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Decitabine and azacytidine are considered as epigenetic drugs that induce DNA methyltransferase (DNMT)-DNA crosslinks, resulting in DNA hypomethylation and damage. Although they are already applied against myeloid cancers, important aspects of their mode of action remain unknown, highly limiting their clinical potential. Using a combinatorial approach, we reveal that the efficacy profile of both compounds primarily depends on the level of induced DNA damage. Under low DNMT activity, only decitabine has a substantial impact. Conversely, when DNMT activity is high, toxicity and cellular response to both compounds are dramatically increased, but do not primarily depend on DNA hypomethylation or RNA-associated processes. By investigating proteome dynamics on chromatin, we show that decitabine induces a strictly DNMT-dependent multifaceted DNA damage response based on chromatin recruitment, but not expression-level changes of repair-associated proteins. The choice of DNA repair pathway hereby depends on the severity of decitabine-induced DNA lesions. Although under moderate DNMT activity, mismatch (MMR), base excision (BER), and Fanconi anaemia-dependent DNA repair combined with homologous recombination are activated in response to decitabine, high DNMT activity and therefore immense replication stress induce activation of MMR and BER followed by non-homologous end joining., (© 2024 Aumer et al.)

Introduction: Interoception, the perception of the internal state of the body, has been shown to be closely linked to emotions and mental health. Of particular interest are interoceptive learning processes that capture associations between environmental cues and body signals as a basis for making homeostatically relevant predictions about the future. One method of measuring respiratory interoceptive learning that has shown promising results is the Breathing Learning Task (BLT). While the original BLT required binary predictions regarding the presence or absence of an upcoming inspiratory resistance, here we extended this paradigm to capture continuous measures of prediction (un)certainty., Methods: Sixteen healthy participants completed the continuous version of the BLT, where they were asked to predict the likelihood of breathing resistances on a continuous scale from 0.0 to 10.0. In order to explain participants' responses, a Rescorla-Wagner model of associative learning was combined with suitable observation models for continuous or binary predictions, respectively. For validation, we compared both models against corresponding null models and examined the correlation between observed and modeled predictions. The model was additionally extended to test whether learning rates differed according to stimuli valence. Finally, summary measures of prediction certainty as well as model estimates for learning rates were considered against interoceptive and mental health questionnaire measures., Results: Our results demonstrated that the continuous model fits closely captured participant behavior using empirical data, and the binarised predictions showed excellent replicability compared to previously collected data. However, the model extension indicated that there were no significant differences between learning rates for negative (i.e. breathing resistance) and positive (i.e. no breathing resistance) stimuli. Finally, significant correlations were found between fatigue severity and both prediction certainty and learning rate, as well as between anxiety sensitivity and prediction certainty., Discussion: These results demonstrate the utility of gathering enriched continuous prediction data in interoceptive learning tasks, and suggest that the updated BLT is a promising paradigm for future investigations into interoceptive learning and potential links to mental health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Brand, Wise, Hess, Russell, Stephan and Harrison.)

Magnetic monopoles, despite their ongoing experimental search as elementary particles, have inspired the discovery of analogous excitations in condensed matter systems. In chiral condensed matter systems, emergent monopoles are responsible for the onset of transitions between topologically distinct states and phases, such as in the case of transitions from helical and conical phase to A-phase comprising periodic arrays of skyrmions. By combining numerical modeling and optical characterizations, we describe how different geometrical configurations of skyrmions terminating at monopoles can be realized in liquid crystals and liquid crystal ferromagnets. We demonstrate how these complex structures can be effectively manipulated by external magnetic and electric fields. Furthermore, we discuss how our findings may hint at similar dynamics in other physical systems and their potential applications.

Observations on the ontogeny and diversity of salamanders provided some of the earliest evidence that shifts in developmental trajectories have made a substantial contribution to the evolution of animal forms. Since the dawn of evo-devo there have been major advances in understanding developmental mechanisms, phylogenetic relationships, evolutionary models, and an appreciation for the impact of ecology on patterns of development (eco-evo-devo). Molecular phylogenetic analyses have converged on strong support for the majority of branches in the Salamander Tree of Life, which includes 764 described species. Ancestral reconstructions reveal repeated transitions between life cycle modes and ecologies. The salamander fossil record is scant, but key Mesozoic species support the antiquity of life cycle transitions in some families. Colonization of diverse habitats has promoted phenotypic diversification and sometimes convergence when similar environments have been independently invaded. However, unrelated lineages may follow different developmental pathways to arrive at convergent phenotypes. This article summarizes ecological and endocrine-based causes of life cycle transitions in salamanders, as well as consequences to body size, genome size, and skeletal structure. Salamanders offer a rich source of comparisons for understanding how the evolution of developmental patterns has led to phenotypic diversification following shifts to new adaptive zones., (© 2021 American Association for Anatomy.)

