FieldSimR: an R package for simulating plot data in multi-environment field trials.

This paper presents a general framework for simulating plot data in multi-environment field trials with one or more traits. The framework is embedded within the R package FieldSimR, whose core function generates plot errors that capture global field trend, local plot variation, and extraneous variation at a user-defined ratio. FieldSimR's capacity to simulate realistic plot data makes it a flexible and powerful tool for a wide range of improvement processes in plant breeding, such as the optimisation of experimental designs and statistical analyses of multi-environment field trials. FieldSimR provides crucial functionality that is currently missing in other software for simulating plant breeding programmes and is available on CRAN. The paper includes an example simulation of field trials that evaluate 100 maize hybrids for two traits in three environments. To demonstrate FieldSimR's value as an optimisation tool, the simulated data set is then used to compare several popular spatial models for their ability to accurately predict the hybrids' genetic values and reliably estimate the variance parameters of interest. FieldSimR has broader applications to simulating data in other agricultural trials, such as glasshouse experiments.

Predictors of 2-Year Post-Discharge Mortality in Hospitalized Older Patients.

BACKGROUND: Understanding prognostic factors for adverse health outcomes is clinically relevant for improving treatment decision-making processes, potentially leading to enhanced patient prognosis. This secondary analysis of a prospective observational study aimed to identify independent factors associated with 2-year post-discharge mortality in acutely hospitalized older patients. METHODS: All-cause mortality and date of death of 115 patients (83.3 ± 6.3 years, females: n = 75, 65.2%) admitted to acute geriatric wards were determined two years after hospital discharge through telephone interviews. Potential prognostic factors measured at hospital admission included demographic and clinical characteristics, nutritional, cognitive, and psychological status, Fried frailty phenotype, functioning in activities of daily living, locomotor capacity, and 24 h in-hospital mobility and objectively measured physical activity (PA) behaviors. RESULTS: The 2-year mortality rate was 36.7% (n = 41). Univariate and multivariate Cox proportional hazards regression models revealed that mean daily PA level (hazards ratio (HR) = 0.59, 95% confidence interval (CI) 0.90-1.00; p = 0.042), frailty (HR = 3.39, 95% CI 1.20-9.51; p = 0.020), and underweight, in contrast to overweight (HR = 3.10, 95% CI 1.07-9.01; p = 0.038), at hospital admission were independently predictive of post-discharge mortality. CONCLUSION: PA, frailty, and underweight at hospital admission should be considered when evaluating long-term survival prognosis, establishing risk profiles, and developing personalized care pathways in acute hospital care of older adults.

Visualizing the trans-synaptic arrangement of synaptic proteins by expansion microscopy.

High fidelity synaptic neurotransmission in the millisecond range is provided by a defined structural arrangement of synaptic proteins. At the presynapse multi-epitope scaffolding proteins are organized spatially at release sites to guarantee optimal binding of neurotransmitters at receptor clusters. The organization of pre- and postsynaptic proteins in trans-synaptic nanocolumns would thus intuitively support efficient information transfer at the synapse. Visualization of these protein-dense regions as well as the minute size of protein-packed synaptic clefts remains, however, challenging. To enable efficient labeling of these protein complexes, we developed post-gelation immunolabeling expansion microscopy combined with Airyscan super-resolution microscopy. Using ~8-fold expanded samples, Airyscan enables multicolor fluorescence imaging with 20-40 nm spatial resolution. Post-immunolabeling of decrowded (expanded) samples provides increased labeling efficiency and allows the visualization of trans-synaptic nanocolumns. Our approach is ideally suited to investigate the pathological impact on nanocolumn arrangement e.g., in limbic encephalitis with autoantibodies targeting trans-synaptic leucine-rich glioma inactivated 1 protein (LGI1).

The neuropeptide pigment-dispersing factor signals independently of Bruchpilot-labelled active zones in daily remodelled terminals of Drosophila clock neurons.

