Draft genome sequence of a Shiga toxin-producing Escherichia coli strain from deer meat showing an IS-element integration in the B-subunit of the Shiga toxin Stx2b gene.

Shiga toxin-producing Escherichia coli (STEC) are important food-borne pathogens. Here we report sequence data of the STEC strain BfR-EC-18960, which has integrated IS elements in the B-subunit of the Shiga toxin Stx2b gene. The strain was isolated from deer meat at a local butchery in Germany in 2021.

Development of the VEGANScreener, a Tool for a Quick Diet Quality Assessment among Vegans in Europe.

BACKGROUND: Plant-based diets are not inherently healthy. Similar to omnivorous diets, they may contain excessive amounts of sugar, sodium, and saturated fats, or lack diversity. Moreover, vegans might be at risk of inadequate intake of certain vitamins and minerals commonly found in foods that they avoid. We developed the VEGANScreener, a tool designed to assess the diet quality of vegans in Europe. METHODS: Our approach combined best practices in developing diet quality metrics with scale development approaches and involved the following: (a) narrative literature synthesis, (b) evidence evaluation by an international panel of experts, and (c) translation of evidence into a diet screener. We employed a modified Delphi technique to gather opinions from an international expert panel. RESULTS: Twenty-five experts in the fields of nutrition, epidemiology, preventive medicine, and diet assessment participated in the first round, and nineteen participated in the subsequent round. Initially, these experts provided feedback on a pool of 38 proposed items from the literature review. Consequently, 35 revised items, with 17 having multiple versions, were suggested for further consideration. In the second round, 29 items were retained, and any residual issues were addressed in the final consensus meeting. The ultimate screener draft encompassed 29 questions, with 17 focusing on foods and nutrients to promote, and 12 addressing foods and nutrients to limit. The screener contained 24 food-based and 5 nutrient-based questions. CONCLUSIONS: We elucidated the development process of the VEGANScreener, a novel diet quality screener for vegans. Future endeavors involve contrasting the VEGANScreener against benchmark diet assessment methodologies and nutritional biomarkers and testing its acceptance. Once validated, this instrument holds potential for deployment as a self-assessment application for vegans and as a preliminary dietary screening and counseling tool in healthcare settings.

Fostering healthy aging through selective nutrition: A long-term comparison of two dietary patterns and their holistic impact on mineral status in middle-aged individuals-A randomized controlled intervention trial in Germany.

Aging is associated with a decline in physiological functions and an increased risk of age-related diseases, emphasizing the importance of identifying dietary strategies for healthy aging. Minerals play a crucial role in maintaining optimal health during aging, making them relevant targets for investigation. Therefore, we aimed to analyze the effect of different dietary pattern on mineral status in the elderly. We included 502 individuals aged 50-80 years in a 36-month randomized controlled trial (RCT) (NutriAct study). This article focuses on the results within the two-year intervention period. NutriAct is not a mineral-modulating-targeted intervention study, rather examining nutrition in the context of healthy aging in general. However, mineral status might be affected in an incidental manner. Participants were assigned to either NutriAct dietary pattern (proportionate intake of total energy consumption (%E) of 35-45 %E carbohydrates, 35-40 %E fats, and 15-25 %E protein) or the German Nutrition Society (DGE) dietary pattern (proportionate intake of total energy consumption (%E) of 55 %E carbohydrates, 30 %E fats, and 15 %E protein), differing in the composition of macronutrients. Data from 368 participants regarding dietary intake (energy, calcium, magnesium, iron, and zinc) and serum mineral concentrations of calcium, magnesium, iron, copper, zinc, selenium, iodine, and manganese, free zinc, and selenoprotein P were analyzed at baseline, as well as after 12 and 24 months to gain comprehensive insight into the characteristics of the mineral status. Additionally, inflammatory status - sensitive to changes in mineral status - was assessed by measurement of C-reactive protein and interleukin-6. At baseline, inadequate dietary mineral intake and low serum concentrations of zinc and selenium were observed in both dietary patterns. Throughout two years, serum zinc concentrations decreased, while an increase of serum selenium, manganese and magnesium concentrations was observable, likely influenced by both dietary interventions. No significant changes were observed for serum calcium, iron, copper, or iodine concentrations. In conclusion, long-term dietary interventions can influence serum mineral concentrations in a middle-aged population. Our findings provide valuable insights into the associations between dietary habits, mineral status, and disease, contributing to dietary strategies for healthy aging.

