Beyond Rubik: The Embodiment-Presence-Interactivity Cube applied to exercise.

Evidence-based interventions are needed to promote engagement in physical activity. Audio-visual stimuli are frequently employed to enhance the exercise experience. Nonetheless, there is a paucity of research that examines the qualities of technological devices that are employed. Using the Embodiment-Presence-Interactivity Cube (Flavián et al., 2019) as a guiding conceptual framework, the aim of this registered report was to examine how each dimension of the cube (i.e., embodiment, presence and interactivity) influenced a range of exercise-related affective and perceptual variables. A counterbalanced within-subjects design was employed (N = 24). Participants completed 20-min exercise bouts on a cycle ergometer under four conditions: Television, augmented reality, 360° video and virtual reality. A repeated-measures ANOVA indicated a significant Condition × Timepoint interaction for affective valence (p = 0.046), with greater embodiment offered by technological devices leading to more positive responses. Analyses also indicated main effects of condition for exercise enjoyment, remembered pleasure and forecasted pleasure, with greater presence of technological devices leading to more positive responses. Technologies that combine high levels of embodiment, presence and interactivity (e.g., virtual reality) appear to yield several benefits in terms of in-task (e.g., affective valence) and post-task (e.g., remembered pleasure) responses for exercise conducted at ventilatory threshold.

A Mutation in Tmem135 Causes Progressive Sensorineural Hearing Loss.

Transmembrane protein 135 (TMEM135) is a 52 kDa protein with five predicted transmembrane domains that is highly conserved across species. Previous studies have shown that TMEM135 is involved in mitochondrial dynamics, thermogenesis, and lipid metabolism in multiple tissues; however, its role in the inner ear or the auditory system is unknown. We investigated the function of TMEM135 in hearing using wild-type (WT) and Tmem135 FUN025/FUN025 ( FUN025 ) mutant mice on a CBA/CaJ background, a normal-hearing mouse strain. Although FUN025 mice displayed normal auditory brainstem response (ABR) at 1 month, we observed significantly elevated ABR thresholds at 8, 16, and 64 kHz by 3 months, which progressed to profound hearing loss by 12 months. Consistent with our auditory testing, 13-month-old FUN025 mice exhibited a severe loss of outer hair cells and spiral ganglion neurons in the cochlea. Our results using BaseScope in situ hybridization indicate that TMEM135 is expressed in the inner hair cells, outer hair cells, and supporting cells. Together, these results demonstrate that the FUN025 mutation in Tmem135 causes progressive sensorineural hearing loss, and suggest that TMEM135 is crucial for maintaining key cochlear cell types and normal sensory function in the aging cochlea.

Large-scale annotated dataset for cochlear hair cell detection and classification.

Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, rat, guinea pig, pig, primate, and human cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 107,000 hair cells which have been identified and annotated as either inner or outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair-cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to give other hearing research groups the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

An optimized approach to study nanoscale sarcomere structure utilizing super-resolution microscopy with nanobodies.

The sarcomere is the fundamental contractile unit in skeletal muscle, and the regularity of its structure is critical for function. Emerging data demonstrates that nanoscale changes to the regularity of sarcomere structure can affect the overall function of the protein dense ~2µm sarcomere. Further, sarcomere structure is implicated in many clinical conditions of muscle weakness. However, our understanding of how sarcomere structure changes in disease, especially at the nanoscale, has been limited in part due to the inability to robustly detect and measure at sub-sarcomere resolution. We optimized several methodological steps and developed a robust pipeline to analyze sarcomere structure using structured illumination super-resolution microscopy in conjunction with commercially-available and fluorescently-conjugated Variable Heavy-Chain only fragment secondary antibodies (nanobodies), and achieved a significant increase in resolution of z-disc width (353nm vs. 62nm) compared to confocal microscopy. The combination of these methods provides a unique approach to probe sarcomere protein localization at the nanoscale and may prove advantageous for analysis of other cellular structures.

Heightened interoception in adults with fibromyalgia.

