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Biology subjects

Murthy, A.

Publications and source records attributed to Murthy, A..

At least 19 recordsLinked to original sources

Task-Relevant Cognitive Load Modulates Fast and Slow Processes Underlying Motor Adaptation

How cognitive control influences the correction of motor errors is an important question. In this study, we examined how the slow and fast processes that constitute motor adaptation are modulated by cognitive load. To address this question, we used a novel approach that differed from traditional dual-task experiments that have assessed the role of fast processes by decreasing attention to the motor adaptation task. Here, cognitive load was manipulated using a decision-making task with easy and hard difficulty levels, while simultaneously adapting to a perturbation and maintaining attention on the task. Our results showed that the hard decision-making task increased cognitive load relative to the easy task, resulting in attenuated steady-state learning. The relative contributions of the fast and slow components were assessed using a dual state-space model, which showed that the former was larger under the high-load condition, whereas the latter was larger under the easy-load condition, consistent with a competition model in which a shared error signal is partitioned between the two processes. We also showed that the effect of cognitive load on fast processes was not attributable to increased reaction times or task performance. Taken together, these results support the notion that faster explicit motor adaptation processes derive from cognitive processes involved in action selection.

neuroscience↗

Inflammatory Fibroblasts Promote Repair After Injury Through Epithelial Proliferation

Fibroblast heterogeneity after lung injury is a well observed phenomenon made highly relevant by the widespread application of single cell RNA-sequencing. The characterization of homeostatic and injury associated states has led to the identification of a population of fibroblasts that emerge during inflammation and express cytokines that may potentially amplify the inflammatory circuit. However, whether these cells actively contribute to inflammation or serve an alternative function within the broader injury-repair cascade remains unclear. By integrating several robust murine lung injury data sets we establish the persistence of the inflammatory fibroblast across multiple injury models and identify a role for these cells in lung repair after injury through effects on alveolar epithelial proliferation. We validate this observation in-vivo using a genetic model of spontaneous lung fibrosis and in-vitro with mixed alveolar organoid cultures of various homeostatic and injury associated fibroblasts wherein we identify a mesenchymal-epithelial BMP signaling axis as a key driver of the AT2 cell injury repair response. Finally, we present supporting evidence from human disease, reinforcing the relevance of this fibroblast subset in pathological settings. These findings extend critical observations made prior to the single-cell era and contribute to our evolving understanding of fibroblast heterogeneity as a key feature of lung repair.

molecular biology↗

Overlapping MHC class I/II Epitopes Program cDC1-like Differentiation of Monocyte-Derived Dendritic Cells via mTORC1 Signaling Inhibition

Viral infection polarizes monocyte-derived dendritic cells (moDC) to initiate type 1 immunity. The availability of overlapping (homologous) MHC class I and II epitopes, an occurrence frequently and primarily associated with intracellular infection, significantly enhances this process; however, the underlying mechanism(s) are unclear. We demonstrate that moDC loaded with homologous MHC epitopes acquire a cDC1-like phenotype in a process governed by mTORC1. mTORC1 pathway inhibition leads to NF-{kappa}B-mediated expression of IL-12 and other type I immune polarizing genes. The observed cDC1-like gene signature was also significantly enhanced in clinical moDC vaccine products made through methodologies that enforced class I and II antigenic homology. Collectively, these findings reveal a novel and previously unrecognized mechanism of immune governance that might also be exploited in cancer immunotherapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/716309v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@15475borg.highwire.dtl.DTLVardef@ffe5fborg.highwire.dtl.DTLVardef@53c761org.highwire.dtl.DTLVardef@46c4ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Transcranial direct current stimulation of the supplementary motor area modulates behavioral and peripheral electrophysiological measures of motor preparation.

