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Abstract Background Physical activity (PA) plays a vital role in maintaining the functional ability that enables well-being in older age (healthy aging), potentially also saving costs for the healthcare system and society. The aim of this study was to examine the association between PA and healthcare and societal costs in a sample of very mild to moderately frail older adults. Methods This cross-sectional study is a secondary analysis using baseline data from the PromeTheus randomized-controlled trial, which included 385 very mild to moderately frail community-dwelling older adults (70 + years) from Germany. Participants self-reported their health-related resource use in the previous 6 months (FIMA questionnaire), which was monetarily valued using standardized unit costs. PA was also self-reported using the German Physical Activity Questionnaire for middle-aged and older adults (German-PAQ-50+) and categorized as ‘insufficient’/’sufficient’ or ‘insufficient’/‘moderate’/‘high’ in accordance with the World Health Organization guidelines for PA. Mean and median healthcare costs (including outpatient, inpatient, rehabilitation, formal care, and medication costs) and societal costs (healthcare costs plus informal care costs) for different PA groups were estimated using generalized linear models and quantile regression, with sociodemographic variables and physical capacity (Short Physical Performance Battery) as covariates. Results Of the sample, 24% were classified as insufficiently, 23% as moderately, and 54% as highly active. Sufficient PA, especially high PA, was associated with lower costs in the 6 months prior to data collection compared to insufficient PA (-€6,237, 95% CI [-10,656; -1,817] and -€8,333, 95% CI [-12,183; -4,483], respectively). The cost difference between PA intensity groups was largely driven by differences in informal care costs and decreased substantially when physical capacity was accounted for in the analyses; e.g., the mean difference in societal costs between sufficient and insufficient PA decreased from -€7,615 (95% CI [-11,404; -3,825]) to -€4,532 (95% CI [-7,930; -1,133]). Conclusion Promoting PA throughout the lifespan as a means of promoting healthy aging and reducing dependency in old age could potentially provide economic benefits and help to mitigate the economic consequences of an aging population with increasing health and long-term care needs. Future longitudinal studies should attempt to disentangle the mediating and confounding role of physical capacity and health status in the association between PA and costs.

Abstract Background Duchenne muscular dystrophy (DMD) is a rare disease that causes progressive muscle degeneration resulting in life-threatening cardiac complications. The objective of this systematic literature review was to describe and grade the published evidence of predictors of cardiac disease in DMD. Methods The review encompassed searches of Embase, MEDLINE ALL, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of cardiac disease in DMD. The certainty of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Results We included 33 publications encompassing 9,232 patients with DMD. We found moderate- to high-quality evidence that cardiac medication (i.e., ACE inhibitors [enalapril and perindopril], β-blockers [carvedilol], and mineralocorticoid receptor antagonists [eplerenone]) are significantly associated with preserved left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular circumferential strain (LVCS). DMD mutations in exons 51 and 52 were found to be significantly associated with lower risk of cardiomyopathy; deletions treatable by exon 53 skipping and mutations in the Dp116 coding region with improved LVEF and prolonged cardiac dysfunction-free survival; and exons 45–50 and 52 with early left ventricular systolic dysfunction (low/very low-quality evidence). We found high-quality evidence that glucocorticoids (deflazacort) are significantly associated with preserved LVEF and improved fractional shortening (FS), and low-quality evidence that glucocorticoids (deflazacort, prednisone, and/or prednisolone) are associated with improved ejection fraction (EF) and lower risk of cardiomyopathy, ventricular dysfunction, and heart failure-related mortality. Full-time mechanical ventilation was found to be significantly correlated with LVEF (low-quality evidence), muscle strength with FS (low-quality evidence), and genetic modifiers (i.e., LTBP4 rs10880 and ACTN3) with LVEF, lower risk of cardiomyopathy and left ventricular dilation (low-quality evidence). Conclusion Several sources of cardiac disease heterogeneity are well-studied in patients with DMD. Yet, the certainty of evidence is generally low, and little is known of the contribution of non-pharmacological interventions, as well as the impact of different criteria for initiation of specific treatments. Our findings help raise awareness of prevailing unmet needs, shape expectations of treatment outcomes, and inform the design of future research.

