bluuebunny/crossref_metadata_2025 huggingface dataset:
Primate sympatry shapes the evolution of their brain architecture
Authors: Robira Benjamin , Perez-Lamarque Benoît
Published: May 2022

The main hypotheses on the evolution of animal cognition emphasise the role of conspecifics in affecting the socio-ecological environment shaping cognition. Yet, space is often simultaneously occupied by multiple species from the same ecological guild. These sympatric species can compete for food, which may thereby stimulate or hamper cognition. Considering brain size as a proxy for cognition, we tested whether species sympatry impacted the evolution of cognition in frugivorous primates. We first retraced the evolutionary history of sympatry between frugivorous primate lineages. We then fitted phylogenetic models of the evolution of the size of several brain regions in frugivorous primates, considering or not species sympatry. We found that the evolution of the whole brain or brain regions used in immediate information processing was best fitted with models not considering sympatry. By contrast, models considering species sympatry best predicted the evolution of brain regions related to long-term memory of interactions with the socio-ecological environment, with a decrease in their size the higher the sympatry. We speculate that species sympatry, by generating intense food depletion, might lead to an over-complexification of resource spatiotemporality that counteracts the benefits of high cognitive abilities and/or might drive niche partitioning and specialisation, thereby inducing lower brain region sizes. In addition, we reported that primate species in sympatry diversify more slowly. This comparative study suggests that species sympatry significantly contributes to shaping primate evolution.
spSeudoMap: Cell type mapping of spatial transcriptomics using unmatched single-cell RNA-seq data
Authors: Bae Sungwoo , Choi Hongyoon , Lee Dong Soo
Published: May 2022

With advances in computational models, the cellular landscape can be tracked in various tissues using spatial transcriptomics. Since many single-cell RNA-seq (scRNA-seq) data have been obtained after cell sorting, such as when investigating immune cells, integrating these singlecell data with spatial data is limited due to a mismatch of cell types composing the two datasets. Here, we present a method, spSeudoMap, which utilizes sorted scRNA-seq data to train a model for predicting cell types of spatial spots by creating virtual cell mixtures that closely mimic the gene expression profile of spatial transcriptomic data. To overcome the mismatch issue, the cell type exclusively present in the spatial data, pseudotype, was defined. The proportion of pseudotype cells and virtual expression profiles in the cell mixture was determined by pseudobulk transcriptomes. The simulated cell mixture was considered a reference dataset, and the model that predicts the cell composition of the mixture was trained to predict the cell fraction of the spatial data using domain adaptation. First, spSeudoMap was evaluated in human and mouse brain tissues, and the main region-specific neuron types extracted from single-cell data could be precisely mapped to the expected anatomical locations. Moreover, the method was applied to human breast cancer data and described the spatial distribution of immune cell subtypes and their interactions in heterogeneous tissue. Taken together, spSeudoMap is a platform that predicts the spatial composition of cell subpopulations using sorted scRNA-seq data, and it may help to clarify the roles of a few but crucial cell types.
Real-time single-molecule observation of chaperone-assisted protein folding
Authors: Marzano Nicholas , Paudel Bishnu , van Oijen Antoine , Ecroyd Heath
Published: May 2022

The ability of Hsp70 molecular chaperones to remodel the conformation of their clients is central to their biological function; however, questions remain regarding the precise molecular mechanisms by which Hsp70 machinery interacts with the client and how this contributes towards efficient protein folding. Here, we used Total Internal Reflection Fluorescence (TIRF) microscopy and single-molecule Fluorescence Resonance Energy Transfer (smFRET) to temporally observe the conformational changes that occur to individual firefly luciferase (Fluc) proteins as they are folded by the bacterial Hsp70 system. For the first time, we observed multiple cycles of chaperone binding-and-release to an individual client during refolding and that high rates of chaperone cycling improves refolding yield. Furthermore, we demonstrate that DnaJ remodels misfolded proteins via a conformational selection mechanism whereas DnaK resolves misfolded states via mechanical unfolding. This study illustrates that the temporal observation of chaperone-assisted folding enables the elucidation of key mechanistic details inaccessible using other approaches.
Evidence for increased parallel information transmission in human brain networks compared to macaques and mice
Authors: Griffa Alessandra , Mach Mathieu , Dedelley Julien , Gutierrez-Barragan Daniel , Gozzi Alessandro , Allali Gilles , Grandjean Joanes , Van De Ville Dimitri , Amico Enrico
Published: May 2022