Converging evidence has shown that the Supplementary Motor Area (SMA) is involved in the preparation of movements. Such preparatory activity has been traditionally thought to lead to shorter reaction times by allowing the motor network to settle into states favourable to motor execution without directly engaging the peripheral musculature, limiting such preparatory states to central neural processes only. We revisited this question by recording motor unit related activity using high-density surface EMG grid electrodes, from the Anterior Deltoid muscle, a proximal muscle, during a delayed reach task. We observed that anodal stimulation of the supplementary motor area (SMA) enhances motor preparation by shortening reaction times, while simultaneously and preferentially recruiting smaller amplitude motor units. Additionally, we found that the SMA stimulation also produced a subsequent increase in movement velocities due to the increase activation of larger amplitude motor units. Taken together, we suggest that motor preparatory states involve an active interaction between central and peripheral processes with direct descending SMA outputs to the spinal cord providing a link between cortical preparation and muscle readiness, resulting in decreased reaction times. In addition, the increased gain of such central to peripheral interactions also increases the subsequent gain of during the execution phase via modulating larger amplitude motor unit activation, resulting in increased response vigour.

neuroscience↗

JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake

Lung cancer is the leading cause of cancer-related death and is frequently accompanied by reduced food intake and cachexia, a debilitating syndrome characterized by weight loss and skeletal muscle wasting. We sought to identify contributors to cachexia using a murine model of lung cancer that reproduces key features of this syndrome. A multiplex cytokine screening approach, integrated with western blot and transcriptomic analyses, identified tumor-derived inflammatory mediators and downstream signaling pathways associated with cachexia. Notably, IL-6 superfamily members were elevated in the tumor and plasma of mice and patients with cachexia. The JAK-STAT3 signaling was upregulated in liver and skeletal muscle, driving the acute phase response and impairing lipid metabolism. Pharmacologic inhibition of JAK1/2 with ruxolitinib improved body weight, fat mass, and overall survival without altering tumor burden. These effects were driven primarily by blunted hypothalamic leptin receptor signaling, which increased food intake early in the disease course. In the liver, JAK inhibition reduced STAT3 activity, restored fatty acid oxidation, and decreased the production of acute-phase proteins. These findings support JAK inhibition as a therapeutic strategy for lung cancer-associated cachexia. Statement of SignificanceCancer cachexia is a lethal complication of lung cancer that lacks effective treatment. We show that JAK inhibition by ruxolitinib restores weight, fat mass, and prolongs survival in murine models of lung cancer. These effects were independent of tumor burden, underscoring the relevance of addressing cachexia to improve survival in cancer patients and supporting clinical testing of JAK inhibition for cancer cachexia

cancer biology↗

Differential kinematic control and co-ordination among redundant joints during whole arm reaching movements

Normative upper limb movements are produced by multiple redundant joints. While the reaching task is specified at the endpoint, such task objectives become implicit at the level of joints. A fundamental question is whether planning and control of joints is solely in the service of the endpoint or whether they also include joint trajectories. Using Spearmans correlation and zero crossings, we found differential kinematic signatures of control between shoulder and elbow joints in contrast to the wrist joint. However, the extent of control among joints was substantially diminished compared to the endpoint. Further, when such control measures were compared to the subspaces of inter-trial joint exploration, we found that online control at proximal joints, such as the shoulder and elbow, were significantly associated in regulating the task space, while control at the wrist (distal) joint was associated in regulating joint redundancy in null space. These results suggest that null space is not entirely uncontrolled as per the uncontrolled manifold hypothesis but selectively controlled by some distal joints. Additionally, across different directions, either the shoulder or the elbow contributed dominantly towards the movement of the endpoint while the other joint was lagging and that this strategy reflected in our kinematic measures of online and trajectory control. Taken together, this study shows how the selective implementation of a leading joint in task space and a lagging joint in null space can enable the control of multi-jointed movements and attenuate the problem of joint redundancy. Significance StatementIn this study, we addressed a fundamental question of how our central nervous system resolves the problem of joint redundancy, as to whether planning and control of joints are solely in the service of endpoint or whether they also include joint trajectories. We found significant kinematic control signatures among joints towards their respective average joint trajectories, especially during the early and middle phases of movement. Furthermore, each joint had a distinct task objective, the proximal shoulder or elbow joints controlled the task space and were responsible for driving the whole-arm movements, while the distal wrist joint regulated joint redundancy.