Background: Type 2 diabetes mellitus (T2DM) is marked by insulin resistance, low grade chronic inflammation, and endothelial dysfunction. Vitamin K2, especially menaquinone-7 (MK-7), might delay T2DM progression and alleviate its consequences. Hence, this study evaluated the effects of MK-7 on serum and urine markers of diabetes in an animal model of T2DM. Methods: Hetero- (fa/+, control) and homozygous (fa/fa, diabetic) male Zucker diabetic fatty (ZDF) rats were supplemented or not with MK-7 for 12 weeks. After euthanasia, vitamin K1, menaquinone-4 and MK-7 serum concentrations were analyzed via reversed phase high pressure liquid chromatography. Glucose (serum), fructosamine (serum) and creatinine (serum and urine) levels were assessed photometrically, serum cystatin C and urinary total protein were turbidimetrically determined. Serum transforming growth factor beta 1 (TGF-β1) and procollagen type III N-terminal peptide (PIIINP) were quantified with enzyme-linked immunosorbent assay. Urinary marker proteins were analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Nephropathy was assessed histologically. Results: Supplementation led to significantly elevated MK-7 serum levels and a significant reduction of PIIINP serum levels in both hetero- and homozygous ZDF rats. Additionally, not statistically significant reductions of TGF-β1 serum levels, proteinuria as well as the nephropathy score were observed. In vivo body mass, serum fructosamine, glucose, cystatin C and creatinine levels were unaffected. Conclusion: MK-7 reduced serum markers of fibrosis, histological features of nephropathy and urinary protein excretion, but failed to affect serum markers of T2DM. The therapeutic potential of MK-7 in T2DM and its mode of action should be further investigated in more detail.

Providing adequate infrastructure for cycling is crucial for increasing its modal share and for supporting the shift towards sustainable mobility. To foster well-targeted, efficient, and effective improvements of infrastructure in favor of cycling, we need data and methods for assessing its current state in an automated, scalable, and reproducible way. Present models are limited due to dependency on proprietary and/or scarce data, being closed-source and not taking into account the many nuances of bikeability on segment scale. Therefore, we propose an open, adjustable, and extendible model of bikeability that relies on open and globally available data sets. It allows to consider aspects of safety, comfort, and the immediate environment. Results from an evaluation study show its applicability while underlining the importance of considering diversity in regional, individual, and purpose-related mobility demands. Future bikeability research may be informed by results of the online survey conducted as part of the evaluation study. The proposed bikeability model can form the foundation for advanced network and accessibility analysis and serves as an important information layer for decision making.

IntroductionThe ability to respond effectively to external perturbations is crucial for avoiding falls. The Stepping Threshold Test (STT) has been developed to assess this reactive balance, but its ability to discriminate between fallers and non-fallers is still unsubstantiated. This study aimed to evaluate the discriminant validity of the STT in distinguishing fallers and non-fallers and its convergent validity.MethodsThirty-six older adults (age = 80 ± 5 years), with 13 (36%) of them reporting a fall history in the past year, completed the STT on a perturbation treadmill. They received surface perturbations of progressively increasing magnitude while standing. Single- and multiple-step thresholds were assessed using an all-step count evaluation (STT-ACE), and a direction-sensitive evaluation strategy (STT-DSE). Receiver operating characteristics and area under the curves (AUC) were analyzed to evaluate the discriminative accuracy. Convergent validity was explored by 13 hypothesized associations with other mobility, psychological, and cognitive assessments.ResultsFallers and non-fallers significantly differed in the STT-DSE (p = 0.033), but not in the STT-ACE or other commonly used mobility assessments. Acceptable discriminative accuracy was obtained for the STT-DSE (AUC = 0.72), but not for the STT-ACE and other mobility assessments (AUC = 0.53–0.68). Twelve (92%) associations were consistent with our hypotheses for the STT-DSE, and ten (77%) for the STT-ACE.ConclusionOur findings provide preliminary evidence that the STT, when using the STT-DSE, may discriminate between older adult fallers and non-fallers. The STT appears to be a valid tool for assessing reactive balance, with its STT-DSE being recommended due to its better discriminant and convergent validity compared to the STT-ACE.

