Biology subjects

Ma, L.

Publications and source records attributed to Ma, L..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

Exploring the Biological Mechanisms of Severe COVID-19 in the Elderly: Insights from an Aged Mouse Model

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global health crisis, particularly affecting the elderly, who are more susceptible to severe outcomes. However, definitive parameters or mechanisms underlying the severity of COVID-19 in elderly people remain confused. Thus, this study seeks to elucidate the mechanism behind the increased vulnerability of elderly individuals to severe COVID-19. We employed an aged mouse model with a mouse-adapted SARS-CoV-2 strain to mimic the severe symptoms observed in elderly patients with COVID-19. Comprehensive analyses of the whole lung were performed using transcriptome and proteome sequencing, comparing data from aged and young mice. For transcriptome analysis, bulk RNA sequencing was conducted using an Illumina sequencing platform. Proteomic analysis was performed using mass spectrometry following protein extraction, digestion, and peptide labeling. We analyzed the transcriptome and proteome profiles of young and aged mice and discovered that aged mice exhibited elevated baseline levels of inflammation and tissue damage repair. After SARS-CoV-2 infection, aged mice showed increased antiviral and inflammatory responses; however, these responses were weaker than those in young mice, with significant complement and coagulation cascade responses. In summary, our study demonstrates that the increased vulnerability of the elderly to severe COVID-19 can be attributed to an attenuated antiviral response and the overactivation of complement and coagulation cascades.

immunology↗

bioRxiv2024

Adaptive immunity shapes innate and epithelial cell landscapes by silencing tonic IFN-gamma in innate lymphoid cells during homeostasis.

During homeostasis, innate and epithelial cells undergo continuous maturation, shaped by microbial, molecular and cellular interactions. While these cells influence adaptive immunity during steady-state conditions, the reciprocal homeostatic role of adaptive immune cells in the maturation and function of innate and epithelial cells remains underexplored. Here, through computational approaches and murine models, we establish that adaptive immunity shapes innate immune and epithelial homeostatic landscapes. Mechanistically, adaptive immunity acts as a brake on type 1 polarization and diversification of innate lymphocytes (ILCs). Without adaptive immunity, the innate cellular interactions within the mesenteric lymph nodes are dominated by an interferon-gamma (IFN{gamma}) signaling network. Moreover, the innate immune and epithelial cells follow distinct phenotypic and functional trajectories, including ILCs acquiring myeloid markers, monocytes adopting an inflammatory path, and colonic epithelial cells expressing altered antimicrobial peptides and losing Paneth-like features. Depleting ILCs, abolishing IFN{gamma} signaling, or restoring adaptive immunity reduces these IFN{gamma}-driven changes. Thus, our findings highlight a homeostatic function of adaptive immunity in modulating innate and epithelial cell communication, diversity, composition, function, and differentiation, notably by limiting ILC-derived IFN{gamma}.

immunology↗

bioRxiv2024

Study on the phenotypic diversity and comprehensive evaluation analysis of 43 ornamental peonies of Sect. Paeonia.

The peony of Sect. Paeonia was a perennial herbaceous plant with numerous ornamental varieties and riched diversity in flower color and shape. It has ornamental, edible, and medicinal value and a long history of cultivation in China. The study of phenotypic diversity of plants is an important foundation for plants of Sect. Paeonia breeding. This study conducted phenotypic diversity analysis, principal component analysis, and cluster analysis on 43 varieties of Sect. Paeonia germplasm resources. Phenotypic traits included 30 qualitative traits and 7 quantitative traits. Through genetic diversity analysis, principal component analysis, comprehensive evaluation, and cluster analysis, we ultimately concluded that plant samples had relatively rich genetic phenotype traits. In principal component analysis, the first 12 principal components have covered the vast majority of information for phenotypic traits. The comprehensive evaluation results of phenotypic traits indicate that the F values of each variety in the germplasm sample were all positive number. The degree of stamen petals played a key role in determining the phenotypic diversity of plants, and the shape of the cotyledons and leaflets may determine the plants stress resistance performance, which provides a reference for breeding new varieties of peonies of Sect. Paeonia.