neuroscience↗

Divergent Pathways of Surfactant Protein C Maturation for Disease-Associated Isoforms

Surfactant Protein C (SP-C), a hydrophobic protein exclusively synthesized and secreted by alveolar type II (AT2) cells, is important for reducing alveolar surface tension in the distal lung. Chronic interstitial pulmonary diseases have been associated with SFTPC mutations. However, a detailed understanding of SP-C maturation in the secretory pathway and disruptions caused by mutations has remained incomplete. The goal of this study was to comprehensively ascertain differences in trafficking and post-translational processing between wild-type and disease-associated SP-C mutants using doxycycline-inducible mouse lung epithelial (MLE-12) cell lines expressing either wildtype SP-C or the common clinical variant SP-CI73T, validated using primary AT2 cells isolated from a murine SP-CI73T pulmonary fibrosis model and induced pluripotent stem cell (iPSC)-derived human alveolar type 2 cells (iAT2s) expressing the same mutant. In all 3 models SP-CWT was highly concentrated in acidic LROs while SP-CI73T accumulated on the plasma membrane, which was corroborated by inhibition of clathrin-mediated endocytosis, surface biotinylation, immunogold EM, immunofluorescent staining in non-permeabilized cells, and proteinase K protection assays supporting divergence of SP-CI73T trafficking from SP-CWT. The exclusion of SP-CI73T from normal routing occurred early in the biosynthetic pathway as Brefeldin A blocked processing of both SP-C proproteins, while a 20{degrees}C temperature shift caused selective accumulation of a processed proSP-CWT intermediate, suggesting initial C-terminal cleavage of proSP-CWT occurs in late-Golgi/ trans-Golgi network (TGN). This cleavage event was sensitive to DC1, an inhibitor of furin-related subtilisin-like proprotein convertase (PPC) family members. Site-directed mutagenesis of canonical residues K160, R167 within a predicted PPC recognition site in the proSP-C BRICHOS domain blocked its processing. Expression constructs encoding inhibitory pre-proprotein (pp) peptide fragments of Furin and ppPC7 each inhibited cleavage of proSP-CWT by MLE-12 cells. Collectively, our data demonstrate that trafficking pathways for maturation of WT and mutant I73T SP-C diverge prior to the TGN where initial cleavage of the COOH-terminal SP-C propeptide occurs via a Furin-like proprotein convertase.

cell biology↗

REGULATORY T CELLS PROTECT AGAINST ABERRANT REMODELING IN A MOUSE MODEL OF PULMONARY FIBROSIS

Regulatory T (Treg) cells are well recognized for their role in immune regulation; however, their role in tissue regeneration is not fully understood. This study demonstrates such a role of Tregs in a published preclinical murine model of spontaneous pulmonary fibrosis (PF) expressing a human PF related mutation in the Surfactant Protein-C (SP-C) gene (SFTPCI73T). Genetic crosses of SP-CI73T mice with Foxp3GFP and Foxp3DTR lines were utilized to study Treg behavior during PF development. We found that FoxP3+Tregs accumulate during the transition from inflammation to fibrogenesis, peaking at 21-28 days after mutant SftpcI73T induction localizing to both perivascular and distal fibrotic lung regions. Diphtheria toxin mediated ablation of Tregs at 17 days worsened fibrosis and increased levels of TGF{beta} and inflammatory cytokines. Tregs expressed Th2 markers (Gata3+) and elaborated factors including amphiregulin (Areg) and Osteopontin (Spp1). Reductionist experiments showed that lung Tregs enhanced organoid formation when co-cultured with alveolar epithelial cells and adventitial fibroblasts, an effect size mimicked using Areg and Spp1 in combination. Our findings demonstrate that immune-mesenchymal-epithelial signaling crosstalk is present in the distal lung wherein Tregs play a protective role by limiting fibrosis and promoting tissue repair, highlighting their broader function beyond immune modulation in lung injury. HIGHLIGHTSO_LIIn a preclinical model of spontaneous pulmonary fibrosis, regulatory T cells (Tregs) were found to infiltrate the lung coincident with the resolution of early injury and transition to fibrogenesis. C_LIO_LIDepletion of Tregs at this transition worsened lung injury and enhanced fibrogenesis. C_LIO_LITregs recovered from the fibrotic lung are Type 2 skewed - GATA3+ and produce growth factors (e.g. Amphiregulin, Osteopontin) that promote lung tissue repair in ex vivo organoid models. C_LI