Effects of plant diversity on productivity strengthen over time due to trait-dependent shifts in species overyielding.

Plant diversity effects on community productivity often increase over time. Whether the strengthening of diversity effects is caused by temporal shifts in species-level overyielding (i.e., higher species-level productivity in diverse communities compared with monocultures) remains unclear. Here, using data from 65 grassland and forest biodiversity experiments, we show that the temporal strength of diversity effects at the community scale is underpinned by temporal changes in the species that yield. These temporal trends of species-level overyielding are shaped by plant ecological strategies, which can be quantitatively delimited by functional traits. In grasslands, the temporal strengthening of biodiversity effects on community productivity was associated with increasing biomass overyielding of resource-conservative species increasing over time, and with overyielding of species characterized by fast resource acquisition either decreasing or increasing. In forests, temporal trends in species overyielding differ when considering above- versus belowground resource acquisition strategies. Overyielding in stem growth decreased for species with high light capture capacity but increased for those with high soil resource acquisition capacity. Our results imply that a diversity of species with different, and potentially complementary, ecological strategies is beneficial for maintaining community productivity over time in both grassland and forest ecosystems.

Management of biliary obstruction in patients with newly diagnosed alveolar echinococcosis: a Swiss retrospective cohort study.

BACKGROUND AND STUDY AIMS: Alveolar echinococcosis, an orphan zoonosis affecting the liver, is of increasing concern worldwide. Most symptomatic cases present at an advanced and inoperable stage, sometimes with biliary obstruction prompting biliary tract interventions. These are, however, associated with a high risk of infectious complications. The aim of this retrospective study was to compare the effectiveness and safety of conservative and interventional treatment approaches in patients with newly diagnosed alveolar echinococcosis and biliary obstruction. PATIENTS AND METHODS: Alveolar echinococcosis patients treated at two referral centres in Switzerland, presenting with hyperbilirubinaemia (total bilirubin >1.5 Upper Limit of Normal) at diagnosis were included, unless another underlying aetiology, i.e. common bile duct stones or decompensated cirrhosis, was identified. Patients were divided into two groups, according to whether they initially received a biliary tract intervention. The primary endpoint was normalisation of bilirubin levels within a 6-month period. Secondary endpoints included, among others, the occurrence of early and late biliary complications, the need for biliary tract interventions during follow-up and overall duration of hospital stays for treatment initiation and for biliary complications. RESULTS: 28 patients were included in this study, of whom 17 received benzimidazole therapy alone and 11 additionally received a biliary tract intervention. Baseline characteristics did not differ between groups. All but one patient in each group achieved the primary endpoint (p=0.747). Biliary tract intervention was associated with faster laboratory improvement (t1/2 1.3 vs 3.0 weeks), but also with more frequent early biliary complications (7/11 vs 1/17, p=0.002) and longer initial hospital stay (18 days vs 7 days, p=0.007). CONCLUSION: Biliary obstruction in patients with newly diagnosed alveolar echinococcosis can be treated effectively with benzimidazole therapy alone. Biliary tract intervention, on the other hand, is associated with a high complication rate and should probably be reserved for patients with insufficient response to benzimidazole therapy.

Sex-specific differences in pain localization in female patients with endometriosis: A comparison of sexless and female human body outlines.

