Biology subjects

Ma, Z.

Publications and source records attributed to Ma, Z..

At least 199 records · Page 11Linked to original sources

bioRxiv2020

Flocked swab might be one main reason causing the high false-negative rate in COVID-19 screening----the advantages of a novel silicone swab

RNA testing using RT-PCR can provide direct evidence for diagnoses of COVID-19 which has brought unexpected disasters and changes to our human society. However, the absorption of cotton swab for RNA lysates may lead to a low concentration of detectable RNA, which might be one of the main reasons for the unstable positive detecting rate. We designed and manufactured a kind of silicone swab with concave-convex structure, and further compared the effects of silicone and cotton swab on RNA extraction. Principal component analysis and Paired Wilcoxcon test suggested that a higher RNA concentration and A260/A280 would be obtained using silicone swab. The results indicated that our silicone swab had a more excellent ability to sample than the cotton swab, characterized by the higher quantity and quality of extracted RNA. Thus, we advised that the current cotton swabs need to be improved urgently in COVID-19 diagnoses and the process of "sample collection" and "sample pre-processing" must be standardized and emphasized. HighlightsThe current cotton swabs need to be improved urgently in COVID-19 screening.

microbiology↗

bioRxiv2020

The physical form of microbial ligands bypasses the need for dendritic cell migration to stimulate adaptive immunity

A central paradigm of immunology is that the innate immune system first detects infectious agents in peripheral tissues, shortly after a pathogen has breached an epithelial barrier. This detection event is mediated by pattern recognition receptors in phagocytes, which then migrate to draining lymph nodes (dLNs), where information of a microbial encounter is conveyed to T and B lymphocytes to generate adaptive immunity. Through the study of fungal moieties, we present data that challenge this model. We found that soluble fungal polysaccharides are immunosilent in the periphery, but become potent immunogens in the dLN. These ligands completely bypass the need of phagocyte migration and, instead, directly activate an immune response that is most similar to those that typify viral infections. These data establish a class of microbial products that violate a central tenet of the immunological lexicon and illustrate that the physical form (not just the chemical structure) impacts innate and adaptive immunity.

immunology↗

bioRxiv2020

New Tricks for an old molecule: Preserved antibacterial activity of ribosomal protein S15 during evolution

Previous studies show that some ribosomal proteins possess antimicrobial peptide (AMP) activity. However, information as such remains rather fragmentary and limited. Here we demonstrated for the first time that amphioxus RPS15, BjRPS15, was a previously uncharacterized AMP, which was not only capable of identifying Gram-negative and -positive bacteria via interaction with LPS and LTA but also capable of killing the bacteria. We also showed that both the sequence and 3D structure of RPS15 and its prokaryotic homologs were highly conserved, suggesting its antibacterial activity is universal across widely separated taxa. Actually this was supported by the facts that the residues positioned at 45-67 formed the core region for the antimicrobial activity of BjRPS15, and its prokaryotic counterparts, including Nitrospirae RPS1933-55, Aquificae RPS1933-55 and P. syringae RPS1950-72, similarly displayed antibacterial activities. BjRPS15 functioned by both interaction with bacterial membrane via LPS and LTA and membrane depolarization as well as induction of intracellular ROS. Moreover, we showed that RPS15 existed extracellularly in amphioxus, shrimp, zebrafish and mice, hinting it may play a critical role in systematic immunity in different animals. In addition, we found that neither BjRPS15 nor its truncated form BjRPS1545-67 were toxic to mammalian cells, making them promising lead molecules for the design of novel peptide antibiotics against bacteria. Collectively, these indicate that RPS15 is a new member of AMP with ancient origin and high conservation throughout evolution. Author summaryRibosomal protein, a component of ribonucleoprotein particles, is traditionally known involved in protein synthesis in a cell. Here we demonstrated for the first time that amphioxus ribosomal protein 15 was a novel antibacterial protein, capable of recognizing Gram-negative and -positive bacteria as well as killing them. It killed the bacteria by a combined mode of action of disrupting bacterial membrane integrity and inducing radical oxygen species production. We also showed that both eukaryotic ribosomal protein 15 and its prokaryotic counterpart ribosomal protein 19 possessed antibacterial activity, indicating that the antibacterial property is universal for this family of molecules. Moreover, we found that ribosomal protein 15 was present in the circulation system of various animals including shrimp, amphioxus, zebrafish and mice, suggesting it may physiologically play a key role in systematic immunity. Altogether, our study provides a new angle for understanding the biological function of ribosomal proteins.