The small ventrolateral neurons (sLNvs) are key components of the central clock in the Drosophila brain. They signal via the neuropeptide pigment-dispersing factor (PDF) to align the molecular clockwork of different central clock neurons and to modulate downstream circuits. The dorsal terminals of the sLNvs undergo daily morphological changes that affect presynaptic sites organised by the active zone protein Bruchpilot (BRP), a homolog of mammalian ELKS proteins. However, the role of these presynaptic sites for PDF release is ill-defined. Here, we combined expansion microscopy with labelling of active zones by endogenously tagged BRP to examine the spatial correlation between PDF-containing dense-core vesicles and BRP-labelled active zones. We found that the number of BRP-labelled puncta in the sLNv terminals was similar while their density differed between Zeitgeber time (ZT) 2 and 14. The relative distance between BRP- and PDF-labelled puncta was increased in the morning, around the reported time of PDF release. Spontaneous dense-core vesicle release profiles of sLNvs in a publicly available ssTEM dataset (FAFB) consistently lacked spatial correlation to BRP-organised active zones. RNAi-mediated downregulation of brp and other active zone proteins expressed by the sLNvs did not affect PDF-dependent locomotor rhythmicity. In contrast, down-regulation of genes encoding proteins of the canonical vesicle release machinery, the dense-core vesicle-related protein CADPS, as well as PDF impaired locomotor rhythmicity. Taken together, our study suggests that PDF release from the sLNvs is independent of BRP-organised active zones, while BRP may be redistributed to active zones in a time-dependent manner.

The Phenotype of Mesenchymal Stromal Cell and Articular Chondrocyte Cocultures on Highly Porous Bilayer Poly-L-Lactic Acid Scaffolds Produced by Thermally Induced Phase Separation and Supplemented with Hydroxyapatite.

Bilayer scaffolds could provide a suitable topology for osteochondral defect repair mimicking cartilage and subchondral bone architecture. Hence, they could facilitate the chondro- and osteogenic lineage commitment of multipotent mesenchymal stromal cells (MSCs) with hydroxyapatite, the major inorganic component of bone, stimulating osteogenesis. Highly porous poly-L-lactic acid (PLLA) scaffolds with two layers of different pore sizes (100 and 250 µm) and hydroxyapatite (HA) supplementation were established by thermally induced phase separation (TIPS) to study growth and osteogenesis of human (h) MSCs. The topology of the scaffold prepared via TIPS was characterized using scanning electron microscopy (SEM), a microCT scan, pycnometry and gravimetric analysis. HMSCs and porcine articular chondrocytes (pACs) were seeded on the PLLA scaffolds without/with 5% HA for 1 and 7 days, and the cell attachment, survival, morphology, proliferation and gene expression of cartilage- and bone-related markers as well as sulfated glycosaminoglycan (sGAG) synthesis were monitored. All scaffold variants were cytocompatible, and hMSCs survived for the whole culture period. Cross-sections revealed living cells that also colonized inner scaffold areas, producing an extracellular matrix (ECM) containing sGAGs. The gene expression of cartilage and bone markers could be detected. HA represents a cytocompatible supplement in PLLA composite scaffolds intended for osteochondral defects.

Validity, Reliability, Responsiveness, and Feasibility of the Life-Space Assessment Administered via Telephone in Community-Dwelling Older Adults.

BACKGROUND AND OBJECTIVES: The life-space assessment (LSA) is the most commonly used questionnaire to assess life-space mobility (LSM) in older adults, with well-established psychometric properties for face-to-face (FF) administration. However, these properties have not yet been explicitly studied when the LSA is administered by telephone. The aim of this study was to evaluate the concurrent and construct validity, test-retest reliability, responsiveness, and feasibility of a telephone-based LSA version (TE-LSA) in older adults. RESEARCH DESIGN AND METHODS: Fifty community-dwelling older adults (age = 79.3 ± 5.3 years) participated in the study. Concurrent validity was assessed against the FF-LSA construct validity by testing 15 a priori hypotheses on expected associations with LSM determinants, test-retest reliability via 2 telephone surveys 1 week apart, responsiveness after 8.5 ± 1.8 months in participants with improved, stable, and worsened mobility defined by 2 external criteria, and feasibility by the completion rate/time and ceiling/floor effects. RESULTS: Good to excellent agreement between the 2 different administration methods was found (intraclass correlation coefficient [ICC2,1] = 0.73-0.98). Twelve of 15 (80%) hypotheses on construct validity were confirmed. ICCs for test-retest reliability were good to excellent (ICC2,1 = 0.62-0.94). Minimal detectable change for the TE-LSA total score was 20 points. Standardized response means were large for worsened (0.88), moderate for improved (0.68), and trivial for stable participants (0.04). Completion rate was 100% and mean completion time was 5.5 ± 3.3 min. No ceiling or floor effects were observed for the TE-LSA total score. DISCUSSION AND IMPLICATIONS: Telephone administration of the LSA is valid, reliable, responsive, and feasible for assessing LSM in community-dwelling older adults.