BACKGROUND: This study explores sex-specific differences in pain localization using pain drawings in female patients with endometriosis. Traditional human body outlines (HBOs) used for pain drawings are often viewed as male, making accurate pain assessment difficult. The study aims to compare pain localization and extent between patients presented with sexless and female HBOs. METHODS: A total of 49 female patients with endometriosis completed questionnaires and pain drawings (n = 24 and n = 26 with individually designed sexless and female HBOs, respectively). The Ruzika similarity index was used to investigate potential differences in pain drawings between sexless and female HBOs. Hypothesis testing was applied to compare the number of pixels marked in the pain extents and to investigate the suitability of the presented body outline. RESULTS: Sex of HBOs used in pain drawings had no effect on pain area, and no statistically significant differences were found in pain localization or area between female and sexless outlines. Most, but not all participants found the body outlines suitable. CONCLUSIONS: The findings suggest that differences in the resulting areas marked in the pain drawings were negligible and the preferences for sexless pain drawings were not significant, so that a sexless body outline for pain drawings could be a good choice, especially when a study does not focus on one specific sex.

Discovery of Cycloalkyl[c]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors.

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[c]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy-aryl scaffold. X-ray data confirmed the ability of these inhibitors to induce perturbation of key amino acids by appropriately presenting key pharmacophoric elements in the hydrophobic cavity. Selected compounds showed inhibition of VEGF-A secretion in cancer cells and prevention of Arg1 expression and activity in IL4-stimulated macrophages. Moreover, in vivo target gene modulation was demonstrated with compound 35r. Thus, the disclosed HIF-2α inhibitors represent valuable tools for investigating selective HIF-2α inhibition and its effect on tumor biology.

How do distinct facets of tree diversity and community assembly respond to environmental variables in the subtropical Atlantic Forest?

This study assessed the impact of altitude, precipitation, and soil conditions on species richness (SR), phylogenetic diversity (PD), and functional diversity (FD) standardized effect sizes in subtropical Brazilian Atlantic Forest tree communities. We considered specific trait information (FDs) for FD, reflecting recent adaptive evolution, contrasting with deeper phylogenetic constraints in FD. Three functional traits (leaf area-LA, wood density-WD, and seed mass-SM) were examined for their response to these gradients. Generalized least squares models with environmental variables as predictors and diversity metrics as response variables were used, and a fourth-corner correlation test explored trait-environmental relationships. SR decreased with altitude, while PD increased, indicating niche convergence at higher altitudes. Leaf area and seed mass diversity also decreased with altitude. For LA, both FD and FDs were significant, reflecting filtering processes influenced by phylogenetic inheritance and recent trait evolution. For SM, only the specific trait structure responded to altitude. LA and SM showed significant trait-environmental relationships, with smaller-leaved and lighter-seeded species dominant at higher altitudes. Soil gradients affect diversity. Fertile soils have a wider range of LA, indicating coexistence of species with different nutrient acquisition strategies. WD variation is lower for FDs. SM diversity has different relationships with soil fertility for FDs and FD, suggesting phylogeny influences trait variation. Soil pH influences WD and LA under acidic soils, with deeper phylogenetic constraints (FD). Environmental factors impact tree communities, with evidence of trait variation constraints driven by conditions and resources. Subtropical Atlantic forests' tree assemblies are mainly influenced by altitude, pH, and soil fertility, selecting fewer species and narrower trait spectra under specific conditions (e.g., higher altitudes, pH). Functional diversity patterns reflect both phylogenetic and recent evolution constraints, with varying strength across traits and conditions. These findings highlight the intricate processes shaping long-lived species assembly across diverse environments in the Southern Brazilian Atlantic Forest.

Variability in Macro- and Micronutrients of 15 Rarely Researched Microalgae.

Microalgae have enormous potential for human nutrition, yet the European Commission has authorized the consumption of only eleven species. Strains of fifteen rarely researched microalgae from two kingdoms were screened regarding their nutritional profile and value for human health in two cultivation phases. Contents of protein, fiber, lipids, fatty acids, minerals, trace elements and heavy metals were determined. In the growth phase, microalgae accumulated more arginine, histidine, ornithine, pure and crude protein, Mg, Mn, Fe and Zn and less Ni, Mo and I2 compared to the stationary phase. Higher contents of total fat, C14:0, C14:1n5, C16:1n7, C20:4n6, C20:5n3 and also As were observed in microalgae from the chromista kingdom in comparison to microalgae from the plantae kingdom (p < 0.05). Conversely, the latter had higher contents of C20:0, C20:1n9 and C18:3n3 as well as Ca and Pb (p < 0.05). More precisely, Chrysotila carterae appeared to have great potential for human nutrition because of its high nutrient contents such as fibers, carotenoids, C20:6n3, Mg, Ca, Mn, Fe, Se, Zn, Ni, Mo and I2. In summary, microalgae may contribute to a large variety of nutrients, yet the contents differ between kingdoms, cultivation phases and also species.

