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Integration of learned artificial sensation with vision during freely moving navigation
Humans rely on both proprioceptive and visual feedback during reaching, integrating these two sensory streams to improve movement accuracy and precision. Patients using a brain-computer interface will similarly require artificial proprioceptive feedback in addition to vision to finely control a prosthesis. Intracortical microstimulation (ICMS) elicits sensory perceptions that could replace the lost proprioceptive signal. However, some learning may be required for encoding artificial sensation, as current technology does not give access to neurons with all of the desired encoding properties. We developed a freely moving mouse behavioral task in which to test learning and integration of artificial sensory information with natural vision. Mice implanted with a 16-channel microwire array in the primary somatosensory cortex were trained to navigate to randomly selected targets upon the floor of a custom behavioral training chamber. Target location was encoded with visual and/or patterned multichannel ICMS feedback. Mice received multimodal feedback from the beginning of training of the behavioral task, achieving 75% on multimodal trials after approximately 1,000 training trials. Mice also quickly learned to use the ICMS signal to locate invisible targets, achieving 75% proficiency on ICMS-only trials when tested. Critically, we found that performance with ICMS was as good or better than performance with natural vision, and that performance on multimodal trials significantly exceeded unimodal performance (vision or ICMS), demonstrating that animals rapidly learned to integrate natural vision with artificial sensation.
HOP2–MND1 chaperones a diffusing DMC1–ssDNA complex to survey dsDNA for homology recognition during meiotic recombination
Meiotic recombination ensures genetic diversity and accurate chromosome segregation by mediating reciprocal DNA exchange between homologous chromosomes. In this process, the meiosis-specific recombinase DMC1 plays a pivotal role in homology search and pairing, but the molecular mechanisms underlying its function remain unclear. Using single-molecule imaging, we demonstrate that the human DMC1–ssDNA presynaptic complex employs a diffusion-based mechanism to search for homologous DNA. Although this diffusing complex generates a migrating DNA “bubble,” it cannot align with the homologous sequence in the absence of free DMC1 protein. Strikingly, the meiosis-specific cofactor complex HOP2–MND1 compensates for the lack of free DMC1 and enables homology recognition. Notably, HOP2–MND1 achieves this by codiffusing with the presynaptic complex, acting to clamp the ssDNA–dsDNA junctions and maintain an expanded DNA bubble conducive to sequence alignment. Our findings identify DMC1 together with HOP2–MND1 as a functional homology search unit and provide mechanistic insights into how auxiliary factors regulate DMC1-driven strand exchange during meiotic recombination.
Why Biden-era clean energy investment policies had limited political returns
The Biden Administration enacted the largest federal policy framework to incentivize clean energy and decarbonization in U.S. history. We examine whether Biden-era green investments produced political returns by affecting public opinion. Using geolocated survey data linked to investment records and a database of company and politician statements, we assess project visibility and credit attribution. People closer to new renewable energy and green manufacturing facilities are more likely to notice these investments but are not more likely to credit the Biden Administration. Instead, the public sees governors as most responsible. This credit allocation pattern aligns with the political message environment: Governors more frequently claim credit than the White House and companies spread recognition broadly across political actors. This fragmented information environment illustrates the limits of using less traceable forms of green spending to generate electoral gains and public support for climate policy.
Evolutionary remodeling of a remnant GET pathway factor into PEX38, an essential peroxin
PEX19 is a cytosolic receptor that directs membrane proteins posttranslationally to peroxisomes, as well as to mitochondria, lipid droplets, and the endoplasmic reticulum. A comprehensive Trypanosoma PEX19 interactome analysis uncovered PEX38 as an essential Euglenozoa-specific peroxin. PEX38 contains distinct domains that bind the cochaperone Hip and the PEX3-binding motif of PEX19, suggesting a role in stabilizing membrane proteins and preventing premature membrane docking. PEX38 illustrates functional repurposing in organelle biogenesis. It originated from a remnant of the GET/TRC pathway, typically responsible for the targeting of tail-anchored (TA) proteins to the endoplasmic reticulum. While most components of this machinery are absent in Euglenozoa, PEX38 has been retained and adapted to mediate peroxisomal membrane protein targeting. This evolutionary adaptation is unique to Euglenozoa. Because the PEX19–PEX38 interaction is essential for parasite viability and PEX38 has no human homologs, this complex is a promising therapeutic target against trypanosomatid parasites.