Delirium Prevention in Early Rehabilitation During Acute Hospitalization and Implementation of Programs Specifically Tailored to Older Patients with Cognitive Impairment: A Scoping Review with Meta-Analysis.

BACKGROUND: No systematic review on delirium prevention within early, hospital-based rehabilitation on implementation of approaches specifically tailored for patients with cognitive impairment (PwCI), such as Alzheimer's disease or vascular dementia, has been published despite the high relevance of specific medical care in this vulnerable population. OBJECTIVE: To document design and effectiveness of delirium prevention programs by early rehabilitation during acute, hospital-based medical care and implementation of programs specifically tailored to PwCI. METHODS: In a three-step approach, we first identified published systematic reviews of hospital-based, early rehabilitation interventions for older persons (>65 years) in relevant databases. In a second step, we screened each single trial of included reviews according to predefined inclusion criteria. In a third step, we analyzed studies with focus on delirium prevention. RESULTS: Among n = 25 studies identified, almost all intervention programs did not specifically target cognitive impairment (CI). Interventions were heterogeneous (modules: n = 2-19); almost all study samples were mixed/unspecified for cognitive status with more affected patients excluded. Only one study exclusively included delirium patients, and only one included CI patients. Results of random effect meta-analysis showed significant effects of generic programs to reduce delirium incidence during hospitalization by 41% (p < 0.001, odds ratio, 95% confidence interval: 0.59 [0.49, 0.71] with modest heterogeneity (I2: 30%). CONCLUSIONS: Study results document a lack of implementation for delirium prevention programs specifically tailored to PwCI by early, hospital-based rehabilitation. Specifying existing rehab concepts or augmenting them by CI-specific modules may help to develop, optimize, and implement innovative delirium prevention in PwCI in acute medical care.

Mobility outcomes and associated factors of acute geriatric care in hospitalized older patients: results from the PAGER study.

PURPOSE: To examine distinct mobility outcomes (locomotor capacity, physical activity, life-space mobility) of acute geriatric care (AGC) in acutely hospitalized older adults and identify predictors associated with these outcomes. METHODS: The PAGER study was designed as a prospective observational study. Mobility outcomes of 107 hospitalized older patients (age = 83.2 ± 6.4 years, female: n = 68, 63.6%) receiving AGC were measured at hospital admission and discharge. Locomotor capacity was assessed with the Short Physical Performance Battery (SPPB), 24-h physical activity (step count) with an activity monitor, and life-space mobility with the Life-Space Assessment in Institutionalized Settings (LSA-IS). Baseline demographical, clinical, physical, cognitive, and psychological characteristics were analyzed as candidate predictors of mobility outcomes. RESULTS: SPPB (median [interquartile range] 4.0 [2.8-5.0] pt. vs. 5.0 [3.0-6.3] pt.), step count (516 [89-1806] steps vs. 1111 [228-3291] steps), and LSA-IS total score (10.5 [6.0-15.0] pt. vs. 16.3 [12.0-24.1] pt.) significantly improved during AGC (all p < 0.001). Adjusting for baseline status, frailty was identified as an independent negative predictor of SPPB, step count, and LSA-IS at discharge (p = 0.003-0.005). Barthel Index was also independently positively associated with step count (p = 0.017) at discharge, as was the mean daily PA level with SPPB (p = 0.027) at discharge, both independent of baseline status. CONCLUSION: AGC improves distinct mobility outcomes in hospitalized older patients. Frailty was consistently found to be an independent negative predictor of all mobility outcomes. Frailty assessment in AGC may be important to identify patients at risk for decreased treatment gains in mobility. Early PA promotion in AGC seems to be beneficial in improving patients' locomotor capacity.

GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress.

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes nonhomologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard-of-care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in nonmalignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment. SIGNIFICANCE: A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues. This article is featured in Selected Articles from This Issue, p. 5.