Previous research suggests that the processing of internal body sensations (interoception) affects how we experience pain. Some evidence suggests that people with fibromyalgia syndrome (FMS) - a condition characterised by chronic pain and fatigue - may have altered interoceptive processing. However, extant findings are inconclusive, and some tasks previously used to measure interoception are of questionable validity. Here, we used an alternative measure - the Phase Adjustment Task (PAT) - to examine cardiac interoceptive accuracy in adults with FMS. We examined: (i) the tolerability of the PAT in an FMS sample (N = 154); (ii) if there are differences in facets of interoception (PAT performance, PAT-related confidence, and scores on the Private Body Consciousness Scale) between an FMS sample and an age- and gender-matched pain-free sample (N = 94); and (iii) if subgroups of participants with FMS are identifiable according to interoceptive accuracy levels. We found the PAT was tolerable in the FMS sample, with additional task breaks and a recommended hand posture. The FMS sample were more likely to be classified as 'interoceptive' on the PAT, and had significantly higher self-reported interoception compared to the pain-free sample. Within the FMS sample, we identified a subgroup who demonstrated very strong evidence of being interoceptive, and concurrently had lower fibromyalgia symptom impact (although the effect size was small). Conversely, self-reported interoception was positively correlated with FMS symptom severity and impact. Overall, interoception may be an important factor to consider in understanding and managing FMS symptoms. We recommend future longitudinal work to better understand associations between fluctuating FMS symptoms and interoception.

Dynamic mechanisms of exercise to improve body satisfaction: Perceived or actual fat loss?

We examined the dynamic mechanisms of aerobic training (AT) and strength training (ST) to improve body satisfaction. Sixty-six participants were randomised to either the AT or ST condition and completed an 8-week intervention. Participants completed 3 weekly, 30-minute sessions of moderate intensity AT (65-75% VO2 max) or ST (65-75% 1-RM). The energy consumption of each session was approximately equivalent under both conditions. Body satisfaction, body composition, perceived fitness and exercise self-efficacy were measured at baseline and biweekly during the intervention. Exercise improved individuals' body satisfaction (p < .05). When the energy expenditures of AT and ST were equal, there was no difference in body satisfaction improvement. There were dynamic mechanisms underlying the effects of exercise on body satisfaction. Specifically, perceived fitness influenced body satisfaction improvements during the early stages of the exercise program, while changes in body composition influenced body satisfaction toward the end of the exercise program. There were sex differences in the mechanisms underlying body satisfaction. For women, perceived fat was more important in the early intervention period; for men, actual body fat was more valuable in the late intervention period. An effective strategy to improve body satisfaction is to initially target perceived fitness before focusing on changing body composition.

Large-scale annotated dataset for cochlear hair cell detection and classification.

Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 90'000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

The actin cytoskeleton in hair bundle development and hearing loss.

Inner ear hair cells assemble mechanosensitive hair bundles on their apical surface that transduce sounds and accelerations. Each hair bundle is comprised of ∼ 100 individual stereocilia that are arranged into rows of increasing height and width; their specific and precise architecture being necessary for mechanoelectrical transduction (MET). The actin cytoskeleton is fundamental to establishing this architecture, not only by forming the structural scaffold shaping each stereocilium, but also by composing rootlets and the cuticular plate that together provide a stable foundation supporting each stereocilium. In concert with the actin cytoskeleton, a large assortment of actin-binding proteins (ABPs) function to cross-link actin filaments into specific topologies, as well as control actin filament growth, severing, and capping. These processes are individually critical for sensory transduction and are all disrupted in hereditary forms of human hearing loss. In this review, we provide an overview of actin-based structures in the hair bundle and the molecules contributing to their assembly and functional properties. We also highlight recent advances in mechanisms driving stereocilia elongation and how these processes are tuned by MET.

Correlated insulator collapse due to quantum avalanche via in-gap ladder states.

The significant discrepancy observed between the predicted and experimental switching fields in correlated insulators under a DC electric field far-from-equilibrium necessitates a reevaluation of current microscopic understanding. Here we show that an electron avalanche can occur in the bulk limit of such insulators at arbitrarily small electric field by introducing a generic model of electrons coupled to an inelastic medium of phonons. The quantum avalanche arises by the generation of a ladder of in-gap states, created by a multi-phonon emission process. Hot-phonons in the avalanche trigger a premature and partial collapse of the correlated gap. The phonon spectrum dictates the existence of two-stage versus single-stage switching events which we associate with charge-density-wave and Mott resistive phase transitions, respectively. The behavior of electron and phonon temperatures, as well as the temperature dependence of the threshold fields, demonstrates how a crossover between the thermal and quantum switching scenarios emerges within a unified framework of the quantum avalanche.

