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Abstract Androgen receptor (AR)-mediated transcription plays a critical role in development and prostate cancer growth. AR drives gene expression by binding to thousands of cis-regulatory elements (CRE) that loop to hundreds of target promoters. With multiple CREs interacting with a single promoter, it remains unclear how individual AR bound CREs contribute to gene expression. To characterize the involvement of these CREs, we investigate the AR-driven epigenetic and chromosomal chromatin looping changes by generating a kinetic multi-omic dataset comprised of steady-state mRNA, chromatin accessibility, transcription factor binding, histone modifications, chromatin looping, and nascent RNA. Using an integrated regulatory network, we find that AR binding induces sequential changes in the epigenetic features at CREs, independent of gene expression. Further, we show that binding of AR does not result in a substantial rewiring of chromatin loops, but instead increases the contact frequency of pre-existing loops to target promoters. Our results show that gene expression strongly correlates to the changes in contact frequency. We then propose and experimentally validate an unbalanced multi-enhancer model where the impact on gene expression of AR-bound enhancers is heterogeneous, and is proportional to their contact frequency with target gene promoters. Overall, these findings provide insights into AR-mediated gene expression upon acute androgen simulation and develop a mechanistic framework to investigate nuclear receptor mediated perturbations.

Uncertainty quantification (UQ) is a well-established category of methods to estimate the effect of parameter variations on a quantity of interest based on a solid mathematical foundation. In the wind energy field most UQ studies focus on the sensitivity of turbine loads. This article presents a framework, wrapped around a modern Python UQ library, to analyze the impact of uncertain turbine properties on aeroelastic stability. The UQ methodology applies a polynomial chaos expansion surrogate model. A comparison is made between different wind turbine simulation tools on the engineering model level (alaska/Wind, Bladed, HAWC2/HAWCStab2, and Simpack). Two case studies are used to demonstrate the effectiveness of the method to analyze the sensitivity of the aeroelastic damping of an unstable turbine mode to variations of structural blade cross-section parameters. The code-to-code comparison shows good agreement between the simulation tools for the reference model, but also significant differences in the sensitivities.

Abstract Sarcopenia has been associated with adverse health outcomes, including cognitive dysfunction. However, its specific interrelationship with neurocognitive disorders such as mild cognitive impairment (MCI), Alzheimer's disease (AD) or other types of dementia has not been thoroughly explored. This meta‐analysis aims to summarize the existing evidence on this interrelationship. This systematic review was pre‐registered on PROSPERO (CRD42022366309) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 2020 guidelines. Databases, including PubMed, Embase, CINAHL, Scopus, Web of Science, PEDro, SPORTDiscus and the Cochrane Central Register of Controlled Trials, and the data registry ClinicalTrials.gov were searched from inception to 8 June 2023. Observational studies (cross‐sectional and cohort) and interventional studies reporting on the association and prevalence of sarcopenia in MCI, AD or other types of dementia in adults ≥50 years were included. For the meta‐analysis, pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of sarcopenia with the neurocognitive disorders using random‐effects/fixed‐effects models. Subgroup analyses were performed to identify potential sources of heterogeneity. A total of 77 studies consisting of 92 058 subjects were finally included in the qualitative analysis (71 cross‐sectional, 4 cohort and 2 interventional studies). Studies were heterogeneous, using different diagnostic criteria to define both sarcopenia and cognitive status. The majority of studies (n = 38) included Asian community‐dwelling older adults. Most studies investigated the association of sarcopenia with AD (33/77) and MCI (32/77). For studies focusing on other forms of dementia, two studies included Lewy body dementia and one study included Parkinson's dementia, whereas the remaining studies did not specify dementia aetiology (n = 21). Three cohort studies explored the association between sarcopenia and incident MCI, whereas only one cohort study explored the association between dementia and incident sarcopenia. Two interventional studies investigated whether an exercise programme could prevent the progression of sarcopenia in older adults with dementia or AD. The information for the meta‐analysis was extracted from 26 studies. Sarcopenia was significantly associated with MCI (pooled OR = 1.58, 95% CI 1.42–1.76) (n = 14), AD (pooled OR = 2.97, 95% CI 2.15–4.08) (n = 3) and non‐AD dementia (pooled OR = 1.68, 95% CI 1.09–2.58) (n = 9). The significance and magnitude of the associations differed in subgroup analyses by study design, population, definition of sarcopenia or used tool to measure cognitive status. This meta‐analysis showed that sarcopenia is significantly associated with MCI, AD and other types of dementia. These findings suggest the importance of early screening and prevention of sarcopenia in older people with cognitive dysfunction, although further longitudinal research is needed to clarify the causal relationship.

