bioRxiv Science⌕ Search

Biology subjects

Ma, M.

Publications and source records attributed to Ma, M..

At least 91 records · Page 5Linked to original sources

Time-varying Functional Connectivity Predicts Fluctuations in Sustained Attention in a Serial Tapping Task

The mechanisms for how large-scale brain networks contribute to sustained attention is unknown. Attention fluctuates from moment to moment and this continuous change is consistent with dynamic changes in functional connectivity between brain networks involved in the internal and external allocation of attention. In this study, we investigated how brain network activity varied across different levels of attentional focus (i.e., "zones"). Participants performed a finger-tapping task, and guided by previous research, in-the-zone performance or state was identified by low reaction time variability and out-of-the-zone as the inverse. Employing a novel method of time-varying functional connectivity, called the quasi-periodic pattern analysis (i.e., reliable network-level low-frequency fluctuations), we found that the activity between the default mode network (DMN) and task positive network is significantly more anti-correlated during in-the-zone states versus out-of-the-zone states. Furthermore, it is the fronto-parietal control network (FPCN) that drives this difference. Activity in the dorsal attention network (DAN) and DMN were desynchronized across both zone states. During in-the-zone periods, FPCN synchronized with DAN, while during out-of-the-zone periods, FPCN synchronized with DMN. In contrast, the ventral attention network synchronized more closely with DMN during in-the-zone periods compared to out-of-the-zone periods. These findings demonstrate that time-varying functional connectivity across different brain networks varies with fluctuations in sustained attention.

neuroscience↗

Distinct Local and Global Functions of Aβ Low-Threshold Mechanoreceptors in Mechanical Pain Transmission

The roles of A{beta} low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of SplitCre labeled A{beta}-LTMRs in this regard. Genetic ablation of SplitCre-A{beta}-LTMRs increased mechanical pain but not thermosensation in both acute and chronic inflammatory pain conditions, indicating their modality-specific role in gating mechanical pain transmission. Local optogenetic activation of SplitCre-A{beta}-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a new model, in which A{beta}-LTMRs play distinctive local and global roles in transmitting and alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a new strategy of global activation plus local inhibition of A{beta}-LTMRs for treating mechanical hyperalgesia.

neuroscience↗

Foldy: a web application for interactive protein structure analysis

Foldy is a cloud-based application that allows non-expert scientists to easily access and utilize advanced AI-based structural biology tools, including AlphaFold and DiffDock. Built on Kubernetes, it can be deployed by universities, departments, and labs without requiring hardware resources, but can also be configured to utilize available computers. Foldy enables scientists to predict the structure of proteins and complexes up to 3000 amino acids, visualize Pfam annotations, and dock ligands with AutoDock Vina and DiffDock. Our manuscript describes the user interface and deployment considerations of Foldy, as well as some of our applications. By democratizing access to sophisticated AI-based tools, Foldy can facilitate life science research and promote the wider adoption of structural bioinformatics tools. Our work demonstrates that even the most advanced tools can be made accessible to a broad audience through user-friendly platforms like Foldy, and we believe it will be a valuable resource for researchers across scientific disciplines. The public structures available on the Lawrence Berkeley Labs Foldy deployment can be viewed at https://foldy.lbl.gov. Author SummaryFoldy is a cloud-based application that enables scientists to use AI-based structural biology tools such as AlphaFold and DiffDock without software expertise. Built on Kubernetes, it can be set up by universities, departments, and labs with no need for hardware resources. Foldy can predict the structure of proteins and complexes up to 3000 amino acids, visualize Pfam annotations, and dock ligands with AutoDock Vina and DiffDock. Our public structures can be viewed at https://foldy.lbl.gov. Our manuscript highlights the user interface, deployment considerations, and product applications of Foldy. Its an accessible solution for researchers who are not software experts and can handle the traffic of thousands of users and hundreds of thousands of protein structures and docked ligands. This makes advanced AI-based tools more widely available, paving the way for accelerating life science research. By developing an easy-to-use platform, our work demonstrates that even the most sophisticated AI-based tools can be made accessible to a wide audience. Foldy enables more scientists to draw from the rapidly growing field of structural biology, making it a valuable tool for researchers across scientific disciplines. We look forward to its adoption by the scientific community.

