Biology subjects

Mao, Y.

Publications and source records attributed to Mao, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2021

Localized, time-dependent responses of rat cranial bone to repeated mild traumatic brain injuries

While it is well-established that bone responds dynamically to mechanical loading, the effects of mild traumatic brain injury (mTBI) on cranial bone composition are unclear. We hypothesized that repeated mTBI (rmTBI) would change the microstructure of cranial bones, without gross skull fractures. To address this, young adult female Piebald Viral Glaxo rats received sham, 1x, 2x or 3x closed-head mTBIs delivered at 24h intervals, using a weight-drop device custom built for reproducible impact. Skull bones were collected at 2 or 10 weeks after the final injury/sham procedure, imaged by micro computed tomography and analyzed at predetermined regions of interest. In the interparietal bone, proximal to the injury site, modest increases in bone thickness was observed at 2 weeks, particularly following 3x mTBI. By 10 weeks, 2x mTBI induced a robust increase in the volume and thickness of the interparietal bone, alongside a corresponding decrease in the volume of marrow cavities in the diploe region. In contrast, neither parietal nor frontal skull samples were affected by rmTBI. Our findings demonstrate time- and location-dependent effects of rmTBI on cranial bone structure, highlighting a need to consider microstructural alterations to cranial bone when assessing the consequences of rmTBI.

neuroscience↗

bioRxiv2021

Adaptor linked K63 di-Ubiquitin activates Nedd4/Rsp5 E3 ligase

Nedd4/Rsp5 family E3 ligases mediate numerous cellular processes, many of which require the E3 ligase to interact with PY-motif containing adaptor proteins. Several Arrestin-Related Trafficking adaptors(ARTs) of Rsp5 were self-ubiquitinated for activation, but the regulation mechanism remains elusive. Remarkably, we demonstrate that Art1, Art4, and Art5 undergo K63-linked di-ubiquitination by Rsp5. This modification enhances the PM recruitment of Rsp5 by Art1 or Art5 upon substrate induction, required for cargo protein ubiquitination. In agreement with these observations, we find that di-ubiquitin strengthens the interaction between the Pombe orthologs of Rsp5 and Art1, Pub1 and Any1. Further, we discover that the HECT domain exosite protects the K63-linked di-ubiquitin on the adaptors from cleavage by the deubiquitination enzyme Ubp2. Strikingly, loss of this protection results in the loss of K63-linked di-ubiquitin from the adaptors and diverts the adaptors for K48-linked poly-ubiquitination and proteasome-mediated degradation. Together, our study uncovers a novel ubiquitination modification implemented by Rsp5 adaptor proteins, underscoring the regulatory mechanism of how adaptor proteins control the recruitment and activity of Rsp5 for the turnover of membrane proteins.

cell biology↗

bioRxiv2021

Integrated gene analyses of de novo mutations from 46,612 trios with autism and developmental disorders

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here we analyzed de novo mutations (DNMs) from 15,560 ASD (6,557 are new) and 31,052 DD trios independently and combined as broader neurodevelopmental disorders (NDD) using three models. We identify 615 candidate genes (FDR 5%, 189 potentially novel) by one or more models, including 138 reaching exome-wide significance (p < 3.64e-07) in all models. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes show particular mutational-bias including enrichments for missense (n=41) or truncating DNM (n=12). We find 22 genes with evidence of sex-bias including five X chromosome genes also with significant female burden (DDX3X, MECP2, SMC1A, WDR45, and HDAC8). NDD risk genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data, which provides important insights into disease subtypes and future functional studies.

genetics↗

bioRxiv2021

Mechanistic insights into dynamic mutual regulation of USP14 and proteasome

Proteasomal degradation of ubiquitylated proteins is sophisticatedly regulated at multiple levels1-3. A primary regulatory checkpoint is the removal of ubiquitin chains from substrates by the deubiquitylating enzyme USP14 that associates reversibly with the proteasome. How USP14 is activated and regulates the proteasome function remains unknown4-7. Here we report cryo-electron microscopy (cryo-EM) structures of human USP14 in complex with the 26S proteasome in nine conformational states at 3.0-3.6 [A] resolution, captured during polyubiquitylated protein degradation. Time-resolved cryo-EM analysis of the conformational continuum revealed two parallel pathways of proteasome state transitions induced by USP14 and captured transient conversion of substrate-engaged intermediates into substrate-inhibited intermediates. On the substrate-engaged pathway, USP14 activation allosterically reprograms conformational landscape of the AAA-ATPase motor and stimulates opening of the core particle gate8-10, enabling observation of a near-complete cycle of asymmetric ATP hydrolysis around the ATPase ring during processive substrate unfolding. Dynamic USP14-ATPase interactions decouple the ATPase activity from RPN11-catalysed deubiquitylation11-13 and kinetically introduce three regulatory checkpoints on the proteasome, at the steps of ubiquitin recognition, substrate translocation initiation and ubiquitin chain recycling. These findings provide unprecedented insights into the complete functional cycles of USP14-regulated proteasome and of USP14 activation-deubiquitylation-disassembly and establish mechanistic foundations for USP14-targeted therapeutic discovery.