Abstract Lacustrine methane emissions are strongly mitigated by aerobic methane-oxidizing bacteria (MOB) that are typically most active at the oxic-anoxic interface. Although oxygen is required by the MOB for the first step of methane oxidation, their occurrence in anoxic lake waters has raised the possibility that they are capable of oxidizing methane further anaerobically. Here, we investigate the activity and growth of MOB in Lake Zug, a permanently stratified freshwater lake. The rates of anaerobic methane oxidation in the anoxic hypolimnion reached up to 0.2 µM d−1. Single-cell nanoSIMS measurements, together with metagenomic and metatranscriptomic analyses, linked the measured rates to MOB of the order Methylococcales. Interestingly, their methane assimilation activity was similar under hypoxic and anoxic conditions. Our data suggest that these MOB use fermentation-based methanotrophy as well as denitrification under anoxic conditions, thus offering an explanation for their widespread presence in anoxic habitats such as stratified water columns. Thus, the methane sink capacity of anoxic basins may have been underestimated by not accounting for the anaerobic MOB activity.

BackgroundUsability has been touted as one determiner of success of mobile health (mHealth) interventions. Multiple systematic reviews of usability assessment approaches for different mHealth solutions for physical rehabilitation are available. However, there is a lack of synthesis in this portion of the literature, which results in clinicians and developers devoting a significant amount of time and effort in analyzing and summarizing a large body of systematic reviews. ObjectiveThis study aims to summarize systematic reviews examining usability assessment instruments, or measurements tools, in mHealth interventions including physical rehabilitation. MethodsAn umbrella review was conducted according to a published registered protocol. A topic-based search of PubMed, Cochrane, IEEE Xplore, Epistemonikos, Web of Science, and CINAHL Complete was conducted from January 2015 to April 2023 for systematic reviews investigating usability assessment instruments in mHealth interventions including physical exercise rehabilitation. Eligibility screening included date, language, participant, and article type. Data extraction and assessment of the methodological quality (AMSTAR 2 [A Measurement Tool to Assess Systematic Reviews 2]) was completed and tabulated for synthesis. ResultsA total of 12 systematic reviews were included, of which 3 (25%) did not refer to any theoretical usability framework and the remaining (n=9, 75%) most commonly referenced the ISO framework. The sample referenced a total of 32 usability assessment instruments and 66 custom-made, as well as hybrid, instruments. Information on psychometric properties was included for 9 (28%) instruments with satisfactory internal consistency and structural validity. A lack of reliability, responsiveness, and cross-cultural validity data was found. The methodological quality of the systematic reviews was limited, with 8 (67%) studies displaying 2 or more critical weaknesses. ConclusionsThere is significant diversity in the usability assessment of mHealth for rehabilitation, and a link to theoretical models is often lacking. There is widespread use of custom-made instruments, and preexisting instruments often do not display sufficient psychometric strength. As a result, existing mHealth usability evaluations are difficult to compare. It is proposed that multimethod usability assessment is used and that, in the selection of usability assessment instruments, there is a focus on explicit reference to their theoretical underpinning and acceptable psychometric properties. This could be facilitated by a closer collaboration between researchers, developers, and clinicians throughout the phases of mHealth tool development. Trial RegistrationPROSPERO CRD42022338785; https://www.crd.york.ac.uk/prospero/#recordDetails

The vast majority of disease-associated single nucleotide polymorphisms (SNP) identified from genome-wide association studies (GWAS) are localized in non-coding regions. A significant fraction of these variants impact transcription factors binding to enhancer elements and alter gene expression. To functionally interrogate the activity of such variants we developed snpSTARRseq, a high-throughput experimental method that can interrogate the functional impact of hundreds to thousands of non-coding variants on enhancer activity. snpSTARRseq dramatically improves signal-to-noise by utilizing a novel sequencing and bioinformatic approach that increases both insert size and the number of variants tested per loci. Using this strategy, we interrogated known prostate cancer (PCa) risk-associated loci and demonstrated that 35% of them harbor SNPs that significantly altered enhancer activity. Combining these results with chromosomal looping data we could identify interacting genes and provide a mechanism of action for 20 PCa GWAS risk regions. When benchmarked to orthogonal methods, snpSTARRseq showed a strong correlation with in vivo experimental allelic-imbalance studies whereas there was no correlation with predictive in silico approaches. Overall, snpSTARRseq provides an integrated experimental and computational framework to functionally test non-coding genetic variants.

Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.

BackgroundMagnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS).ObjectiveTo examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM).MethodsPatients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions.ResultsCompared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity.ConclusionSiponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

BackgroundSiponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS.MethodsPost hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND.Endpoints3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits.ResultsData from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p

Background and objectivesTo describe the characteristics of patients with MS reporting cryptococcal meningitis (CM) while treated with fingolimod.MethodsThe Novartis safety database was searched for cases with CM between January 26, 2006, and February 28, 2020. The reporting rate of CM was estimated based on the case reports received and exposure to fingolimod in the postmarketing setting during the relevant period.ResultsA total of 60 case reports of CM were identified, mostly from the United States. The median age was 48 years, and 51.8% were women. Most of the patients had recovered or were recovering at the time of final report. A fatal outcome occurred in 13 cases. During the study period, the rate of CM in patients with MS receiving fingolimod was estimated to be 8 per 100,000 patient-years (95% CI: 6.0; 10.0). The incidence of CM seemed to increase with duration of treatment; however, this relationship remains uncertain due to wide CIs and missing data.DiscussionThe causal relationship between fingolimod treatment and CM is not yet fully understood. The CM mortality rate in fingolimod-treated patients is similar to that reported in HIV-negative patients. Vigilance for signs and symptoms of CM in patients receiving fingolimod, particularly the new onset of headaches and altered mental status, is essential. Early diagnosis and treatment are critical to reducing CM-associated mortality.

Abstract Background Multi-professional specialist palliative homecare (SPHC) teams care for palliative patients with complex symptoms. In Germany, the SPHC directive regulates care provision, but model contracts for each federal state are heterogeneous regarding staff requirements, cooperation with other healthcare providers, and financial reimbursement. The structural characteristics of SPHC teams also vary. Aim We provide a structured overview of the existing model contracts, as well as a nationwide assessment of SPHC teams and their structural characteristics. Furthermore, we explore whether these characteristics serve to find specifc patterns of SPHC team models, based on empirical data. Methods This study is part of the multi-methods research project “SAVOIR”, funded by the German Innovations Fund. Most model contracts are publicly available. Structural characteristics (e.g. number, professions, and affiliations of team members, and external cooperation) were assessed via an online database (“Wegweiser Hospiz- und Palliativversorgung”) based on voluntary information obtained from SPHC teams. All the data were updated by phone during the assessment process. Data were descriptively analysed regarding staff, cooperation requirements, and reimbursement schemes, while latent class analysis (LCA) was used to identify structural team models. Results Model contracts have heterogeneous contract partners and terms related to staff requirements (number and qualifications) and cooperation with other services. Fourteen reimbursement schemes were available, all combining different payment models. Of the 283 SPHC teams, 196 provided structural characteristics. Teams reported between one and 298 members (mean: 30.3, median: 18), mainly nurses and physicians, while 37.8% had a psychosocial professional as a team member. Most teams were composed of nurses and physicians employed in different settings; for example, staff was employed by the team, in private practices/nursing services, or in hospitals. Latent class analysis identified four structural team models, based on the team size, team members’ affiliation, and care organisation. Conclusion Both the contractual terms and teams’ structural characteristics vary substantially, and this must be considered when analysing patient data from SPHC. The identified patterns of team models can form a starting point from which to analyse different forms of care provision and their impact on care quality.

A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod. We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020. As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients. Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting. The epigenetic regulator enhancer of zeste homologue 2 (EZH2) co-occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neuronal gene networks-granting privileges associated with both fates. This function of EZH2 was associated with T350 phosphorylation and establishment of a non-canonical polycomb subcomplex. Our study provides mechanistic insights into the plasticity of the lineage-infidelity state governed by AR reprogramming that enabled us to redirect cell fate by modulating EZH2 and AR, highlighting the clinical potential of reversing resistance phenotypes.