Neste artigo, demonstra-se (1) a densidade textual e coesão da abertura da Ilíada (Il. 1.1-42); (2) a enfática, ainda que implícita, comparação da cólera de Aquiles à de Apolo nessa passagem; e (3) as formas subliminares de se comunicar o poder de Apolo nos versos 8 a 42, ou seja, antes de sua epifania propriamente dita por meio da peste que atinge os aqueus. Para isso, procede-se sobretudo a um rastreamento das repetições sonoras e ao exame da arquitetura métrica para verificar como esses fenômenos poéticos reiteram ou suplementam o sentido superficial do texto poético.

Background: A complement imbalance in lung alveolar tissue can play a deteriorating role in COVID-19, leading to acute respiratory distress syndrome (ARDS). CD55 is a transmembrane glycoprotein that inhibits the activation of the complement system at the intermediate cascade level, blocking the activity of the C3 convertase. Objective: In our study, lung specimens from COVID-19 and ARDS-positive COVID+/ARDS+ patients were compared with COVID-19 and ARDS-negative COVID–/ARDS– as well as COVID–/ARDS+ patients. Methods: Histochemical staining and immunolabeling of CD55 protein were performed. Results: The COVID–/ARDS– specimen showed higher expression and homogeneous distribution of glycosaminoglycans as well as compactly arranged elastic and collagen fibers of the alveolar walls in comparison to ARDS-affected lungs. In addition, COVID–/ARDS– lung tissues revealed stronger and homogenously distributed CD55 expression on the alveolar walls in comparison to the disrupted COVID–/ARDS+ lung tissues. Conclusions: Even though the collapse of the alveolar linings and the accumulation of cellular components in the alveolar spaces were characteristic of COVID+/ARDS+ lung tissues, evaluating CD55 expression could be relevant to understand its relation to the disease. Furthermore, targeting CD55 upregulation as a potential therapy could be an option for post-infectious complications of COVID-19 and other inflammatory lung diseases in the future.

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).

[This corrects the article DOI: 10.1371/journal.pone.0265879.].

Abstract 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.

As protein-based therapeutics often exhibit a limited stability in liquid formulations, there is a growing interest in the development of solid protein formulations due to improved protein stability in the solid state. We used small-scale (

GABAB receptors mediate the effects of the main inhibitory neurotransmitter in the brain. Here, authors identify the cytoskeletal protein filamin A as a key player that controls the exact location and function of GABAB receptors at the cell surface.

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

In this paper, an experimental and numerical investigation of the effect of leading-edge erosion in transonic blades was performed. The measurements were carried out on a linear blade cascade in the Transonic Cascade Wind Tunnel of DLR in Cologne at two operating points with an inflow Mach number of 1.05 and 1.12. The numerical simulations were performed by ANSYS Germany. The type and specifications of the erosion for the study were derived from real engine blades and applied to the leading edges of the experimental cascade blades using a waterjet process, as well as modeled in detail and meshed within the numerical setup. Numerical simulations and extensive wake measurements were carried out on the cascades to evaluate the aerodynamic performance. The increase in losses was quantified to be 4 percent, and a reduction in deflection and a rise in pressure were detected at both operating points.

Background: CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop 89Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial. Methods: CI-8993 and human isotype IgG1 control were conjugated to the metal ion chelator p-isothiocyanatobenzyl-desferrioxamine (Df). Quality of conjugates were assessed by SE-HPLC, SDS-PAGE, and FACS. After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. [89Zr]Zr-Df-CI-8993 alone (1 mg/kg, 4.6 MBq) or in combination with 30 mg/kg unlabelled CI-8993, as well as isotype control [89Zr]Zr-Df-IgG1 (1 mg/kg, 4.6 MBq) were assessed in human VISTA knock-in female (C57BL/6 N-Vsirtm1.1(VSIR)Geno, huVISTA KI) or control C57BL/6 mice bearing syngeneic MB49 bladder cancer tumours; and in BALB/c nu/nu mice bearing pancreatic Capan-2 tumours. Results: Stable constructs with an average chelator-to-antibody ratio of 1.81 were achieved. SDS-PAGE and SE-HPLC showed integrity of CI-8993 was maintained after conjugation; and ELISA indicated no impact of conjugation and radiolabelling on binding to human VISTA. PET imaging and biodistribution in MB49 tumour-bearing huVISTA KI female mice showed specific localisation of [89Zr]Zr-Df-CI-8993 to VISTA in spleen and tumour tissues expressing human VISTA. Specific tumour uptake was also demonstrated in Capan-2 xenografted BALB/c nu/nu mice. Conclusions: We radiolabelled and validated [89Zr]Zr-Df-CI-8993 for specific binding to huVISTA in vivo. Our results demonstrate that 89Zr-labelled CI-8993 is now suitable for targeting and imaging VISTA expression in human trials. [ABSTRACT FROM AUTHOR]