Oscillometric pulse wave analysis for detecting low flow arteriovenous fistula.

BACKGROUND: Pulse wave analysis may be useful to assess fistula function. We aimed to prospectively evaluate if convenient oscillometric devices are applicable to detect flow below 500 ml/min in a real life clinical setting. METHODS: Pulse waves were recorded ambilaterally with the vicorder® device at the brachial artery in 53 patients on haemodialysis with native fistula. Primary variables consisted of the mean slope between the systolic maximum and the diacrotic notch (Slope2), the sum of the mean slopes in the four characteristic sections of pulse waves (Slope∑) and the amplitude of relative volumetric change in the measuring cuff at the upper arm (AMP). Fistula flow was measured with the use of duplex sonography using a standardized approach. RESULTS: Parameter values above or below the median indicated measurement at the non-fistula side, with sensitivities/specificities of 0.79/0.79 (p < 0.001) for Slope 2, 0.64/0.64 (p = 0.003) for Slope∑ and 0.81/0.81 (p < 0.001) for AMP if measurements at the fistula and non-fistula arm were considered. ROC-analyses of parameter values measured at the fistula to detect low flow demonstrated AUCs (with CI) of 0.652 (0.437-0.866, p = 0.167) for Slope2, 0.732 (0.566-0.899, p = 0.006) for Slope∑ and 0.775 (0.56-0.991, p = 0.012) for AMP. The point with maximal youden's index was regarded as optimal cut-off, which corresponded to sensitivities and specificities of 0.8/0.56 for slope2, 0.86/ 0.56 for Slope∑ and 0.93/0.78 for AMP. CONCLUSION: Functional surveillance with oscillometry is a promising clinical application to detect a low fistula flow. Among all investigated pulse wave parameters AMP revealed the highest diagnostic accuracy.

[A rare cause of chronic pelvic pain]. / Een bijzondere oorzaak van chronische buikpijn.

BACKGROUND: Chronic pelvic pain, a continuous or intermittent, non-menstrual and non-cyclic pelvic pain, lasting for at least six months and of sufficient severity to interfere with daily activities, remains a medical challenge. Thorough evaluation is advised as unrecognized abnormalities can be present. CASE DESCRIPTION: A 22-years-old nulligravid with a inguinal herniorrhaphy during infancy was referred with chronic pelvic pain. The left ovary and tube were trapped in the inguinal canal. Laparoscopy confirmed the left ovary and tube adherent to the anterior abdominal wall. Dissection with adhesiolysis freed the dislocated left tube and ovary. A laparoscopic transabdominal pre-peritoneal (TAPP) procedure was performed to prevent hernia recurrence. The patient is since then pain free. CONCLUSION: Chronic pelvic pain can be a sing of an adnexal dislocation, which is a rare complication following inguinal hernia repair. Medical history is of great importance to reveal this unexpected condition.

Performance of two-dimensional shear wave elastography and transient elastography compared to liver biopsy for staging of liver fibrosis.