biochemistry↗

bioRxiv2021

Phase transition specified by a binary code patterns the vertebrate eye cup

The developing vertebrate eye cup is partitioned into the neural retina (NR), the retinal pigmented epithelium (RPE) and the ciliary margin (CM). By single cell analysis, we showed that a gradient of FGF signaling regulates demarcation and subdivision of the CM and controls its stem cell-like property of self-renewal, differentiation and survival. This regulation by FGF is balanced by an evolutionarily conserved Wnt signaling gradient induced by the lens ectoderm and the periocular mesenchyme, which specifies the CM and the distal RPE. These two morphogen gradients converge in the CM where FGF signaling promotes Wnt signaling by stabilizing {beta}-catenin in a GSK3{beta}-independent manner. We further showed that activation of Wnt signaling converts the NR to either the CM or the RPE depending on the level of FGF signaling. Conversely, activation of FGF transforms the RPE to the NR or CM dependent on Wnt activity. We demonstrated that the default fate of the eye cup is the NR, but synergistic FGF and Wnt signaling promotes CM formation both in vivo and in retinal organoid culture of human iPS cells. Our study reveals that the vertebrate eye develops through phase transition determined by a combinatorial code of FGF and Wnt signaling.

developmental biology↗

bioRxiv2021

Visualizing conformational space of functional biomolecular complexes by deep manifold learning

The cellular functions are executed by biological macromolecular complexes in nonequilibrium dynamic processes, which exhibit a vast diversity of conformational states. Solving conformational continuum of important biomolecular complexes at atomic level is essential to understand their functional mechanisms and to guide structure-based drug discovery. Here we introduce a deep learning framework, named AlphaCryo4D, which enables atomic-level cryogenic electron microscopy reconstructions of conformational continuum. AlphaCryo4D integrates 3D deep residual learning with manifold embedding of energy landscapes, which simultaneously improves 3D classification accuracy and reconstruction resolution via an energy-based particle-voting algorithm. By applications of this approach to analyze five experimental datasets, we demonstrate its generality in breaking resolution barrier of visualizing dynamic components of functional complexes, in choreographing continuous inter-subunit motions and in exploring their hidden conformational space. Our approach expands the realm of structural ensemble determination to the nonequilibrium regime at atomic level, thus potentially transforming biomedical research and therapeutic development.

bioinformatics↗

bioRxiv2021

Effects of sub-threshold transcutaneous auricular vagus nerve stimulation on cerebral blood flow

BackgroundTranscutaneous auricular vagus nerve stimulation (taVNS) has shown promise as a non-invasive alternative to vagus nerve stimulation (VNS) with implantable devices, which has been used to treat drug-resistant epilepsy and treatment-resistant depression. Prior work has used functional MRI to investigate the brain response to taVNS, and more recent work has also demonstrated potential therapeutic effects of high-frequency sub-threshold taVNS in rheumatoid arthritis. However, no studies to date have measured the effects of high-frequency sub-threshold taVNS on cerebral blood flow (CBF). Objective/HypothesisThe objective of this study was to determine whether high-frequency (20 kHz) sub-threshold taVNS induces significant changes in CBF. MethodsArterial spin labeling (ASL) MRI scans were performed on 20 healthy subjects in a single-blind placebo-controlled repeated measures experimental design. The ASL scans were performed before and after 15 minutes of either sub-threshold taVNS treatment or a sham control. ResultstaVNS induced significant changes in CBF in the superior posterior cerebellum that were largely localized to bilateral Crus I and Crus II. Post hoc analyses showed that the changes were driven by a treatment-related decrease in CBF. ConclusionsFifteen minutes of high-frequency sub-threshold taVNS can induce sustained CBF decreases in the bilateral posterior cerebellum in a cohort of healthy subjects. This study lays the foundation for future studies in clinical popluations to assess whether similar effects can be observed and are related to treatment outcomes.

