a mitotically quiescent state yet remain poised to re-enter the cell cycle to replenish themselves and regenerate the tissue. Using a panomics approach we show that the PAX7/NEDD4L axis acts against muscle stem cell activation in homeostatic skeletal muscle. Our findings suggest that PAX7 transcriptionally activates the E3 ubiquitin ligase Nedd4L and that the conditional genetic deletion of Nedd4L impairs muscle stem cell quiescence, with an upregulation of cell cycle and myogenic differentiation genes. Loss of Nedd4L in muscle stem cells results in the expression of doublecortin (DCX), which is exclusively expressed during their in vivo activation. Together, these data establish that the ubiquitin proteasome system, mediated by Nedd4L, is a key contributor to the muscle stem cell quiescent state in adult mice.

Abstract The world’s coasts and deltas are progressively threatened by climate change and human activities. The degree at which coastlines can adapt to these changes strongly depends on the sediment availability. The availability of muddy sediments is however poorly known. This study aims at developing a mud budget for the world’s largest system of uninterrupted tidal flats: the Wadden Sea. The resulting mud budget is nearly closed: ~ 12 million ton/year enters the system on its western end, ~ 1.5 million ton/year is added by local rivers, while ~ 12 million ton annually deposits or is extracted by anthropogenic activities. A mud deficit already exists in the downdrift areas, which will only become more pronounced with increased sea level rise rates. Mud is thus a finite resource similar to sand, and should be treated as such in sediment management strategies. Resolving future challenges will therefore require a cross-border perspective on sediment management.

Abstract Objectives The implementation of the Lung Allocation Score (LAS) in the Eurotransplant international collaborative framework decreased waiting list mortality, but organ shortage remains a significant problem. Transplantation of two single lungs from one donor into two recipients (lung twinning) may decrease waiting list mortality. We sought to analyze if this strategy can lead to an acceptable intermediate-term outcome. Methods Since the LAS-implementation we performed 32 paired single-lung transplantations from 16 postmortal donors. Data and outcome were analyzed retrospectively comparing recipients receiving the first lung (first twins) with recipients receiving the second lung (second twins), left versus right transplantation and restrictive versus obstructive disease. Results Survival at one year was 81% and 54% at five years. Veno-venous ECMO had been successfully used as bridge-to-transplant in three patients with ECMO-explantation immediately after surgery. Bronchial anastomotic complications were not observed in any patient. First twins and second twins exhibited similar survival (p = 0.82) despite higher LAS in first twins (median 45 versus 34, p

Abstract The regulation of proteostasis is fundamental for maintenance of muscle mass and function. Activation of the TGF-β pathway drives wasting and premature aging by favoring the proteasomal degradation of structural muscle proteins. Yet, how this critical post-translational mechanism is kept in check to preserve muscle health remains unclear. Here, we reveal the molecular link between the post-transcriptional regulation of m6A-modified mRNA and the modulation of SMAD-dependent TGF-β signaling. We show that the m6A-binding protein YTHDF2 is essential to determining postnatal muscle size. Indeed, muscle-specific genetic deletion of YTHDF2 impairs skeletal muscle growth and abrogates the response to hypertrophic stimuli. We report that YTHDF2 controls the mRNA stability of the ubiquitin ligase ASB2 with consequences on anti-growth gene program activation through SMAD3. Our study identifies a post-transcriptional to post-translational mechanism for the coordination of gene expression in muscle.

Young adults and teenagers spend a significant amount of time each day using social media, but very few of them have thought about the ethical implications of what they post or view on these platforms. This activity provides students with the opportunity to (1) log and evaluate the amount of time and types of posts they are creating on social media, and (2) view a made-up social media story from Snapchat where student can assess their own ethical sensitivity (Rest, J. R. (1983). Morality. In P. H. Mussen (Ed.), Handbook of child psychology: Vol. 3: Cognitive development 4th ed. (pp. 556-629). John Wiley) for a variety of ethical issues. Courses: Communication Ethics, Social Media and Communication, Communication, Diversity, and Inclusion. Objectives: The objectives of this single-class activity are to: (1) reflect on one's own usage and communication behavior on social media; (2) identify and reflect on ethical dilemmas and moral awareness; (3) discuss the intersections of communication ethics and social media; and (4) articulate how social media and digitally mediated communication impact communication ethics and communication behavior.