bioinformatics↗

Phase transition of maternal RNAs during vertebrate oocyte-to-embryo transition

The oocyte-to-embryo transition (OET) is regulated by maternal products stored in the oocyte cytoplasm, independent of transcription. How maternal products are precisely remodeled to dictate the OET remains an open question. In this work, we discover the dynamic phase transition of maternal RNAs during Xenopus OET. We have identified 863 maternal transcripts that transition from a soluble state to a detergent-insoluble one after oocyte maturation. These RNAs are enriched in the animal hemisphere and many of them encode key cell cycle regulators. In contrast, 165 transcripts, including nearly all Xenopus germline RNAs and some vegetally localized somatic RNAs, undergo an insoluble-to-soluble phase transition. This phenomenon is conserved in zebrafish. Our results demonstrate that the phase transition of germline RNAs influences their susceptibility to RNA degradation machinery and is mediated by the remodeling of germ plasm. This work thus uncovers novel remodeling mechanisms that act on RNAs to regulate vertebrate OET.

developmental biology↗

Single-Soma Deep RNA sequencing of Human DRG Neurons Reveals Novel Molecular and Cellular Mechanisms Underlying Somatosensation

The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human DRG (hDRG) neurons - critical information to decipher their functions - are lacking due to technical difficulties. Here, we developed a novel approach to isolate individual hDRG neuron somas for deep RNA sequencing (RNA-seq). On average, >9,000 unique genes per neuron were detected, and 16 neuronal types were identified. Cross-species analyses revealed remarkable divergence among pain-sensing neurons and the existence of human-specific nociceptor types. Our deep RNA-seq dataset was especially powerful for providing insight into the molecular mechanisms underlying human somatosensation and identifying high potential novel drug targets. Our dataset also guided the selection of molecular markers to visualize different types of human afferents and the discovery of novel functional properties using single-cell in vivo electrophysiological recordings. In summary, by employing a novel soma sequencing method, we generated an unprecedented hDRG neuron atlas, providing new insights into human somatosensation, establishing a critical foundation for translational work, and clarifying human species-specific properties.

neuroscience↗

Oxygen is a critical regulator of cellular metabolism and function in cell culture

Cell culture is generally considered to be hyperoxic. However, the importance of cellular oxygen consumption is often underappreciated, with rates of oxygen consumption often sufficient to cause hypoxia at cell monolayers. We initially focused on cultured adipocytes as a terminally differentiated cell-type with substantial oxygen consumption rates to support diverse cellular functions. Under standard conditions, cultured adipocytes are hypoxic and highly glycolytic. Increasing oxygen diverted glucose flux toward mitochondria and resulted in thousands of gene expression changes that pointed toward alleviated physiological transcriptional responses to hypoxia. Phenotypically, providing more oxygen increased adipokine secretion and rendered adipocytes more sensitive to insulin and lipolytic stimuli. The functional benefits of increasing pericellular oxygen were transferable to other cellular systems including hPSC-derived hepatocytes and cardiac organoids. Our findings suggest that oxygen is limiting in many terminally-differentiated cell culture systems, and that controlling oxygen availability can improve the quality and translatability of cell models.

cell biology↗

Integrated Model of the Vertebrate Augmin Complex

Accurate segregation of chromosomes is required to maintain genome integrity during cell division. This feat is accomplished by the microtubule-based spindle. To build a spindle rapidly and with high fidelity, cells take advantage of branching microtubule nucleation, which exponentially amplifies microtubules during cell division. Branching microtubule nucleation relies on the hetero-octameric augmin complex, but understanding how augmin promotes branching has been hindered by a lack of structural information about the complex. Here, we report an integrated model of vertebrate augmin, combining cryo-electron microscopy, advanced protein structural prediction, and the visualization of fused bulky tags via negative stain electron microscopy. This strategy allowed us to identify the location and orientation of each subunit within the structure. Evolutionary analysis of augmins structure reveals that it is highly conserved across diverse eukaryotes, and that augmin contains a previously-unidentified microtubule binding site. Moreover, we identify homology with the kinetochore-localized NDC80 complex. This new model of the augmin complex provides insight towards the mechanism and evolution of branching microtubule nucleation.

molecular biology↗

Deficiency in the cell-adhesion molecule dscaml1 impairs hypothalamic CRH neuron development and neuroendocrine stress axis function