Interoception, the perception of internal bodily states, is thought to be inextricably linked to affective qualities such as anxiety. Although interoception spans sensory to metacognitive processing, it is not clear whether anxiety is differentially related to these processing levels. Here we investigated this question in the domain of breathing, using computational modeling and high-field (7 T) fMRI to assess brain activity relating to dynamic changes in inspiratory resistance of varying predictability. Notably, the anterior insula was associated with both breathing-related prediction certainty and prediction errors, suggesting an important role in representing and updating models of the body. Individuals with low versus moderate anxiety traits showed differential anterior insula activity for prediction certainty. Multi-modal analyses of data from fMRI, computational assessments of breathing-related metacognition, and questionnaires demonstrated that anxiety-interoception links span all levels from perceptual sensitivity to metacognition, with strong effects seen at higher levels of interoceptive processes., Competing Interests: Declaration of interests F.V. has been invited to scientific meetings, consulted and/or served as speaker, and received compensation from Lundbeck, Servier, Recordati, Janssen, Otsuka, LivaNova, and Chiesi. None of these links are related to this work. The authors declare no other competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Mobile health (mHealth) interventions can increase physical activity (PA); however, their long-term impact is not well understood., Objective: The primary aim of this study is to understand the immediate and long-term effects of mHealth interventions on PA. The secondary aim is to explore potential effect moderators., Methods: We performed this study according to the Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched PubMed, the Cochrane Library, SCOPUS, and PsycINFO in July 2020. Eligible studies included randomized controlled trials of mHealth interventions targeting PA as a primary outcome in adults. Eligible outcome measures were walking, moderate-to-vigorous physical activity (MVPA), total physical activity (TPA), and energy expenditure. Where reported, we extracted data for 3 time points (ie, end of intervention, follow-up ≤6 months, and follow-up >6 months). To explore effect moderators, we performed subgroup analyses by population, intervention design, and control group type. Results were summarized using random effects meta-analysis. Risk of bias was assessed using the Cochrane Collaboration tool., Results: Of the 2828 identified studies, 117 were included. These studies reported on 21,118 participants with a mean age of 52.03 (SD 14.14) years, of whom 58.99% (n=12,459) were female. mHealth interventions significantly increased PA across all the 4 outcome measures at the end of intervention (walking standardized mean difference [SMD] 0.46, 95% CI 0.36-0.55; P<.001; MVPA SMD 0.28, 95% CI 0.21-0.35; P<.001; TPA SMD 0.34, 95% CI 0.20-0.47; P<.001; energy expenditure SMD 0.44, 95% CI 0.13-0.75; P=.01). Only 33 studies reported short-term follow-up measurements, and 8 studies reported long-term follow-up measurements in addition to end-of-intervention results. In the short term, effects were sustained for walking (SMD 0.26, 95% CI 0.09-0.42; P=.002), MVPA (SMD 0.20, 95% CI 0.05-0.35; P=.008), and TPA (SMD 0.53, 95% CI 0.13-0.93; P=.009). In the long term, effects were also sustained for walking (SMD 0.25, 95% CI 0.10-0.39; P=.001) and MVPA (SMD 0.19, 95% CI 0.11-0.27; P<.001). We found the study population to be an effect moderator, with higher effect scores in sick and at-risk populations. PA was increased both in scalable and nonscalable mHealth intervention designs and regardless of the control group type. The risk of bias was rated high in 80.3% (94/117) of the studies. Heterogeneity was significant, resulting in low to very low quality of evidence., Conclusions: mHealth interventions can foster small to moderate increases in PA. The effects are maintained long term; however, the effect size decreases over time. The results encourage using mHealth interventions in at-risk and sick populations and support the use of scalable mHealth intervention designs to affordably reach large populations. However, given the low evidence quality, further methodologically rigorous studies are warranted to evaluate the long-term effects., (©Annette Mönninghoff, Jan Niklas Kramer, Alexander Jan Hess, Kamila Ismailova, Gisbert W Teepe, Lorainne Tudor Car, Falk Müller-Riemenschneider, Tobias Kowatsch. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 30.04.2021.)

We experimentally and numerically show that chirality can play a major role in the nonlinear optical response of soft birefringent materials, by studying the nonlinear propagation of laser beams in frustrated cholesteric liquid crystal samples. Such beams exhibit a periodic nonlinear response associated with a bouncing pattern for the optical fields, as well as a self-focusing effect enhanced by the chirality of the birefringent material. Our results open new possible designs of nonlinear optical devices with low power consumption and tunable interactions with localized topological solitons.