Brain communication, defined as information transmission through white-matter connections, is at the foundation of the brain’s computational capacities that subtend almost all aspects of behavior: from sensory perception shared across mammalian species, to complex cognitive functions in humans. How did communication strategies in macroscale brain networks adapted across evolution to accomplish increasingly complex functions? By applying a graph- and information-theory approach to assess information-related pathways in mouse, macaque and human brains, we show a brain communication gap between selective information transmission in non-human mammals, where brain regions share information through single polysynaptic pathways, and parallel information transmission in humans, where regions share information through multiple parallel pathways. In humans, parallel transmission acts as a major connector between unimodal and transmodal systems. The layout of information-related pathways is unique to individuals across different mammalian species, pointing at the individual-level specificity of information routing architecture. Our work provides evidence that different communication patterns are tied to the evolution of mammalian brain networks.
Cryo-EM structure ofex vivofibrils associated with extreme AA amyloidosis prevalence in a cat shelter
Authors: Schulte Tim , Chaves-Sanjuan Antonio , Mazzini Giulia , Speranzini Valentina , Lavatelli Francesca , Ferri Filippo , Palizzotto Carlo , Mazza Maria , Milani Paolo , Nuvolone Mario , Vogt Anne-Cathrine , Palladini Giovanni , Merlini Giampaolo , Bolognesi Martino , Ferro Silvia , Zini Eric , Ricagno Stefano
Published: May 2022

AA amyloidosis is a systemic disease characterized by deposition of misfolded serum amyloid A protein (SAA) into cross-β amyloid in multiple organs in humans and animals. AA amyloidosis occurs at high SAA serum levels during chronic inflammation. The disease can be transmitted horizontally, likely facilitated by prion-like mechanism, in captive animals leading to extreme disease prevalence, e.g. 70% in captive cheetah and 57-73% in domestic short hair (DSH) cats kept in shelters.

Herein, we present the 3.3 Å cryo-EM structure of an AA amyloid extractedpost-mortemfrom the kidney of a DSH cat with renal failure. The structure reveals a cross-β architecture assembled from two 76-residue long proto-filaments. Despite >70% sequence homology to mouse and human SAA, the cat SAA variant adopts a distinct amyloid fold. Based on shared disease profiles and almost identical protein sequences, we propose a similar amyloid fold of deposits identified previously in captive cheetah.
Individual Differences in Audio-Visual Binding Can Predict the Varied Severity of Motion Sickness
Authors: Zilka Revital , Bonneh Yoram
Published: May 2022

In neuroscience, research often focuses on the group, while ignoring large individual differences, which are left poorly understood. One such example is the large individual variability in the susceptibility to motion-sickness (MS), the feeling of sickness that typically occurs during travel or movement. Current explanations of MS focus on the sensory conflict in the perception of motion, primarily between the vestibular and the visual systems, e.g., when feeling motion but not seeing it. To account for the large individual differences in MS, we hypothesized that people feel motion sickness only when the conflicting stimuli are perceived as bound together, and their tendency to bind conflicting multi-sensory information is an individual trait. To test this hypothesis, we measured the persistence of audio-visual binding using the McGurk effect in which watching a moving mouth alters the auditory perception of phonemes. We used a temporal audio-visual mismatch to probe the persistence of binding and computed a temporal binding window for each individual (n=21) in 3 tasks: syllable Identification (McGurk), simultaneity judgement, and syllable synchronization judgement. To assess the severity of MS, we used 2 subjective symptom questionnaires. We found that the temporal binding window of the McGurk stimuli in two of the tasks varied across individuals and was positively correlated (R>0.8) with the MS questionnaire severity scores. These results support our hypothesis and shed new light on the enigmatic differences between individuals regarding their susceptibility to motion-sickness. They also highlight the potential strength of studies focusing on individual differences and neurological diversity.

Significance Statement

Motion sickness is the feeling of sickness that typically occurs during travel or movement. Although it is commonly linked to a sensory mismatch, the large differences in its susceptibility across people remains poorly understood. In the current study, we link these individual differences to a multi-modal temporal binding window, which measures the persistence of perceiving multi-modal stimuli as coming from the same source despite temporal discrepancies. We demonstrated this link by finding a high correlation between the temporal binding window of an audio-visual illusion (the McGurk effect) and the subjective reports of the susceptibility to motion sickness. These results shed new light on the enigmatic differences between individuals regarding their susceptibility to motion sickness and highlight the potential strength of studies focusing on individual differences and neurological diversity.
High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer
Authors: Salcher Stefan , Sturm Gregor , Horvath Lena , Untergasser Gerold , Fotakis Georgios , Panizzolo Elisa , Martowicz Agnieszka , Pall Georg , Gamerith Gabriele , Sykora Martina , Augustin Florian , Schmitz Katja , Finotello Francesca , Rieder Dietmar , Sopper Sieghart , Wolf Dominik , Pircher Andreas , Trajanoski Zlatko
Published: May 2022

Non-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity with diverse immune cell infiltration patterns, which has been linked to both, therapy sensitivity and resistance. However, full understanding of how immune cell phenotypes vary across different patient and tumor subgroups is lacking. Here, we dissect the NSCLC tumor microenvironment at high resolution by integrating 1,212,463 single-cells from 538 samples and 309 patients across 29 datasets, including our own dataset capturing cells with low mRNA content. Based on the cellular composition we stratified patients into immune deserted, B cell, T cell, and myeloid cell subtypes. Using bulk samples with genomic and clinical information, we identified specific cellular components associated with tumor histology and genotypes. Analysis of cells with low mRNA content uncovered distinct subpopulations of tissue-resident neutrophils (TRNs) that acquire new functional properties in the tissue microenvironment, providing evidence for the plasticity of TRNs. TRN-derived gene signature was associated with anti-PD-L1 treatment failure in a large NSCLC cohort.