The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress-associated neurological and behavioral dysfunctions, it is critical to identify the mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identified Down syndrome cell adhesion molecule like-1 (dscaml1) as an integral mediator of CRH neuron development and necessary for establishing normal stress axis function. In dscaml1 mutant animals, hypothalamic CRH neurons had higher crhb (the CRH homolog in fish) expression, increased cell number, and reduced cell death compared to wild-type controls. Physiologically, dscaml1 mutant animals had higher baseline stress hormone (cortisol) levels and attenuated responses to acute stressors. Together, these findings identify dscaml1 as an essential factor for stress axis development and suggest that HPA axis dysregulation may contribute to the etiology of human DSCAML1 -linked neuropsychiatric disorders.

developmental biology↗

Dinoflagellate Proton-Pump Rhodopsin Gene in Long Island Sound: Diversity and Spatiotemporal Distribution

Microbial proton-pump rhodopsin (PPR), an alternative light-harvesting mechanism to chlorophyll-based photosystems, may contribute significantly to solar energy entry into the marine ecosystem. PPR transforms solar energy to cellular energy used for various metabolic processes in the cells or flagellar movement. Although rhodopsins or their encoding genes have been documented in a wide phylogenetic range of cultured dinoflagellates, information is limited about how widespread and how spatiotemporally dynamical dinoflagellate PPR (DiPPR) are in the marine ecosystem. In this study, using the quantitative PCR method, we investigated the abundance and diversity of DiPPR genes in Long Island Sound (LIS), a temperate estuary, both spatially and temporally in 2010. DiPPR genes were found year-round and throughout LIS, with higher abundances in the eutrophic Western Sound and during April and July. The gene diversity data suggest that there are at least five distinct rhodopsin-harboring groups of dinoflagellates throughout the year. The abundance of DiPPR genes, measured as copy number per mL seawater, appeared not to be influenced by water temperature and nitrogen nutrient concentration; however, weak negative correlations with orthophosphate concentration and salinity and a positive correlation with the abundance of typical-DiPPR-harboring dinoflagellates were observed. The association of DiPPR with phosphorus nutrition warrants further studies.

molecular biology↗

The effector recognition by synthetic sensor NLR receptors requires the concerted action of multiple interfaces within and outside the integrated domain

Plant sensor nucleotide-binding leucine-rich repeat (NLR) receptors detect pathogen effectors through their integrated domains (IDs). The RGA5 sensor NLR recognizes its corresponding effectors AVR-Pia and AVR1-CO39 from the blast fungus Magnaporthe oryzae through direct binding to its heavy metal-associated (HMA) ID to trigger the RGA4 helper NLR-dependent resistance in rice. Here we report a mutant of RGA5 named RGA5HMA5 that confers complete resistance in transgenic rice plants to the M. oryzae strains expressing the noncorresponding effector AVR-PikD. RGA5HMA5 carries three engineered interfaces, two of which lie in the HMA ID and the other in the C-terminal Lys-rich stretch tailing the ID. However, the RGA5 variants having one or two of the three interfaces, including replacing all the Lys residues with Glu residues in the Lys-rich stretch, failed to activate RGA4-dependent cell death of rice protoplasts. Altogether, this work demonstrates that sensor NLRs require a concerted action of multiple surfaces within and outside the IDs to both recognize noncorresponding effectors and activate helper NLR-mediated resistance, and has implications in structure-guided designing of sensor NLRs.

plant biology↗

Complex subsets but redundant clonality after B cells egress from spontaneous germinal centers

Affinity matured self-reactive antibodies are found in autoimmune diseases like systemic lupus erythematous. Here we used fate-mapping reporter mice and single cell transcriptomics coupled to antibody repertoire analysis to characterize the post-germinal center (GC) B cell compartment in a new mouse model of autoimmunity. Antibody secreting cells (ASCs) and memory B cells (MemBs) from spontaneous GCs grouped into multiple subclusters. ASCs matured into two terminal clusters, with distinct secretion, antibody repertoire and metabolic profiles. MemBs contained FCRL5+ and CD23+ subsets, with different in vivo localization in the spleen. GC-derived FCRL5+ MemBs share transcriptomic and repertoire properties with atypical B cells found in aging and infection and localize to the marginal zone, suggesting a similar contribution to recall responses. While transcriptomically diverse, ASC and MemB subsets maintained an underlying clonal redundancy. Therefore, self-reactive clones could escape subset-targeting therapy by perpetuation of self-reactivity in distinct subsets.