molecular biology↗

Molecular surface mimicry enables CRBN to target G3BP2 for degradation

Molecular glue degraders (MGDs) are small molecule compounds that repurpose the ubiquitin-proteasome system to induce degradation of challenging therapeutic targets. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin-4/RING E3 ubiquitin ligase (CRL4CRBN), and impose a gain-of-function activity to recruit, ubiquitinate and degrade so-called neosubstrate proteins. Known neosubstrates bind the CRBN/MGD neosurface on the CRBN CULT domain through a structural G-loop recognition motif that mimics contacts of a natural CRBN degron. Here we report the binding mode of G3BP2, a CRBN neosubstrate that bypasses the G-loop requirement by engaging an unconventional binding site on the CRBN LON domain. The MGD-induced ternary complex interface does not resemble known protein-protein interactions (PPI) with CRBN. Instead, CRBN mimics an endogenous binding partner of G3BP2 and repurposes a preexisting PPI hotspot on the target protein. Our findings provide a novel generalizable concept for the rationalization of unconventional neosubstrate binding modes on CRBN, demonstrate unprecedented potential for the reprogrammability of this substrate receptor by MGDs, and offer opportunities for rational expansion of the target repertoire accessible to this modality.

molecular biology↗

Aberrant Transitional Alveolar Epithelial Cells Promote Pathogenic Activation of Lung Fibroblasts in Preclinical Fibrosis Modeling

Pulmonary fibrosis (PF) is a chronic progressive lung disease histopathologically characterized by fibrotic remodeling and the presence of pathological epithelial and mesenchymal cell populations in the distal lung parenchyma. Within the epithelial compartment, a subset of alveolar type 2 cells (AT2s) enter and persist in an aberrant transitional state. Whether and how these aberrant transitional cells participate in lung fibrosis is not known. To address this, we exploited the SftpcC121G mouse model, where we previously demonstrated that chronic expression of a PF-associated point mutation (C121G) in the AT2-specific surfactant protein C (Sftpc) gene results in spontaneous and progressive fibrosis driven by intrinsic AT2 dysfunction. We utilized single cell RNA sequencing to demonstrate the emergence of pathologic epithelial and mesenchymal cells in the SftpcC121G murine lung fibrosis model, including aberrant transitional alveolar epithelial cells as well as transitional and fibrotic fibroblasts. Aberrant transitional alveolar epithelial cells share similar transcriptional profiles to human aberrant basaloid cells, including the upregulation of profibrotic gene markers (Fn1, Ctgf, Tgfb2, Pdgfb, Spp1), and develop a unique interactome with pathogenic lung fibroblasts. We developed a method to reliably flow sort aberrant transitional alveolar epithelial cells, and we highlight their ability to cause fibrotic activation of fibroblasts in ex vivo organoid assays and using conditioned supernatant, suggesting a profibrotic secretome. We conclude that aberrant transitional alveolar epithelial cells actively contribute to fibrotic lung remodeling through pathogenic activation of alveolar fibroblasts.

cell biology↗

Marginated neutrophils in the lungs effectively compete for nanoparticles targeted to the endothelium, serving as a part of the reticuloendothelial system

