Data integration and analysis for circadian medicine

Data integration, data sharing, and standardized analyses are important enablers for data-driven medical research. Circadian medicine is an emerging field with a particularly high need for coordinated and systematic collaboration between researchers from different disciplines. Datasets in circadian medicine are multimodal, ranging from molecular circadian profiles and clinical parameters to physiological measurements and data obtained from (wearable) sensors or reported by patients. Uniquely, data spanning both the time dimension and the spatial dimension (across tissues) are needed to obtain a holistic view of the circadian system. The study of human rhythms in the context of circadian medicine has to confront the heterogeneity of clock properties within and across subjects and our inability to repeatedly obtain relevant biosamples from one subject. This requires informatics solutions for integrating and visualizing relevant data types at various temporal resolutions ranging from milliseconds and seconds to minutes and several hours. Associated challenges range from a lack of standards that can be used to represent all required data in a common interoperable form, to challenges related to data storage, to the need to perform transformations for integrated visualizations, and to privacy issues. The downstream analysis of circadian rhythms requires specialized approaches for the identification, characterization, and discrimination of rhythms. We conclude that circadian medicine research provides an ideal environment for developing innovative methods to address challenges related to the collection, integration, visualization, and analysis of multimodal multidimensional biomedical data.Peer Reviewe

What Do We Want From Explainable Artificial Intelligence (XAI)? -- A Stakeholder Perspective on XAI and a Conceptual Model Guiding Interdisciplinary XAI Research

Previous research in Explainable Artificial Intelligence (XAI) suggests that a main aim of explainability approaches is to satisfy specific interests, goals, expectations, needs, and demands regarding artificial systems (we call these stakeholders' desiderata) in a variety of contexts. However, the literature on XAI is vast, spreads out across multiple largely disconnected disciplines, and it often remains unclear how explainability approaches are supposed to achieve the goal of satisfying stakeholders' desiderata. This paper discusses the main classes of stakeholders calling for explainability of artificial systems and reviews their desiderata. We provide a model that explicitly spells out the main concepts and relations necessary to consider and investigate when evaluating, adjusting, choosing, and developing explainability approaches that aim to satisfy stakeholders' desiderata. This model can serve researchers from the variety of different disciplines involved in XAI as a common ground. It emphasizes where there is interdisciplinary potential in the evaluation and the development of explainability approaches.Comment: 57 pages, 2 figures, 1 table, to be published in Artificial Intelligence, Markus Langer, Daniel Oster and Timo Speith share first-authorship of this pape

Physical mechanisms of ESCRT-III-driven cell division.

Living systems propagate by undergoing rounds of cell growth and division. Cell division is at heart a physical process that requires mechanical forces, usually exerted by assemblies of cytoskeletal polymers. Here we developed a physical model for the ESCRT-III-mediated division of archaeal cells, which despite their structural simplicity share machinery and evolutionary origins with eukaryotes. By comparing the dynamics of simulations with data collected from live cell imaging experiments, we propose that this branch of life uses a previously unidentified division mechanism. Active changes in the curvature of elastic cytoskeletal filaments can lead to filament perversions and supercoiling, to drive ring constriction and deform the overlying membrane. Abscission is then completed following filament disassembly. The model was also used to explore how different adenosine triphosphate (ATP)-driven processes that govern the way the structure of the filament is changed likely impact the robustness and symmetry of the resulting division. Comparisons between midcell constriction dynamics in simulations and experiments reveal a good agreement with the process when changes in curvature are implemented at random positions along the filament, supporting this as a possible mechanism of ESCRT-III-dependent division in this system. Beyond archaea, this study pinpoints a general mechanism of cytokinesis based on dynamic coupling between a coiling filament and the membrane

Relation of nNOS isoforms to mitochondrial density and PGC-1alpha expression in striated muscles of mice