Abstract Background The number of palliative care patients with complex needs is increasing in developed countries. In addition to physical aspects and symptom control, psychosocial aspects are of great importance for palliative care patients. The aim of this study was to understand which psychosocial aspects are important to patients, relatives and health professionals within the setting of a palliative care unit in comparison with specialised palliative home-care (SPHC). Methods We used a qualitative design based on semistructured interviews, which were coded via qualitative content analysis. The study took place in the state of Hesse, Germany, and data collection was conducted in 2017 (interviews from the ELSAH study, which was conducted in a SPHC) and 2018 (supplementary interviews conducted in a palliative care unit). The results from both settings were compared. Results In the palliative care unit, 10 health professionals, 11 patients and 8 relatives were interviewed. In the outpatient setting, we interviewed 30 health professionals, 14 patients and 14 relatives. We identified four key psychosocial issues related to palliative care that were relevant in both the inpatient and outpatient settings: care planning, patient-centred care, a protected environment with feelings of safety, and psychological well-being. In addition, immediate availability of medical staff, greater relief of the relatives and better accessibility of psychological care were more important in the inpatient setting than in the specialised palliative home care setting. Conclusions Knowledge and application of the identified key issues may improve patient-centred palliative care. Accessibility of psychological care and immediate availability of medical staff may be important factors for enhancing psychological well-being in the inpatient palliative care setting. Consideration of the identified key issues may help to develop more collaborative transitions between the palliative care unit and the SPHC and may help to provide palliative care patients and their families with care that is appropriate and feasible for them. Trial registration The underlying comparative study of the outpatient setting of specialised palliative home-care (ELSAH) was registered within the German Clinical Trials Register DRKS-ID: DRKS00012421, ( https://drks.de/search/de/trial/DRKS00012421 ) on 19th May 2017.

IntroductionAdolescents with mental disorders show an increased risk of suicidal phenomena. Vice versa, suicidality is a serious adverse event of psychotropic drug therapy in adolescents. There are only a few new psychotropic agents approved for this young age group. We evaluated the (pre-pandemic) prevalence of off-label use as well as detailed blood concentrations of outpatient psychotropic medication and sex differences in a clinical population of suicidal adolescents.MethodsThe urine presence and serum levels of psychotropic substances of adolescents hospitalized due to their acute suicidality but without a known actual suicide attempt (i.e., no acute intoxication or serious self-injuries) were investigated routinely between 01.03.2017 and 31.01.2018. Urine (N = 205) and blood samples (N = 193) were taken at the beginning of closed inpatient admission, i.e., the results of the laboratory analysis reflect outpatient drug intake. The serum levels of psychopharmacological medication and OTC medication were measured.ResultsOur sample consists of 231 cases (boys: N = 54; girls: N = 177, ratio: 1:3.3), aged 12–17 years (average age: 15,4 years). The most prevalent psychiatric diagnoses were depressive episodes (54%) and adjustment disorders (25%), and girls were more often diagnosed with depressive disorders than boys (boy/girl ratio: 1:9.5, p

BackgroundDepression and anxiety are common and debilitating mental disorders with severe negative repercussions at both individual and societal levels. Although virtual reality (VR) has emerged as a safe and effective tool for the treatment of anxiety disorders, studies of the therapeutic application of VR to treat depression are more limited. ObjectiveThe purpose of this study was to test whether a novel type of individualized VR (iVR) can be used to improve self-compassion and decrease depressive symptoms and to evaluate the usability and acceptability of this approach, as rated by participants. The iVR system was designed and developed based on the feedback obtained from a previous study, with improved appearance and feel of the avatar and enhanced graphical quality. MethodsA total of 36 young adult participants were recruited from a university community social media site. Participants were aware that the study was investigating a treatment for depression but were not recruited based on depression diagnosis. Participants were asked to complete 2 iVR sessions, spaced 2 weeks apart. At baseline and upon completion of each iVR session, participants were asked to complete validated measures of self-compassion and depression. Upon completion of both iVR sessions, additional measures were administered to assess participants’ perceptions about the perceived usability and system acceptability of the iVR approach. ResultsSelf-compassion was assessed at the beginning of session 1 (preintervention baseline) and at the end of session 1 (postintervention assessment). Owing to COVID-19 constraints, 36% (13/36) of the participants were unable to complete the follow-up iVR session. Self-compassion was assessed again for the remaining 64% (23/36) of the participants at the end of session 2 (postintervention assessment). Within-group analyses revealed that self-compassion was significantly increased at the end of both session 1 (P=.01) and session 2 (P=.03) relative to baseline. There was also a nonsignificant trend for depressive symptoms to be low at the end of session 2 relative to baseline. Both quantitative and qualitative participant data supported the iVR approach as being acceptable and usable. ConclusionsAlthough these data must be treated as preliminary owing to the small sample size and potential selection bias, the data provide encouraging initial evidence that iVR might be a useful tool to enhance self-compassion and reduce depressive symptoms, highlighting the need for randomized controlled trials in the future.