Chiral gliding: Right-handed navigation of filamentous cyanobacteria
Cyanobacteria are the earliest known organisms that produced oxygen through photosynthesis, leading to the oxygen atmosphere that allowed the evolution of more complex life forms. Many species of cyanobacteria exhibit gliding motility along surfaces to navigate complex environments and adapt to fluctuating conditions. Here, we studied the gliding motility of filamentous cyanobacteria Lyngbya lagerheimii at the transition between different physical environments. We show that on a dry surface, a filament adopts a curved shape that turns right while gliding. When a filament switches the gliding direction, the curvature is initially preserved and a filament can turn left as long as it backtracks along a slime trace. We propose a model of chiral motility that explains the bending based on the right-handed rotation of gliding filaments and a velocity mismatch between the leading and the trailing end of the filament. The mechanism involves a unique way of transferring the structural chirality to the macroscale and also a unique physical navigation mechanism.
The Rab5 effector Rabankyrin-5 mediates endosomal fusion and trafficking of human papillomavirus during early entry
The fusion of newly formed early endosomal vesicles after endocytosis is a crucial step in viral infection. It facilitates the transition of many viruses from viral internalization to downstream intracellular trafficking within the endosomal network, ultimately enabling their delivery to intracellular replication sites. Despite its significance, the molecular mechanisms regulating the fusion of these vesicles remain poorly understood. In this study, we show that Rabankyrin-5, a Rab5 effector, is essential for the fusion of human papillomavirus (HPV)-carrying early endosomes during viral entry. Additionally, Rabankyrin-5 acts as a dynein adaptor, directly binding both the HPV minor capsid protein L2 and the dynein motor complex to link virus-carrying early endosomes to the dynein transport machinery, thereby promoting virus movement along microtubules. These dual functions enable the coordinated integration of endosomal fusion with microtubule-based transport during the early stages of viral entry.
From peptides to DNA: All required steps can be catalyzed
Ensuring information flow (heredity) and metabolic processes (catalysis) are two important prerequisites for early evolution. The widely accepted “RNA world” theory proposes that ancient RNAs ensured both heredity and catalysis during the transition from prebiotic to biotic evolution. However, alternative hypothetical molecules and processes have also been proposed, suggesting that catalytic peptides may have existed before polynucleotides, and that their sequences were later reverse translated into genes. Our objective was to experimentally address these alternative theories by asking whether the steps required for the hypothetical conversion of peptide sequences into DNA could be catalyzed by the existing molecular kit. The reactions we tested comprise i) step-wise degradation of peptides by a processive amino peptidase, sequentially releasing amino acids, ii) matching the identity of released amino acids to codons by aptazymes (RNA adapters that recognize amino acids and self-cleave and release specific codon triplets in response), and iii) ligating codon triplets into longer RNAs that can be reverse-transcribed into DNA. In a hypothetical processive system based on these reactions, the resulting DNA sequence would match the sequence of amino acids in the starting peptide. Our results suggest that all these steps can be catalyzed, and therefore the possibility of reverse translation occurring at some point in early evolution should not be disregarded.
Mesophases as stepping stones to enhance crystallization kinetics in nanoparticle self-assembly
Manipulation of kinetic pathways is essential to self-assemble nanoparticle building blocks into complex ordered structures, as the emergence of intermediate metastable states could either facilitate or hinder crystallization of the target lattice. Molecular simulations and Markovian and transition state theory are used to validate our conjecture that intermediary mesophases, with partial but long-range translational or orientational structural ordering, accelerate crystallization kinetics from the disordered structure. Using four representative models, two lyotropic single-component and two thermotropic binary mixture systems, we demonstrate that mesophases with intermediate entropies, such as nematic fluid, rotator solid, and microsegregated mesophases, speed up the overall crystallization rate. This enhancement occurs by effectively splitting a larger isotropic-to-crystal free energy barrier into two smaller barriers corresponding to isotropic-to-mesophase and mesophase-to-crystal transitions, with mesophase “bulk” macrostates being kinetically more favorable than microscopic fluctuations. The single-step isotropic-to-crystal transition occurs through a composite-cluster pathway that includes mesophase microdomains; an isotropic-crystal interfacial energy greater than or comparable to the sum of the isotropic-mesophase and mesophase-crystal interfacial energies is associated with enhanced two-step crystallization rate. Overall, our findings validate the conjecture, which offers additional guidance for selecting nanoparticle designs and conditions that promote efficient crystallization pathways.