plant biology↗

bioRxiv2024

High-Efficiency Capture and Proteomic Analysis of Plasma-Derived Extracellular Vesicles through Affinity Purification

Plasma-derived extracellular vesicles (EVs) are promising sources of biomarkers. It is still a challenge to isolate EVs from a small amount of human plasma for downstream proteomic analysis. The separation process is hindered by contamination with high-abundance blood proteins and lipoprotein particles, which adversely impact proteomic analyses. Moreover, although EVs immune-separation via magnetic beads often integrates with flow sorting and western blotting (WB), it lacks compatibility with nanoparticle tracking analysis (NTA) and proteomic analysis. To address these issues, we have developed a functional affinity magnetic bead, EVlent (Extracellular Vesicles isoLated Efficiently, Naturally, and Totally), enabling the rapid and efficient separation of EVs from plasma. By optimizing the quantities of magnetic beads and plasma used, we characterized the isolated EVs through WB, NTA, and transmission electron microscopy (TEM), showing a successfully separation of EVs from plasma. Proteomic analysis of these EVs identified over 2,000 proteins and 15,000 peptides from just 100 L of plasma, and nearly 1,000 proteins from trace samples as small as 5 L. Additionally, this isolation method significantly reduced contaminants, including plasma proteins and lipoproteins, compared to ultracentrifugation. Finally, we applied this strategy to plasma samples of healthy individuals and those with Parkinsons disease, identifying four potential biomarkers that provide a promising guidance for clinical diagnosis.

biochemistry↗

bioRxiv2024

A high-performance genetically encoded sensor for cellular imaging of PKC activity in vivo

We report a genetically encoded fluorescence lifetime sensor for protein kinase C (PKC) activity, named CKAR3, based on Forster resonance energy transfer. CKAR3 exhibits a 10-fold increased dynamic range compared to its parental sensors and enables in vivo imaging of PKC activity during animal behavior. Our results reveal robust PKC activity in a sparse neuronal subset in the motor cortex during locomotion, in part mediated by muscarinic acetylcholine receptors.

neuroscience↗

bioRxiv2024

A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent pro-inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity. We explored a series of ML901 analogues and identified ML471, which exhibits improved potency against trophozoites and enhanced selectivity against a human cell line. Additionally, it has no inhibitory activity against human ubiquitin-activating enzyme (UAE) in vitro. ML471 exhibits low nanomolar activity against asexual blood stage P. falciparum and potent activity against liver stage parasites, gametocytes and transmissible gametes. It is fast-acting and exhibits a long in vivo half-life. ML471 is well-tolerated and shows single dose oral efficacy in the SCID mouse model of P. falciparum malaria. We confirm that ML471 is a pro-inhibitor that is converted into a tight binding Tyr-ML471 conjugate by the PfTyrRS enzyme. A crystal structure of the PfTyrRS/ Tyr-ML471 complex offers insights into improved potency, while molecular docking into UAE provides a rationale for improved selectivity.