Abstract Background Age-related decline in physical capacity can lead to frailty, associated with an increased vulnerability to adverse health outcomes and greater healthcare utilization. In an aging population, effective strategies to prevent physical decline and frailty, and preserve independence are needed. Prevention programs for vulnerable community-dwelling older adults are, however, often not yet established and implemented in routine practice. Research on the feasibility, implementation, and (cost-)effectiveness of multifactorial, interdisciplinary intervention programs that take advantage of available services of healthcare providers is also limited. The main aim of this study is to evaluate the effectiveness of such an intervention program (PromeTheus) to prevent functional and mobility decline for more participation in community-dwelling (pre-)frail older adults. Methods The study is designed as a three-center, randomized controlled trial with a 12-month intervention period. Four hundred community-dwelling (pre-)frail (Clinical Frailty Scale score 4–6) older adults (≥70 years) will be randomized in a 1:1 ratio to the intervention group (IG) or the control group (CG). The IG will receive the PromeTheus program consisting of obligatory home-based physical exercises (Weight-bearing Exercise for Better Balance) accompanied by physiotherapists and facultative counseling services (person-environment-fit, coping with everyday life, nutrition, group-based activities) delivered via existing healthcare structures (e.g., social workers, nutritionists). The CG will receive usual care and a one-time counseling session on recommendations for physical activity and nutrition. Primary outcomes assessed at months 6 and 12 are the function component of the Late-Life Function and Disability Instrument and the University of Alabama at Birmingham Life-Space Assessment. Secondary outcomes are disability, physical capacity and activity, frailty, nutritional status, falls, fear of falling, health status, and psychosocial components. Process and economic evaluations are also conducted. Primary statistical analyses will be based on the intention-to-treat principle. Discussion Compared to usual care, the PromeTheus program is expected to result in higher function and mobility, greater independence and lower need for care, and more participation. As the PromeTheus program draws on existing German healthcare structures, its large-scale translation and delivery will be feasible, if evidence of (cost-)effectiveness and successful implementation can be demonstrated. Trial registration German Clinical Trials Register, . Registered on March 11, 2021.

Abstract Background Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. Methods Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. Results Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p

Primeiras estórias é um volume de contos de J. Guimarães Rosa (1962), alguns deles usando de maneira empenhada a tradição clássica. “Famigerado”, por exemplo, evoca o episódio de Polifemo no canto 9 da Odisseia. O conto que eu discuto é “Fatalidade”, que envolve a Ilíada, especialmente o duelo entre Heitor e Aquiles. Ele conta a história de um estranho, o frágil José de Tal, de apelido Zé Centeralfe (trocadilho com center-half), que chega à casa do delegado local, nomeado Meu Amigo pelo narrador. Zé pede ajuda à autoridade para resolver seus problemas com o valentão Herculinão, o qual não para de importunar a esposa de Zé. O casal mudou duas vezes de povoado e acaba na cidade do delegado, o qual, durante boa parte desse curto conto, sugere por alguns modos não-verbais que José deveria matar o valentão. Mas, diferente de The man who shot Liberty Valance, duas são as armas que, quase ao fim, matam o valentão, a de Zé e a do Delegado, ambas disparadas virtualmente ao mesmo tempo. Imediatamente antes de Zé deixar a casa do delegado, este refere-se àquele como “nosso necessitado Aquiles”, explicitando a referência potencial à Ilíada, confirmada pelo papel que o delegado tem no tiroteio final como Atena. Mas ele também evoca Zeus na forma como fala sobre o destino. Os críticos divergem sobre o ponto de vista do narrador (cinismo? condenação crítica), todavia, para leitores que estabelecem o paralelo com a Ilíada (Aquiles perde Pátroclo por meio de seu próprio erro), a perda de José – ele perde sua tênue esperança na eficácia de uma lei impessoal – é evidenciada. Não há lugar para a tática da anta – esconder-se, mesmo que você seja grande – nem para um valentão. Ao mesmo tempo, Rosa talvez convide seus leitores a comparar o conto a seu grande épico Grande sertão: veredas ou reavaliá-lo à luz da sua obra posterior, contos gradualmente menores e mais elusivos.