Genesis of skeletal muscle relies on the differentiation and fusion of mono-nucleated muscle progenitor cells into the multi-nucleated muscle fiber syncytium. The temporally-controlled cellular and morphogenetic changes underlying this process are initiated by a series of highly coordinated transcription programs. At the core, the myogenic differentiation cascade is driven by muscle-specific transcription factors, i.e., the Myogenic Regulatory Factors (MRFs). Despite extensive knowledge on the function of individual MRFs, very little is known about how they are coordinated. Ultimately, highly specific coordination of these transcription programs is critical for their masterfully timed transitions, which in turn facilitates the intricate generation of skeletal muscle fibers from a naïve pool of progenitor cells. The Mediator complex links basal transcriptional machinery and transcription factors to regulate transcription and could be the integral component that coordinates transcription factor function during muscle differentiation, growth, and maturation. In this study, we systematically deciphered the changes in Mediator complex subunit expression in skeletal muscle development, regeneration, aging, and disease. We incorporated our in vitro and in vivo experimental results with analysis of publicly available RNA-seq and single nuclei RNA-seq datasets and uncovered the regulation of Mediator subunits in different physiological and temporal contexts. Our experimental results revealed that Mediator subunit expression during myogenesis is highly dynamic. We also discovered unique temporal patterns of Mediator expression in muscle stem cells after injury and during the early regeneration period, suggesting that Mediator subunits may have unique contributions to directing muscle stem cell fate. Although we observed few changes in Mediator subunit expression in aging muscles compared to younger muscles, we uncovered extensive heterogeneity of Mediator subunit expression in dystrophic muscle nuclei, characteristic of chronic muscle degeneration and regeneration cycles. Taken together, our study provides a glimpse of the complex regulation of Mediator subunit expression in the skeletal muscle cell lineage and serves as a springboard for mechanistic studies into the function of individual Mediator subunits in skeletal muscle.

Abstract Background Mechanical thrombectomy has been shown to reduce thrombus burden and pulmonary artery pressure (PAP) and to improve right ventricular (RV) function in patients with high-risk or intermediate-high-risk pulmonary embolism (PE). As hemodynamic data after mechanical thrombectomy for PE are scarce, we aimed to assess the hemodynamic effects of mechanical thrombectomy in acute PE with right heart overload. Methods In this prospective, open-label study, patients with acute symptomatic, computed tomography-documented PE with signs of right heart overload underwent mechanical thrombectomy using the FlowTriever System. Right heart catheterization was performed immediately before and after thrombectomy and after three months. Transthoracic echocardiography was performed before thrombectomy, discharge, and at three months. This analysis was done after 20 patients completed three months of follow-up. Results Twenty-nine patients (34% female) underwent mechanical thrombectomy, of which 20 completed three months follow-up with right heart catheterization. Most patients were at high (17%) or intermediate-high (76%) risk and had bilateral PE (79%). Before thrombectomy, systolic PAP (sPAP) was severely elevated (mean 51.3 ± 11.6 mmHg). Mean sPAP dropped by -15.0 mmHg (95% confidence interval [CI]: -18.9 to -11.0; p

Abstract Background Current COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO). Methods This is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT. Results Thirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support. Conclusions Late administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS.