biochemistry↗

bioRxiv2024

Wheat TaNADPO promotes spot blotch resistance

Bipolaris sorokiniana is a common soil-borne fungal pathogen that can infect various organs of wheat (Triticum aestivum L.), causing diseases such as spot blotch, common root rot, head blight, and black point. The genetic basis of wheat resistance to B. sorokiniana is not yet fully understood. In this study, a natural population of 1,302 global common wheat germplasms was established and inoculated with B. sorokiniana at the seedling stage in a greenhouse. Resistance to spot blotch was assessed, revealing that only about 3.8% of the germplasms exhibited moderate or higher resistance levels. A genome-wide association study (GWAS) using high-density 660K single nucleotide polymorphism (SNP) data identified a region on chromosome 1BL (621.2-674.0 Mb) with 9 SNPs significantly associated (p < 10e-4) with spot blotch resistance, designated as Qsb.hebau-1BL. RNA sequencing and qRT-PCR assays showed that the gene TraesCS1B02G410300, encoding nicotinamide-adenine dinucleotide phosphate-binding oxidoreductase (TaNADPO), was significantly induced by B. sorokiniana. Five SNP variations were found in the promoter region of TaNADPO in wheat lines with or without Qsb.hebau-1BL. Transient expression of TaNADPO in Nicotiana benthamiana leaves showed a cytoplasmic subcellular localization of the fusion protein with a green fluorescent protein (GFP) tag. Wheat transgenic lines overexpressing TaNADPO exhibited significantly enhanced resistance to spot blotch compared to wildtype plants, with higher accumulation of reactive oxygen species (ROS). The knockout EMS mutant of Triticum turgidum NADPO (tdnadpo-K2561, Gln125*) showed significantly reduced resistance to spot blotch and lower ROS accumulation compared to wildtype plants. In summary, TaNADPO has been identified as a crucial gene for resistance to B. sorokiniana, providing valuable insights for developing spot blotch-resistant wheat varieties through molecular breeding techniques.

genetics↗

bioRxiv2024

Metabolic conservation by protein quality control in Campylobacter jejuni underlies the antibiotic tolerance

Bacterial persistence enables survival during lethal antibiotic exposure and is implicated in recurrent infections, yet the physiology underlying bacterial persistence in many pathogens remains poorly defined. Here we show that exposure of Campylobacter jejuni to ampicillin or ciprofloxacin generates an antibiotic-persistent subpopulation. Rather than undergoing global metabolic shutdown, persister cells adopted a metabolically constrained state characterized by selective maintenance of oxidative phosphorylation and bioenergetic metabolism through coordinated proteostasis control. The ATP-dependent protease ClpP was essential for entry into this persistent state. Loss of ClpP disrupted proteostasis of the electron transport chain, specifically impaired bd-like terminal oxidase integrity, and reduced survival in vivo and in macrophages. These findings identify ClpP-dependent maintenance of redox and bioenergetic homeostasis as critical determinants of C. jejuni persistence and highlight metabolic remodeling as a defining feature of antibiotic tolerance. These insights may inform future therapeutic strategies aimed at disrupting persistence and improving antibiotic efficacy.

microbiology↗

bioRxiv2024

Organizational principles of the primate cerebral cortex at the single-cell level

The primate cerebral cortex, the major organ for cognition, consists of an immense number of neurons. However, the organizational principles governing these neurons remain unclear. By accessing the single-cell spatial transcriptome of over 25 million neuron cells across the entire macaque cortex, we discovered that the distribution of neurons within cortical layers is highly non-random. Strikingly, over three-quarters of these neurons are located in distinct neuronal clusters. Within these clusters, different cell types tend to collaborate rather than function independently. Typically, excitatory neuron clusters mainly consist of excitatory-excitatory combinations, while inhibitory clusters primarily contain excitatory-inhibitory combinations. Both cluster types have roughly equal numbers of neurons in each layer. Importantly, most excitatory and inhibitory neuron clusters form spatial partnerships, indicating a balanced local neuronal network and correlating with specific functional regions. These findings suggest that different brain regions of the primate cortex may exhibit similar mechanisms at the neuronal population level.

neuroscience↗

bioRxiv2024

tauX: A Gene Expression Ratio Strategy to Improve Machine Learning Applications in Precision Medicine