Signatures of hot carriers and hot phonons in the re-entrant metallic and semiconducting states of Moiré-gapped graphene.

Stacking of graphene with hexagonal boron nitride (h-BN) can dramatically modify its bands from their usual linear form, opening a series of narrow minigaps that are separated by wider minibands. While the resulting spectrum offers strong potential for use in functional (opto)electronic devices, a proper understanding of the dynamics of hot carriers in these bands is a prerequisite for such applications. In this work, we therefore apply a strategy of rapid electrical pulsing to drive carriers in graphene/h-BN heterostructures deep into the dissipative limit of strong electron-phonon coupling. By using electrical gating to move the chemical potential through the "Moiré bands", we demonstrate a cyclical evolution between metallic and semiconducting states. This behavior is captured in a self-consistent model of non-equilibrium transport that considers the competition of electrically driven inter-band tunneling and hot-carrier scattering by strongly non-equilibrium phonons. Overall, our results demonstrate how a treatment of the dynamics of both hot carriers and hot phonons is essential to understanding the properties of functional graphene superlattices.

Myosin motors in sensory hair bundle assembly.

Mechanosensory hair bundles are assembled from actin-based stereocilia that project from the apical surface of hair cells in the inner ear. Stereocilia architecture is critical for the transduction of sound and accelerations, and structural defects in these mechano-sensors are a clinical cause of hearing and balance disorders in humans. Unconventional myosin motors are central to the assembly and shaping of stereocilia architecture. A sub-group of myosin motors with MyTH4-FERM domains (MYO7A, MYO15A) are particularly important in these processes, and hypothesized to act as transporters delivering structural and actin-regulatory cargos, in addition to generating force and tension. In this review, we summarize existing evidence for how MYO7A and MYO15A operate and how their dysfunction leads to stereocilia pathology. We further highlight emerging properties of the MyTH4/FERM myosin family and speculate how these new functions might contribute towards the acquisition and maintenance of mechano-sensitivity.

Self-Forming p-n Junction Diode Realized with WSe2 Surface and Edge Dual Contacts.

Owing to their practical applications, two-dimensional semiconductor p-n diodes have attracted enormous attention. Over the past decade, various methods, such as chemical doping, heterojunction structures, and metallization using metals with different work functions, have been reported for fabrication of such devices. In this study, a lateral p-n junction diode is formed in tungsten diselenide (WSe2 ) using a combination of edge and surface contacts. The appearance of amorphous tungsten oxide at etched WSe2 , and the formation of a junction near the edge contact, are verified by high-resolution transmission electron microscopy. The device demonstrates high on/off ratio for both the edge and surface contacts, with respective values of 107 and 108 . The diode can achieve extremely high mobility of up to 168 cm2 V-1 s-1 and a rectification ratio of 103 . The ideality factor is 1.11 at a back gate voltage VG   = 60 V at 300 K. The devices with encapsulation of hexagonal boron nitride exhibit good stability to atmospheric exposure, over a measured period of 2 months. In addition, the architecture of the contacts, which is based on a single-channel device, should be advantageous for the implementation of more complicated applications such as inverters, photodetectors, and light-emitting diodes.

Molecular transistors as substitutes for quantum information applications.

Applications of quantum information science (QIS) generally rely on the generation and manipulation of qubits. Still, there are ways to envision a device with a continuous readout, but without the entangled states. This concise perspective includes a discussion on an alternative to the qubit, namely the solid-state version of the Mach-Zehnder interferometer, in which the local moments and spin polarization replace light polarization. In this context, we provide some insights into the mathematics that dictates the fundamental working principles of quantum information processes that involve molecular systems with large magnetic anisotropy. Transistors based on such systems lead to the possibility of fabricating logic gates that do not require entangled states. Furthermore, some novel approaches, worthy of some consideration, exist to address the issues pertaining to the scalability of quantum devices, but face the challenge of finding the suitable materials for desired functionality that resemble what is sought from QIS devices.

Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia.

The motor protein myosin-15 is necessary for the development and maintenance of mechanosensory stereocilia, and mutations in myosin-15 cause hereditary deafness. In addition to transporting actin regulatory machinery to stereocilia tips, myosin-15 directly nucleates actin filament ("F-actin") assembly, which is disrupted by a progressive hearing loss mutation (p.D1647G, "jordan"). Here, we present cryo-electron microscopy structures of myosin-15 bound to F-actin, providing a framework for interpreting the impacts of deafness mutations on motor activity and actin nucleation. Rigor myosin-15 evokes conformational changes in F-actin yet maintains flexibility in actin's D-loop, which mediates inter-subunit contacts, while the jordan mutant locks the D-loop in a single conformation. Adenosine diphosphate-bound myosin-15 also locks the D-loop, which correspondingly blunts actin-polymerization stimulation. We propose myosin-15 enhances polymerization by bridging actin protomers, regulating nucleation efficiency by modulating actin's structural plasticity in a myosin nucleotide state-dependent manner. This tunable regulation of actin polymerization could be harnessed to precisely control stereocilium height.

Asymmetrically Engineered Nanoscale Transistors for On-Demand Sourcing of Terahertz Plasmons.

Terahertz (THz) plasma oscillations represent a potential path to implement ultrafast electronic devices and circuits. Here, we present an approach to generate on-chip THz signals that relies on plasma-wave stabilization in nanoscale transistors with specific structural asymmetry. A hydrodynamic treatment shows how the transistor asymmetry supports plasma-wave amplification, giving rise to pronounced negative differential conductance (NDC). A demonstration of these behaviors is provided in InGaAs high-mobility transistors, which exhibit NDC in accordance with their designed asymmetry. The NDC onsets once the drift velocity in the channel reaches a threshold value, triggering the initial plasma instability. We also show how this feature can be made to persist beyond room temperature (to at least 75 °C), when the gating is configured to facilitate a transition between the hydrodynamic and ballistic regimes (of electron-electron transport). Our findings represent a significant step forward for efforts to develop active components for THz electronics.

Graphene on Chromia: A System for Beyond-Room-Temperature Spintronics.

Evidence of robust spin-dependent transport in monolayer graphene, deposited on the (0001) surface of the antiferromagnetic (AFM)/magneto-electric oxide chromia (Cr2 O3 ), is provided. Measurements performed in the non-local spin-Hall geometry reveal a robust signal that is present at zero external magnetic field and which is significantly larger than any possible ohmic contribution. The spin-related signal persists well beyond the Néel temperature (≈307 K) that defines the transition between the AFM and paramagnetic states, remaining visible at the highest studied temperature of close to 450 K. This robust character is consistent with prior theoretical studies of the graphene/Cr2 O3 system, predicting that the lifting of sub-lattice symmetry in the graphene shall induce an effective spin-orbit term of ≈40 meV. Overall, the results indicate that graphene-on-chromia heterostructures are a highly promising framework for the implementation of spintronic devices, capable of operation well beyond room temperature.

DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks.

PURPOSE: In acute myeloid leukemia (AML), recurrent DNA methyltransferase 3A (DNMT3A) mutations are associated with chemoresistance and poor prognosis, especially in advanced-age patients. Gene-expression studies in DNMT3A-mutated cells identified signatures implicated in deregulated DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here, we tested whether pharmacologically induced replication fork stalling, such as with cytarabine, creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations. EXPERIMENTAL DESIGN: Leukemia cell lines, genetic mouse models, and isogenic cells with and without DNMT3A(mut) were used to evaluate sensitivity to nucleoside analogues such as cytarabine in vitro and in vivo, followed by analysis of DNA damage and signaling, replication restart, and cell-cycle progression on treatment and after drug removal. Transcriptome profiling identified pathways deregulated by DNMT3A(mut) expression. RESULTS: We found increased sensitivity to pharmacologically induced replication stress in cells expressing DNMT3A(R882)-mutant, with persistent intra-S-phase checkpoint activation, impaired PARP1 recruitment, and elevated DNA damage, which was incompletely resolved after drug removal and carried through mitosis. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine washout demonstrated a higher rate of fork collapse in DNMT3A(mut)-expressing cells. RNA-seq studies supported deregulated cell-cycle progression and p53 activation, along with splicing, ribosome biogenesis, and metabolism. CONCLUSIONS: Together, our studies show that DNMT3A mutations underlie a defect in recovery from replication fork arrest with subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during replication stress. See related commentary by Viny, p. 573.