neuroscience↗

bioRxiv2021

ERp44 is Required for Endocardial Cushion Development by Regulating VEGFA Secretion in Myocardium

Rationale: Endocardial cushions are precursors of the valvoseptal complex that separates the four heart chambers and control blood flow through the heart. Abnormalities in endocardial cushion development lead to atrioventricular septal defects (AVSDs), which affect 1 in 2,100 live births. Several genes have been implicated in the development of endocardial cushions. Specifically, endoplasmic reticulum-resident protein 44 (ERp44) has been found to play a role in the early secretory pathway, but its function in heart development has not been well studied. Objective: The goal of this study was to investigate the role of ERp44 in heart development in mice. Approach and Results: Using conventional and tissue-specific knockout mouse models, we demonstrated that ERp44 plays a specific role in heart development. ERp44 knockout (KO) mice were smaller in size, and most mice died during early postnatal life. KO hearts exhibited the typical phenotypes of congenital heart diseases, such as abnormal heart shapes as well as severe septal and valvular defects. Similar phenotypes were found in cTnt-cre+/-; Erp44fl/fl mice, which indicated that myocardial ERp44 principally controls endocardial cushion formation. Further studies demonstrated that the deletion of ERp44 significantly decreased the proliferation of cushion cells and impaired the endocardial-mesenchymal transition (EndMT), which was followed by endocardial cushion dysplasia. Finally, we found that ERp44 directly bound to VEGFA and controlled its release. Conclusions: ERp44 contributes to the development of the endocardial cushion by affecting the EndMT of cushion cells by regulating VEGFA release in myocardial cells.

developmental biology↗

bioRxiv2021

LmbU directly regulates SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780, which are located outside the lmb cluster and inhibit lincomycin biosynthesis in Streptomyces lincolnensis

The productions of antibiotics are usually regulated by cluster-situated regulators (CSRs), which can directly regulate the genes within the corresponding biosynthetic gene cluster (BGC). However, few studies have looked into the regulation of CSRs on the targets outside the BGC. Here, we screened the targets of LmbU in the whole genome of S. lincolnensis, and found 14 candidate targets, among of which, 8 targets can bind to LmbU by EMSAs. Reporter assays in vivo revealed that LmbU repressed transcription of SLINC_RS02575 and SLINC_RS05540, while activated transcription of SLINC_RS42780. In addition, disruptions of SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780 promoted the production of lincomycin, and qRT-PCR showed that SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780 inhibited transcription of the lmb genes, indicating that all the three regulators can negatively regulate lincomycin biosynthesis. Whats more, the homologues of LmbU and its targets SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780 are widely found in actinomycetes, while the distributions of DNA-binding sites (DBS) of LmbU are diverse, indicating the regulatory mechanisms of LmbU homologues in various strains are different and complicated. IMPORTANCELincomycin is widely used in clinic treatment and animal husbandry. Our previous study firstly demonstrated that LmbU, a novel transcriptional regulator family, functions as a CSR and positively regulates lincomycin biosynthesis. Here, we revealed that LmbU may act as a pleiotropic transcriptional regulator, and directly regulates SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780 which are located outside the lmb cluster and negatively regulate lincomycin biosynthesis. Interestingly, the homologues of LmbU and its targets are widely found in actinomycetes, indicating the regulatory patterns of LmbU to the targets may exist in a variety of strains. Collectively, our findings elucidated the molecular mechanism with which LmbU regulates the target genes outside the lmb culster, and draw a network diagram of LmbU regulation on lincomycin biosynthesis. This lays a solid foundation for the realization of high-yield of lincomycin in industry, and provides the theoretical basis for the functional research of LmbU family proteins.

molecular biology↗

bioRxiv2021

Mechanical Forces during Lymph Node Expansion Govern Fibroblastic Reticular Network Remodeling

Emergent physical properties of tissues are not readily understood by reductionist studies of their constituent cells. Here, we show molecular signals controlling cellular physical properties, collectively determining tissue mechanics of lymph nodes, an immunologically-relevant, adult mammalian tissue. Lymph nodes paradoxically maintain robust tissue architecture in homeostasis yet are continually poised for extensive tissue expansion upon immune challenge. We find that following immune challenge, cytoskeletal mechanics of a cellular meshwork of fibroblasts determine tissue tension independently of extracellular matrix scaffolds. We determine that CLEC-2/podoplanin signalling regulates the cell surface mechanics of fibroblasts, permitting cell elongation and interdigitation through expedited access to plasma membrane reservoirs. Increased tissue tension through the stromal meshwork gates the initiation of fibroblast proliferation, restoring homeostatic cellular ratios and tissue structure through expansion.

