Biology subjects

Ye, H.

Publications and source records attributed to Ye, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion

TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under androgen receptor (AR) regulated TMPRSS2 expression. T:E fusion is associated with PTEN loss, and is highly associated with decreased INPP4B expression, which together may compensate for ERG-mediated suppression of AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses IRS2 and AKT activation. In contrast, ERG downregulation did not increase INPP4B, suggesting its decrease is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression is decreased in PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a nonredundant function. As ERG in T:E fusion tumors is AR regulated, we further assessed whether AR inhibition increases AKT activity in T:E fusion tumors. A T:E fusion positive PDX had increased AKT activity in vivo and response to AKT inhibition in vitro after androgen deprivation. Moreover, two clinical trials of neoadjuvant AR inhibition prior to radical prostatectomy showed greater increases in AKT activation in the T:E fusion positive versus negative tumors. These findings indicate that AKT activation may mitigate the efficacy of AR targeted therapy in T:E fusion PCa, and that these patients may most benefit from combination therapy targeting AR and AKT.

cancer biology↗

bioRxiv2024

Magnetoelectric Microrobots for Spinal Cord Injury Regeneration

Regenerative medicine continually seeks effective methods to address spinal cord injuries (SCI), which are known for their limited regenerative potential. Despite advances in neural progenitor cell (NPC) transplants for spinal cord injuries, challenges related to graft survival, reliable in vivo differentiation, and neural integration significantly hinder real functional recovery and limit clinical outcomes. This study introduces NPCbots, biohybrid microrobots engineered by integrating human-induced pluripotent stem cell-derived NPCs with magnetoelectric nanoparticles composed of cobalt ferrite-barium titanate. These enable magnetic navigation and neuronal stimulation, enhancing targeted therapeutic interventions. Our lab-on-a-chip system allows for the mass production of NPCbots, ensuring their differentiation and biocompatibility. Remarkably, in a zebrafish model of SCI, NPCbots stimulated by an alternating magnetic field demonstrated rapid in vivo differentiation and integration into damaged neural pathways, significantly enhancing neural regeneration. Within three days, injured zebrafish treated with NPCbots exhibited almost normal swimming behavior and significantly improved exploratory behavior, showcasing the potential of NPCbots to swiftly repair neural structures and restore the central nervous systems functionality in spinal cord injury models through non-invasive means. Additionally, precise in vitro and in vivo manipulation of NPCbots indicates their broader application in various neurodegenerative disorders, offering a promising route for effective spinal cord and neurological recovery.

neuroscience↗

bioRxiv2024

Host-derived Lactobacillus plantarum alleviates hyperuricemia by improving gut microbial community and hydrolase-mediated degradation of purine nucleosides

AbstractGut microbiota has been considered to be associated with the development of hyperuricemia (HUA) and gout. Some prebiotics from different sources had the potential alleviation function in HUA. However, whether host-derived potential probiotics, like Lactobacillus, from the gut of HUA animals could prevent the development of HUA is still uncertain. In this study, we established a HUA geese model and isolated a Lactobacillus plantarum strain, SQ001, from the cecum of HUA geese. Nucleoside co-culture and metabolomics analyses revealed that L. plantarum SQ001 is involved in the absorption and hydrolysis of nucleosides. Whole genome analysis showed there are four genes related with nucleosides hydrolysis in L. plantarum SQ001. The function of iunH, a nucleoside hydrolase gene, was further confirmed by heterologous expression and knockout assays. Oral administration of L. plantarum SQ001 in HUA geese models upregulated the Lactobacillus abundance and reduced serum uric acid (UA) levels. Likewise, in mouse models, L. plantarum SQ001 increased the L. plantarum abundance and lowered serum UA levels by reducing hepatic UA synthesis protein XO and renal UA reabsorption protein GLUT9 expression, while increasing renal UA excretion protein ABCG2 expression. Our findings demonstrated that host-derived probiotics from geese could alleviate gut microbe dysbiosis and HUA in its host and mouse model. This study provides insights into the potential probiotic role of Lactobacillus plantarum in HUA or gout therapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/606206v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@698e7eorg.highwire.dtl.DTLVardef@a2091org.highwire.dtl.DTLVardef@e0348aorg.highwire.dtl.DTLVardef@19958ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Beyond Auditory Relay: Dissecting the Inferior Colliculus's Role in Sensory Prediction, Cognitive Decision-Making, and Reward Prediction

The Inferior Colliculus (IC) has traditionally been regarded as an important relay in the auditory pathway, primarily involved in relaying auditory information from the brainstem to the thalamus. However, this study uncovers the multifaceted role of the IC in bridging auditory processing, sensory prediction, and reward prediction. Through extracellular recordings in monkeys engaged in a sound duration-based deviation detection task, we observed a "climbing effect" in neuronal firing rates, indicative of an enhanced response over sound sequences linked to sensory prediction rather than reward anticipation. Moreover, our findings demonstrate reward prediction errors within the IC, highlighting its complex integration in auditory and reward processing. Further analysis revealed a direct correlation between IC neuronal activity and behavioral choices, suggesting its involvement in decision-making processes. This research highlights a more complex role for the IC than traditionally understood, showcasing its integral role in cognitive and sensory processing and emphasizing its importance in integrated brain functions.