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has not achieved this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens. We show that marginated neutrophils uptake of many of these "endothelial-targeted" nanocarriers is on par with endothelial uptake. This generalizes across diverse nanomaterials and targeting moieties and was even found with physicochemical lung tropism (i.e., without targeting moieties). Further, we observed this in ex vivo human lungs and in vivo healthy mice, with an increase in marginated neutrophil uptake of nanoparticles caused by local or distant inflammation. These findings have implications for nanomedicine development for lung diseases. These data also suggest that marginated neutrophils, especially in the lungs, should be considered a major part of the reticuloendothelial system (RES), with a special role in clearing nanoparticles that adhere to the lumenal surfaces of blood vessels. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/597904v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@17e0518org.highwire.dtl.DTLVardef@809eb6org.highwire.dtl.DTLVardef@33d9a7org.highwire.dtl.DTLVardef@169863_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

Systematic perturbation screens decode regulators of inflammatory macrophage states and identify a role for TNF mRNA m6A modification

Macrophages adopt dynamic cell states with distinct effector functions to maintain tissue homeostasis and respond to environmental challenges. During chronic inflammation, macrophage polarization is subverted towards sustained inflammatory states which contribute to disease, but there is limited understanding of the regulatory mechanisms underlying these disease-associated states. Here, we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human monocyte-derived macrophages (hMDMs) to uncover regulatory circuits of inflammatory macrophage states. This process identifies regulators of five distinct inflammatory states associated with key features of macrophage function. Among these, the mRNA m6A writer components emerge as novel inhibitors of a TNF-driven cell state associated with multiple inflammatory pathologies. Loss of m6A writer components in hMDMs enhances TNF transcript stability, thereby elevating macrophage TNF production. A PheWAS on SNPs predicted to impact m6A installation on TNF revealed an association with cystic kidney disease, implicating an m6A-mediated regulatory mechanism in human disease. Thus, systematic phenotypic characterization of primary human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.

immunology↗

Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis

Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a key upstream signaling hub driving disease in these dysfunctional AT2 cells and augment this pathway to restore alveolar epithelial metabolic function, thus successfully alleviating lung fibrosis in vivo.

molecular biology↗

Internal feedback enables rapid trajectory control during goal-directed finger and whole-arm reaching movements

Goal-directed eye, hand, and finger movements follow invariant kinematics consisting of approximate straight-line trajectories and bell-shaped velocity profiles. A fundamental unresolved issue is whether these trajectories are planned or whether they are a consequence of trajectory-free online control. We address this question using Spearmans rank correlation, zero-crossing rate, and z-scores, and analyze within-trial variability to investigate differences in the time evolution of trajectories during the presence or absence of a goal in finger and whole-arm reaching movements, along with analyzing rapid goal-directed saccadic eye movements. We found that the central nervous system (CNS) implements control to follow an average trajectory, where goal-directed movements show an enhanced degree of trajectory control. Further, we found behavioral signatures of rapid control that might operate on these planned trajectories as early as [~]60 ms in finger movements and [~]70 ms in whole-arm reaching movements. Such early signatures of control suggest that the system could exploit internal feedback along with fast feedback processes to implement meaningful corrections during simple voluntary unperturbed movements. The analysis also revealed that the controller gains varied along the movement and peaked distinctly at early (20 %) and late (90 %) phases of finger and arm movements, implying that trajectory control may be accomplished through implicit way-point objectives during the execution of the movement. These later corrections were missing during the late phase of eye movements, pointing to a predominant role of delayed sensory feedback mediating corrections in the context of finger and arm movements during this period.