biophysics↗

bioRxiv2021

The cortical hubs related to recovery of consciousness

Background and ObjectivesThe neural mechanism that enables the recovery of consciousness in patients with unresponsive wakefulness syndrome (UWS) remains unclear. The aim of the current study is to characterize the cortical hub regions related to the recovery of consciousness in patients with UWS. MethodsVoxel-wise degree centrality analysis was adopted to identify the cortical hubs related to the recovery of consciousness, for which a total of 27 UWS patients were used, including 13 patients who emerged from UWS (UWS-E), and 14 patients who remained in UWS (UWS-R) at least three months after the experiment performance. Furthermore, other recoverable unconscious states including three independent deep sleep datasets (n = 12, 9, 9 respectively) and three independent anesthesia datasets (n = 27, 14, 6 respectively) were adopted as validation groups. Spatial similarity of the hub characteristic with the validation groups between the UWS-E and UWS-R was compared using the dice coefficient. Finally, with the cortical regions persistently shown as hubs across UWS-E and validation states, functional connectivity analysis was further performed to explore the connectivity patterns underlying the recovery of consciousness. ResultsFour cortical hubs were identified with significantly higher degree centrality for UWS-E than UWS-R, including the anterior precuneus, left inferior parietal lobule, left inferior frontal gyrus, and left middle frontal gyrus, of which the degree centrality value also positively correlated with the patients Glasgow Outcome Scale (GOS) score. Furthermore, the anterior precuneus was found to show significantly higher similarity of hub characteristics as well as functional connectivity pattern between UWS-E and validation groups, compared with UWS-R. DiscussionThe results suggest that the recovery of consciousness may be relevant to the integrity of cortical hubs, especially the anterior precuneus. The identified cortical hub regions could serve as potential targets for noninvasive stimulation aimed at promoting the patients consciousness recovery.

neuroscience↗

bioRxiv2021

Asymmetric structures and conformational plasticity of the uncleaved full-length human immunodeficiency virus (HIV-1) envelope glycoprotein trimer

The functional human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer [(gp120/gp41)3] is produced by cleavage of a conformationally flexible gp160 precursor. Gp160 cleavage or the binding of BMS-806, an entry inhibitor, stabilizes the pre-triggered, "closed" (State-1) conformation recognized by rarely elicited broadly neutralizing antibodies. Poorly neutralizing antibodies (pNAbs) elicited at high titers during natural infection recognize more "open" Env conformations (States 2 and 3) induced by binding the receptor, CD4. We found that BMS-806 treatment and crosslinking decreased the exposure of pNAb epitopes on cell-surface gp160; however, after detergent solubilization, crosslinked and BMS-806-treated gp160 sampled non-State-1 conformations that could be recognized by pNAbs. Cryo-electron microscopy of the purified BMS-806-bound gp160 revealed two hitherto unknown asymmetric trimer conformations, providing insights into the allosteric coupling between trimer opening and structural variation in the gp41 HR1N region. The individual protomer structures in the asymmetric gp160 trimers resemble those of other genetically modified or antibody-bound cleaved HIV-1 Env trimers, which have been suggested to assume State-2-like conformations. Asymmetry of the uncleaved Env potentially exposes surfaces of the trimer to pNAbs. To evaluate the effect of stabilizing a State-1-like conformation of the membrane Env precursor, we treated cells expressing wild-type HIV-1 Env with BMS-806. BMS-806 treatment decreased both gp160 cleavage and the addition of complex glycans, implying that gp160 conformational flexibility contributes to the efficiency of these processes. Selective pressure to maintain flexibility in the precursor of functional Env allows the uncleaved Env to sample asymmetric conformations that potentially skew host antibody responses toward pNAbs. IMPORTANCEThe envelope glycoprotein (Env) trimers on the surface of human immunodeficiency virus (HIV-1) mediate the entry of the virus into host cells and serve as targets for neutralizing antibodies. The functional Env trimer is produced by cleavage of the gp160 precursor in the infected cell. We found that the HIV-1 Env precursor is highly plastic, allowing it to assume different asymmetric shapes. This conformational plasticity is potentially important for Env cleavage and proper modification by sugars. Having a flexible, asymmetric Env precursor that can misdirect host antibody responses without compromising virus infectivity would be an advantage to a persistent virus like HIV-1.