Abstract Fluidity of a given membrane decreases at lower ambient temperatures, whereas it rises at increasing temperatures, which is achieved through changes in membrane lipid composition. In consistence with homeoviscous adaptation theory, lower temperatures result in increased tissue concentrations of polyunsaturated fatty acids (PUFAs) in Daphnia magna, suggesting a higher PUFA requirement at lower temperatures. However, so far homeoviscous adaptation has been suggested for single or geographically separated Daphnia genotypes only. Here, we investigated changes in relative fatty acid (FA) tissue concentrations in response to a lower temperature (15°C) within a D. magna population. We determined juvenile growth rates (JGR) and FA patterns of 14 genotypes that were grown on Chlamydomonas klinobasis at 15°C and 20°C. We report significant differences of JGR and the relative body content of various FAs between genotypes at either temperature and between temperatures. Based on slopes of reaction norms, we found genotype‐specific changes in FA profiles between temperatures suggesting that genotypes have different strategies to cope with changing temperatures. In a hierarchical clustering analysis, we grouped genotypes according to differences in direction and magnitude of changes in relative FA content, which resulted in three clusters of genotypes following different patterns of changes in FA composition. These patterns suggest a lower importance of the PUFA eicosapentaenoic acid (EPA, C20:5ω3) than previously assumed. We calculated an unsaturation index (UI) as a proxy for membrane fluidity at 15°C, and we neither found significant differences for this UI nor for fitness, measured as JGR, between the three genotype clusters. We conclude that these three genotype clusters represent different physiological solutions to temperature changes by altering the relative share of different FAs, but that their phenotypes converge with respect to membrane fluidity and JGR. These clusters will be subjected to different degrees of PUFA limitation when sharing the same diet.

Abstract Background Botulinum neurotoxin (BoNT) is currently the best therapeutic option in the treatment for cervical dystonia (CD). Additional treatments like physiotherapy (PT) may even improve the results of the BoNT injection with type A (BoNT-A), but there are no definite recommendations. In the last few years, some studies showed tendencies for PT as an adjuvant therapy to benefit. However, high-quality studies are required. Methods This study is a multicentre, randomized, single-blind, controlled trial to demonstrate the effectiveness of a multimodal PT program compared to a nonspecific cupping therapy, additionally to the BoNT-A therapy. Two hundred participants will be assigned into the multimodal PT plus BoNT intervention arm or the BoNT plus cupping arm using randomization. Primary endpoint is the total Score of Toronto Western Spasmodic Rating Scale (TWSTRS). Secondary endpoints are the mobility of the cervical spine (range of motion, ROM), the TWSTRS subscales, and the quality of life (measured by questionnaires: CDQ-24 and SF-36). Patients will be single-blind assessed every 3 months according to their BoNT injection treatment over a period of 9 months. Discussion The study aims to determine the effectiveness and therefore potential benefit of an additional multimodal physiotherapy for standardized treatment with BoNT-A in patients with CD, towards the BoNT-therapy alone. This largest randomized controlled trial in this field to date is intended to generate missing evidence for therapy guidelines. Trial registration The study was registered in the German Clinical Study Register before the start of the patient recruitment ( DRKS00020411 ; date: 21.01.2020).

High-speed atomic force microscopes (HS-AFMs) with high temporal resolution enable dynamic phenomena to be visualized at nanoscale resolution. However, HS-AFMs are more complex and costlier than conventional AFMs, and particulars of an open-source HS-AFM controller have not been published before. These high entry barriers hinder the popularization of HS-AFMs in both academic and industrial applications. In addition, HS-AFMs generally have a small imaging area that limits the fields of implementation. This study presents an open-source controller that enables a low-cost simplified AFM to achieve a maximum tip-sample velocity of 5,093 µm/s (9.3 s/frame, 512 × 512 pixels), which is nearly 100 times higher than that of the original controller. Moreover, the proposed controller doubles the imaging area to 46.3 × 46.3 µm2 compared to that of the original system. The low-cost HS-AFM can successfully assess the severity of atopic dermatitis (AD) by measuring the nanotexture of human skin corneocytes in constant height DC mode. The open-source controller-based HS-AFM system costs less than $4,000, which provides resource-limited research institutes with affordable access to high-throughput nanoscale imaging to further expand the HS-AFM research community.