The expression of neuronal NO synthase (nNOS) alpha- and beta-isoforms in skeletal muscle is well documented but only little information is available about their regulation/functions. Using different mouse models, we now assessed whether the expression of nNOS-isoforms in muscle fibers is related to mitochondria content/activity and regulated by peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Catalytic histochemistry revealed highest nNOS-concentrations to be present in type-2 oxidative muscle fibers. Differences in mitochondrial density between nNOS-KO-mice and WT-littermates established by morphometry after transmission electron microscopy were significant in the oxidative portion of the tibialis anterior muscle (TA) but not in rectus femoris muscle (RF) indicating an nNOS-dependent mitochondrial pool in TA. Quantitative immunoblotting displayed the nNOS alpha-isoform to preponderate in those striated muscles of C57BL/6-mice that comprise of many type-2 oxidative fibers, e.g. TA, while roughly even levels of the two nNOS-isoforms were expressed in those muscles that mainly consist of type-2 glycolytic fibers, e.g. RF. Differences in citrate synthase-activity in muscle homogenates between nNOS-KO-mice and WT-littermates were positively related to nNOS alpha-isoform levels. In transgenic-mice over-expressing muscular PGC-1alpha compared to WT-littermates, immunoblotting revealed a significant shift in nNOS-expression in favor of the alpha-isoform in six out of eight striated muscles (exceptions: soleus muscle and tongue) without consistent relationship to changes in the expression of mitochondrial markers. In summary, our study demonstrated the nNOS alpha-isoform expression to be related to mitochondrial content/activity and to be up-regulated by up-stream PGC-1alpha in striated muscles, particularly in those enriched with type-2 oxidative fibers implying a functional convergence of the two signaling systems in these fibers

The patterned assembly and stepwise Vps4-mediated disassembly of composite ESCRT-III polymers drives archaeal cell division

ESCRT-III family proteins form composite polymers that deform and cut membrane tubes in the context of a wide range of cell biological processes across the tree of life. In reconstituted systems, sequential changes in the composition of ESCRT-III polymers induced by the AAA-adenosine triphosphatase Vps4 have been shown to remodel membranes. However, it is not known how composite ESCRT-III polymers are organized and remodeled in space and time in a cellular context. Taking advantage of the relative simplicity of the ESCRT-III-dependent division system in Sulfolobus acidocaldarius, one of the closest experimentally tractable prokaryotic relatives of eukaryotes, we use super-resolution microscopy, electron microscopy, and computational modeling to show how CdvB/CdvB1/CdvB2 proteins form a precisely patterned composite ESCRT-III division ring, which undergoes stepwise Vps4-dependent disassembly and contracts to cut cells into two. These observations lead us to suggest sequential changes in a patterned composite polymer as a general mechanism of ESCRT-III-dependent membrane remodeling. </p

Involvement of Lgl and Mahjong/VprBP in Cell Competition

Mahjong is a novel Lethal giant larvae-binding protein that plays a vital role in cell competition in both flies and mammals

Prehabilitation of elderly frail or pre-frail patients prior to elective surgery (PRAEP-GO): study protocol for a randomized, controlled, outcome assessor-blinded trial

Background: Frailty is expressed by a reduction in physical capacity, mobility, muscle strength, and endurance. (Pre-) frailty is present in up to 42% of the older surgical population, with an increased risk for peri- and postoperative complications. Consequently, these patients often suffer from a delayed or limited recovery, loss of autonomy and quality of life, and a decrease in functional and cognitive capacities. Since frailty is modifiable, prehabilitation may improve the physiological reserves of patients and reduce the care dependency 12 months after surgery. Methods: Patients >= 70 years old scheduled for elective surgery or intervention will be recruited in this multicenter, randomized controlled study, with a target of 1400 participants with an allocation ratio of 1:1. The intervention consists of (1) a shared decision-making process with the patient, relatives, and an interdisciplinary and interprofessional team and (2) a 3-week multimodal, individualized prehabilitation program including exercise therapy, nutritional intervention, mobility or balance training, and psychosocial interventions and medical assessment. The frequency of the supervised prehabilitation is 5 times/week for 3 weeks. The primary endpoint is defined as the level of care dependency 12 months after surgery or intervention. Discussion: Prehabilitation has been proven to be effective for different populations, including colorectal, transplant, and cardiac surgery patients. In contrast, evidence for prehabilitation in older, frail patients has not been clearly established. To the best of our knowledge, this is currently the largest prehabilitation study on older people with frailty undergoing general elective surgery