In brief

Salcher, Sturm, Horvath et al. integrate single-cell datasets to generate the largest transcriptome atlas in NSCLC, refining patient stratification based on tumor immune phenotypes, and revealing associations of histological subtypes and genotypes with specific cellular composition patterns.

Coverage of cells with low mRNA content by single-cell sequencing identifies distinct tissue-resident neutrophil subpopulations, which acquire new properties within the tumor microenvironment. Gene signature from tissue-resident neutrophils is associated with immune checkpoint inhibitor treatment failure. The integrated atlas is publicly available online (https://luca.icbi.at), allowing the dissection of tumor-immune cell interactions in NSCLC.

Highlights

High-resolution single-cell atlas of the tumor microenvironment (TME) in NSCLC.

Histological tumor subtypes and driver genes imprint specific cellular TME patterns.

scRNA-seq of cells with low transcript count identifies distinct tissue-resident neutrophil (TRN) subpopulations and non-canonical functional properties in the TME niche.

TRN gene signature identifies patients who are refractory to treatment with PD-L1 inhibitors.

Abstract Figure
A combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop
Authors: Trotter Justin H. , Wang Cosmos Yuqi , Zhou Peng , Südhof Thomas C.
Published: May 2022

Disrupted synaptic inhibition is implicated in most psychiatric disorders, yet the molecular mechanisms that shape and sustain inhibitory synapses are poorly understood. Here, we find that the function of a subset of inhibitory synapses in brain is controlled by binding of presynaptic Neurexin-3 to postsynaptic dystroglycan, adhesion molecules that are associated with cognitive impairments. We found that Neurexin-3 alternative splicing at two sites, SS2 and SS4, acts as an ‘and/or’ logic gate to regulate the release probability, but not the number, of inhibitory synapses in olfactory bulb and prefrontal cortex. The same SS2 and SS4 splice variants that enable inhibitory synapse function also allow binding of Neurexin-3 to dystroglycan. Inactivation of postsynaptic dystroglycan, in turn, produces a similar decrease in release probability as the presynaptic Neurexin-3 deletion. Furthermore, a minimal dystroglycan-binding construct of Neurexin-3 fully sustains inhibitory synaptic function, suggesting that trans-synaptic dystroglycan binding is not only necessary but also sufficient for inhibitory synapse function. Thus, Neurexin-3 enables a normal release probability at inhibitory synapses via a trans-synaptic feedback loop requiring binding of presynaptic Neurexin-3 to postsynaptic dystroglycan.
TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons
Authors: Yue Wendy W.S. , Yuan Lin , Bráz Joao M. , Basbaum Allan I. , Julius David
Published: May 2022

TRPV1, a capsaicin- and heat-sensitive ion channel, is expressed by peripheral nociceptors and has been implicated in various inflammatory and neuropathic pain conditions. Although pharmacological modulation of TRPV1 has attracted therapeutic interest, their utility is limited because TRPV1 agonists and antagonists thus far examined show thermo-modulatory side effects in animal models and human clinical trials. These on-target effects may result from the perturbation of TRPV1 receptors on nociceptors, which transduce signals to central thermoregulatory circuits and also release pro-inflammatory factors from their peripheral terminals, such as the vasodilative neuropeptide calcitonin gene-related peptide (CGRP). Alternatively, they may originate from the modulation of TRPV1 on vascular smooth muscle cells (vSMCs), where channel activation promotes arteriole constriction. Here, we ask which of these pathways is most responsible for the body temperature perturbations elicited by TRPV1 drugs in vivo. We address this question by selectively eliminating TRPV1 expression in sensory neurons or vSMCs and show that only the former abrogates agonist-induced hypothermia and antagonist-induced hyperthermia. Furthermore, lesioning the central projections of TRPV1-positive sensory nerve fibers also abrogates drug-mediated thermo-modulation, whereas eliminating CGRP has no effect. Thus, TRPV1 drugs alter core body temperature by modulating sensory input to the central nervous system, rather than through peripheral actions on the vasculature. These findings suggest how mechanically distinct TRPV1 antagonists may diminish inflammatory pain without affecting core body temperature.
Liquid-like VASP condensates drive actin polymerization and dynamic bundling
Authors: Graham Kristin , Chandrasekaran Aravind , Wang Liping , Ladak Aly , Lafer Eileen M. , Rangamani Padmini , Stachowiak Jeanne C.
Published: May 2022