immunology↗

Androgen Receptor is a Determinant of Melanoma Targeted Drug Resistance

Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAFV600 mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between pathways involved in BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We recently showed that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells soon after BRAFi exposure. Increased AR expression is by itself sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi resistant subpopulations and elevated EGFR and SERPINE1 expression of likely clinical significance. Inhibition of AR expression and activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, enhances MHC I expression and CD8+ T cells infiltration. Our findings point to targeting AR as a possible co-adjuvant approach for the prevention and management of the disease.

cancer biology↗

Robust differential composition and variability analysis for multisample cell omics

Cell omics such as single-cell genomics, proteomics and microbiomics allow the characterisation of tissue and microbial community composition, which can be compared between conditions to identify biological drivers. This strategy has been critical to unveiling markers of disease progression such as cancer and pathogen infection. For cell omic data, no method for differential variability analysis exists, and methods for differential composition analysis only take a few fundamental data properties into account. Here we introduce sccomp, a generalised method for differential composition and variability analyses able to jointly model data count distribution, compositionality, group-specific variability and proportion mean-variability association, with awareness against outliers. Sccomp is an extensive analysis framework that allows realistic data simulation and cross-study knowledge transfer. Here, we demonstrate that mean-variability association is ubiquitous across technologies showing the inadequacy of the very popular Dirichlet-multinomial modelling and provide mandatory principles for differential variability analysis. We show that sccomp accurately fits experimental data, with a 50% incremental improvement over state-of-the-art algorithms. Using sccomp, we identified novel differential constraints and composition in the microenvironment of primary breast cancer. Significance statementDetermining the composition of cell populations is made possible by technologies like single-cell transcriptomics, CyTOF and microbiome sequencing. Such analyses are now widespread across fields (~800 publications/month, Scopus). However, existing methods for differential abundance do not model all data features, and cell-type/taxa specific differential variability is not yet possible. Increase in the variability of tissue composition and microbial communities is a well-known indicator of loss of homeostasis and disease. A suitable statistical method would enable new types of analyses to identify component-specific loss of homeostasis for the first time. This and other innovations are now possible through our discovery of the mean-variability association for compositional data. Based on this fundamental observation, we have developed a new statistical model, sccomp, that enables differential variability analysis for composition data, improved differential abundance analyses, with cross-sample information borrowing, outlier identification and exclusion, realistic data simulation, based on experimental datasets, cross-study knowledge transfer.

bioinformatics↗

Adenosine A2A Receptor (A2AR) agonists improve survival in K28-hACE2 mice following SARS CoV-2 infection

Effective and available therapies for the treatment of COVID-19 disease are limited. Apadenoson is a highly potent selective anti-inflammatory adenosine A2A receptor (A2AR) agonist and potential treatment option for COVID-19 patients. Apadenoson, when administered after infection with SARS CoV-2, was found to decrease weight loss, improve clinical symptoms, reduce levels of a several proinflammatory cytokines and chemokines in bronchial lavage (BAL) fluid, and promote increased survival in K18hACE2 transgenic mice. Of note, administering apadenoson after, but not prior to Covid-19 infection, caused a rapid decrease in lung viral burden. The work presented provides the foundation for further examination of these drugs as a therapy option for COVID-19. SummaryApadenoson therapy improves COVID-19 outcome

microbiology↗

In vitro phenotypic and transcriptomic variation in Neisseria musculi morphotypes correlate with colonization variability and persistence in vivo