Capnocytophaga canimorsus is a rare cause of serious infections with a high mortality of 10% to 30%. It is usually found in the oral cavity of cats and dogs and can cause severe sepsis in immunocompromised patients. An 81-year-old female Caucasian patient presented with C. canimorsus sepsis after a dog bite in her finger three days before presentation to our emergency department. She initially was presented to us with sepsis, thrombopenia, and schistocytes in her laboratory findings, suggesting the differential diagnoses of the multiple subtypes of thrombotic microangiopathy. She was admitted to the medical intensive care unit of the University Hospital of Saarland because of septic shock with circulatory insufficiency. The patient received plasmapheresis, antibiotics, and dialysis, under which she improved significantly. The fingertip of the affected finger developed necrosis and had to be amputated. Furthermore, the patient was diagnosed with a mitral valve endocarditis, a very rare complication of C. canimorsus infection. It was treated conservatively with antibiotics and was no longer detectable 8 weeks after the diagnosis. Surgical intervention was not needed. The case describes well that it is still difficult to distinguish between thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), and sepsis-induced coagulopathy (SIC), especially in the early phases of acute disease, especially in C. canimorsus-induced sepsis.

Reading motivation is a fundamental basis for reading behavior and performance. For learners, interest is an exceedingly important component of reading motivation. Prior research has shown that students' text-based interest varies significantly between texts. However, it is still unclear why one text elicits greater interest over another. Therefore, in this study, we investigated whether different text characteristics, such as text genre, topic, and protagonists' gender, are systematically related to students' text-based interest. Furthermore, we examined differences between girls and boys. We used data from a sample of 504 fourth-grade elementary school students to answer these questions. Eight texts were manipulated experimentally with respect to text genre, topic, and protagonists' gender. Students were assigned randomly to read one of the eight texts. Structural equation models showed that students' text-based interest was related to text genre, topic, and students' gender. Moreover, students' gender interacted significantly with text topic and protagonists' gender, with boys less interested in texts with a more female-typed text topic and in texts with female protagonists. The findings imply that text characteristics might help educators select reading material to encourage students' text-based interest. The results are discussed in terms of research and educational practice.

ABSTRACTTreatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of melanoma patients. However, ICIs can cause an overactivation of the immune system followed by diverse immunological side effects known as immune-related adverse events (irAE). Currently, the toxicity of irAE is limiting the usage of ICIs. Here, we studied circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and T cells in course of irAE after the ICI therapy. Our longitudinal study involved 31 melanoma patients with and without adverse events during anti-PD-1 monotherapy or anti-CTLA-4/PD-1 combination therapy. Peripheral blood samples were analyzed before ICI start, during ICI treatment, at the time point of irAE and during immunosuppressive treatment to cure irAE. We observed an enhanced progression-free survival among patients with irAE. In patients with irAE, we found an upregulation of CD69 on CD8+ T cells and a decreased frequency of regulatory T cells (Tregs). Moreover, lower frequencies of Tregs correlated with more severe side effects. Patients treated with immunomodulatory drugs after irAE manifestation tend to show an elevated number of M-MDSCs during an immunosuppressive therapy. We suggest that an activation of CD8+ T cells and the reduction of Treg frequencies could be responsible for the development of irAE.

Abstract Background Congenital cytomegalovirus (cCMV) infection can cause severe neurological damage, growth retardation, hearing loss, and microcephaly in infants. We aimed at assessing healthcare costs of infants with recorded cCMV diagnosis in an administrative claims database in the first 2 years of life. Methods We conducted a retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database. Incremental healthcare costs during the first and second year of life were assessed by matching (1:60) infants with cCMV diagnoses ≤ 90 days after birth (cCMV90 cohort) to infants without cCMV diagnosis (“representative” controls) and infants with cCMV diagnoses ≤ 21 days after birth plus specific symptoms (cCMV21-S) to infants without cCMV and any ICD-10-GM records (besides Z00-Z99) until 4th preventive health check-up (“healthy” controls). Due to missing data, mean imputation was applied for aids and remedies costs. Results We identified 54 and 24 infants born 2014–2018 for the cCMV90 and cCMV21-S cohorts, respectively. During the first year, mean (median) healthcare costs were significantly higher in cCMV90 cases vs. “representative” controls (€22,737 (€9759) vs. €3091 (€863), p