Anomalous enhancement of thermal conduction across twisted van der Waals heterointerfaces
The advent of interlayer twist has introduced a groundbreaking paradigm, unveiling novel physical phenomena spanning from correlated insulating states to superconductivity. This unprecedented platform facilitates the manipulation of electrons and extends its capabilities to the effective control of bosons. For phonons, a consensus has been reached that interlayer twist greatly suppresses phonon transport as it breaks the symmetry of the lattice. Here, we report a counterintuitive experimental observation in which the interlayer twist can significantly promote the transportation of phonons across an intrinsically asymmetric heterointerface. Employing the time-domain thermoreflectance mapping technique, our results show a 2.5-fold increase in interfacial thermal conductance (ITC) in twisted bilayer MoS 2 /WS 2 heterostructures relative to initial commensurate configurations. Combined experimental and atomic simulation results reveal the inelastic scattering-dominated nature of thermal transport at MoS 2 /WS 2 heterointerfaces. The introduction of interlayer twist amplifies this effect, triggering a reconstruction of nonequilibrium phonon temperature distributions at the interface. This phenomenon activates efficient optical-to-acoustic phonon conversion through inelastic scattering and creates additional transport channels that overcome the intrinsic phonon mismatch in heterostructures. Our work establishes a paradigm for enhancing ITC by strategically introducing interlayer perturbations to amplify inelastic scattering effects. This breakthrough opens broad avenues for advanced thermal management in integrated circuits.
Cell fate acquisition at a de novo developmental boundary in the maize leaf
The formation of boundaries separating developmental fields with distinct gene expression and cell fate trajectories is a universal feature of noncolonial multicellular organisms. Developmental boundaries arise reiteratively during ontogeny and are characterized by stiff, slowly dividing cells that demarcate adjacent and divergent morphogenetic domains; the genetic mechanisms of cell fate acquisition within these boundaries are incompletely understood. Grass leaves are initiated at a developmental boundary in the periphery of the shoot apical meristem, an organogenic pool of plant stem cells that generates all lateral organs in the plant shoot. During later primordial growth, maize leaves form a de novo developmental boundary that ultimately separates the distal, photosynthetic leaf blade from the proximal, clasping leaf sheath. Morphogenesis at this blade/sheath boundary in maize leaves generates an epidermal outgrowth called the ligule and two tissue-wedges forming the auricle, a hinge-like structure with major effects on leaf angle, light capture, and yield. Here, we use cell lineage mapping, morphometric measures of cell division and expansion, cell-specific multidimensional transcriptomic analyses, and topological landscape modeling to investigate the mechanisms of cell fate acquisition at the ligule/auricle morphogenetic boundary in the maize leaf. The data suggest a model where auricle initial cells are recruited from blade founder cells at this boundary, via repression of blade identity during early stages in auricle ontogeny. Thereafter, auricle primordial cells assume a developmental genetic trajectory that is distinct from the blade, sheath, and ligule, thereby acquiring a unique auricle cell fate in the maize leaf.
Leveraging the kinetic isotope effect by compact H-bond motifs for electrochemical hydrogen isotope separation
Electrochemical hydrogen isotope separation has been constrained for decades by the similar energy barriers of the rate-determining O–H and O–D bond cleavage step in water isotopologues. Herein, we compact H-bond connectivity through screening a series of additives to stimulate electrochemical proton quantum tunneling (QT) behaviors of “through-barrier”, which are virtually impossible for heavier D-relevant motions. The average H-bond length of H 2 O⋯OH − is 3.4% shorter (2.78 Å) with isopropanol additive at the engineered interface. Fundamentally, QT effects are magnified by selectively promoting proton transfer-involved reactions through strengthening the H-bond and filling the H-bond gap, which are further proved by both experimental Arrhenius plots with near small-curvature tunneling approximation and a stronger proton excursion in path integral molecular dynamics simulations. Hence, a record-high H 2 O separation factor of 276 is realized at room temperature with a three-order-of-magnitude growth of H/D kinetic isotope effect constant up to 10,165. Significantly, a large-scale multistage reactor is engineered to obtain continuous enrichment of heavy water with a deuterium atomic fraction over 80%.