molecular biology↗

bioRxiv2020

The size of helical pitch is important for microtubule plus end dynamic instability

Microtubule (MT) dynamic instability is a conserved phenomenon underlying essential cellular functions such as cell division, cell migration and intracellular transport, and is a key target of many chemotherapeutic agents. However, it remains unclear how the organization of tubulin dimers at the nanometer scale translates into dynamic instability as an emergent property at the micrometer scale. Tubulin dimers are organized into left-handed helical MT lattice, and most present-day MTs converge at a 1.5 dimer helical pitch that causes a seam in an otherwise symmetric helix. Because presently there are no experimental methods that can precisely manipulate tubulin subunit with sub-dimer resolution, the impact of helical pitch on dynamic instability remains unknown. Here by using stochastic simulations of microtubule assembly dynamics we demonstrate that helical pitch plays essential roles in MT plus end dynamic instability. By systematically altering helical pitch size, one half-dimer at a time, we found that a helical pitch as small as one half-dimer is sufficient to inhibit short-term MT length plateaus associated with diminishing GTP-tubulin cap. Notably, MT plus end dynamics quantitatively scale with the size of helical pitch, rather than being clustered by the presence or absence of helical symmetry. Microtubules with a 1.5 dimer helical pitch exhibit growth and shrinkage phases and undergo catastrophe and rescue similar to experimentally observed microtubules. Reducing helical pitch to 0 promotes rapid disassembly, while increasing it causes microtubules to undergo persistent growth, and it is the 1.5 dimer helical pitch that yields the highest percentage of MTs that undergo alternating growth and shrinkage without being totally disassembled. Finally, although the 1.5 dimer helical pitch is conserved among most present-day MTs, we find that other parameters, such as GTP hydrolysis rate, can partially compensate for changes in helical pitch. Together our results indicate that helical pitch is a determinant of MT plus end dynamic instability and that the evolutionarily conserved 1.5 dimer helical pitch promotes dynamic instability required for microtubule-dependent cellular functions.

cell biology↗

bioRxiv2020

Deep manifold learning reveals hidden dynamics of proteasome autoregulation

The 26S proteasome regulates proteostasis and myriad cellular processes. Here we reconstitute the hidden dynamics of human 26S proteasome during protein degradation using cryo-EM data-driven deep learning, which identified 64 proteasomal conformers. These conformers revealed substrate-dependent conformational entanglement of two 19S regulatory particles in the doubly capped holocomplexes. The rate-limiting step in single-nucleotide exchange dynamics of the AAA-ATPase motor is ATPase re-engagement with the substrate, while the rate-limiting step in proteasomal degradation is the initiation of substrate unfolding by the AAA-ATPase motor following deubiquitylation. Nine rare conformers delineated novel ubiquitin-binding sites on the RPN2 and 5 subunits, along with a ubiquitylation site on RPN10, which were verified using site-directed mutagenesis and liquid chromatography-tandem mass spectrometry. Opening of the 20S core particle gate was found to upregulate proteolytic activity by allosterically promoting nucleophilic attack on the scissile peptide bond. Our systematic analyses illuminate a grand hierarchical allostery underlying ubiquitin-mediated proteasome autoregulation.

biochemistry↗

bioRxiv2020

The hybrid nature of task-evoked activity: Inside-out neural dynamics in intracranial EEG and Deep Learning