neuroscience↗

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

The cancer associated cachexia syndrome (CACS) is a systemic metabolic disorder resulting in loss of body weight due to skeletal muscle and adipose tissues atrophy. CACS is particularly prominent in lung cancer patients, where it contributes to poor quality of life and excess mortality. Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-{gamma} agonist, rosiglitazone. Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. Our data suggest that PPAR-{gamma} agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer. Key points- The PPAR-{gamma} agonist, rosiglitazone, restores circulating adiponectin levels in mice with lung cancer. - Rosiglitazone preserves skeletal muscle and adipose tissue mass in mice with lung cancer. - The preservation of muscle mass with rosiglitazone is associated with increases in AMPK and AKT activity. - Stimulation of adiponectin signaling increases AMPK activity, anabolic signaling, and protein synthesis in muscle cell culture.

cancer biology↗

Disruption of Prostaglandin F2α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2, and its cognate receptor FPr (Ptfgr) are implicated as a TGF{beta}1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER -SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER -Sftpc I73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER -Sftpc I73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER -Sftpc I73T /FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2/ FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2 signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

molecular biology↗

A molecular mechanism for membrane chaperoning by a late embryogenesis abundant protein

Environmental stress can result in substantial damage to proteins, membranes, and genetic material, impacting organismal survival1-3. Stress tolerance can be conferred by intrinsically disordered proteins (IDPs)4 that lack stable tertiary structure. IDPs from the large family of late embryogenesis abundant (LEA) proteins confer a fitness advantage when heterologously expressed5,6. Such protection suggests a general molecular function leading to stress tolerance, although the mechanisms remain unclear. Here, we report that a tardigrade LEA protein that confers stress tolerance in yeast acts as a molecular chaperone for the mitochondrial membrane. This protein, named HeLEA1, localizes to the mitochondrial matrix, and harbors conserved LEA sequence motifs that undergo dynamic disorder-to-helical transition upon binding to negatively charged membranes. Yeast expressing HeLEA1 show increased mitochondrial membrane fluidity, increased membrane potential, and enhanced tolerance to hyperosmotic stress under non-fermentative growth without significantly altering mitochondrial lipid composition or triggering a generic stress response. We demonstrate that membrane binding ameliorates excess surface tension, possibly by stabilizing lipid packing defects. Evolutionary analysis suggests that HeLEA1 homologs localize to different membrane-bound organelles and share similar sequence and biophysical features. We suggest that membrane chaperoning by LEA proteins represents a general biophysical solution that can operate across the domains of life.

biophysics↗

Shoulder muscle recruitment during the delay period encodes a reach movement plan which is sensitive to task context

Understanding how motor plans are transformed into appropriate patterns of muscle activity is a central question in motor control. While muscle activity during the delay period has not been reported using conventional EMG approaches, we isolated motor unit activity using a high-density surface EMG signal from the anterior deltoid muscle to test whether heterogeneity in motor units could reveal early preparatory activity. Consistent with our previous work (Rungta et al., 2021), we observed early selective recruitment of small-amplitude size motor units during the delay period for hand movements like early recruitment of small-amplitude motor units in neck muscles of non-human primates performing delayed saccade tasks. This early activity was spatially specific and increased with time and resembled an accumulation to threshold model that correlated with movement onset time. Such early recruitment of ramping motor units was also observed at the single trial level as well. In contrast, no such recruitment of large amplitude size motor units, called non-rampers, was observed during the delay period. Instead, non-rampers became spatially specific and predicted movement onset time after the delay period. Interestingly, spatially specific delay period activity was only observed for hand movements but was absent for isometric force-driven cursor movements. Nonetheless, muscle activity was correlated with the time it took to initiate movements in both task conditions for non-rampers. Overall, our results reveal a novel heterogeneity in the EMG activity which allows the expression of early motor preparation via small amplitude size motor units which are differentially activated during initiation of movements. Significance statementWe studied the spatial and temporal aspects of response preparation in the anterior deltoid muscle using high-density surface EMG. Our results show that early spatially specific ramping activity that predicted reaction times could be accessed from muscle activity but was absent during isometric force-driven cursor movements. Such ramping activity could be quantified using an accumulator framework across trials, as well as within single trials but was not observed in isometric reach tasks involving cursor movements.

neuroscience↗