Machine learning algorithms identify patterns that would otherwise be difficult to observe in high-dimensional molecular and clinical data. For this reason, machine learning has the potential to have a profound impact on clinical decision making and drug target discovery. Nevertheless, there remain considerable technical challenges in adapting these tools for clinical use. These challenges include clinical feature engineering, model selection, and defining optimal strategies for model training. For cancer care, RNA sequencing of patient tumor biopsies has already proven to be a powerful molecular assay to characterize tumor-intrinsic and -extrinsic phenotypes influencing therapeutic response. To improve the predictive performance of RNA-sequencing data, we developed the tauX machine learning framework to refine gene expression features and improve the performance of machine learning algorithms. The tauX framework uses aggregated ratios of positively and negatively associated predictive genes to simplify the prediction task. We showed a significant improvement in predictive performance using a large database of synthetic gene expression profiles. We also show how the tauX framework can be used to elucidate the mechanisms of response and resistance to checkpoint blockade therapy using data from the Stand Up to Cancer (SU2C) Lung Response Cohort and The Cancer Genome Atlas (TCGA). The tauX strategy achieved superior predictive performance compared to models built upon established feature engineering strategies or widely used cancer gene expression signatures. The tauX framework is available as a freely deployable docker container (https://hub.docker.com/r/pfeiljx/taux).

bioinformatics↗

bioRxiv2024

Decoding the anti-aging effect of retinol in reshaping the human skin microbiome niches

Retinol has been widely added to skincare products due to its ability to promote the proliferation of skin keratinocytes and regulate skin cell collagen expression. While it is known the skin harbors a myriad of commensal bacteria, the impact of retinol on the skin microbiome, as well as the role of the skin microbiome in mediating the anti-aging properties of retinol, remains poorly understood. In this study, we incorporated phenomics, metagenomics and metabolomics to explore the human skin alterations during the anti-aging process mediated by retinol, and potential interactions between retinol, skin microbiome and metabolites. Topical retinol significantly improved skin conditions, including enhancing skin hydration, acidifying the epidermis, strengthening the skin barrier, and reducing the number and volume of wrinkles. Furthermore, retinol also reshaped the skin microecology by altering the structure and function of the skin microbiome as well as the host and microbial metabolites. Through GEM construction, we identified 2 skin microorganism, Sericytochromatia sp. and Corynebacterium kefirresidentii capable of oxidizing retinol to retinal. Over 10 skin microbes can utilize UDP-glucose as a carbon source, potentially accelerating RAG hydrolysis and increasing glucuronic acid consumption. The retinoic acid and retinol generated by RAG hydrolysis are reused by skin cells and microbes, enhancing retinol metabolism and its effective duration. This combined effect between the skin microbiome and retinol improves skin condition and anti-aging efficacy.

microbiology↗

bioRxiv2024

Deep generative models generate mRNA sequences with enhanced translation capacity and stability

Despite the tremendous success of messenger RNA (mRNA) COVID-19 vaccines, the extension of this modality to a broader spectrum of diseases necessitates substantial enhancements, particularly in the design of mRNAs with elevated expression levels and extended durability. Here we present GEMORNA, a deep generative model designed to generate novel mRNA coding sequences (CDSs) and untranslated regions (UTRs) with superior translation capacity, comparable to the sophisticated task of language translation and free-form poetry composition with accurate grammar and semantics. Our AI model was trained on an extensive collection of RNA sequences from diverse families, further enhanced with labeled data to refine its performance. Remarkably, we demonstrate that our AI-generated mRNAs exhibited 8.2-fold and 15.9-fold increases in firefly luciferase expression compared to benchmark mRNAs in two different cell types. Additionally, Our AI- designed COVID-19 mRNA vaccine elicited a 4-fold increase in anti-COVID antibody titer in mice relative to BNT162b2. Furthermore, GEMORNAs versatility extends to circular mRNA design, which we facilitated a 27-fold increase in human erythropoietin protein expression in vivo than a systematically optimized benchmark sequence. We also created circular mRNAs with substantial improvements in expression levels, durability and anti-tumor cell cytotoxicity in mRNA-transduced CAR-T cells compared with an experimentally validated benchmark. In summary, GEMORNA generates novel mRNA sequences with significant performance improvements and has the potential to enable a wide range of therapeutic and vaccine applications.