Capturing ribosomal structures in cellular extracts with cryoPRISM: A purification-free cryoEM approach reveals novel structural states
Structural analyses of ribosomes by single particle cryogenic electron microscopy (cryoEM) have traditionally relied on purified or reconstituted samples, with particles often trapped in desired states using genetic, pharmacological, or biochemical perturbations. While informative, such in vitro methods often fail to capture the full diversity of structural states and associated protein factors present in cells. In contrast, in situ cryoelectron tomography preserves cellular context but is limited by low throughput and modest resolution. Here, we present cryoPRISM (purification-free ribosome imaging from subcellular mixtures), a rapid ex vivo workflow encompassing cell lysis, vitrification, and image analysis methods for high-resolution analyses of ribosomal structures directly from cell lysates. Applying cryoPRISM in Escherichia coli , we resolved more than 20 distinct ribosomal states spanning assembly, translation initiation, elongation, trans-translation, and quiescence, including a novel configuration of EF-G bound to idle ribosomes with the ribosome hibernation factor ribosome-associated inhibitor A. Given its speed, accessibility, and ability to preserve native interactions and structural heterogeneity, we anticipate that cryoPRISM will be broadly applicable for uncovering ribosomal biology across diverse organisms and conditions.
Sibling number and early interactions shape social competence for life
The social environment experienced during development plays a crucial role in shaping social competence—the ability to respond appropriately to social challenges. Sibling number and the social interactions between them are key components of the early lives in many animals. While these components are well known to influence social development in humans, their role in nonhuman animals remains unclear. Here, we show that both the number of siblings and opportunities for social interaction are essential for developing social competence in the highly social cichlid Neolamprologus pulcher . Fish reared in large broods (LB) displayed more affiliative and fewer aggressive or submissive behaviors during early life compared to those reared in small broods (SB) or in large broods with restricted opportunities for interactions (4 × 8). Later in life, LB fish were more socially competent. Thus, social competence arises not from the number of individuals or interactions alone, but from the combination of both.
Neuronal TDP-43 regulates myelin formation via neurexin 1 mRNA stabilization
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) develop as spatial pathologies in which neurons and glial cells are interconnected. TAR DNA-binding protein 43 (TDP-43) is a major pathological protein that is inextricably associated with ALS and FTLD. In this study, we investigated the roles of neuronal TDP-43 in neuron–oligodendrocyte interactions using neuron-specific TDP-43 knockout (TDP-43cKO) mice. TDP-43 depletion in neurons induced hypomyelination, which was confirmed by immunohistochemistry and ultrastructural analysis. In addition, conduction disturbance was revealed by electrophysiological analysis. The hypomyelination of TDP-43cKO mouse was restored by cytoplasmic TDP-43 supplementation in neurons. Neuron-specific transcriptome analysis revealed that neurexin 1 (NRXN1) is the regulatory target of TDP-43, which promotes myelin formation. The hypomyelination of TDP-43cKO mice was also restored by NRXN1b supplementation in neurons. We further confirmed that TDP-43 stabilizes Nrxn1 mRNA by binding to the Nrxn1 3’untranslated region (3’UTR). Although TDP-43cKO exhibited impaired recognition memory, the supplementation of NRXN1 in the hippocampus recovered the memory disturbances. In conclusion, this study demonstrates the neuron–oligodendrocyte interaction mediated by neuronal TDP-43 via NRXN1 mRNA stabilization. These findings shed light on neuron–oligodendrocyte interaction in the disease mechanisms of ALS/FTLD.
