Miracle-dz/UniFAR-FTUs huggingface dataset:
Locomotion control during curb descent: Bilateral ground reaction variables covary consistently during the double support phase regardless of future foot placement constraints

During community ambulation, anticipatory adaptations in gait are key for navigating built, populated and natural environments. It has been argued that some instability in gait can be functionally beneficial in situations demanding high maneuverability, and while the mechanisms utilized to maintain locomotor balance are well understood, relatively less is known about how the control of gait stability changes to facilitate upcoming maneuvers in challenging environments. The double support phase may be important in this regard; since both feet can push off the ground simultaneously, there is greater control authority over the body’s movement during this phase. Our goal was to identify how this control authority is exploited to prepare for upcoming maneuvers in challenging environments. We used synergy indices to quantify the degree of coordination between the ground reaction forces and moments under the two feet for stabilizing the resultant force and moment on the body during the double support phase of curb descent. In contrast to our expectations, we observed that the kinetic synergy indices during curb descent were minimally influenced by expected foot targeting maneuvers for the subsequent step. Only the resultant moment in the frontal plane showed reduced stability when targeting was required, but the synergy index was still high, indicating that the resultant moment was stable. Furthermore, the synergy indices indicated that the main function of the ground reaction variables is to maintain stability of whole-body rotations during double support, and this prerogative was minimally influenced by the subsequent foot targeting tasks, likely because the cost of losing balance while descending a curb would be higher than the cost of mis-stepping on a visual target. Our work demonstrates the salience of stabilizing body rotations during curb negotiation and improves our understanding of locomotor control in challenging environments.
The free fatty acid–binding pocket is a conserved hallmark in pathogenic β-coronavirus spike proteins from SARS-CoV to Omicron

As COVID-19 persists, severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor-binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA-binding stabilizes a locked S conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic β-coronaviruses (β-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2 and VOCs bind the essential FFA linoleic acid (LA), while binding is abolished by one mutation in common cold-causing HCoV-HKU1. In the SARS-CoV S structure, LA stabilizes the locked conformation while the open, infectious conformation is LA-free. Electron tomography of SARS-CoV-2 infected cells reveals that LA-treatment inhibits viral replication, resulting in fewer, deformed virions. Our results establish FFA-binding as a hallmark of pathogenic β-CoV infection and replication, highlighting potential antiviral strategies. One-Sentence Summary Free fatty acid-binding is conserved in pathogenic β-coronavirus S proteins and suppresses viral infection and replication.
Replicative ageing perturbs the metabolic signature of murine C2C12 skeletal myotubes

Introduction Chronological ageing is associated with mitochondrial dysfunction and increased reactive oxygen species (ROS) production in skeletal muscle. However, the effects of replicative ageing on skeletal muscle cellular metabolism are not well known. Using an established myoblast model of cellular (replicative) ageing, we investigated the impact of ageing on energy metabolism in murine C2C12 myotubes. Methods Control (P7-11) and replicatively ‘aged’ (P48-51) C2C12 myoblasts were differentiated over 72-120 h. Mitochondrial bioenergetics were investigated by respirometry and mitochondrial superoxide and cellular ROS were measured in the absence and presence of antimycin A (AA). Genes related to mitochondrial remodelling and the antioxidant response were quantified by RT-qPCR. Intracellular metabolites were quantified using an untargeted 1H-NMR metabolomics pipeline. Results Mitochondrial coupling efficiency (Control: 79.5 vs. Aged: 70.3%, P=0.006) and relative oxidative ATP synthesis (Control: 48.6 vs. Aged: 31.7%, P=0.022) were higher in control vs. aged myotubes, but rates of mitochondrial superoxide production were lower (Control: 2.4×10−5 ± 0.4 × 10−5 vs. Aged: 9.7×10−5 ± 1.6×10−5 RFU/sec/cell; P=0.035). Replicatively aged myotubes had greater mRNA expression of mfn2 and Tfam compared to control. Yet, Nrf2 and PGC-1α expression were 2.8-fold and 3.0-fold higher in control versus aged myotubes over 24 h and 48 h (P<0.05), respectively. Branched chain amino acids L-leucine, L-isoleucine and L-valine, and L-carnitine were less abundant in aged versus control myotubes. Conclusion(s) Replicative ageing is associated with bioenergetic uncoupling, increased ROS production and impaired amino acid metabolism. Our findings suggest that cellular mitochondrial dysfunction and altered energy metabolism may exacerbate the age-related decline in skeletal muscle mass and function.
Rapid evolution of sex role specialization in a hermaphrodite under sex-limited selection