The organization of actin filaments into bundles is required for cellular processes such as motility, morphogenesis, and cell division. Filament bundling is controlled by a network of actin binding proteins. Recently, several proteins that comprise this network have been found to undergo liquid-liquid phase separation. How might liquid-like condensates contribute to filament bundling? Here, we show that the processive actin polymerase and bundling protein, VASP, forms liquid-like droplets under physiological conditions. As actin polymerizes within VASP droplets, elongating filaments partition to the edges of the droplet to minimize filament curvature, forming an actin-rich ring within the droplet. The rigidity of this ring is balanced by the droplet’s surface tension, as predicted by a continuum-scale computational model. However, as actin polymerizes and the ring grows thicker, its rigidity increases and eventually overcomes the surface tension of the droplet, deforming into a linear bundle. The resulting bundles contain long, parallel actin filaments that grow from their tips. Significantly, the fluid nature of the droplets is critical for bundling, as more solid droplets resist deformation, preventing filaments from rearranging to form bundles. Once the parallel arrangement of filaments is created within a VASP droplet, it propagates through the addition of new actin monomers to achieve a length that is many times greater than the initial droplet. This droplet-based mechanism of bundling may be relevant to the assembly of cellular architectures rich in parallel actin filaments, such as filopodia, stress fibers, and focal adhesions.
Design of an ultrafast pulsed ponderomotive phase plate for cryo-electron tomography
Authors: Du Daniel X. , Fitzpatrick Anthony W. P.
Published: May 2022

Ponderomotive phase plates have shown temporally consistent phase contrast is possible within electron microscopes via high fluence static laser modes resonating in Fabry-Perot cavities. Here, we explore using pulsed laser beams as an alternative method of generating high fluences. We find through forward-stepping finite element models that picosecond-or-less interactions are required for meaningful fluences phase shifts, with higher pulse energies and smaller beam waists leading to the predicted higher fluences. An additional model based on quasiclassical assumptions is used to discover the shape of the phase plate by incorporating the oscillatory nature of the electric field. From these results, we find the transient nature of the laser pulses removes the influence of Kapitza-Dirac diffraction patterns that appear in the static resonator cases. The addition of a second laser aligned 90° to the first induces anisotropy to the shape of the phase plate. By incorporating a shifting-electron-beam algorithm, the effects of a finite electron beam crossover are also simulated. A total pulse energy of 8.7 μJ is enough to induce the required π/2 phase shift for Zernike-like phase microscopy. As a brief thought experiment, we also explore the usage of high frequency lasers in a standard electron emission scheme to see if a pulsed electron beam is even necessary. Ultimately, frequency requirements limit the laser to nanosecond pulse durations, causing the required pulse energies to reach unreasonable levels before adequate phase shifts are achieved.
Functional substitutions of amino acids that differ between GDF11 and GDF8 impact skeletal development and skeletal muscle
Authors: Lian John , Walker Ryan G. , D’Amico Andrea , Vujic Ana , Mills Melanie J. , Messemer Kathleen A. , Mendello Kourtney R. , Goldstein Jill M. , Leacock Krystynne A. , Epp Soraya , Stimpfl Emma V. , Thompson Thomas B. , Wagers Amy J. , Lee Richard T.
Published: May 2022

Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGFβ family proteins that interact with nearly identical signaling receptors and antagonist proteins. However, GDF11 appears to activate SMAD2/3in vitroandin vivomore potently than GDF8. The ligands possess divergent structural properties, whereby substituting unique GDF11 amino acids into GDF8 enhanced activity of the resulting chimeric GDF8. We investigated potentially distinct endogenous activities of GDF11 and GDF8in vivoby genetically modifying their mature signaling domains. Full recoding of the GDF8 mature domain to that of GDF11 yielded mice lacking GDF8, with GDF11 levels ∼50-fold higher than normal, and exhibiting modestly decreased muscle mass, with no apparent negative impacts on health or survival to adulthood. Substitution of two specific amino acids in the fingertip region of GDF11 with the corresponding GDF8 residues resulted in prenatal axial skeletal transformations, consistent withGdf11-deficient mice, without apparent perturbation of skeletal or cardiac muscle development or homeostasis. These experiments uncover distinctive features between the GDF11 and GDF8 mature domainsin vivoand identify specific requirement for GDF11 in early-stage skeletal development.