[Therapy of physical frailty]. / Therapie der physischen Frailty.

As an overarching geriatric syndrome, frailty describes a potentially reversible transitional stage between functional autonomy and irreversible disability. Thus, frailty addresses a "window of opportunity" in which functional limitations can be successfully treated. This article provides an overview of the therapeutic approaches and their scientific evidence.

Outcomes of left bundle branch area pacing compared to His bundle pacing as a primary pacing strategy: Systematic review and meta-analysis.

BACKGROUND: Novel pacing technologies, such as His bundle pacing (HBP) and left bundle branch area pacing (LBBaP), have emerged to maintain physiological ventricular activation. We investigated the outcomes of LBBP with HBP for patients requiring a de novo permanent pacing. METHODS AND RESULTS: Systematic review of randomized clinical trials and observational studies comparing LBBaP with HBP until March 01, 2023 was performed. Random and fixed effects meta-analyses of the effect of pacing technology on outcomes were performed. Study outcomes included pacing metrics, QRS duration, lead revision, procedure parameters, all-cause mortality and heart failure hospitalization (HFH). Overall, 10 studies with 1596 patients were included. Implant success rate was higher in LBBaP compared with HBP (RR 1.24, 95% CI: 1.08 to 1.42, p = .002). LBBaP was associated with lower capture threshold at implantation (mean difference (MD) -0.62 V, 95% CI: -0.74 to -0.51 V, p < .0001) and at follow-up (MD -0.74 V, 95% CI: -0.96 to -0.53, p < .0001), shorter procedure duration (MD -14.66 min, 95% CI: -23.54 to -5.78, p = .001) and shorter fluoroscopy time (MD -4.2 min, 95% CI: -8.4 to -0.0, p = .05). Compared with HBP, LBBaP was associated with a decreased risk of all-cause mortality (RR: 0.50, 95% CI: 0.33 to 0.77, p = .002) and HFH (RR: 0.57, 95% CI: 0.33 to 1.00, p = .05). No statistical differences were found in lead revisions and QRS duration before and after pacing. CONCLUSION: This meta-analysis found that LBBaP was superior to HBP regarding pacing metrics and implant success rate as an initial pacing strategy, although absence of head-to-head randomized comparison warrants caution in interpretation of the results.

Enhanced synaptic protein visualization by multicolor super-resolution expansion microscopy.

Significance: Understanding the organization of biomolecules into complexes and their dynamics is crucial for comprehending cellular functions and dysfunctions, particularly in neuronal networks connected by synapses. In the last two decades, various powerful super-resolution (SR) microscopy techniques have been developed that produced stunning images of synapses and their molecular organization. However, current SR microscopy methods do not permit multicolor fluorescence imaging with 20 to 30 nm spatial resolution. Aim: We developed a method that enables 4-color fluorescence imaging of synaptic proteins in neurons with 20 to 30 nm lateral resolution. Approach: We used post-expansion immunolabeling of eightfold expanded hippocampal neurons in combination with Airyscan and structured illumination microscopy (SIM). Results: We demonstrate that post-expansion immunolabeling of approximately eightfold expanded hippocampal neurons enables efficient labeling of synaptic proteins in crowded compartments with minimal linkage error and enables in combination with Airyscan and SIM four-color three-dimensional fluorescence imaging with 20 to 30 nm lateral resolution. Using immunolabeling of Synaptobrevin 2 as an efficient marker of the vesicle pool allowed us to identify individual synaptic vesicles colocalized with Rab3-interacting molecule 1 and 2 (RIM1/2), a marker of pre-synaptic fusion sites. Conclusions: Our optimized expansion microscopy approach improves the visualization and location of pre- and post-synaptic proteins and can thus provide invaluable insights into the spatial organization of proteins at synapses.

[Lifestyle-integrated functional exercise for fall prevention : How and why do walking characteristics change?] / Lebensstilintegriertes funktionelles Training zur Sturzprävention : Wie und warum verändert sich das Gehverhalten?