Aims: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular events and exhibit myocardial changes including left ventricular (LV) hypertrophy and fibrosis, overall referred to as ‘uremic cardiomyopathy’. Although different CKD animal models have been studied for cardiac effects, lack of consistent reporting on cardiac function and pathology complicates clear comparison of these models. Therefore, this study aimed at a systematic and comprehensive comparison of cardiac function and cardiac pathophysiological characteristics in eight different CKD models and mouse strains, with a main focus on adenine-induced CKD. Methods and results: CKD of different severity and duration was induced by subtotal nephrectomy or adenine-rich diet in various strains (C57BL/6J, C57BL/6 N, hyperlipidemic C57BL/6J ApoE−/−, 129/Sv), followed by the analysis of kidney function and morphology, blood pressure, cardiac function, cardiac hypertrophy, fibrosis, myocardial calcification and inflammation using functional, histological and molecular techniques, including cardiac gene expression profiling supplemented by oxidative stress analysis. Intriguingly, despite uremia of variable degree, neither cardiac dysfunction, hypertrophy nor interstitial fibrosis were observed. However, already moderate CKD altered cardiac oxidative stress responses and enhanced oxidative stress markers in each mouse strain, with cardiac RNA sequencing revealing activation of oxidative stress signaling as well as anti-inflammatory feedback responses. Conclusion: This study considerably expands the knowledge on strain- and protocol-specific differences in the field of cardiorenal research and reveals that several weeks of at least moderate experimental CKD increase oxidative stress responses in the heart in a broad spectrum of mouse models. However, this was insufficient to induce relevant systolic or diastolic dysfunction, suggesting that additional “hits” are required to induce uremic cardiomyopathy. Translational perspective: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular adverse events and exhibit myocardial changes, overall referred to as ‘uremic cardiomyopathy’. We revealed that CKD increases cardiac oxidative stress responses in the heart. Nonetheless, several weeks of at least moderate experimental CKD do not necessarily trigger cardiac dysfunction and remodeling, suggesting that additional “hits” are required to induce uremic cardiomyopathy in the clinical setting. Whether the altered cardiac oxidative stress balance in CKD may increase the risk and extent of cardiovascular damage upon additional cardiovascular risk factors and/or events will be addressed in future studies.

Purpose: ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with 89Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo. Methods: ATG-101, anti-PD-L1, and an isotype control were conjugated with p-SCN-Deferoxamine (Df). The Df-conjugated antibodies were radiolabelled with 89Zr, and their radiochemical purity, immunoreactivity, and serum stability were assessed. We conducted PET/MRI and biodistribution studies on [89Zr]Zr-Df-ATG-101 in BALB/c nude mice bearing PD-L1-expressing MDA-MB-231 breast cancer xenografts for up to 10 days after intravenous administration of [89Zr]Zr-labelled antibodies. The specificity of [89Zr]Zr-Df-ATG-101 was evaluated through a competition study with unlabelled ATG-101 and anti-PD-L1 antibodies. Results: The Df-conjugation and [89Zr]Zr -radiolabelling did not affect the target binding of ATG-101. Biodistribution and imaging studies demonstrated biological similarity of [89Zr]Zr-Df-ATG-101 and [89Zr]Zr-Df-anti-PD-L1. Tumour uptake of [89Zr]Zr-Df-ATG-101 was clearly visualised using small-animal PET imaging up to 7 days post-injection. Competition studies confirmed the specificity of PD-L1 targeting in vivo. Conclusion: [89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101. [ABSTRACT FROM AUTHOR]

Em Suplicantes, uma das mais políticas tragédias de Eurípides, é produzida uma aproximação surpreendente entre o mundo do mito e o do espectador. Embora Teseu, seu protagonista, seja representado como um “rei democrático”, nela não está presente uma cena que possa ser equiparada à experiência da mais típica instituição da democracia ateniense, a deliberação coletiva definidora da assembleia aberta a todos os cidadãos. Todavia, em diferentes momentos do primeiro episódio, chega-se bastante perto. Assim, o objetivo deste texto é discutir como essa tragédia representa formas de deliberação e consenso, para o que se investiga os meandros de dois cenários que levam a uma política de guerra de ataque desenvolvidos no drama, um em Argos, outro, em Atenas.