Clear-cell renal cell carcinoma (ccRCC) is a common therapy resistant disease with aberrant angiogenic and immunosuppressive features. Patients with metastatic disease are treated with targeted therapies based on clinical features: low-risk patients are usually treated with anti-angiogenic drugs and intermediate/high-risk patients with immune therapy. However, there are no biomarkers available to guide treatment choice for these patients. A recently published phase II clinical trial observed a correlation between ccRCC patients' clustering and their response to targeted therapy. However, the clustering of these groups was not distinct. Here, we analyzed the gene expression profile of 469 ccRCC patients, using featured selection technique, and have developed a refined 66-gene signature for improved sub-classification of patients. Moreover, we have identified a novel comprehensive expression profile to distinguish between migratory stromal and immune cells. Furthermore, the proposed 66-gene signature was validated using a different cohort of 64 ccRCC patients. These findings are foundational for the development of reliable biomarkers that may guide treatment decision-making and improve therapy response in ccRCC patients.

Biorefining of renewable feedstocks is one of the most promising routes to replace fossil-based products. Since many common fermentation hosts, such as Saccharomyces cerevisiae, are naturally unable to convert many component plant cell wall polysaccharides, the identification of organisms with broad catabolism capabilities represents an opportunity to expand the range of substrates used in fermentation biorefinery approaches. The red basidiomycete yeast Rhodosporidium toruloides is a promising and robust host for lipid- and terpene-derived chemicals. Previous studies demonstrated assimilation of a range of substrates, from C5/C6 sugars to aromatic molecules similar to lignin monomers. In the current study, we analyzed the potential of R. toruloides to assimilate d-galacturonic acid, a major sugar in many pectin-rich agricultural waste streams, including sugar beet pulp and citrus peels. d-Galacturonic acid is not a preferred substrate for many fungi, but its metabolism was found to be on par with those of d-glucose and d-xylose in R. toruloides A genomewide analysis by combined transcriptome sequencing (RNA-seq) and RB-TDNA-seq revealed those genes with high relevance for fitness on d-galacturonic acid. While R. toruloides was found to utilize the nonphosphorylative catabolic pathway known from ascomycetes, the maximal velocities of several enzymes exceeded those previously reported. In addition, an efficient downstream glycerol catabolism and a novel transcription factor were found to be important for d-galacturonic acid utilization. These results set the basis for use of R. toruloides as a potential host for pectin-rich waste conversions and demonstrate its suitability as a model for metabolic studies with basidiomycetes.IMPORTANCE The switch from the traditional fossil-based industry to a green and sustainable bioeconomy demands the complete utilization of renewable feedstocks. Many currently used bioconversion hosts are unable to utilize major components of plant biomass, warranting the identification of microorganisms with broader catabolic capacity and characterization of their unique biochemical pathways. d-Galacturonic acid is a plant component of bioconversion interest and is the major backbone sugar of pectin, a plant cell wall polysaccharide abundant in soft and young plant tissues. The red basidiomycete and oleaginous yeast Rhodosporidium toruloides has been previously shown to utilize a range of sugars and aromatic molecules. Using state-of-the-art functional genomic methods and physiological and biochemical assays, we elucidated the molecular basis underlying the efficient metabolism of d-galacturonic acid. This study identified an efficient pathway for uronic acid conversion to guide future engineering efforts and represents the first detailed metabolic analysis of pectin metabolism in a basidiomycete fungus.