The evolution of separate sexes from hermaphroditism is thought to have occurred independently many times, and is linked to the evolution of sex chromosomes. Even though we have a good understanding of the theoretical steps in the evolution of sex chromosomes from a hermaphrodite ancestor, the initial stages are still hard to study because many sex chromosome systems are old. We addressed this problem by experimentally selecting a hermaphrodite via sex-limited experimental evolution for several generations, simulating the early stages in the evolution of a sex chromosome. More specifically, we used a GFP (green fluorescent protein) marker as a proxy for a sex-determining locus, and selected replicate populations of the simultaneously hermaphroditic flatworm Macrostomum lignano for fitness via the male sex role, female sex role, or both (i.e. a control). After 14 generations, a fitness assay revealed clear evidence for incipient sex role specialization, presumably reflecting the release from constraints usually imposed by selection on the other sex role. Importantly, however, this was not simply explained by differential sex allocation in the different selection regimes - insofar as morphological traits reflect the underlying trade-off over resource allocation to the male and female sex functions - because testis and ovary sizes did not diverge among treatments. Our study shows that sex role specialization can occur rapidly as a result of sex-limited selection, which is consistent with genetic constraints between sex-roles, and in line with the first predicted steps towards the evolution of a new sex chromosome system.
A revised perspective on the evolution of troponin I and troponin T in vertebrates

The troponin (Tn) complex, responsible for the Ca2+ activation of striated muscle, is composed of three interacting protein subunits: TnC, TnI, and TnT, encoded by TNNC, TNNI, and TNNT genes. TNNI and TNNT are sister gene families, and in mammals the three TNNI paralogs (TNNI1, TNNI2, TNNI3), which encode proteins with tissue-specific expression, are each in close genomic proximity with one of the three TNNT paralogs (TNNT2, TNNT3, TNNT1, respectively). It has been widely presumed that all vertebrates broadly possess genes of these same three classes, although earlier work has overlooked jawless fishes (cyclostomes) and cartilaginous fishes (chimaeras, rays and sharks), which are distantly related to other jawed vertebrates. With a new phylogenetic and synteny analysis of a diverse array of vertebrates including these taxonomic groups, we define five distinct TNNI classes (TNNI1-5), with TNNI4 and TNNI5 being only present in non-mammalian vertebrates and typically found in tandem, and four classes of TNNT (TNNT1-4). These genes are located in four genomic loci that were generated by the 2R whole-genome duplication events. TNNI3, encoding ‘cardiac TnI’ in mammals, was independently lost in cartilaginous and ray-finned fishes. Ray-finned fishes predominantly express TNNI1 in the heart. TNNI5 is highly expressed in shark hearts and contains an N-terminal extension similar to that of TNNI3 found in tetrapod hearts. Given that TNNI3 and TNNI5 are distantly related, this supports the hypothesis that the N-terminal extension may be an ancestral feature of vertebrate TNNI and not an innovation unique to TNNI3, as has been commonly believed.
Heavy metals in moss guide environmental justice investigation: a case study using community science in Seattle, WA, USA

Heavy metals concentrations often vary at small spatial scales not captured by air monitoring networks, with implications for environmental justice in industrial-adjacent communities. Pollutants measured in moss tissues are commonly used as a screening tool to guide use of more expensive resources, like air monitors. Such studies, however, rarely address environmental justice issues or involve the residents and other decision-makers expected to utilize results. Here, we piloted a community science approach, engaging over 55 people from nine institutions, to map heavy metals using moss in two industrial-adjacent neighborhoods. This area, long known for disproportionately poor air quality, health outcomes, and racial inequities, has only one monitor for heavy metals. Thus, an initial understanding of spatial patterns is critical for gauging whether, where, and how to invest further resources towards investigating heavy metals. Local youth led sampling of the moss Orthotrichum lyellii from trees across a 250×250-m sampling grid (n = 79) and generated data comparable to expert-collected samples (n = 19). We mapped 21 chemical elements measured in moss, including 6 toxic ‘priority’ metals: arsenic, cadmium, chromium, cobalt, lead, and nickel. Compared to other urban O. lyellii studies, local moss had substantially higher priority metals, especially arsenic and chromium, encouraging community members to investigate further. Potential hotspots of priority metals varied somewhat but tended to peak near the central industrial core where many possible emissions sources, including legacy contamination, converge. Informed by these findings, community members successfully advocated regulators for a second study phase – a community-directed air monitoring campaign to evaluate residents’ exposure to heavy metals – as is needed to connect moss results back to the partnership’s core goal of understanding drivers of health disparities. This follow-up campaign will measure metals in the PM10 fraction owing to clues in the current study that airborne soil and dust may be locally important carriers of priority metals. Future work will address how our approach combining bioindicators and community science ultimately affects success addressing longstanding environmental justice concerns. For now, we illustrate the potential to co-create new knowledge, to help catalyze and strategize next steps, in a complex air quality investigation.
Quantifying the fraction of new mutations that are recessive lethal