synthetic biology↗

bioRxiv2024

Unveiling the PHR-centered regulatory network orchestrating the phosphate starvation signaling in Chinese fir (Cunninghamia lanceolata)

Phosphorus (P) is an essential mineral element for plant growth and is absorbed and utilized in the form of inorganic phosphate (Pi). However, Pi deficiency largely restricts plant growth in forest ecosystems, while the molecular mechanism of Pi deficiency in woody plants remains unclear. Here, we show that PHOSPHATE STARVATION RESPONSE (PHRs) were central regulators of Pi starvation signaling in Chinese fir, a gymnosperm woody plant. Pi deficiency repressed the shoot growth by decreasing the net photosynthesis rate, reducing the size and number of needle leaves, suppressing the plant height, and reducing the biomass accumulation of shoots in Chinese fir seedlings. Thirteen Chinese fir PHRs (ClPHRs) were characterized, which evolved differently from model and angiosperm woody plants. ClPHRs did not respond to Pi deficiency at the transcriptional level, whereas three ClPHRs responded to Pi deficiency by increasing the nuclear/cytoplasmic protein abundance ratio. Four ClPHRs can restore Pi starvation signaling by activating transcription of AtPHT1;1 and AtPHT1;4 in the atphr1 mutant. Notably, ClPHR7, which is evolutionarily distinct from AtPHR1, was the only ClPHR that could respond to Pi deficiency and restore Pi starvation signals. ClPHR7 could also interact with SPX through protein-protein interaction analysis. Thus, the SPX-PHR regulatory module was also present in gymnosperm woody plants, but the exactly responsible proteins were evolutionarily different from those of model plants. In summary, our results revealed the function of the SPX-PHR regulatory module in Pi starvation signaling and provided genetic information for engineered woody plants with high Pi use efficiency.

plant biology↗

bioRxiv2024

Molecular mechanism of the flotillin complex in membrane microdomain organization

Flotillin-1 and flotillin-2 form hetero-oligomers to create flotillin membrane microdomains essential for endocytosis and protein sorting. However, the mechanisms of flotillin oligomerization and microdomain organization remain incompletely understood. Here, we present the cryo-EM structure of human flotillin complex, showing that flotillin-1 and -2 form a 44-mer, membrane attached, and dome-shaped structure that defines a 30-nm circular membrane domain. The cryo-ET data demonstrates that while attached to the cytoplasmic leaflet in situ, flotillin complexes possess intrinsic structural plasticity on the native membrane. Each flotillin complex may represent a fundamental unit of membrane microdomains, with their clustering enabling the formation of larger and more elaborate domains. We further reveal that phosphorylation at residues Y160 (flotillin-1) and Y163 (flotillin-2) may act as a molecular switch to modulate complex assembly, potentially regulating its function in endocytosis. These findings demonstrate the molecular mechanism of flotillin-mediated membrane segregation and microdomain formation, and suggest a previously unrecognized role of flotillin in sequestrating membrane proteins.

biochemistry↗

bioRxiv2024

Discovery and binding site identification of a single-stranded DNA-binding protein that interacts with double-stranded DNA

Scientists have conducted in-depth studies on single-stranded DNA (ssDNA) binding and protein interaction network of single-stranded DNA binding proteins (SSBs). SSBs are widely present in cells from lower prokaryotes to higher mammals and are important proteins for ssDNA protection. In-depth studies in recent years have revealed a wide range of interactions between SSBs and other proteins. Studies have shown that in addition to playing the role of ssDNA protector, SSBs are also important members of biochemical pathways such as DNA replication and recombination. In this study, a single-stranded DNA binding protein SSF encoded by E. coli F plasmid with highly conserved N-terminal region was demonstrated to have ssDNA binding ability similar to E. coli SSB through gel migration experiments. At the same time, the dsDNA binding ability of SSF was also demonstrated, and the dissociation constant of this interaction (in the range of microliters) was determined by Micro-scale Thermophoresis (MST). Through the above experiments, a previously unreported SSB with dsDNA binding ability was revealed, and the region interacting with dsDNA was determined to be the C-terminal unstructured region. This study lays a foundation for further understanding of the mechanism of bacterial conjugation conducted by F plasmid, as well as the potential dsDNA binding ability and biological significance of other SSBs.