BACKGROUND: Staging of liver fibrosis traditionally relied on liver histology; however, transient elastography (TE) and more recently two-dimensional shear wave elastography (2D-SWE) evolved to noninvasive alternatives. Hence, we evaluated the diagnostic accuracy of 2D-SWE assessed by the Canon Aplio i800 ultrasound system using liver biopsy as reference and compared the performance to TE. METHODS: In total, 108 adult patients with chronic liver disease undergoing liver biopsy, 2D-SWE and TE were enrolled prospectively at the University Hospital Zurich. Diagnostic accuracies were evaluated using the area under the receiver operating characteristic (AUROC) analysis, and optimal cut-off values by Youden's index. RESULTS: Diagnostic accuracy of 2D-SWE was good for significant (≥F2; AUROC 85.2%, 95% confidence interval (95%CI):76.2-91.2%) as well as severe fibrosis (≥F3; AUROC 86.8%, 95%CI: 78.1-92.4%) and excellent for cirrhosis (AUROC 95.6%, 95%CI: 89.9-98.1%), compared to histology. TE performed equally well (significant fibrosis: 87.5%, 95%CI: 77.7-93.3%; severe fibrosis: 89.7%, 95%CI: 82.0-94.3%; cirrhosis: 96%, 95%CI: 90.4-98.4%), and accuracy was not statistically different to 2D-SWE. 2D-SWE optimal cut-off values were 6.5, 9.8 and 13.1 kPa for significant fibrosis, severe fibrosis and cirrhosis, respectively. CONCLUSIONS: Performance of 2D-SWE was good to excellent and well comparable with TE, supporting the application of this 2D-SWE system in the diagnostic workup of chronic liver disease.

The supply of multiple ecosystem services requires biodiversity across spatial scales.

The impact of local biodiversity loss on ecosystem functioning is well established, but the role of larger-scale biodiversity dynamics in the delivery of ecosystem services remains poorly understood. Here we address this gap using a comprehensive dataset describing the supply of 16 cultural, regulating and provisioning ecosystem services in 150 European agricultural grassland plots, and detailed multi-scale data on land use and plant diversity. After controlling for land-use and abiotic factors, we show that both plot-level and surrounding plant diversity play an important role in the supply of cultural and aboveground regulating ecosystem services. In contrast, provisioning and belowground regulating ecosystem services are more strongly driven by field-level management and abiotic factors. Structural equation models revealed that surrounding plant diversity promotes ecosystem services both directly, probably by fostering the spill-over of ecosystem service providers from surrounding areas, and indirectly, by maintaining plot-level diversity. By influencing the ecosystem services that local stakeholders prioritized, biodiversity at different scales was also shown to positively influence a wide range of stakeholder groups. These results provide a comprehensive picture of which ecosystem services rely most strongly on biodiversity, and the respective scales of biodiversity that drive these services. This key information is required for the upscaling of biodiversity-ecosystem service relationships, and the informed management of biodiversity within agricultural landscapes.

Biotic homogenization and differentiation of plant communities in tropical and subtropical forests.

Anthropogenic impacts on biodiversity can lead to biotic homogenization (BH) and biotic differentiation (BD). BH is a process of increasing similarity in community composition (including taxonomic, functional, and phylogenetic components), whereas BD is a process of decreasing similarity over space and time. Here, we conducted a systematic review of BH and BD in plant communities in tropical and subtropical forests to identify trends and knowledge gaps. Our bibliometric search in the Web of Science returned 1989 papers, of which 151 matched our criteria and were included in the analysis. The Neotropical region had the largest number of articles, and Brazil was the most represented country with 92 studies. Regarding the type of change, homogenization was more frequent than differentiation (noted in 69.6% of publications). The taxonomic diversity component was measured more often than functional and phylogenetic diversity components. Most studies (75.6%) assessed homogenization and differentiation based on a single observation in time; as opposed to few studies that monitored plant community over multiple years. Forest fragmentation was cited as the main determinant of homogenization and differentiation processes (57.2% of articles). Our results highlight the importance of evaluating community composition over time and more than taxonomic components (i.e., functional and phylogenetic) to advance understanding of homogenization and differentiation. Both processes were scale dependent and not mutually exclusive. As such, future research should consider differentiation as a potential transition phase to homogenization and that potential differences in both processes may depend on the spatial and temporal scale adopted. Understanding the complexity and causes of homogenization and differentiation is essential for biodiversity conservation in a world increasingly affected by anthropogenic disturbances.