Programmed meiotic errors facilitate dichotomous sperm production in the silkworm, <i>Bombyx mori</i>
The goal of meiosis is typically to produce haploid gametes (eggs or sperm). Failure to do so is catastrophic for fertility. However, Lepidopteran (moths and butterflies) males produce two sperm morphs: nucleated (eupyrene) sperm and anucleated (apyrene) sperm, both of which are essential for fertilization. The meiotic differences in the two types of spermatogenesis are unclear, and our knowledge of the molecular differences between eupyrene and apyrene spermatogenesis is extremely limited in all systems. The only factor identified as being required for apyrene spermatogenesis is Sex-lethal ( Sxl ). Here, we show through cytological analysis of meiotic events that there are several key differences in the genesis of apyrene and eupyrene sperm. Specifically, during meiosis I, apyrene spermatocytes fail to decondense and pair their chromosomes during meiotic prophase I. Telomeres fail to localize to the nuclear periphery, and full-length synaptonemal complex does not form. We also find evidence of an abnormal second cell division during apyrene meiosis. RNA sequencing of both eupyrene- and apyrene-producing testes reveals distinct changes in transcriptional programs, including down-regulation of a myriad of cell division genes during apyrene meiosis. By comparing wildtype and Sxl -knockout apyrene testes, we found that Sxl is not required for regulating the expression of the cell division genes but instead may play a role in blocking hormone signaling from altering testis cell identity. Together, our findings reveal significant insights into two converging molecular pathways that promote the formation of dimorphic sperm in Lepidoptera.
Geometrical preference of anchoring sites in the unicellular organism <i>Stentor coeruleus</i>
Organisms often inhabit environments comprising complex structures across various scales. Animals rely on visual information from surrounding geometrical structures for navigation. Even at the microscale, various microsediments form complex structures in microbial habitats. The movement of microorganisms is passively affected by collisions and hydrodynamic interactions with surrounding structures. However, the influence of microenvironmental geometry on behavioral changes of unicellular organisms that lack visual perception remains unclear. Here, we developed geometrically structured chambers to investigate anchoring site preferences in the swimming ciliate Stentor coeruleus . Our experiments revealed that S. coeruleus preferentially anchored in narrow regions characterized by specific geometrical features, including corner angle, depth, and curvature at the corner end. Before anchoring, free-swimming S. coeruleus changed its behavior to move along the boundary wall of the chambers, accompanied by Ca 2+ -induced asymmetrical body deformation. To further investigate how S. coeruleus moves along the wall continuously, we conducted a hydrodynamic simulation and revealed that the asymmetric morphology causes asymmetric propulsive forces, explaining wall-following behavior through physical interactions with a wall. Thus, morphological change near a wall causes wall-following behavior, facilitating the identification of these narrow anchoring sites. Our findings indicate that environmental geometry drives behavioral transitions in S. coeruleus through simple biophysical processes, enabling spatial selection without visual cues. Overall, these results suggest that microgeometry plays a key role in shaping ecological niches for unicellular microorganisms.
Natural History of Patients With Histologically Proven Acute Eosinophilic Myocarditis
BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.
Unraveling the maturation pathway of a eukaryotic virus through cryo-EM
Virus maturation is a fundamental biological process involving large-scale structural reorganizations that drive functional activation and lead to infectivity. Understanding the steps from the initial procapsid assembly to mature virions is essential, both for comprehending viral life cycles and for developing antiviral therapies. However, capturing these steps has been challenging due to the transient and elusive nature of intermediate states. The nonenveloped, T = 4, ssRNA-containing, Nudaurelia capensis omega virus (NωV) is a highly accessible model system that exemplifies the maturation process of a eukaryotic virus. During maturation, the particle shrinks in outer diameter from 482 Å (pH 7.6) to 428 Å (pH 5.0). It is possible to mimic the maturation process in vitro by lowering the pH of a population of procapsids produced in heterologous systems. Indeed, by controlling the pH in vitro, it is possible to produce homogenous populations of intermediate NωV virus-like particles (VLPs) that occur too fleetingly to be observed in vivo. Here, we report structural models, based on cryoelectron microscopy (cryo-EM), of five intermediates in the NωV maturation process. The structures of the intermediate particles reveal unique, quaternary position-dependent trajectories and refolding of subunit N and C-terminal regions, including the formation of the autocatalytic cleavage site at N570. The detailed structures reported here, coupled with previously determined structures of the procapsids and mature particles, allow the maturation pathway to be described in detail for a eukaryotic virus.