BACKGROUND: The lifestyle-integrated functional exercise (LiFE) program has been shown to increase physical activity. It remains unclear, however, how these changes translate into long vs. short walking episodes. OBJECTIVE: The aim of this work was to investigate changes in short vs. long walking episodes between baseline and 6­month follow-up and to determine which factors are associated with these changes. MATERIAL AND METHODS: This was a two-arm randomized noninferiority study with 309 older adults (mean age 78.7 ± 0.3 years; 73.5% female) at risk of falling who exercised either in a group (gLiFE; n = 153) or individually (LiFE; n = 156). Walking episodes were measured using activPAL 4micro sensors: a distinction was made between walking episodes < 10s, < 20s, and > 60 s. Changes in walking episodes between baseline and 6­month follow-up were analyzed, including calculation of effect sizes (Cohen's d). Determinants of changes in the walking episodes were analyzed using multiple regression. RESULTS: The walking episodes < 10s and < 20 s showed a significant increase in both intervention groups but not for > 60 s. The overall daily walking duration and average steps per day had an influence on changes in the walking episodes between baseline and 6 months. Parameters of objective and subjective function explained a very small but significant amount of the variance. CONCLUSION: The LiFE program seems to work on a behavioral rather than on a functional level. By accumulating short walking episodes, large gains in physical activity can potentially be achieved. This can be of health-promoting benefit especially for persons living in institutional settings or for those who are cautious or even anxious to undertake longer walking episodes (e.g., outdoors).

Feasibility, effectiveness and acceptability of two perturbation-based treadmill training protocols to improve reactive balance in fall-prone older adults (FEATURE): protocol for a pilot randomised controlled trial.

INTRODUCTION: Perturbation-based balance training (PBT) targets the mechanism of falls (eg, slipping, tripping) to specifically train the recovery actions needed to avoid a fall. This task-specific training has shown great promise as an effective and efficient intervention for fall prevention in older adults. However, knowledge about the dose-response relationship of PBT, as well as its feasibility and acceptability in older adults with increased risk of falling is still limited. Thus, the aim of this study is to compare the effectiveness of two different treadmill PBT protocols for improving reactive balance control in fall-prone older adults, and to evaluate the feasibility and acceptability of these protocols. METHODS AND ANALYSIS: The study is designed as a pilot randomised controlled trial with a 6-week intervention and 6-week follow-up period. Thirty-six community-dwelling, fall-prone (Timed Up and Go >12 s, habitual gait speed <1.0 m/s and/or fall history) older adults will be randomised (1:1) to receive six (weeks 1-6) or two treadmill PBT sessions (weeks 1+6) plus four conventional treadmill training sessions (weeks 2-5). Training sessions are conducted 1×/week for 30 min. Each PBT will include 40 perturbations in anterior-posterior and mediolateral directions. Reactive balance after perturbations in standing (Stepping Threshold Test (STT)) and walking (Dynamic Stepping Threshold Test (DSTT)) will be assessed as the primary outcome for effectiveness. Secondary outcomes are spatiotemporal and kinematic parameters collected during STT, DSTT and PBT, maximum perturbation magnitude for each PBT session, static and dynamic balance, physical capacity, physical activity, concerns with falling and executive functions. Feasibility will be assessed via training adherence, drop-out rate, perturbations actually performed and adverse events; and acceptability via self-designed questionnaire and focus groups. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the Medical Faculty Heidelberg (S-602/2022). Findings will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: DRKS00030805.

Does Vitamin K2 Influence the Interplay between Diabetes Mellitus and Intervertebral Disc Degeneration in a Rat Model?

Intervertebral disc (IVD) degeneration is a common cause of low back pain in diabetes mellitus type 2 (T2DM) patients. Its pathogenesis and the vitamin (vit.) K2 influence on this disease remain unclear. Lumbar motion segments of male Zucker Diabetes Fatty (ZDF) rats (non-diabetic [control] and diabetic; fed without or with vit. K2) were used. Femur lengths and vertebral epiphyseal cross-section areas were measured. IVDs were histopathologically examined. Protein synthesis and gene expression of isolated IVD fibrochondrocytes were analyzed. T2DM rats showed histopathological IVD degeneration. Femur lengths and epiphyseal areas were smaller in T2DM rats regardless of vit. K2 feeding. Fibrochondrocytes synthesized interleukin (IL)-24 and IL-10 with no major differences between groups. Alpha smooth muscle actin (αSMA) was strongly expressed, especially in cells of vit. K2-treated animals. Gene expression of aggrecan was low, and that of collagen type 2 was high in IVD cells of diabetic animals, whether treated with vit. K2 or not. Suppressor of cytokine signaling (Socs)3 and heme oxygenase (Hmox)1 gene expression was highest in the cells of diabetic animals treated with vit. K2. Vit. K2 influenced the expression of some stress-associated markers in IVD cells of diabetic rats, but not that of IL-10 and IL-24.