The presence and impact of recessive lethal mutations has been widely documented in diploid outcrossing species. However, precise estimates in different species of the proportion of mutations that are recessive lethal remain limited. Here, we attempt to quantify the fraction of new mutations that are recessive lethal using Fit∂a∂i, a commonly-used method for inferring the distribution of fitness effects (DFE) using the site frequency spectrum. Using simulations, we demonstrate that Fit∂a∂i cannot accurately estimate the fraction of recessive lethal mutations, as expected given that Fit∂a∂i assumes that all mutations are additive by default. Consistent with the idea that mis-specification of the dominance model can explain this performance, we find that Fit∂a∂i can accurately infer the fraction of additive lethal mutations. Moreover, we demonstrate that in both additive and recessive cases, inference of the deleterious non-lethal portion of the DFE is minimally impacted by a small proportion (<10%) of lethal mutations. Finally, as an alternative approach to estimate the proportion of mutations that are recessive lethal, we employ models of mutation-selection-drift balance using existing genomic parameters and segregating recessive lethals estimates for humans and Drosophila melanogaster. In both species, we find that the segregating recessive lethal load can be explained by a very small fraction (<1%) of new nonsynonymous mutations being recessive lethal. Our results refute recent assertions of a much higher recessive lethal mutation fraction (4-5%), while highlighting the need for additional information on the joint distribution of selection and dominance coefficients.
Upregulated Ca2+ release from the endoplasmic reticulum leads to impaired presynaptic function in Alzheimer’s disease

Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca2+ influx through membrane-resident voltage-gated Ca2+ channels (VGCCs). Also, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively present in axonal terminals of neurons and plays a modulatory role in synaptic transmission by regulating Ca2+ levels. Alzheimer’s disease (AD) is marked by enhanced Ca2+ release from the ER and downregulation of Ca2+ buffering proteins. However, the precise consequence of impaired Ca2+ signalling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in-silico experiments of intracellular Ca2+ signalling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca2+ signalling on neurotransmitter release in AD. Our model predicts that enhanced Ca2+ release from the ER increases the probability of neurotransmitter release in AD. Moreover, over very short timescales (30-60 msec), the model exhibits activity-dependent and enhanced short-term plasticity in AD, indicating neuronal hyperactivity—a hallmark of the disease. Similar to previous observations in AD animal models, our model reveals that during prolonged stimulation (~450 msec), pathological Ca2+ signalling increases depression and desynchronization with stimulus, causing affected synapses to operate unreliably. Overall, our work provides direct evidence in support of a crucial role played by altered Ca2+ homeostasis mediated by intracellular stores in AD.
Multiple Starting Lines: Pre-college Characteristics of Community College and Four-year Institution Engineering Students

In response to the pressing need to expand and diversify the engineering workforce, there has been a focus on using community colleges as pathways to four-year engineering programs. To date, there has been little empirical research on the effectiveness of transfer via this pathway for engineering specifically. This analysis compares the pre-college characteristics for students who identify as “pre-engineering” in community colleges with students who initially enrolled in or successfully transferred to a four-year undergraduate degree in engineering. It draws on data from a nationally representative study of 31 four-year engineering institutions and the 15 community colleges which produce the largest number of pre-engineering students in the United States. Specifically, this analysis focuses on the following pre-college characteristic categories: 1) sociodemographic characteristics; 2) high school academic preparation and achievement; and 3) personal and social experiences with which they arrive to college. Findings demonstrate considerable differences between the entering characteristics of community college preengineering students, successful transfers, and students first-enrolling in four-year engineering programs for all three categories. Based on these empirical results, we offer recommendations for programs to implement to work toward improving the community college-to-four-year engineering program transfer pipeline.
Maintenance of quantitative genetic variance in complex, multitrait phenotypes: the contribution of rare, large effect variants in 2 Drosophila species