Bradycardia in Athletes: Prevalence, Mechanisms, and Risks
BACKGROUND: Sinus bradycardia is a well-recognized physiological adaptation in endurance athletes, primarily attributed to sinus node remodeling or increased vagal modulation. Although genetic influences on resting heart rate (HR) have been observed, the genetic contribution to athletic bradycardia has not been elucidated. METHODS: We phenotyped current and former elite endurance athletes in the Pro@Heart cohort study using multimodal cardiac imaging, cardiopulmonary exercise testing, and Holter monitoring. Genetic susceptibility to bradycardia was assessed using a validated HR-associated polygenic risk score (HR-PRS), in which lower scores are associated with a lower HR, and compared with healthy nonathletic controls. Clinical and genetic features of bradycardic endurance athletes with minimum HR ≤40 bpm on a Holter monitor (bradycardic athletes [BAs]) were compared with non-BAs). A healthy cohort of nonathletes from the ASPREE study (Aspirin in Reducing Events in the Elderly) were used for genetic comparisons. RESULTS: Among 465 endurance athletes (median age, 23 [18–49] years, 75% men), 175 (38%) had a minimum HR on a Holter monitor ≤40 bpm, of whom 7 (2% of total) had a HR ≤30bpm. Pauses ≥2 s were observed in 115 (25%) athletes, of whom 12 (3% of total) had pauses ≥3 s. Mobitz I second-degree atrioventricular block was observed in 15 (3% of total) athletes. BAs were younger and fitter and exhibited greater athletic cardiac remodeling than non-BAs. Mean HR-PRS was significantly lower in all athletes compared with ASPREE nonathletes ( P <0.001) and in BAs compared with non-BAs ( P =0.006). When the distribution of HR-PRS within our athletic cohort was considered, athletes with scores in the bottom quartile had a lower minimum HR (median HR, 41 [35–45] bpm versus 45 [40–49] bpm, P <0.001) and higher bradycardia burden (14 [2–37]% versus 2 [0%–25]%, P <0.001) than those with scores in the top quartile. After adjusting for age, sex, fitness, and indexed right atrial volume, HR-PRS was independently associated with lower minimum HR and increased the odds of resting bradycardia by 2-fold (odds ratio [OR], 2.2 [95% CI, 1.3–3.9]; P= 0.004). Neither bradycardia nor pauses were associated with increased risk of adverse outcomes over 5.5 years. CONCLUSIONS: Resting bradycardia (HR ≤40 bpm) and pauses of 2 to 3 s are present in a significant proportion of endurance athletes and are well tolerated. Our data suggest that both fitness and genetic variation contribute to sinus node function in endurance athletes. Intriguingly, HR-PRS differed between athletes and nonathletes, raising the possibility that genetics may be a determinant of athleticism.
When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase
Complex I is known as the primary entry point for electrons within the mitochondrial electron transport system (ETS). However, the glycerol-3-phosphate (G3P) shuttle, composed of cytosolic and mitochondrial G3P dehydrogenase (cG3PDH and mtG3PDH, respectively), transfer reducing equivalents from the cytosol to the mitochondrial matrix. The mtG3PDH feeds electrons into the ETS via FADH 2 oxidation, but with theoretically lower energy conversion efficiency than complex I. It is thus believed to be an “alternative” pathway, only supporting mitochondrial respiration when complex I fails. mtG3PDH also plays an important role in reactive oxygen species (ROS) production. To investigate the role of this understudied protein in mitochondrial bioenergetics and redox homeostasis, we generated Drosophila melanogaster mutant lines for mtG3PDH (GPO1) using a CRISPR/Cas9-based approach and determined several physiological and metabolic parameters. A drastically higher mortality rate was observed among the GPO1 flies, as well as a lethargic behavior characterized by an inability to climb. These results are in accordance with an impaired mitochondrial efficiency (ATP/O) mainly due to decreased ATP production (~60% decrease) and O 2 consumption (~33% decrease), rather than elevated ROS. In fact, GPO1 flies produced ~70% less ROS than controls, likely due to the reduced direct and reverse electron transfer-related ROS production from mtG3PDH. These results support an essential role of mtG3PDH in mitochondrial bioenergetic, challenging its alternative aspect, and confirming its importance in mitochondrial redox homeostasis.