Los impactos antropogénicos sobre la biodiversidad pueden resultar en la homogenización y diferenciación biótica. La homogenización biótica consiste en una creciente similitud de la composición comunitaria (incluidos los componentes taxonómicos, funcionales y filogenéticos), mientras que la diferenciación biótica conlleva la disminución en similitudes a lo largo del tiempo y el espacio. En este trabajo realizamos una revisión sistemática de la homogenización y diferenciación biótica en las comunidades vegetales en los bosques tropicales y subtropicales para identificar tendencias y vacíos de conocimiento. Nuestra búsqueda bibliométrica en Web of Science produjo 1989 artículos, de los cuales 151 cumplieron con nuestros criterios y fueron incluidos en el análisis. La región neotropical tuvo el mayor número de artículos y Brasil fue el país más representado con 92 estudios. Con respecto al tipo de cambio, la homogenización fue más frecuente que la diferenciación (reportada en 69.6% de las publicaciones). El componente de diversidad taxonómica se midió más veces que los componentes de diversidad funcional y filogenética. La mayoría de los estudios (75.6%) examinó la homogenización y la diferenciación con base en una sola observación en el tiempo; unos cuantos estudios sí monitorearon las comunidades vegetales a través de varios años. Se citó a la fragmentación del bosque como el principal determinante de los procesos de homogenización y diferenciación (57.2% de los artículos). Nuestros resultados resaltan la importancia de la evaluación de la composición de la comunidad a través del tiempo y más allá de los componentes taxonómicos para propiciar el entendimiento de la homogenización y la diferenciación. Ambos procesos dependieron de la escala y no se excluyeron mutuamente. Por lo tanto, las siguientes investigaciones deberían considerar a la diferenciación como una fase potencial de transición hacia la homogenización y que las posibles diferencias en ambos procesos podrían depender de la escala espacial y temporal aplicada. Son esenciales el entendimiento de la complejidad y las causas de la homogenización y la diferenciación para la conservación de la biodiversidad en un planeta que cada vez se ve más afectado por las perturbaciones antropogénicas.

Brain-enriched RagB isoforms regulate the dynamics of mTORC1 activity through GATOR1 inhibition.

Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to appropriately regulate cellular anabolism and catabolism. During nutrient restriction, different organs in an animal do not respond equally, with vital organs being relatively spared. This raises the possibility that mTORC1 is differentially regulated in different cell types, yet little is known about this mechanistically. The Rag GTPases, RagA or RagB bound to RagC or RagD, tether mTORC1 in a nutrient-dependent manner to lysosomes where mTORC1 becomes activated. Although the RagA and B paralogues were assumed to be functionally equivalent, we find here that the RagB isoforms, which are highly expressed in neurons, impart mTORC1 with resistance to nutrient starvation by inhibiting the RagA/B GTPase-activating protein GATOR1. We further show that high expression of RagB isoforms is observed in some tumours, revealing an alternative strategy by which cancer cells can retain elevated mTORC1 upon low nutrient availability.

Errorless learning and assistive technology did not improve the negative prognosis for severe dressing impairment after stroke if persisting for two weeks: A randomized controlled trial.

Following severe cerebrovascular accidents, patients are often unable to dress themselves. Little is known about the persistence and treatment of this impairment. Study 1 followed 23 patients who were (1) completely dependent on others for help with dressing (2) for two weeks continually until their discharge from the rehabilitation unit. Study 2, a randomized controlled trial of 24 patients, examined the effects of errorless learning and RehaGoal App-based dressing practice on recovery in dressing ability-impaired patients who also experienced visuospatial neglect and/or apraxia. The control and intervention groups both underwent a standard therapy in the rehab unit; the intervention group additionally received dressing training (seven sessions of 45 min). The primary outcome measure was the score on an adapted version of the Nottingham Stroke Dressing Assessment; secondary outcome measures were the Barthel Index and Functional Independence Measure. Less than one-third of the patients in Study1, showed improvement. In Study 2, the intervention produced no specific effect on patients' dressing ability. However, apraxia and neglect predicted improvement for both groups. If patients depend completely on assistance for dressing for two weeks, prospects for recovery are limited. Future studies should include additional intervention sessions and incorporate treatments for neglect or apraxia.

Guiding patients with traumatic brain injury through the instrumental activities of daily living with the RehaGoal App: a feasibility study.