Asymptomatic colonization of the upper respiratory tract is a common trait of the two human restricted pathogens, Neisseria gonorrhoeae and Neisseria meningitidis. In vivo models of pathogenic neisserial infections are heterologous systems that permit short-term colonization but do not fully recapitulate infections in humans. Studying Neisseria musculi (Nmus), an oral commensal, in laboratory mice allows investigation of Neisseria-host interactions that avoids host restriction barriers. Nmus produces smooth and rough morphotypes on solid media. We compared the in vitro phenotypes, biofilm transcriptomes, in vivo colonization patterns and burdens of the two Nmus morphotypes. We observed that the two morphotypes differ in biofilm formation, pilin production, transformation frequency, and aggregation in vitro. These phenotypes strongly correlated with differential expression of a set of genes in the Nmus biofilms including those that encoded factors for bacterial attachment. In vivo, the smooth morphotype stably colonized the oral cavities of all inoculated A/J and C57BL/6J mice at higher burdens relative to the rough. Interestingly, both morphotypes colonized the oral cavities of A/Js at higher magnitudes than in C57BL/6Js. Gut colonization by the smooth morphotype was qualitatively higher than the rough. Nasal colonization in the A/Js were transient following nasal inoculations. Collectively, our results demonstrate that colonization by Nmus can be affected by various factors including Nmus morphotypes, inoculation routes, anatomical niches, and host backgrounds. The Nmus-mouse model can use variable morphotype-host combinations to study the dynamics of neisserial asymptomatic colonization and persistence in multiple extragenital niches. IMPORTANCEAnimal models for human adapted pathogenic Neisseria spp. do not fully mimic human infections and are complicated by host restriction barriers that can hinder long-term persistence. Such barriers can be avoided by studying Neisseria spp. native to the animal host used for disease models. Neisseria musculi (Nmus) isolated from wild mice colonizes the oral cavity and gut of laboratory mice for extended periods. Nmus shares host interaction factors with species pathogenic to humans and thus provides a native system to study orthologs of factors that may facilitate asymptomatic colonization and persistence in the human upper respiratory tract. We investigated the Nmus-mouse system to compare in vitro and in vivo phenotypes of two Nmus morphotypes. Our results support the hypothesis that the two morphotypes vary in different aspects of Neisseria-host interactions. Future use of the Nmus-host system will help identify molecular mechanisms required for neisserial asymptomatic colonization, dissemination, and persistence.

microbiology↗

The endoplasmic reticulum membrane protein complex (EMC) negatively regulates intestinal homeostasis through the Hippo signaling pathway

Disruption of tissue homeostasis often results in many diseases. Balanced control of stem cell proliferation and differentiation underlines tissue homeostasis. However, how endogenous factors influence the proliferation and differentiation of intestinal stem cells (ISCs) under physiological conditions remains not fully understood. Here, we find that the endoplasmic reticulum membrane protein complex (EMC) negatively regulates ISC proliferation in adult Drosophila midgut. Compromising EMC function in progenitors leads to excessive ISC proliferation and intestinal homeostasis disruption. Mechanistically, the EMC complex associates with and stabilizes Hippo (Hpo), the key component of the Hpo signaling pathway. In the absence of the EMC complex, Yki (Yorkie) is activated to promote ISC proliferation. Furthermore, the role of the EMC complex in stem cell proliferation control is evolutionarily conserved. Thus, our study uncovers the molecular mechanism of the EMC complex in controlling stem cell proliferation. Our results provide new insight into the underlying mechanisms of how stem cell proliferation is properly controlled under physiological conditions.

cell biology↗

DNA methylation in transposable elements disrupts the connection between three-dimensional chromatin organization and gene expression upon rice genome duplication.

Polyploidy serves as a major force in plant evolution and domestication of cultivated crops. However, the relationship and underlying mechanism between three-dimensional (3D) chromatin organization and gene expression upon rice genome duplication is largely unknown. Here we compared the 3D chromatin structures between diploid (2C) and autotetraploid (4C) rice by high-throughput chromosome conformation capture analysis, and found that 4C rice presents weakened intra-chromosomal interactions compared to its 2C progenitor. Moreover, we found that changes of 3D chromatin organizations including chromatin compartments, topologically associating domain (TAD) and loops uncouple from gene expression. Moreover, DNA methylations in the regulatory sequences of genes in compartment A/B switched regions and TAD boundaries are not related to their expressions. Importantly, in contrast to that there was no significant difference of methylation levels in TEs in promoters of differentially expressed genes (DEGs) and non-DEGs between 2C and 4C rice, we found that the hypermethylated transposable elements across genes in compartment A/B switched regions and TAD boundaries suppress the expression of these genes. We propose that the rice genome doubling might modulate TE methylation which results in the disconnection between the alteration of 3D chromatin structure and gene expression.

plant biology↗