Summary Statement

Replacement of amino acids unique to GDF11 and GDF8 into the native locus of the other ligand yields measurable, differential skeletal and muscle phenotypes, revealing distinct features between the ligands.
Spatiotemporal atlas of the fetal brain depicts cortical developmental gradient in Chinese population
Authors: Xu Xinyi , Sun Cong , Sun Jiwei , Shi Wen , Shen Yao , Zhao Ruoke , Luo Wanrong , Li Mingyang , Wang Guangbin , Wu Dan
Published: May 2022

The fetal brains experience rapid and complex development in utero during the second and third trimesters. MRI atlas of the fetal brain in this period enables us to quantify the normal fetal brain development in the spatiotemporal domain. In this study, we constructed a high quality spatiotemporal atlas between 23-38 weeks gestational age (GA) from 90 healthy Chinese fetuses using a pairwise and groupwise registration-based pipeline. We quantified the fetal cortical morphology and characterized the developmental trajectories of each morphological index. The cortical thickness exhibited a biphasic growth pattern; the developmental trend of curvature fitted well into the Gompertz model; sulcal depth increased linearly while surface area expanded exponentially. The cortical thickness and curvature trajectories consistently pointed to a characteristic time-point during development around 31 weeks of GA. The characteristic GA and growth rate obtained from individual cortical regions suggested a central-to-peripheral developmental gradient, with the earliest development in the parietal lobe, and we also observed within-lobe regional orders, which may be linked to biophysical events such as dendritic arborization and thalamocortical fibers ingrowth. The proposed atlas was also compared with an existing fetal atlas from a Caucasian/mixed population. Finally, we examined the structural asymmetry of the fetal brains and found extensive asymmetry that dynamically changed with development. The current study depicted a comprehensive profile of fetal cortical development and the established atlas could be used as a normative reference for neurodevelopmental and diagnostic purposes, especially in the Chinese population.
Efficacy and Safety of TurmXTRA® 60N in Delayed-onset Muscle Soreness in Healthy, Recreationally Active Subjects: a Randomized, Double-blind, Placebo-controlled Trial
Authors: Thanawala Shefali , Shah Rajat , Karlapudi Vasu , Desomayanandam Prabakaran , Bhuvanendran Arun
Published: May 2022

Background

Delayed onset of muscle soreness (DOMS) and its physiological consequences has an important influence on the individual’s adherence to the exercise routine.

Objective

This study aimed to evaluate the efficacy, safety, and tolerability of TurmXTRA® 60N (WDTE60N) on DOMS in comparison with placebo in recreationally active healthy subjects.

Methods

The present study was a randomized, double-blind, placebo-controlled parallel group study. Thirty healthy and recreationally active subjects (average age: 28.23±4.20 years) were randomized to receive WDTE60N (WDTE60N group; n=15) or placebo (placebo group; n=15). Study treatments were initiated 29 days prior to the eccentric exercise and continued for 4 days after the exercise. Primary endpoint was the change in pain intensity measured by the visual analog scale (VAS) at the end of study treatment (at 96 hours after eccentric exercise) from baseline (measured immediately after exercise).

Results

The VAS score indicated that subjects from the WDTE60N group reported significantly less pain after eccentric exercise compared to placebo group (AUC0-96h: 286.8±46.7 vs. 460±40.5, respectively; p<0.0001). Wellbeing status, assessed using the adapted version of Hooper & MacKinnon questionnaire, calculated as individual and cumulative scores of the domains - fatigue, mood, general muscle soreness, sleep quality and stress demonstrated significant improvement in all domains as well as in overall wellbeing in WDTE60N group as compared to placebo group (p<0.0001). Serum lactate dehydrogenase (LDH) was significantly lower in the WDTE60N group compared to placebo group (AUC0-96h: 23623.7±2532.0 vs. 26138.6±3669.5, respectively; p=0.0446).

Conclusion

The WDTE60N intake before and after eccentric exercise significantly reduced subjective perception of muscle soreness and serum LDH activity, and increased psychological wellbeing after eccentric exercise in recreationally active subjects.
Estimating clade-specific diversification rates and palaeodiversity dynamics from reconstructed phylogenies
Authors: Mazet Nathan , Morlon Hélène , Fabre Pierre-Henri , Condamine Fabien L.
Published: May 2022

Understanding palaeodiversity dynamics through time and space is a central goal of macroevolution. Estimating palaeodiversity dynamics has been historically addressed with fossil data because it directly reflects the past variations of biodiversity. Unfortunately, some groups or regions lack a good fossil record, and dated phylogenies can be useful to estimate diversification dynamics. Recent methodological developments have unlocked the possibility to investigate palaeodiversity dynamics by using phylogenetic birth-death models with non-homogeneous rates through time and across clades. One of them seems particularly promising to detect clades whose diversity has declined through time. However, empirical applications of the method have been hampered by the lack of a robust, accessible implementation of the whole procedure, therefore requiring users to conduct all the steps of the analysis by hand in a time-consuming and error-prone way.

Here we propose an automation of Morlon et al. (2011) clade-shift model with additional features accounting for recent developments and we implement it in the R package RPANDA. We also test the approach with simulations focusing on its ability to detect shifts of diversification and to infer palaeodiversity dynamics. Finally, we illustrate the automation by investigating the palaeodiversity dynamics of Cetacea, Vangidae, Parnassiinae, and Cycadales.