Objectives: The intracellular NLRP3 inflammasome is an important regulator of sterile inflammation. Recent data suggest that inflammasome particles can be released into circulation. The effects of exercise on circulating extracellular apoptosis-associated speck-like protein (ASC) particles and their effects on endothelial cells are not known.Methods: We established a flow cytometric method to quantitate extracellular ASC specks in human serum. ASC specks were quantitated in 52 marathon runners 24–72 h before, immediately after, and again 24–58 h after the run. For mechanistic characterization, NLRP3 inflammasome particles were isolated from a stable mutant NLRP3 (p.D303N)-YFP HEK cell line and used to treat primary human coronary artery endothelial cells.Results: Athletes showed a significant increase in serum concentration of circulating ASC specks immediately after the marathon (+52% compared with the baseline, p < 0.05) and a decrease during the follow-up after 24–58 h (12% reduction compared with immediately after the run, p < 0.01). Confocal microscopy revealed that human endothelial cells can internalize extracellular NLRP3 inflammasome particles. After internalization, endothelial cells showed an inflammatory response with a higher expression of the cell adhesion molecule ICAM1 (6.9-fold, p < 0.05) and increased adhesion of monocytes (1.5-fold, p < 0.05).Conclusion: These findings identify extracellular inflammasome particles as novel systemic mediators of cell–cell communication that are transiently increased after acute extensive exercise with a high mechanical muscular load.

O objetivo deste artigo é discutir como a tensão entre a destruição própria da guerra e a experiência propiciada por atividades musicais ou, mitopoeticamente, da esfera das Musas (mousiké) perpassa o canto XVIII da Ilíada, culminando na narração da forja do novo escudo de Aquiles por Hefesto. As principais passagens discutidas são a reunião das Nereidas como um khóros que participa do lamento de Tétis por Aquiles, a forma como Aquiles conceitualiza seu antigo conjunto de armas e alguns dos aspectos ressaltados no encontro propriamente dito de Tétis e Hefesto. Quanto ao Escudo, além de rastrear-se a tensão entre destruição e mousiké que o perpassa, mostra-se como essa ajuda a esclarecer dois conjuntos de versos problemáticos, 535-38 e 604-5.

Specific de novo mutations in the CSNK2A1 gene, which encodes CK2α, the catalytic subunit of protein kinase CK2, are considered as causative for the Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS is a rare congenital disease with a high phenotypic diversity ranging from neurodevelopmental disabilities to multi-systemic problems and characteristic facial features. A frequent OCNDS mutation is the exchange of Lys198 to Arg at the center of CK2α′s P+1 loop, a key element of substrate recognition. According to preliminary data recently made available, this mutation causes a significant shift of the substrate specificity of the enzyme. We expressed the CK2αLys198Arg recombinantly and characterized it biophysically and structurally. Using isothermal titration calorimetry (ITC), fluorescence quenching and differential scanning fluorimetry (Thermofluor), we found that the mutation does not affect the interaction with CK2β, the non-catalytic CK2 subunit, and that the thermal stability of the protein is even slightly increased. However, a CK2αLys198Arg crystal structure and its comparison with wild-type structures revealed a significant shift of the anion binding site harboured by the P+1 loop. This observation supports the notion that the Lys198Arg mutation causes an alteration of substrate specificity which we underpinned here with enzymological data.

Nanoscale positioning has numerous applications in both academia and industry. A growing number of applications require devices with long working distances and nanoscale resolutions. Friction–inertia piezoelectric positioners, which are based on the stick–slip mechanism, achieve both nanometer resolution and centimeter-scale travel. However, the requirements of complex preload mechanism, precision machining, and precise assembly increase the cost of conventional friction–inertia nanopositioners. Herein we present the design of an open-source XYZ-axis nanopositioning system. Utilizing a magnet-based stick–slip driving mechanism, the proposed XYZ nanopositioner provides several advantages, including sub-nanometer resolution, a payload capacity of up to 12 kg (horizontal), compact size, low cost, and easy assembly; furthermore, the system is adjustment-free. The performance tests validate the precision of the system in both scanning and stepping operation modes. Moreover, the resonant spectra affirm the rigidity and dynamic response of the mechanism. In addition, we demonstrate the practical applications of this nanopositioner in various measurement techniques, including scanning electron microscopy, vibrometry, and atomic force microscopy. Furthermore, we present 11 variations of the nanopositioner designs that are either compatible with ultra-high-vacuum systems and other existing systems, 3D printable, or hacking commercial linear slides.