Expansion microscopy in honeybee brains for high-resolution neuroanatomical analyses in social insects.

The diffraction limit of light microscopy poses a problem that is frequently faced in structural analyses of social insect brains. With the introduction of expansion microscopy (ExM), a tool became available to overcome this limitation by isotropic physical expansion of preserved specimens. Our analyses focus on synaptic microcircuits (microglomeruli, MG) in the mushroom body (MB) of social insects, high-order brain centers for sensory integration, learning, and memory. MG undergo significant structural reorganizations with age, sensory experience, and during long-term memory formation. However, the changes in subcellular architecture involved in this plasticity have only partially been accessed yet. Using the western honeybee Apis mellifera as an experimental model, we established ExM for the first time in a social insect species and applied it to investigate plasticity in synaptic microcircuits within MG of the MB calyces. Using combinations of antibody staining and neuronal tracing, we demonstrate that this technique enables quantitative and qualitative analyses of structural neuronal plasticity at high resolution in a social insect brain.

Clonal diploid and autopolyploid breeding strategies to harness heterosis: insights from stochastic simulation.

KEY MESSAGE: Reciprocal recurrent selection sometimes increases genetic gain per unit cost in clonal diploids with heterosis due to dominance, but it typically does not benefit autopolyploids. Breeding can change the dominance as well as additive genetic value of populations, thus utilizing heterosis. A common hybrid breeding strategy is reciprocal recurrent selection (RRS), in which parents of hybrids are typically recycled within pools based on general combining ability. However, the relative performances of RRS and other breeding strategies have not been thoroughly compared. RRS can have relatively increased costs and longer cycle lengths, but these are sometimes outweighed by its ability to harness heterosis due to dominance. Here, we used stochastic simulation to compare genetic gain per unit cost of RRS, terminal crossing, recurrent selection on breeding value, and recurrent selection on cross performance considering different amounts of population heterosis due to dominance, relative cycle lengths, time horizons, estimation methods, selection intensities, and ploidy levels. In diploids with phenotypic selection at high intensity, whether RRS was the optimal breeding strategy depended on the initial population heterosis. However, in diploids with rapid-cycling genomic selection at high intensity, RRS was the optimal breeding strategy after 50 years over almost all amounts of initial population heterosis under the study assumptions. Diploid RRS required more population heterosis to outperform other strategies as its relative cycle length increased and as selection intensity and time horizon decreased. The optimal strategy depended on selection intensity, a proxy for inbreeding rate. Use of diploid fully inbred parents vs. outbred parents with RRS typically did not affect genetic gain. In autopolyploids, RRS typically did not outperform one-pool strategies regardless of the initial population heterosis.

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress.

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

Validity and reliability of the Apple Health app on iPhone for measuring gait parameters in children, adults, and seniors.

This study assessed the concurrent validity and test-retest-reliability of the Apple Health app on iPhone for measuring gait parameters in different age groups. Twenty-seven children, 28 adults and 28 seniors equipped with an iPhone completed a 6-min walk test (6MWT). Gait speed (GS), step length (SL), and double support time (DST) were extracted from the gait recordings of the Health app. Gait parameters were simultaneously collected with an inertial sensors system (APDM Mobility Lab) to assess concurrent validity. Test-retest reliability was assessed via a second iPhone-instrumented 6MWT 1 week later. Agreement of the Health App with the APDM Mobility Lab was good for GS in all age groups and for SL in adults/seniors, but poor to moderate for DST in all age groups and for SL in children. Consistency between repeated measurements was good to excellent for all gait parameters in adults/seniors, and moderate to good for GS and DST but poor for SL in children. The Health app on iPhone is reliable and valid for measuring GS and SL in adults and seniors. Careful interpretation is required when using the Health app in children and when measuring DST in general, as both have shown limited validity and/or reliability.