Simulations showed that we accurately detected shifts of diversification although false shift detections were higher for time-dependent diversification models with extinction. The median global error of palaeodiversity dynamics estimated with the automated model is low showing that the method can capture diversity declines. We detected shifts of diversification for three of the four empirical examples considered (Cetacea, Parnassiinae and Cycadales). Our analyses unveil a waxing-and-waning pattern due to a phase of negative net diversification rate embedded in the trees after isolating recent radiations.

Our work makes possible to easily apply non-homogeneous models of diversification in which rates can vary through time and across clades to reconstruct palaeodiversity dynamics. By doing so, we detected palaeodiversity declines among three of the four groups tested, highlighting that such periods of negative net diversification might be common. We discuss the extent to which this approach might provide reliable estimates of extinction rates and we provide guidelines for users.
Cryo-EM structures reveal a dynamic transformation process of human alpha-2-macroglobulin working as a protease inhibitor
Authors: Huang Xiaoxing , Wang Youwang , Yu Cong , Zhang Hui , Ru Qiang , Li Xinxin , Song Kai , Zhou Min , Zhu Ping
Published: May 2022

Human alpha-2-macroglobulin is a well-known proteases inhibitor against a broad spectrum of proteases. It also plays important roles in immunity, inflammation, and infections. Here, we report cryo-EM structures of human alpha-2-macroglobulin of the native state, the transformed state induced by its authentic substrate, human trypsin, and serial intermediate states between the native and the fully induced state. These structures exhibit distinct conformations, which reveal a dynamic transformation process of alpha-2-macroglobulin acting as a protease inhibitor. The results shed light on the molecular mechanism of alpha-2-macroglobulin entrapping substrates, and help to understand how alpha-2-macroglobulin possesses variant physiological functions.
Protection of high-frequency low-intensity pulsed electric fields and BDNF for SH-SY5Y cells against hydrogen peroxide-induced cell damage
Authors: Lin Guan-Bo , Chen Wei-Ting , Kuo Yu-Yi , Chen You-Ming , Liu Hsu-Hsiang , Chao Chih-Yu
Published: May 2022

Neurodegenerative diseases pose a significant global health threat. In particular, Alzheimer’s disease, the most common type causing dementia, remains an incurable disease. Alzheimer’s disease is thought to be associated with an imbalance of reactive oxygen species (ROS) in neurons, and scientists considered ROS modulation as a promising strategy for novel remedies. In the study, human neural cell line SH-SY5Y was used in probing the effect of combining non-invasive high-frequency low-intensity pulsed electric field (H-LIPEF) and brain-derived neurotrophic factor (BDNF) in protection against hydrogen peroxide (H2O2)-induced neuron damage. Our result finds that the combination approach has intensified the neuroprotective effect significantly, perhaps due to H-LIPEF and BDNF synergistically increasing the expression level of the phosphorylated epidermal growth factor receptor (p-EGFR), which induces the survival-related mitogen-activated protein kinases (MAPK) proteins. The study confirmed the activation of extracellular signal-regulated kinase (ERK) and the downstream pro-survival and antioxidant proteins as the mechanism underlying neuron protection. These findings highlighted the potential of H-LIPEF combined with BDNF in the treatment of neurodegenerative diseases. Furthermore, BDNF-mimetic drugs combining with non-invasive H-LIPEF to patients is a promising approach worthy of further research. This points to strategies for selecting drugs to cooperate with electric fields in treating neurodegenerative disorders.
Distinct gaits of self-propelled quadriflagellate microswimmers
Authors: Cortese Dario , Wan Kirsty Y.
Published: May 2022

Legged animals often coordinate multiple appendages for both underwater and terrestrial loco-motion. Quadrupeds in particular, change their limb movements dynamically to achieve a number of gaits, such as the gallop, trot, and pronk. Surprisingly, micron-sized unicellular algae are also capable of coordinating four flagella to produce microscale versions of these gaits for swimming. Here we present a fully-3D model of a quadriflagellate microswimmer comprising five beads and systematically investigate the effect of gait on swimming dynamics, propulsion speed, efficiency, and induced flow patterns. We find that by changing gait alone, distinct motility patterns emerge from the same basic microswimmer design. Our findings suggest that different species of morphologically-similar microorganisms (e.g. with identical number and placement of appendages) evolved distinct flagellar coordination patterns as a consequence of different ecological drivers. By comparing the flagella-induced flows in terms of volumetric clearance rate, we further explore the implications of distinct gaits for single-cell dispersal, feeding, and predator-avoidance.
General solution to biological signalling games: costly signalling and beyond
Authors: Számadó Szabolcs , Zachar István , Czégel Dániel , Penn Dustin J.
Published: May 2022