immunology↗

bioRxiv2020

Infrared heater warming system markedly reduces dew formation: An overlooked factor in arid ecosystems

Dew plays a vital role in ecosystem processes in arid and semi-arid regions and is expected to be affected by climate warming. Infrared heater warming systems have been widely used to simulate climate warming effects on ecosystem. However, how this warming system affects dew formation has been long ignored and rarely addressed. In a typical alpine grassland ecosystem on the Northeast of the Tibetan Plateau, we measured dew amount and duration by artificial condensing surfaces, leaf wetness sensors and in situ dew formation on plants from 2012 to 2017. We also measured plant traits related to dew conditions. The results showed that (1) warming reduced the dew amount by 41.6%-91.1% depending on the measurement method, and reduced dew duration by 32.1 days compared to the ambient condition. (2) Different plant functional groups differed in dew formation. (3) Under the infrared warming treatment, the dew amount decreased with plant height, while under the ambient conditions, the dew amount showed the opposite trend. We concluded that warming with an infrared heater system greatly reduces dew formation, and if ignored, it may lead to overestimation of the effects of climate warming on ecosystem processes in climate change simulation studies.

ecology↗

bioRxiv2020

The bacterial quorum sensing signal DSF hijacks Arabidopsis thaliana sterol biosynthesis to suppress plant innate immunity

Quorum sensing (QS) is a recognized phenomenon that is crucial for regulating population-related behaviors in bacteria. However, the direct specific effect of QS molecules on host biology is largely under-studied. In this work, we show that the QS molecule DSF (cis-11-methyl-dodecenoic acid) produced by Xanthomonas campestris pv. campestris can suppress pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) in Arabidopsis thaliana, mediated by flagellin-induced activation of flagellin receptor FLS2. The DSF-mediated attenuation of innate immunity results from the alteration of oligomerization states and endocytic internalization of plasma membrane FLS2. DSF altered the lipid profile of Arabidopsis, with a particular increase of the phytosterol species, which impairs the general endocytosis pathway mediated by clathrin and FLS2 nano-clustering on the plasma membrane. The DSF effect on receptor dynamics and host immune responses could be entirely reversed by sterol removal. Together, our results highlighted the importance of sterol homeostasis to plasma membrane organization and demonstrate a novel mechanism by which pathogenic bacteria use their communicating molecule to manipulate PAMP-triggered host immunity. SIGNIFICANCE STATEMENTBacteria rely on small signalling molecules called quorum sensing (QS) signals to communicate and coordinate their behaviors. QS is known to regulate gene expression, production of virulence factors, and biofilm formation for pathogenic bacteria to effectively colonize their hosts and cause diseases. In this work, we found a class of QS molecule called diffusible-signal factor (DSF), produced by devastating phytopathogenic bacteria such as Xanthomonas spp. and Xylella fastidiosa, could communicate directly with plant host and subvert plant innate immunity by inducing plant sterol production and thereby, attenuating receptor signalling through hindering the receptor clustering and plant endocytosis. The results significantly enrich our understanding of the mechanisms in the tug-of-war between bacterial pathogenesis and host immunity.

plant biology↗

bioRxiv2019

TrpML-mediated astrocyte microdomain Ca2+ transients regulate astrocyte-tracheal interactions in CNS

Astrocytes exhibit spatially-restricted near-membrane microdomain Ca2+ transients in their fine processes. How these transients are generated and regulate brain function in vivo remains unclear. Here we show that Drosophila astrocytes exhibit spontaneous, activity-independent microdomain Ca2+ transients in their fine processes. Astrocyte microdomain Ca2+ transients are mediated by the TRP channel TrpML, stimulated by reactive oxygen species (ROS), and can be enhanced in frequency by the neurotransmitter tyramine via the TyrRII receptor. Interestingly, many astrocyte microdomain Ca2+ transients are closely associated with tracheal elements, which dynamically extend filopodia throughout the central nervous system (CNS) to deliver O2 and regulate gas exchange. Many astrocyte microdomain Ca2+ transients are spatio-temporally correlated with the initiation of tracheal filopodial retraction. Loss of TrpML leads to increased tracheal filopodial numbers, growth, and increased CNS ROS. We propose that local ROS production can activate astrocyte microdomain Ca2+ transients through TrpML, and that a subset of these microdomain transients promotes tracheal filopodial retraction and in turn modulate CNS gas exchange.