biochemistry↗

bioRxiv2024

The dual resistance mechanism of CYP325G4 and CYP6AA9 in Culex pipiens pallens legs according to transcriptome and proteome analysis

Mosquitoes within the Culex pipiens complex play a crucial role in human disease transmission. Insecticides, especially pyrethroids, are used to control these vectors. Mosquito legs are the main entry point and barrier for insecticides to gain their neuronal targets. However, the resistance mechanism in mosquito legs is unclear. Herein, we employed transcriptomic analyses and isobaric tags for relative and absolute quantitation techniques to investigate the resistance mechanism, focusing on Cx. pipiens legs. We discovered 2346 differentially expressed genes (DEGs) between deltamethrin-resistant (DR) and deltamethrin-sensitive (DS) mosquito legs, including 41 cytochrome P450 genes. In the same comparison, we identified 228 differentially expressed proteins (DEPs), including six cytochrome P450 proteins). Combined transcriptome and proteome analysis revealed only two upregulated P450 genes, CYP325G4 and CYP6AA9. The main clusters of DEGs and DEPs were associated with metabolic processes, such as cytochrome P450-mediated metabolism of drugs and xenobiotics. Transcription analysis revealed high CYP325G4 and CYP6AA9 expression in the DR strain at 72 hours post-eclosion compared with that in the DS strain, particularly in the legs. Mosquitoes knocked down for CYP325G4 were more sensitive to deltamethrin than the controls. CYP325G4 knockdown reduced the expression of several chlorinated hydrocarbon (CHC)-related genes, which altered the cuticle thickness and structure. Conversely, CYP6AA9 knockdown increased CHC gene expression without altering cuticle thickness and structure. P450 activity analysis demonstrated that CYP325G4 and CYP6AA9 contributed to metabolic resistance in the midgut and legs. This study identified CYP325G4 as a novel mosquito deltamethrin resistance factor, being involved in both metabolic and cuticular resistance mechanisms. The previously identified CYP6AA9 was investigated for its involvement in metabolic resistance and potential cuticular resistance in mosquito legs. These findings enhance our comprehension of resistance mechanisms, identifying P450s as promising targets for the future management of mosquito vector resistance, and laying a theoretical groundwork for mosquito resistance management. Author SummaryCulex pipiens mosquitoes are the primary vector of the filamentous nematode, Wuchereria bancrofti and also involved in the transmission of other pathogens, such as West Nile virus (WNV), avian malarias, and avian pox virus. Insecticides, particularly pyrethroids, continue to be the primary method to control these significant vectors. Worryingly, resistance to insecticides has become widespread and is rapidly intensifying in Culex mosquitoes throughout China, posing a threat to the efficacy of insecticides. Legs are the main sites of contact with ITNs and sprayed insecticides, and the insecticides have to penetrate the leg cuticle to reach their targets.Therefore, the resistance mechanisms in mosquito legs deserve further investigation. Several reports have found a certain amount of P450 in insect legs. Unfortunately, none of the above reports have conducted further functional studies on P450s in the legs. Here, we have identified two P450 enzymes, CYP325G4 and CYP6AA9, through the integrated analysis of transcriptomics and proteomics. CYP325G4 enriched in the cuticle of resistant mosquitoes might possess a dual resistance mechanism involving metabolic resistance and cuticle resistance. CYP6AA9 was slightly different, possibly exerting metabolic resistance as its main function and also being involved in cuticle synthesis. Understanding the dual resistance mechanism of P450s in the metabolism of pyrethroid insecticides will have an important role in optimizing vector control strategies.