Explaining signal reliability poses a central problem in animal communication. According to Zahavi’s Handicap Principle (HP), signals are honest only when they are costly at the evolutionary equilibrium – hence the term ‘handicap’; otherwise, deception evolves, and communication breaks down. The HP has no theoretical or empirical support, despite claims to the contrary, and yet this idea remains immensely popular. Theoretical evaluations of the HP are difficult, however, because finding the equilibrium cost function in signalling games is notoriously complicated. Here we show how cost functions can be calculated for any arbitrary pairwise asymmetric signalling game at the evolutionary equilibrium. We clarify the relationship between signalling costs at equilibrium and the conditions for reliable signalling. We show that these two terms are independent and the costs of signalling at honest equilibrium have no effect on the stability of communication. We show that honest signals can take any cost value, even negative, being beneficial for the signaller independently of the receiver’s response at equilibrium, without requiring further constraints. Our results are general, and apply to seminal signalling models, including Grafen’s model of sexual selection and Godfray’s model of parent-offspring communication. Our results refute the claim that signals must be costly at the evolutionary equilibrium to be reliable, as predicted by the HP and so-called “costly signalling” theory. The handicap paradigm can thus be fully rejected. We provide testable predictions to help advance the field and establish a better explanation for honest signals.
Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants
Authors: Tan Shudan , Hu Xue , Li Yufeng , Wu Zihan , Zhao Jinghua , Lu Guoliang , Yu Zhaoli , Du Binhe , Liu Yan , Li Li , Chen Yuchen , Li Ye , Yao Yanfeng , Zhang Xiaoyu , Rao Juhong , Gao Ge , Peng Yun , Liu Hang , Yuan Zhiming , Liu Jia , Wang Qianran , Hu Hengrui , Gao Xiaobo , Zhou Hui , Yu Hang , Xu Yingjie , Yu Wei , Feng Lin , Wang Manli , Shan Chao , Lu Jing , Lin Jinzhong
Published: May 2022

The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike(S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the Wild-type, B.1.1.7, B.1.351, B.1.617.2, and the omicron B.1.1.529 variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. We also proved the safety of RQ3013 in NHP models. Our results provided key support for the evaluation of RQ3013 in clinical trials.
Covalent Disruptor of YAP-TEAD Association Suppresses Defective Hippo Signaling
Authors: Fan Mengyang , Lu Wenchao , Che Jianwei , Kwiatkowski Nicholas , Gao Yang , Seo Hyuk-Soo , Ficarro Scott B. , Gokhale Prafulla C. , Liu Yao , Geffken Ezekiel A. , Lakhani Jimit , Song Kijun , Kuljanin Miljan , Ji Wenzhi , Jiang Jie , He Zhixiang , Tse Jason , Boghossian Andrew S. , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Mancias Joseph D. , Marto Jarrod A. , Dhe-Paganon Sirano , Zhang Tinghu , Gray Nathanael S.
Published: May 2022

The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range ofin vitroand cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptoticBMFgene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to anin vivocompatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.
Contrast-polarity specific mapping optimizes neuronal computation for collision detection
Authors: Dewell RB , Zhu Y , Eisenbrandt M , Morse R , Gabbiani F
Published: May 2022

Neurons receive information through their synaptic inputs, but the functional significance of how those inputs are mapped on to a cell’s dendrites remains unclear. We studied this question in a grasshopper visual neuron that tracks approaching objects and triggers escape behavior before an impending collision. In response to black approaching objects, the neuron receives OFF excitatory inputs that form a retinotopic map of the visual field onto compartmentalized, distal dendrites. Subsequent processing of these OFF inputs by active membrane conductances allows the neuron to discriminate the spatial coherence of such stimuli. In contrast, we show that ON excitatory synaptic inputs activated by white approaching objects map in a random manner onto a more proximal dendritic field of the same neuron. This random synaptic arrangement results in the neuron’s inability to discriminate the coherence of white approaching stimuli. Yet, the neuron retains the ability to discriminate stimulus coherence for checkered stimuli of mixed ON/OFF polarity. The coarser mapping and processing of ON stimuli thus has a minimal impact, while reducing the total energetic cost of the circuit. Further, we show that these differences in ON/OFF neuronal processing are behaviorally relevant, being tightly correlated with the animal’s escape behavior to light and dark stimuli of variable coherence. Our results show that the synaptic mapping of excitatory inputs affects the fine stimulus discrimination ability of single neurons and document the resulting functional impact on behavior.
Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome
Authors: Bonsor Daniel A. , Alexander Patrick , Snead Kelly , Hartig Nicole , Drew Matthew , Messing Simon , Finci Lorenzo I. , Nissley Dwight V. , McCormick Frank , Esposito Dominic , Rodriguez-Viciana Pablo , Stephen Andrew G. , Simanshu Dhirendra K.
Published: May 2022