neuroscience↗

bioRxiv2019

An open database of resting-state fMRI in awake rats

Rodent models are essential to translational research in health and disease. Investigation in rodent brain function and organization at the systems level using resting-state functional magnetic resonance imaging (rsfMRI) has become increasingly popular, owing to its high spatial resolution and whole-brain coverage. Due to this rapid progress, shared rodent rsfMRI databases can be of particular interest and importance to the scientific community, as inspired by human neuroscience and psychiatric research that are substantially facilitated by open human neuroimaging datasets. However, such databases in rats are still lacking. In this paper, we share an open rsfMRI database acquired in 90 rats with a well-established awake imaging paradigm that avoids anesthesia interference. Both raw and preprocessed data are made publically available. Procedures in data preprocessing to remove artefacts induced by the scanner, head motion, non-neural physiological noise are described in details. We also showcase inter-regional functional connectivity and functional networks calculated from the database.

neuroscience↗

bioRxiv2019

Pan-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and impact of treatment are poorly understood. We analyzed exome sequencing data from 457 paired primary tumor and metastatic samples from 136 breast, colorectal and lung cancer patients, including untreated (n=99) and treated (n=100) metastatic tumors. Treated metastases often harbored private driver mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in untreated lymph node metastases (n=17/29, 59%) and distant metastases (n=20/70, 29%), but less frequent in treated distant metastases (n=9/94, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which we estimated commonly occurred 2-4 years prior to diagnosis across these cancers. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumor development and that metastasis-private mutations are not drivers of cancer spread but instead associated with drug resistance.

cancer biology↗

bioRxiv2019

TIGIT-Fc Promote Immune Tolerance at the Feto-maternal Interface

The perfect synchronization of maternal immune-endocrine mechanisms and those of the foetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-foetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual dendritic cells (dDCs) increased the production of interleukin 10 and induced the dDCs to powerfully polarize the decidual CD4+ T cells towards a classic TH2 phenotype. The administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4+ forkhead box P3+ (Foxp3+) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in a mouse model of abortive stress. Moreover, we proposed that progesterone play a direct role in the transcriptional regulation of the TIGIT gene in decidual immune cell subsets. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.

immunology↗

bioRxiv2019

Global brain signal in awake rats

Although often used as a nuisance in resting-state functional magnetic resonance imaging (rsfMRI), the global brain signal in humans and anesthetized animals has important neural basis. However, our knowledge of the global signal in awake rodents is sparse. To bridge this gap, we systematically analyzed rsfMRI data acquired with a conventional single-echo (SE) echo planar imaging (EPI) sequence in awake rats. The spatial pattern of rsfMRI frames during peaks of the global signal exhibited prominent co-activations in the thalamo-cortical and hippocampo-cortical networks, as well as in the basal forebrain, hinting that these neural networks might contribute to the global brain signal in awake rodents. To validate this concept, we acquired rsfMRI data using a multi-echo (ME) EPI sequence and removed non-neural components in the rsfMRI signal. Consistent co-activation patterns were obtained in extensively de-noised ME-rsfMRI data, corroborating the finding from SE-rsfMRI data. Furthermore, during rsfMRI experiments we simultaneously recorded neural spiking activities in the hippocampus using GCaMP-based fiber photometry. The hippocampal calcium activity exhibited significant correspondence with the global rsfMRI signal. These data collectively suggest that the global rsfMRI signal contains significant neural components that involve coordinated activities in the thalamo-cortical and hippocampo-cortical networks. These results provide important insight into the neural substrate of the global brain signal in awake rodents.

neuroscience↗

bioRxiv2019

Stress induces cytoprotective TDP-43 nuclear bodies through lncRNA NEAT1-promoted phase separation

Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/802058v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1963bb9org.highwire.dtl.DTLVardef@2b00eforg.highwire.dtl.DTLVardef@14a7a2forg.highwire.dtl.DTLVardef@9ba973_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights(Up to four bullet points. The length of each highlight cannot exceed 85 characters, including spaces) O_LIStress induces phase-separated TDP-43 NBs to alleviate cytotoxicity C_LIO_LIThe two RRMs interact with different RNAs and act distinctly in the assembly of TDP-43 NBs C_LIO_LILncRNA NEAT1 promotes TDP-43 LLPS and is upregulated in stressed neurons C_LIO_LIThe ALS-causing D169G mutation is NB-defective and forms pTDP-43 cytoplasmic foci C_LI SummaryDespite the prominent role of TDP-43 in neurodegeneration, its physiological and pathological functions are not fully understood. Here, we report an unexpected function of TDP-43 in the formation of dynamic, reversible, liquid droplet-like nuclear bodies (NBs) in response to stress. Formation of NBs alleviates TDP-43-mediated cytotoxicity in mammalian cells and fly neurons. Super-resolution microscopy reveals a "core-shell" organization of TDP-43 NBs, antagonistically maintained by the two RRMs. TDP-43 NBs are partially colocalized with nuclear paraspeckles, whose scaffolding lncRNA NEAT1 is dramatically upregulated in stressed neurons. Moreover, increase of NEAT1 promotes TDP-43 liquid-liquid phase separation (LLPS) in vitro. Finally, we uncover that the ALS-associated mutation D169G impairs the NEAT1-mediated TDP-43 LLPS and NB assembly, causing excessive cytoplasmic translocation of TDP-43 to form stress granules that become phosphorylated TDP-43 cytoplasmic foci upon prolonged stress. Together, our findings suggest a stress-mitigating role and mechanism of TDP-43 NBs, whose dysfunction may be involved in ALS pathogenesis.

neuroscience↗

bioRxiv2019

LncRNA-UCA1 inhibits the astrocyte activation in the temporal lobe epilepsy via regulating JAK/STAT signaling pathway

This article aimed to reveal the mechanism of Urothelial cancer associated 1 (UCA1) regulated astrocyte activation in temporal lobe epilepsy (TLE) rats via JAK/STAT signaling pathway. A model of TLE was established based on rats via kainic acid (KA) injection. All rats were divided into sham group, KA group, normal control (NC) + KA group and UCA1 + KA group. The Morris water maze was used to test the learning and memory ability of rats, and the expression of UCA1 in hippocampus was determined by qRT-PCR. Surviving neurons were counted by Nissl staining, and expression of glial cells glial fibrillary acidic protein, p-JAK1, and p-STAT and glutamate/aspartate transporter (GLAST) was analyzed by immunofluorescence and Western blot. A rat model of TLE was established by intraperitoneal injection of KA. QRT-PCR and fluorescence study showed that UCA1 inhibited astrocyte activation in hippocampus of epileptic rats. Meanwhile, the MWM analysis indicated that UCA1 improved the learning and memory in epilepsy rats. Moreover, the Nissl staining showed that UCA1 might has protective effect on neuronal injury induced by KA injection. Furthermore, the immunofluorescence and Western blot analysis revealed that the overexpression of UCA1 inhibited KA-induced abnormal elevation of GLAST, astrocyte activation of JAK/STAT signaling pathway, as well as hippocampus of epilepsy rats. UCA1 inhibited hippocampal astrocyte activation and GLAST expression in TLE rats via regulating JAK/STAT signaling, and improved the adverse reactions caused by epilepsy.

neuroscience↗

bioRxiv2019

How brain reacts to attack at a local region

The architecture of brain networks has been extensively studied in multiple species. However, exactly how the brain network reconfigures when a local region stops functioning remains elusive. By combining chemogenetics and resting-state functional magnetic resonance imaging (rsfMRI) in awake rodents, we investigated the causal impact of acutely inactivating a hub region (i.e. dorsal anterior cingulate cortex) on brain network properties. We found that disrupting hub activity profoundly changed the function the default-mode network (DMN), and this change was associated with altered DMN-related behavior. Suppressing hub activity also impacted the topological architecture of the whole-brain network in network resilience, segregation and small worldness, but not network integration. This study has established a system that allows for mechanistically dissecting the relationship between local regions and brain network properties. Our data provide direct evidence supporting the hypothesis that acute dysfunction of a brain hub can cause large-scale network changes. This study opens an avenue of manipulating brain networks by controlling hub-node activity.

neuroscience↗

bioRxiv2019

Does microbiome-associated disease affect the inter-subject heterogeneity of human microbiome?