Abstract Background Such patient-reported outcome measures (PROMs) and patient-centered outcome measures as the Integrated Palliative Care Outcome Scale (IPOS), Phase of Illness, and IPOS Views on Care (IPOS VoC), facilitate patient-centered care and help improve quality. To ensure sustainability, implementation and usage should be adapted according to setting. When settings involve several distinct teams that differ in terms of views and working practices, it is more difficult to integrate outcome measures into daily care. The ELSAH study aimed to learn how health professionals working in specialized outpatient palliative care (SOPC) viewed the use of these outcome measures in daily care, and what they express is needed for successful sustainable, state-wide application. Methods We used a parallel mixed-methods design involving three focus groups (n = 14) and an online-survey based on normalization process theory (n = 76). Most participants were nurses and physicians from 19 SOPC-teams in Hesse, Germany. We used a triangulation protocol including convergence coding matrices to triangulate findings. Results The majority of health professionals were able to integrate the outcome measures into their working lives and said that it had become a normal part of their day-to-day work. To ensure their sustainable integration into daily care, the motivation and concerns of health professionals should be taken into consideration. Health professionals must clearly recognize how the measures help improve daily care and quality evaluation. Conclusions To implement the outcome measures in a number of teams, it will be necessary to take individual team characteristics into account, because they influence motivation and concerncs. Further, it will be necessary to offer opportunities for them to engage in peer support and share information with other teams. The sustainable use of outcome measures in SOPC will require continuous support within each team as well as across teams. When several distinct teams are working in the same setting, a cross-team coordination unit can help to coordinate their work efficiently. Trial registration German Clinical Trials Register DRKS-ID: DRKS00012421; www.germanctr.de/DRKS00012421

Abstract Forced migrant women experience high levels of violence across their journeys and violence can be characterised as having three overarching forms: structural, symbolic, and interpersonal. It is important to understand the intersecting nature of gendered forms of symbolic, structural and interpersonal violence, and their impact on the mental health of forced migrant women in order to develop holistic IPV and resettlement programs and interventions. This article adopts an ecological framework of violence and qualitative methods with mental health service providers and survivors of IPV to understand the intersections of different forms of violence and their impact on mental health as they relate to the lived experiences of Arabic-speaking forced migrant survivors currently residing in Melbourne, Australia. Our research has three key findings: (1) that forced migrant women living in Melbourne, Australia experience intersecting forms of violence during resettlement (2) Structural and symbolic violence against forced migrant women persists regardless of marital status (3) Autonomy and independence plays a vital role in the mental health and wellbeing of forced migrant women. Our findings reveal that structural and symbolic violence increase the risk of IPV for forced migrant women during resettlement and that even when forced migrant women leave IPV situations, structural and symbolic violence persist and exacerbate mental ill-health. This article also reveals the importance autonomy and independence in both the perpetration of violence and in healing and recovery.

Aircraft configurations with propellers have been drawing more attention in recent times, partly due to new propulsion concepts based on hydrogen fuel cells and electric motors. These configurations are prone to whirl flutter, which is an aeroelastic instability affecting airframes with elastically supported propellers. It commonly needs to be mitigated already during the design phase of such configurations, requiring, among other things, unsteady aerodynamic transfer functions for the propeller. However, no comprehensive assessment of unsteady propeller aerodynamics for aeroelastic analysis is available in the literature. This paper provides a detailed comparison of nine different low- to mid-fidelity aerodynamic methods, demonstrating their impact on linear, unsteady aerodynamics, as well as whirl flutter stability prediction. Quasi-steady and unsteady methods for blade lift with or without coupling to blade element momentum theory are evaluated and compared to mid-fidelity potential flow solvers (UPM and DUST) and classical, derivative-based methods. Time-domain identification of frequency-domain transfer functions for the unsteady propeller hub loads is used to compare the different methods. Predictions of the minimum required pylon stiffness for stability show good agreement among the mid-fidelity methods. The differences in the stability predictions for the low-fidelity methods are higher. Most methods studied yield a more unstable system than classical, derivative-based whirl flutter analysis, indicating that the use of more sophisticated aerodynamic modeling techniques might be required for accurate whirl flutter prediction.

Plain Language Summary Reproductive coercion and abuse (RCA) is behaviour that interferes with a person’s decision to become pregnant or to continue a pregnancy. We classified RCA into behaviours that attempt to promote pregnancy or to prevent/end a pregnancy. Drawing on data collected from 5107 people seeking counselling support for their pregnancy from two Australian services, this research explored how common the different types of RCA are. The research also looked at whether a person’s age or whether the person identified as being from a migrant or refugee community or as an Aboriginal and/or Torres Strait Islander person made any difference to the type of RCA they experienced. We found that 15.4% of people reported RCA, with similar proportions reporting behaviours attempting to promote pregnancy and prevent/end pregnancy. Around 2% reported experiencing both forms of RCA. We found that there were no differences in frequency of RCA based on age or whether the person identified as being from a migrant or refugee background, although we found that people who identified as Aboriginal and/or Torres Strait Islander were proportionally more likely to experience RCA that was pregnancy promoting. Given how common RCA is, regardless of age and background, we recommend sensitive and culturally respectful enquiry around experiences of RCA be included in any conversations around sexual and reproductive health care and education.