The actuation and levitation of air-suspended objects by a magnetic field, due to its noncontact and holonomic manipulation modes, are important technological capabilities for device applications. However, owing to a higher density of conventional ferromagnets or nanoparticle-containing polymers and strong magnetic fields required for actuation, fabricating lightweight materials with a sensitive magnetic response for weight critical applications is challenging. Here, we report ultralight aerogel-based magnets (aero-magnets) comprising assembled ferromagnetic nanomaterials with highly magnetic anisotropy where the magnetic domains can be programmed by external predesigned fields. To demonstrate the breadth of manufacturing methods for this breed of aero-magnet composites, both silica/nanocellulose aerogel hosts and ferromagnetic nanorod/nanoplatelet guests have been explored. Single and double domains with out-of-plane magnetization are programmed into the aero-magnets and characterized by magnetic force microscopy. The levitation and actuation of the aero-magnets are realized while exposed to a small external magnetic field of 11 mT and introduced to a switching circuit. Furthermore, the elastic moduli of the aero-magnets are estimated by dynamic magnetic responses of the ferromagnetic nanoparticles tightly tethered in the aerogel hosts under rapid cyclic fields. These programmable aero-magnets could serve as monolithic magnetic actuator units in the fields of tiny robots and aerospace components.

Optical properties can be programmed on mesoscopic scales by patterning host materials while ordering their nanoparticle inclusions. While liquid crystals are often used to define the ordering of nanoparticles dispersed within them, this approach is typically limited to liquid crystals confined in classic geometries. In this work, the orientational order that liquid crystalline colloidal hosts impose on anisotropic nanoparticle inclusions is combined with an additive manufacturing method that enables engineered, macroscopic three-dimensional (3D) patterns of co-aligned gold nanorods and cellulose nanocrystals. These gels exhibit polarization-dependent plasmonic properties that emerge from the unique interaction between the host medium's anisotropic optical properties defined by orientationally ordered cellulose nanocrystals, from the liquid crystal's gold nanorod inclusions, and from the complexity of spatial patterns accessed with 3D printing. The gels' optical properties that are defined by the interplay of these effects are tuned by controlling the gels' order, which is tuned by adjusting the gels' cellulose nanocrystal concentrations. Lithe optical responsiveness of these composite gels to polarized radiation may enable unique technological applications like polarization-sensitive optical elements., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Cirolanides wassenichae sp. nov., is described from the phreatic zone of the Edwards Aquifer, Texas, USA where it is sympatric with Cirolanides texensis Benedict, 1896. Its status as a new species is based on both morphological and molecular data. Number of antennula articles (3-5 vs 9-15), size (mean sizes of 9.5 and 8.8 mm vs 11.1 and 10.4 mm for males and females, respectively), morphology of pereopods 1-3 (haptorial to semi-haptorial in 1-3 vs only 1 haptorial), and shape of pleotelson (squared, slightly indented vs rounded) are key morphological characteristics that distinguish C. wassenichae sp. nov. from C. texensis. Phylogenies based on cytochrome oxidase 1 and large ribosomal subunit 28S show that divergent morphologies correspond to reciprocally monophyletic groups for both nuclear and mitochondrial datasets. The genus Cirolanides is in need of revision, as our description of C. wassenichae sp. nov. renders C. texensis paraphyletic.

Background: The isometric steady-state following active lengthening is associated with greater torque production and lower activation, as measured by electromyographic activity (EMG), in comparison with a purely isometric contraction (ISO) at the same joint angle. This phenomenon is termed residual force enhancement (RFE). While there has been a great deal of research investigating the basic mechanisms of RFE, little work has been performed to understand the everyday relevance of RFE. The purpose of this study was to investigate whether neuromuscular control strategies differ between ISO and RFE by measuring torque steadiness of the human ankle plantar flexors., Methods: Following ISO maximal voluntary contractions in 12 males (25 ± 4 years), an active lengthening contraction was performed at 15°/s over a 30° ankle excursion, ending at the same joint angle as ISO (5° dorsiflexion; RFE). Surface EMG of the tibialis anterior and soleus muscles was recorded during all tasks. Torque steadiness was determined as the standard deviation (SD) and coefficient of variation (CV) of the torque trace in the ISO and RFE condition during activation-matching (20% and 60% integrated EMG) and torque-matching (20% and 60% maximal voluntary contraction) experiments. Two-tailed, paired t tests were used, within subjects, to determine the presence of RFE/activation reduction (AR) and whether there was a difference in torque steadiness between ISO and RFE conditions., Results: During the maximal and submaximal conditions, there was 5%-9% RFE with a 9%-11% AR ( p < 0.05), respectively, with no difference in antagonist coactivation between RFE and ISO ( p > 0.05). There were no differences in SD and CV of the torque trace for the 20% and 60% activation-matching or the 60% and maximal torque-matching trials in either the RFE or ISO condition ( p > 0.05). During the 20% torque-matching trial, there were ∼37% higher values for SD and CV in the RFE as compared with the ISO condition ( p < 0.05). A significant moderate-to-strong negative relationship was identified between the reduction in torque steadiness following active lengthening and the accompanying AR ( p < 0.05)., Conclusion: It appears that while the RFE-associated AR provides some improved neuromuscular economy, this comes at the cost of increased torque fluctuations in the isometric steady-state following active lengthening during submaximal contractions.