Space is a critical and also challenging frontier in human microbiome research. It has been argued that lack of consideration of scales beyond individual and ignoring of microbe dispersal are two crucial roadblocks in preventing deep understanding of the heterogeneity of human microbiome. Assessing and interpreting the spatial distribution (dispersal) of microbes explicitly are particularly challenging, but implicit approaches such as Taylors power law (TPL) can still be effective and offer significant insights into the heterogeneity in abundance and distribution of human microbiomes. Here, we investigate the relationship between human microbiome-associated diseases (MADs) and the inter-subject microbiome heterogeneity, or heterogeneity-disease relationship (HDR), by harnessing the power of TPL extensions and by analyzing a big dataset of 25 MAD studies covering all five major microbiome habitats and majority of the high-profile MADs including obesity and diabetes. Our HDR analysis revealed that in approximately 10%-17% of the cases, disease effects were significant--the healthy and diseased cohorts exhibited statistically significant differences. In majority of the MAD cases, the microbiome was sufficiently resilient to endure the disturbances of MADs. Furthermore, comparative analysis with traditional DDR (diversity-disease relationship) results is presented. We postulate that HDR reveals evolutionary characteristics because it utilizes the TPL parameter that implicitly characterizes spatial behavior (dispersion), which is primarily shaped by microbe-host co-evolution and is more robust against disturbances including diseases, while diversity in DDR analysis is primarily an ecological-scale characteristic and is less robust against diseases. Nevertheless, both HDR and DDR cross-verified remarkable resilience of human microbiomes against MADs.\n\nImportanceIt has been argued that lack of consideration of scales beyond individual and ignoring of microbe dispersal are two crucial roadblocks in preventing deep understanding of the heterogeneity of human microbiome. Assessing and interpreting the spatial distribution (dispersal) of microbes explicitly are particularly challenging, but implicit approaches such as Taylors power law (TPL) can still be effective. Here, we investigate the relationship between human microbiome-associated diseases (MADs) and the inter-subject microbiome heterogeneity, or heterogeneity-disease relationship (HDR), by harnessing the power of TPL extensions and by analyzing a big dataset of 25 MAD studies covering all five major microbiome habitats and majority of the high-profile MADs including obesity and diabetes. We postulate that HDR reveals evolutionary characteristics because it utilizes the TPL parameter that implicitly characterizes spatial behavior (dispersion), which is primarily shaped by microbe-host co-evolution and is more robust against disturbances including diseases than the traditional diversity-disease relationship (DDR).

microbiology↗

bioRxiv2019

Human reproductive system microbiomes exhibited significantly different heterogeneity scaling with gut microbiome, but the intra-system scaling is invariant

Maintaining sexual reproduction in a highly competitive world is still one of the major mysteries of biology given the apparently high efficiency of asexual reproduction. Co-evolutionary theories such as the Red Queen hypothesis would suggest that the microbiomes in human reproductive systems, specifically the microbiomes contained in semen and vaginal fluids, should reach some level of homogeneity thanks to arguably the most conspicuous microbiome transmission between two sexes. The long-term sexual coevolution should favor the dynamic homogeneity or stability, which should also be beneficial for sexual reproduction such as sperm survival or fertilization on physiological/ecological time scale. We present a piece of quantitative evidence in the form of microbial community spatial heterogeneity to support the stability notion by analyzing three big datasets of the human vaginal, semen and gut microbiome. Methodologically, we applied a recent community-level extension to the classic Taylors power law (Taylor 1961, 1988: Nature), which reached the rare status of ecological law and has found applications beyond biology. The power law analysis revealed that human vaginal and semen microbiomes exhibited the same scaling parameter size in their community spatial (inter-individual) heterogeneities, while both exhibited significantly different heterogeneity scaling parameter with the human gut microbiome. Both ecological and evolutionary theories, such as hologenome/holobiont and Red Queen, even first principle, would predict that microbiome transmissions between two sexes should have homogenizing effects on the composition and stability of the microbiomes in human reproductive systems.\n\nImportanceMaintaining sexual reproduction in a highly competitive world is still one of the major mysteries of biology given the apparently high efficiency of asexual reproduction. Co-evolutionary theories such as the Red-Queen hypothesis would suggest that the microbiomes in human reproductive systems, specifically the microbiomes contained in semen and vaginal fluids, should reach some level of homogeneity thanks to arguably the most conspicuous microbiome transmission between two sexes. The long-term sexual co-evolution should favor the dynamic homogeneity or stability, which should also be beneficial for sexual reproduction such as sperm survival or fertilization on physiological/ecological time scale. We present a piece of quantitative evidence in the form of microbial community spatial heterogeneity to support the stability notion by analyzing three big datasets of the human vaginal, semen and gut microbiome. Both ecological and evolutionary theories would predict that microbiome transmissions between two sexes should have homogenizing effects in human reproductive systems.