PURPOSE: Individuals with traumatic brain injuries (TBI) often experience executive function impairments that impact activities of daily living. Assistive technologies can help overcome these disabilities and Goal Management Training (GMT) provides an effective therapeutic approach for treating such impairments. To capture the benefits of GMT with assistive technology we developed the RehaGoal App. In this study, we investigate whether combining a modified GMT (mGMT) with the RehaGoal App is feasible in terms of study design, and preliminary evaluation of the attainment of self-defined goals. We also examine if the app produces useful metrics data, tests its usability, and gauges its potential for improving goal attainment. METHODS: We used a case study design to evaluate four individuals with impairments in executive functions after TBI. They underwent an 8-week mGMT and RehaGoal App intervention to achieve a self-defined goal. To investigate the intervention's feasibility, we collected Goal Attainment Scale (GAS) scores at two-time points, neuropsychological data at study start, System Usability Scale (SUS) scores at study end, and metrics data throughout the study period. RESULTS: Participant retention and compliance rates were high. All participants improved on GAS. Metrics data was collected successfully and revealed different participant usage behaviours. Overall, the SUS scores of the participants indicated excellent app usability. CONCLUSIONS: The intervention was feasible but the study design should be modified. Preliminary evaluation of GAS, SUS, and metrics data provided useful insights on user behaviour, app usability, and its role in achieving self-defined goals. The app received overall positive participant ratings.IMPLICATION FOR REHABILITATIONMetric data can be useful as it can give therapists additional opportunities to gain more information about the realization of intervention tasks between the therapy sessions allowing them to use this information to adjust therapy elements.RehaGoal App in combination with a modified GMT may be able to support participants with impairment in executive functions in completing the task of daily living.The study shows that the RehaGoal App is feasible in rehabilitation for a small sample size and that it may be scaled up in the future larger randomized controlled trial.

Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR to promote mitotic protein translation and faithful cell division.

DENR and MCTS1 have been identified as oncogenes in several different tumor entities. The heterodimeric DENR·MCTS1 protein complex promotes translation of mRNAs containing upstream Open Reading Frames (uORFs). We show here that DENR is phosphorylated on Serine 73 by Cyclin B/CDK1 and Cyclin A/CDK2 at the onset of mitosis, and then dephosphorylated as cells exit mitosis. Phosphorylation of Ser73 promotes mitotic stability of DENR protein and prevents its cleavage at Asp26. This leads to enhanced translation of mRNAs involved in mitosis. Indeed, we find that roughly 40% of all mRNAs with elevated translation in mitosis are DENR targets. In the absence of DENR or of Ser73 phosphorylation, cells display elevated levels of aberrant mitoses and cell death. This provides a mechanism how the cell cycle regulates translation of a subset of mitotically relevant mRNAs during mitosis.

Time-resolved FRET screening identifies small molecular modifiers of mutant Huntingtin conformational inflexibility in patient-derived cells.

Huntington's disease (HD) is the most common monogenic neurodegenerative disease and is fatal. CAG repeat expansions in mutant Huntingtin (mHTT) exon 1 encode for polyglutamine (polyQ) stretches and influence age of onset and disease severity, depending on their length. mHTT is more structured compared to wild-type (wt) HTT, resulting in a decreased N-terminal conformational flexibility. mHTT inflexibility may contribute to both gain of function toxicity, due to increased mHTT aggregation propensity, but also to loss of function phenotypes, due to decreased interactions with binding partners. High-throughput-screening techniques to identify mHTT flexibility states and potential flexibility modifying small molecules are currently lacking. Here, we propose a novel approach for identifying small molecules that restore mHTT's conformational flexibility in human patient fibroblasts. We have applied a well-established antibody-based time-resolved Förster resonance energy transfer (TR-FRET) immunoassay, which measures endogenous HTT flexibility using two validated HTT-specific antibodies, to a high-throughput screening platform. By performing a small-scale compound screen, we identified several small molecules that can partially rescue mHTT inflexibility, presumably by altering HTT post-translational modifications. Thus, we demonstrated that the HTT TR-FRET immunoassay can be miniaturized and applied to a compound screening workflow in patient cells. This automated assay can now be used in large screening campaigns to identify previously unknown HD drugs and drug targets.