physiology↗

bioRxiv2024

Parkinson's Disease-Linked Kir4.2 Mutation R28C Leads to Loss of Ion Channel Function

Parkinsons disease (PD) is a complex, progressive neurodegenerative disorder driven by multiple pathogenetic factors, including oxidative stress, mitochondria dysfunction, neuroinflammation, and ion imbalance. Recent evidence highlights the significant role of potassium channels in the pathophysiology of PD. We recently identified a PD-linked genetic mutation in the KCNJ15 gene (KCNJ15p.R28C), encoding the inwardly rectifying potassium channel Kir4.2, within a four-generation family with familial PD. However, the role of the Kir4.2 channel in neurodegenerative diseases remains largely unexplored. This study aimed to elucidate the impact of the KCNJ15p.R28C (Kir4.2R28C) mutation on the biophysical and biochemical properties of Kir4.2. Employing Kir4.2-overexpressing HEK293T cells as a model, we investigated how the mutation affects the channels functional properties, total protein expression, intracellular processing in the endoplasmic reticulum and lysosomes, and plasma membrane trafficking. Patch clamp studies revealed that the Kir4.2R28C mutation results in loss of channel function with significant dominant-negative effects. This dysfunction is partially attributed to the substantial reduction in overall mutant channel protein expression compared to the wild-type (Kir4.2WT). We observed that both Kir4.2WT and Kir4.2R28C proteins undergo glycosylation during the post-translational modification process, albeit with differing protein turnover efficiencies. Furthermore, the Kir4.2R28C mutant exhibits reduced stability and compromised plasma membrane trafficking capacity compared to Kir4.2WT. These findings suggest that the Kir4.2R28C mutant has unique biomolecular and biophysical characteristics distinct from the Kir4.2WT channel, which potentially elucidates its role in the pathogenesis of PD. Key Points[tpltrtarr] Inwardly rectifying potassium channels are increasingly recognized for their critical role in the complex pathogenesis of Parkinsons disease (PD) [tpltrtarr]We previously identified a genetic mutation, Kir4.2R28C, in the inwardly rectifying potassium channel Kir4.2, which strongly segregates with familial PD in a multi- generational pedigree. [tpltrtarr]This study confirms Kir4.2R28C as a loss-of-function mutation with significant dominant- negative effects, impairing channel activity even in heterozygous conditions. [tpltrtarr]The Kir4.2R28C mutation significantly reduces overall protein levels, impairs protein stability and disrupts plasma membrane trafficking in in vitro cell models.

cell biology↗

bioRxiv2024

Development of the overlapping network modules in the human brain

Developmental connectomic studies have shown that the modular organization of functional networks in the human brain undergoes substantial reorganization with age to support cognitive growth. However, these studies implicitly assume that each brain region belongs to one and only one specific network module, ignoring the potential spatial overlap between functional modules. How the overlapping functional modular architecture develops and whether this development is related to structural signatures remain unknown. Using longitudinal multimodal structural, functional, and diffusion MRI data from 305 children (aged 6-14 years), we investigated the development of the overlapping modular architecture of functional networks, and further explored their structural associations. Specifically, an edge-centric network model was used to identify the overlapping functional modules, and the nodal overlap in module affiliations was quantified using the entropy measure. We showed a remarkable regional inhomogeneity in module overlap in children, with higher entropy in the ventral attention, somatomotor, and subcortical networks and lower entropy in the visual and default-mode networks. Furthermore, the overlapping modules developed in a linear, spatially dissociable manner from childhood to adolescence, with significantly reduced entropy in the prefrontal cortex and putamen and increased entropy in the parietal lobules. Personalized overlapping modular patterns capture individual brain maturity as characterized by brain age. Finally, the overlapping functional modules can be significantly predicted by integrating gray matter morphology and white matter network properties. Our findings highlight the maturation of overlapping network modules and their structural substrates, thereby advancing our understanding of the principles of connectome development.

neuroscience↗