ABSTRACT: Background: Early prognostication of COVID-19 severity will potentially improve patient care. Biomarkers, such as TNF-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein 10 (IP-10), and C-reactive protein (CRP), might represent possible tools for point-of-care testing and severity prediction. Methods: In this prospective cohort study, we analyzed serum levels of TRAIL, IP-10, and CRP in patients with COVID-19, compared them with control subjects, and investigated the association with disease severity. Results: A total of 899 measurements were performed in 132 patients (mean age 64 years, 40.2% females). Among patients with COVID-19, TRAIL levels were lower (49.5 vs 87 pg/ml, P = 0.0142), whereas IP-10 and CRP showed higher levels (667.5 vs 127 pg/ml, P

Many pregnant and postpartum individuals who misuse prescription opioids report either physical or psychological pain. The pain-related factors underlying perinatal opioid misuse are poorly understood. The purpose of this study was to explore the pain-related experiences of individuals with histories of perinatal prescription opioid misuse. This study used a qualitative descriptive design. Between October 2021 and July 2022, a convenience sample of 12 childbearing-aged females with histories of perinatal opioid misuse were recruited and individually interviewed about their pain-related experiences. Semi-structured interviews were recorded, transcribed verbatim, and manually coded using thematic analysis. Twelve participants consented to participate and provided 14 interviews. Three major themes emerged to highlight participant's experiences with pain and misuse of prescription opioids: 1) pain sources, 2) impact of pain, and 3) pain management. Participants indicated in their interviews their childhood and adult trauma experiences created risk of initiating misuse prior to pregnancy and continued prescription opioid misuse perinatally. Both psychological and physical pain experiences were stated by participants as frequently undertreated. Participants perceived undertreatment of both types of pain influenced decisions to self-manage with prescription opioid and illegal substances of abuse. The participants' shared experiences provide insights for targeted pain-related nursing interventions that could help reduce the initiation and perpetuation of misuse and assist the journey to recovery. [ABSTRACT FROM AUTHOR]

The different labelling systems defined by the functional theories of harmony have been developed from about 1870 to 1950, without the help of computers. The complexity of harmonic labels spans from pure triads over added characteristic dissonances, over alterations of the fifth, up to non-chord notes like suspensions. Computer-based evaluation of functional label expressions shows that thereby their cardinality increases up to several thousands. For this, we present the basic theory, a concrete program implemented in Prolog, and some empirical results. The software is capable of analysing historic published analyses by inductively collecting all appearing labels, as well as theories as such, where the set of labels is given deductively, by regular expressions. A major application is the mining for possible modulation chords, i.e. different functional labels which result in (enharmonically) the same pitch classes. That this strategy had actually been applied by composers manually is explained by significant examples from the Romantic period.

BackgroundCongenital cytomegalovirus (cCMV) infection can have a broad range of manifestations. This study aimed to assess cCMV-associated sequelae and healthcare resource utilization (HCRU) in infants during the first year of life in Germany.MethodsA retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database was conducted. cCMV-associated sequelae and HCRU during the first year of life were assessed by matching (1:60) infants with at least one inpatient/outpatient cCMV diagnosis (ICD-10-GM: P35.1) ≤90 days after birth (cCMV90 cohort) and infants with at least one inpatient cCMV diagnosis plus specific sequelae ≤21 days after birth (cCMV21-S) to infants without cCMV or CMV (ICD-10-GM: B25) diagnosis (control group), respectively. Outcomes were analyzed during the first 365 days of life.ResultsBetween 2014-2018, we identified 54 newborns for cCMV90 and 24 newborns for cCMV21-S cohort. Compared to the 3,240 and 1,440 controls, respectively, more cCMV90 infants (83.3% vs. 41.9%, pConclusionscCMV-infection shows a considerable disease and healthcare burden during the first year of life. More than 80% of the identified newborns with cCMV suffered from at least one associated sequela during the first year of life, including long-term sequelae such as SNHL (40%) and visual impairment (13%). Additional steps for prevention of cCMV infection and associated sequelae as well as a comprehensive monitoring of disease burden are needed.