bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractThe 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

ABSTRACTBackgroundDelayed onset of muscle soreness (DOMS) and its physiological consequences has an important influence on the individual’s adherence to the exercise routine.ObjectiveThis study aimed to evaluate the efficacy, safety, and tolerability of TurmXTRA® 60N (WDTE60N) on DOMS in comparison with placebo in recreationally active healthy subjects.MethodsThe 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).ResultsThe 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).ConclusionThe 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

AbstractUnderstanding 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

AbstractHuman 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

ABSTRACTNeurodegenerative 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.
General solution to biological signalling games: costly signalling and beyond
Authors: Számadó Szabolcs , Zachar István , Czégel Dániel , Penn Dustin J. 
Published: May 2022

AbstractExplaining 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

AbstractThe 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

AbstractThe 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

AbstractNeurons 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

ABSTRACTSHOC2 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

ABSTRACTVoltage-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

AbstractPopulations 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

AbstractDuring 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.