Abstract Background Self-reported life-space assessment methods so far focus on community-dwelling persons, with a lack of validated assessment methods for institutionalized settings. This study evaluated construct validity, test-retest reliability, sensitivity to change, and feasibility of a new Life-Space Assessment for Institutionalized Settings (LSA-IS) in geriatric patients. Methods Psychometric properties of the LSA-IS in 119 hospitalized geriatric patients (83.0 ± 6.2 years) with and without cognitive impairment (CI) [Mini-Mental State Examination: 22.4 ± 4.9 scores] were evaluated within a comprehensive validation design. For the total group and subgroups according to cognitive status, construct validity was assessed by calculating Spearman’s rank correlation coefficients (rho) with established construct variables, test–retest reliability by intra-class correlation coefficients (ICCs), sensitivity to change by standardized response means (SRMs) calculated for effects of early ward-based rehabilitation during hospital stay. Results The LSA-IS (total score) demonstrated good test–retest reliability (ICC = .704), and large sensitivity to change (SRM = .806), while construct validity was small to high indicated by significant correlations of the LSA-IS to construct variables (rho = .208–716), depending on relative construct association. On average results of LSA-IS sub-scores confirmed results of the total score. Subgroups according to cognitive status did not differ for most analyzed variables. A completion rate of 100% and a completion time of 3.2 ± 1.2 min documented excellent feasibility. Conclusions The interview-based LSA-IS has proven to be valid, reliable, sensitive, and feasible in hospitalized, multi-morbid, geriatric patients with and without CI documenting good psychometric properties for institutionalized settings. Trial registration DRKS00016028

O número de conflitos com as mais diferentes causas (geopolíticas, econômicas, sociais, religiosas, étnicas etc.) que, pela sua violência e/ou por razões retóricas, são rotulados como guerra (amiúde do bem contra o mal) só faz aumentar. Tendo em vista esse contexto contemporâneo, proponho discutir se e como a Ilíada, poema no qual a Guerra de Troia é pensada como uma forma de retribuição ou vingança, abre certos espaços de ação (livre?) externos à necessidade da aniquilação do outro intrínseca a tal enfrentamento bélico, em particular, manifestações de piedade em relação ao inimigo.

Africa houses approximately one third of the global cattle, sheep and goat population. Here the authors show that manure accumulation in livestock enclosures can emit significant quantities of the greenhouse gas N2O for decades after abandonment, totaling 5% of continental anthropogenic N2O emissions.

Este texto resume as atividades principais do Grupo de Pesquisa “Gêneros poéticos na Grécia antiga: tradição e contexto” (USP/CNPq), bem como um estudo de caso demonstrativo das discussões desenvolvidas no âmbito do grupo.

Formalized breeding schemes are a key component of breeding program design and a gateway to conducting plant breeding as a quantitative process. Unfortunately, breeding schemes are rarely defined, expressed in a quantifiable format, or stored in a database. Furthermore, the continuous review and improvement of breeding schemes is not routinely conducted in many breeding programs. Given the rapid development of novel breeding methodologies, it is important to adopt a philosophy of continuous improvement regarding breeding scheme design. Here, we discuss terms and definitions that are relevant to formalizing breeding pipelines, market segments and breeding schemes, and we present a software tool, Breeding Pipeline Manager, that can be used to formalize and continuously improve breeding schemes. In addition, we detail the use of continuous improvement methods and tools such as genetic simulation through a case study in the International Institute of Tropical Agriculture (IITA) Cassava east-Africa pipeline. We successfully deploy these tools and methods to optimize the program size as well as allocation of resources to the number of parents used, number of crosses made, and number of progeny produced. We propose a structured approach to improve breeding schemes which will help to sustain the rates of response to selection and help to deliver better products to farmers and consumers.