evolutionary biology↗

bioRxiv2019

Stringent Response Governs the Virulence and Oxidative Stress Resistance of Francisella tularensis

Francisella tularensis is a Gram-negative bacterium responsible for causing tularemia in the northern hemisphere. F. tularensis has long been developed as a biological weapon due to its ability to cause severe illness upon inhalation of as few as ten organisms and based on its potential to be used as a bioterror agent is now classified as a Tier 1 Category A select agent by the CDC. The stringent response facilitates bacterial survival under nutritionally challenging starvation conditions. The hallmark of stringent response is the accumulation of the effector molecules ppGpp and (p)ppGpp known as stress alarmones. The relA and spoT gene products generate alarmones in several Gram-negative bacterial pathogens. RelA is a ribosome-associated ppGpp synthetase that gets activated under amino acid starvation conditions whereas, SpoT is a bifunctional enzyme with both ppGpp synthetase and ppGpp hydrolase activities. Francisella encodes a monofunctional RelA and a bifunctional SpoT enzyme. Previous studies have demonstrated that stringent response under nutritional stresses increases expression of virulence-associated genes encoded on Francisella Pathogenicity Island. This study investigated how stringent response governs the oxidative stress response of F. tularensis. We demonstrate that RelA/SpoT-mediated ppGpp production alters global gene transcriptional profile of F. tularensis in the presence of oxidative stress. The lack of stringent response in relA/spoT gene deletion mutants of F. tularensis makes bacteria more susceptible to oxidants, attenuates survival in macrophages, and virulence in mice. Mechanistically, we provide evidence that the stringent response in Francisella contributes to oxidative stress resistance by enhancing the production of antioxidant enzymes.\n\nImportanceThe unique intracellular life cycle of Francisella in addition to nutritional stress also exposes the bacteria to oxidative stress conditions upon its brief residence in the phagosomes, and escape into the cytosol where replication takes place. However, the contribution of the stringent response in gene regulation and management of the oxidative stress response when Francisella is experiencing oxidative stress conditions is not known. Our results provide a link between the stringent and oxidative stress responses. This study further improves our understanding of the intracellular survival mechanisms of F. tularensis.

microbiology↗

bioRxiv2019

Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors

G-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct G proteins, such as Gs, Gi, Gq or G12/13, as well as {beta}-arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of G proteins to directly interact with {beta}-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gi protein family members and {beta}-arrestin. Gi:{beta}-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gi:{beta}-arrestin scaffolds enhances our understanding of GPCR signalling.

cell biology↗

bioRxiv2019

Multi-Scale Network Regression for Brain-Phenotype Associations

Complex brain networks are increasingly characterized at different scales, including global summary statistics, community connectivity, and individual edges. While research relating brain networks to demographic and behavioral measurements has yielded many insights into brain-phenotype relationships, common analytical approaches only consider network information at a single scale, thus failing to incorporate rich information present at other scales. Here, we designed, implemented, and deployed Multi-Scale Network Regression (MSNR), a penalized multivariate approach for modeling brain networks that explicitly respects both edge- and community-level information by assuming a low rank and sparse structure, both encouraging less complex and more interpretable modeling. Capitalizing on a large neuroimaging cohort (n = 1, 051), we demonstrate that MSNR recapitulates interpretable and statistically significant association between functional connectivity patterns with brain development, sex differences, and motion-related artifacts. Notably, compared to single-scale methods, MSNR achieves a balance between prediction performance and model complexity, with improved interpretability. Together, by jointly exploiting both edge- and community-level information, MSNR has the potential to yield novel insights into brain-behavior relationships.

neuroscience↗