A.The standard approach in neuroscience research infers from the external stimulus (outside) to the brain (inside) through stimulus-evoked activity. Recently challenged by Buzsaki, he advocates the reverse; an inside-out approach inferring from the brains activity to the neural effects of the stimulus. If so, stimulus-evoked activity should be a hybrid of internal and external components. Providing direct evidence for this hybrid nature, we measured human intracranial stereo-electroencephalography (sEEG) to investigate how prestimulus variability, i.e., standard deviation, shapes poststimulus activity through trial-to-trial variability. We first observed greater poststimulus variability quenching in trials exhibiting high prestimulus variability. Next, we found that the relative effect of the stimulus was higher in the later (300-600ms) than the earlier (0-300ms) poststimulus period. These results were extended by our Deep Learning LSTM network models at the single trial level. The accuracy to classify single trials (prestimulus low/high) increased greatly when the models were trained and tested with real trials compared to trials that exclude the effects of the prestimulus-related ongoing dynamics (corrected trials). Lastly, we replicated our findings showing that trials with high prestimulus variability in theta and alpha bands exhibits faster reaction times. Together, our results support the inside-out approach by demonstrating that stimulus-related activity is a hybrid of two factors: 1) the effects of the external stimulus itself, and 2) the effects of the ongoing dynamics spilling over from the prestimulus period, with the second, i.e., the inside, dwarfing the influence of the first, i.e., the outside. B. Significance StatementOur findings signify a significant conceptual advance in the relationship between pre- and poststimulus dynamics in humans. These findings are important as they show that we miss an essential component - the impact of the ongoing dynamics - when restricting our analyses to the effects of the external stimulus alone. Consequently, these findings may be crucial to fully understand higher cognitive functions and their impairments, as can be seen in psychiatric illnesses. In addition, our Deep Learning LSTM models show a second conceptual advance: high classification accuracy of a single trial to its prestimulus state. Finally, our replicated results in an independent dataset and task showed that this relationship between pre- and poststimulus dynamics exists across tasks and is behaviorally relevant.

neuroscience↗

bioRxiv2020

Condensation of Rubisco into a proto-pyrenoid in higher plant chloroplasts

Photosynthetic CO2 fixation in plants is limited by the inefficiency of the CO2-assimilating enzyme Rubisco (D-ribulose-1,5-bisphosphate carboxylase/ oxygenase)1-3. In plants possessing the C3 pathway, which includes most major staple crops, Rubisco is typically evenly distributed throughout the chloroplast stroma. However, in almost all eukaryotic algae Rubisco aggregates within a microcompartment known as the pyrenoid, in association with a CO2-concentrating mechanism that improves photosynthetic operating efficiency under conditions of low inorganic carbon4. Recent work has shown that the pyrenoid matrix is a phase-separated, liquid-like condensate5. In the alga Chlamydomonas reinhardtii, condensation is mediated by two components: Rubisco and the linker protein EPYC1 (Essential Pyrenoid Component 1)6,7. Here we show that expression of mature EPYC1 and a plant-algal hybrid Rubisco leads to spontaneous condensation of Rubisco into a single phase-separated compartment in Arabidopsis chloroplasts, with liquid-like properties similar to a pyrenoid matrix. The condensate displaces the thylakoid membranes and is enriched in hybrid Rubisco containing the algal Rubisco small subunit required for phase separation. Promisingly, photosynthetic CO2 fixation and growth is not impaired in stable transformants compared to azygous segregants. These observations represent a significant initial step towards enhancing photosynthesis in higher plants by introducing an algal CO2-concentrating mechanism, which is predicted to significantly increase the efficiency of photosynthetic CO2 uptake8,9.

plant biology↗

bioRxiv2020

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

Mammalian cells have to adapt to environmental challenges that range from mild to severe stress. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe stress conditions, cells induce a transient hibernation-like mechanism that anticipates recovery. We demonstrate that this Adaptive Pausing Response (APR) is a coordinated cellular response that limits ATP supply and consumption though mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery from severe stress. We further show that recovery from severe stress involves adaptive ISR (Integrated Stress Response) signaling that in turn permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress through the APR, a mechanism that preserves vital elements of cellular function under harsh environmental conditions.

molecular biology↗

bioRxiv2020

Higher-order sensorimotor circuit of the brain' global network supports human consciousness

The neural correlates of consciousness, defined as the minimum neuronal mechanisms sufficient for any conscious percept, are usually subject to different interpretations depending on whether one uses measures of local or global brain activities. We argue that the local regions may support consciousness by serving as hubs within the brains global network. We adopt a unique functional magnetic resonance imaging resting state dataset that encompasses various conscious states, including non-rapid eye movement (NREM)-sleep, rapid eye movement (REM)-sleep, anesthesia, and brain injury patients. Using a graph-theoretical measure for detecting local hubs within the brains global network, we identify various higher-order sensory and motor regions as hubs with significantly reduced degree centrality during unconsciousness. Additionally, these regions form a sensorimotor circuit which correlates with levels of consciousness. Our findings suggest that integration of higher-order sensorimotor function may be a key mechanism of consciousness. This opens novel perspectives for therapeutic modulation of unconsciousness.

neuroscience↗