SHOC2 acts as a strong synthetic lethal interactor with MEK inhibitors in multiple KRAS cancer cell lines. SHOC2 forms a heterotrimeric complex with MRAS and PP1C that is essential for regulating RAF and MAPK-pathway activation by dephosphorylating a specific phosphoserine on RAF kinases. Here we present the high-resolution crystal structure of SHOC2-MRAS-PP1C (SMP) complex and apo-SHOC2. Our structures reveal that SHOC2, MRAS and PP1C form a stable ternary complex where all three proteins synergistically interact with each other. Our results show that dephosphorylation of RAF substrates by PP1C is enhanced upon interacting with SHOC2 and MRAS. The SMP complex only forms when MRAS is in an active state and is dependent on SHOC2 functioning as a scaffolding protein in the complex by bringing PP1C and MRAS together. Our results provide structural insights into the role of the SMP complex in RAF activation, how mutations found in Noonan syndrome enhance the complex formation and reveal new avenues for therapeutic interventions.
Mechanosensitive pore opening of a prokaryotic voltage-gated sodium channel
Authors: Strege Peter R. , Cowan Luke M. , Alcaino Constanza , Mazzone Amelia , Ahern Christopher A. , Milescu Lorin S. , Farrugia Gianrico , Beyder Arthur
Published: May 2022

Voltage-gated ion channels orchestrate electrical activities that drive mechanical functions in contractile tissues such as the heart and gut. In turn, contractions change membrane tension and impact ion channels. Voltage-gated ion channels are mechanosensitive, but the mechanisms of mechanosensitivity remain poorly understood. Here, we leverage the relative simplicity of NaChBac, a prokaryotic sodium channel from Bacillus halodurans, to investigate its mechanosensitivity. In whole-cell experiments on heterologously transfected HEK293 cells, shear stress reversibly altered the kinetic properties of NaChBac and increased its maximum current, comparably to the mechanosensitive eukaryotic sodium channel NaV1.5. In single-channel experiments, patch suction reversibly increased the open probability of a NaChBac mutant with inactivation removed. A simple kinetic mechanism featuring a mechanosensitive pore opening transition explained the overall response to force, whereas an alternative model with mechanosensitive voltage sensor activation diverged from the data. Structural analysis of NaChBac identified a large displacement of the hinged intracellular gate, and mutagenesis at the hinge abolished NaChBac mechanosensitivity, further supporting the proposed mechanism. Overall, our results suggest that NaChBac responds to force because its pore is intrinsically mechanosensitive. This mechanism may apply to other voltage-gated ion channels, including NaV1.5.
Rapid evolution in response to climate-change-induced drought and its demographic and genetic controls
Authors: Benning John W. , Faulkner Alexai , Moeller David A.
Published: May 2022

Populations often vary in their evolutionary responses to a shared environmental perturbation. A key hurdle in building more predictive models of rapid evolution is understanding this variation – why do some populations and traits evolve while others do not? We combined long-term demographic and environmental data, estimates of quantitative genetic variance components, a resurrection experiment, and individual-based evolutionary simulations to gain mechanistic insights into contrasting evolutionary responses to a severe multiyear drought. We examined five traits in two populations of a native California plant,Clarkia xantiana, at three timepoints over 7 years. Earlier flowering phenology evolved in only one of the two populations, though both populations experienced similar drought severity and demographic declines and were estimated to have considerable additive genetic variance for flowering phenology. Pairing demographic and experimental data with evolutionary simulations suggested that while seed banks in both populations likely constrained evolutionary responses, a stronger seed bank in the non-evolving population resulted in evolutionary stasis. Gene flow through time via germ banks may be an important, underappreciated control on rapid evolution in response to extreme environmental perturbations.
The structure of anticorrelated networks in the human brain
Authors: Martínez Gutiérrez Endika , Jiménez Marín Antonio , Stramaglia Sebastiano , Cortes Jesus M.
Published: May 2022

During the performance of a specific task or at rest, the activity of different brain regions shares statistical dependencies that reflect functional connections. While these relationships have been studied intensely for positively correlated networks, considerably less attention has been paid to negatively correlated networks, a.k.a. anticorrelated networks (ACNs). Here, we have addressed this issue by making use of two neuroimaging datasets: one of N=192 young healthy adults; and another of N=40 subjects that was divided into two groups of young and old participants. We first provided a full description of the anatomical composition of the different ACNs, each of which participated in distinct resting-state networks (RSNs). In terms of their frequency of participation, from highest to the lowest, the major anticorrelated brain areas are the precuneus, the anterior supramarginal gyrus and the central opercular cortex. Subsequently, by evaluating the more detailed structure of ACNs, we show it is possible to find significant differences in these in association with specific conditions, in particular by comparing groups of young and old participants. Our main finding is that of increased anticorrelation for cerebellar interactions in older subjects. Overall, our results give special relevance to ACNs and they suggest they may serve to disentangle unknown alterations in certain conditions, as might occur in neurodegenerative diseases at early onset or in some psychiatric conditions.