The interaction of evolutionary processes to determine quantitative genetic variation has implications for contemporary and future phenotypic evolution, as well as for our ability to detect causal genetic variants. While theoretical studies have provided robust predictions to discriminate among competing models, empirical assessment of these has been limited. In particular, theory highlights the importance of pleiotropy in resolving observations of selection and mutation, but empirical investigations have typically been limited to few traits. Here, we applied high dimensional Bayesian Sparse Factor Genetic modelling to 3,385 gene expression traits from Drosophila melanogaster and from D. serrata to explore how genetic variance is distributed across high-dimensional phenotypic space. Surprisingly, most of the heritable trait covariation was due to few lines (genotypes) with extreme (>3 IQR from the median) values. This observation, in the two independently sampled species, suggests that the House of Cards (HoC) model might apply not only to individual expression traits, but also to emergent co-expression phenotypes. Intriguingly, while genotypes extreme for a multivariate factor also tended to have a higher proportion of individual traits that were extreme, we also observed genotypes that were outliers for multivariate factors but not for any individual traits. We observed other consistent differences between heritable multivariate factors with outlier lines versus those factors that conformed to a Gaussian distribution of genetic effects, including differences in gene functions. We use these observations to identify further data required to advance our understanding of the evolutionary dynamics and nature of standing genetic variation for quantitative traits.
Does fatigue influence joint-specific work and ground force production during the first steps of maximal accelerative running?

The rate of initial acceleration during the first steps of a maximal-effort (sprint) run often determines success or failure in prey capture and predator evasion, and is a vital factor of success in many modern sports. However, accelerative events are commonly performed after having already run considerable distances, and the associated fatigue should impair muscle force production and thus reduce acceleration rate. Despite this, the effects of running-induced fatigue on our ability to accelerate as well as the running technique used to achieve it has been incompletely studied. We recorded 3-D kinematics and ground reaction forces during the first three steps of the acceleration phase from a standing start before and after performing a high-speed, multi-directional, fatiguing run-walk protocol in well-trained running athletes who were habituated to accelerative sprinting. We found that the athletes were able to maintain their rate of initial acceleration despite changing running technique, which was associated with use of a more upright posture, longer ground contact time, increased vertical ground reaction impulse, decreased hip flexion and extension velocities, and a shift in peak joint moments, power, and positive work from the hip to the knee joint; no changes were detected in ankle joint function. Thus, a compensatory increase in knee joint function alleviated the reduction in hip flexor-extensor capacity. These acute adaptations may indicate that the hip extensors (gluteal and hamstring muscle groups) were more susceptible to fatigue than the ankle and knee musculature, and may thus be a primary target for interventions promoting fatigue resistance.
Fluid manipulations uncover mechanosensation for zebrafish left-right establishment during one-hour time interval

Humans and other vertebrates define body axis left-right asymmetry in the early stages of embryo development. The mechanism behind left-right establishment is not fully understood. Although it is known that the symmetry break occurs in a dedicated organ called the left-right organizer (LRO) and involves motile cilia generating fluid flow therein, it has been a matter of debate whether the process of symmetry breaking relies on a chemosensory or a mechanosensory mechanism. Novel tailored manipulations for LRO fluid extraction in living zebrafish embryos allowed us to pinpoint a decisive developmental period for breaking left-right symmetry during development. This critical time-window was narrowed to one hour and is characterized by a mild counterclockwise flow. The experimental challenge in our approach consisted of emptying the LRO of any potential fluid, abrogating simultaneously flow force and chemical determinants. Our findings revealed an unprecedented recovery capacity of the embryo to re-inflate and re-circulate the fluid inside the LRO exposing unknown properties of this transient organ. Live extraction and replacement of LRO fluid while changing dilution or viscosity demonstrated that early left-right patterning depends on fluid flow mechanics rather than on the nature of the fluid content. Our results advocate for a mechanosensory mechanism ruling left-right early development. Teaser Zebrafish uses mechanosensation during one-hour time-window to initiate left-right development
Active mechanics of sea star oocytes

Actomyosin is a canonical example of an active material, driven out of equilibrium in part through the injection of energy by myosin motors. This influx of energy allows actomyosin networks to generate cellular-scale contractility, which underlies cellular processes ranging from division to migration. While the molecular players underlying actomyosin contractility have been well characterized, how cellular-scale deformation in disordered actomyosin networks emerges from filament-scale interactions is not well understood. Here, we address this question in vivo using the meiotic surface contraction wave of Patiria miniata oocytes. Using pharmacological treatments targeting actin polymerization, we find that the cellular deformation rate is a nonmonotonic function of cortical actin density peaked near the wild type density. To understand this, we develop an active fluid model coarse-grained from filament-scale interactions and find quantitative agreement with the measured data. This model further predicts the dependence of the deformation rate on the concentration of passive actin crosslinkers and motor proteins, including the surprising prediction that deformation rate decreases with increasing motor concentration. We test these predictions through protein overexpression and find quantitative agreement. Taken together, this work is an important step for bridging the molecular and cellular length scales for cytoskeletal networks in vivo.