Signature of Spin-Resolved Quantum Point Contact in p-Type Trilayer WSe2 van der Waals Heterostructure.

In this study, an electrostatically induced quantum confinement structure, so-called quantum point contact, has been realized in a p-type trilayer tungsten diselenide-based van der Waals heterostructure with modified van der Waals contact method with degenerately doped transition metal dichalcogenide crystals. Clear quantized conductance and pinch-off state through the one-dimensional confinement were observed by dual-gating of split gate electrodes and top gate. Conductance plateaus were observed at a step of e2/h in addition to quarter plateaus such as 0.25 × 2e2/h at a finite bias voltage condition indicating the signature of intrinsic spin-polarized quantum point contact.

Relationships among behavioural regulations, physical activity, and mental health pre- and during COVID-19 UK lockdown.

A nationwide survey was conducted during the first UK lockdown to further understanding of the degree to which motives for exercise were associated with physical activity (PA) behaviours and, in turn, how PA behaviours were associated with mental health. A cross-sectional design was employed and data were collected by use of a one-off online survey (N = 392; 18-85 years; M BMI = 25.48; SD BMI = 5.05; 314 women). Exercise motives, PA, and mental health were measured by use of the Behavioural Regulations in Exercise Questionnaire-3, Brunel Lifestyle Physical Activity Questionnaire, and General Health Questionnaire-12, respectively. Participants were also asked to specify their average step count per day, if they used a mobile device for this purpose (n = 190). Analyses comprised hierarchical regressions and partial correlations. Results indicated that behavioural regulations were more strongly associated with planned PA pre-lockdown, compared to during lockdown. There were no differences observed in explained variance between pre- and during lockdown for unplanned PA and steps per day. Planned and unplanned PA were significant explanatory variables for mental health both pre- and during lockdown, but sedentary behaviour was not. Partial correlations, with BMI and age partialled out, showed that steps per day were not correlated with mental health either pre- or during lockdown. The range of variables used to explain planned and unplanned PA and mental health suggest that people's motives to exercise were tempered by lockdown. For those who routinely measured their steps per day, the step count was unrelated to their mental health scores both pre- and during lockdown. It appears that engagement in regular PA confers some minor benefits for mental health.

Physical activity and mental well-being under COVID-19 lockdown: a cross-sectional multination study.

BACKGROUND: COVID-19 lockdowns have reduced opportunities for physical activity (PA) and encouraged more sedentary lifestyles. A concomitant of sedentariness is compromised mental health. We investigated the effects of COVID-19 lockdown on PA, sedentary behavior, and mental health across four Western nations (USA, UK, France, and Australia). METHODS: An online survey was administered in the second quarter of 2020 (N = 2541). We measured planned and unplanned dimensions of PA using the Brunel Lifestyle Physical Activity Questionnaire and mental health using the 12-item General Health Questionnaire. Steps per day were recorded only from participants who used an electronic device for this purpose, and sedentary behavior was reported in hours per day (sitting and screen time). RESULTS: In the USA and Australia samples, there was a significant decline in planned PA from pre- to during lockdown. Among young adults, Australians exhibited the lowest planned PA scores, while in middle-aged groups, the UK recorded the highest. Young adults exhibited the largest reduction in unplanned PA. Across nations, there was a reduction of ~ 2000 steps per day. Large increases in sedentary behavior emerged during lockdown, which were most acute in young adults. Lockdown was associated with a decline in mental health that was more pronounced in women. CONCLUSIONS: The findings illustrate the deleterious effects of lockdown on PA, sedentary behavior, and mental health across four Western nations. Australian young and lower middle-aged adults appeared to fare particularly badly in terms of planned PA. The reduction in steps per day is equivalent to the non-expenditure of ~ 100 kcal. Declines in mental health show how harmful lockdowns can be for women in particular.