neuroscience↗

bioRxiv2024

Small Extracellular Vesicles from Human Bone Marrow Mesenchymal Stromal Cells enhance migration and regulate gene expression of reparative mechanisms in human dermal fibroblasts

Studies have showed that mesenchymal stromal cells (MSCs) could secrete a variety of bioactive particles, including small extracellular vesicles (sEVs), a type of membrane bound vesicle produced by cells, that might be a key intermediate to the beneficial paracrine effects of MSC therapy. In this study, we harvested the conditioned medium (CM) from both human bone marrow mesenchymal stromal cells (hBM-MSCs) and normal human dermal fibroblasts (NHDFs), fractionated CM of each into the sEV fraction and non-small extracellular vesicle (NsEV) fraction and compared their functions on NHDF-based migration and proliferation assays, as crucial processes in wound healing, coupled with transcriptomic analysis through mRNA sequencing to assess the regulation on gene expression of the recipient NHDFs by secretome exposure. Our findings show that both sEV and NsEV as well as CM from hBM-MSCs showed an overall promotive effect on migration behaviour of NHDFs, but MSC-sEV seems to be more potent for NHDF migration among different MSC secretome fractions and is also superior in effect to the corresponding sEVs produced by the recipient NHDFs (HDF-sEV). Gene ontology analysis revealed enrichment of pathways related to migration, corroborating in vitro results; changes in genes within the regulation of proliferation pathway were also significant. Our study provides referential significance for the choice of cellular secretome fractions to be used in wound healing studies and trials. The secretome fractionation and functional comparison strategy using cell-based model and comparative transcriptomics analysis would be a useful tool for comprehensive functional evaluation of cellular secretome.

cell biology↗

bioRxiv2024

Activation of PIEZO1 Inhibits Kidney Cystogenesis

The disruption of calcium signaling associated with polycystin deficiency has been proposed as the primary event underlying the increased abnormally patterned epithelial cell growth characteristic of Polycystic Kidney Disease. Calcium can be regulated through mechanotransduction, and the mechanosensitive cation channel Piezo1 has been implicated in sensing of intrarenal pressure and in urinary osmoregulation. However, a possible role for PIEZO1 in kidney cystogenesis remains undefined. We hypothesized that cystogenesis in ADPKD reflects altered mechanotransduction, suggesting activation of mechanosensitive cation channels as a therapeutic strategy for ADPKD. Here, we show that Yoda-1 activation of PIEZO1 increases intracellular Ca2+ and reduces forskolin-induced cAMP levels in mIMCD3 cells. Yoda-1 reduced forskolin-induced IMCD cyst surface area in vitro and in mouse metanephros ex vivo in a dose-dependent manner. Knockout of polycystin-2 dampened the efficacy of PIEZO1 activation in reducing both cAMP levels and cyst surface area in IMCD3 cells. However, collecting duct-specific Piezo1 knockout neither induced cystogenesis in wild-type mice nor affected cystogenesis in the Pkd1RC/RC model of ADPKD. Our study suggests that polycystin-2 and PIEZO1 play a role in mechanotransduction during cystogenesis in vitro, and ex vivo, but that in vivo cyst expansion may require inactivation or repression of additional suppressors of cystogenesis and/or growth. Our study provides a preliminary proof of concept for PIEZO1 activation as a possible component of combination chemotherapy to retard or halt cystogenesis and/or cyst growth.

cell biology↗

bioRxiv2024

CA1i pyramidal neurons mediate the role of NMDA receptor subunit GluN3A in depressive behavior and D-serine anti-depression

The hippocampus is a highly complex structure, defined by profound structural, functional, and molecular heterogeneity. The GluN3A subunit, which forms non-classic N-methyl-D-aspartate receptors (NMDARs), is enriched in the hippocampal CA1 subregion and has a poorly understood functional role, especially in stress-related behavioral regulation. Here, we employed chronic social defeat stress (CSDS) and GluN3A knockout (KO) mouse models combined with behavioral, molecular, genetic, pharmacological, and circuit-level analyses to investigate the role of hippocampal GluN3A in stress coping. We found that CSDS selectively reduced GluN3A expression in the intermediate CA1 (CA1i) region. Decreased GluN3A expression in CA1i, from either stress or genetic deletion, promoted passive coping behaviors, whereas overexpression of GluN3A in CA1i reversed the phenotype under both conditions. Mechanistically, consistent with GluN3A enrichment in pyramidal neurons, c-fos staining and fiber photometry revealed that GluN3A was essential for CA1i pyramidal neuronal activation during coping behaviors. Further chemogenetic manipulations demonstrated that activating CA1i neurons facilitated active coping, while inhibition induced passivity. Moreover, local administration of D-serine, an agonist of GluN3A-containing NMDARs, rapidly shifted coping behavior from passive to active by activating CA1i neurons via GluN3A-dependent mechanisms. Circuit tracing revealed that CA1i neurons project to multiple sub-hippocampal and cortico-limbic regions, and GluN3A overexpression selectively enhanced downstream neuronal activity in CA3 and infralimbic cortex, but not in the nucleus accumbens. Together, these findings identify GluN3A as a key molecule linking hippocampal subregional specialization with adaptive stress coping, and suggest that the rapid, resilience-promoting effects of D-serine are also GluN3A-dependent.

neuroscience↗

bioRxiv2024

Engineering PEG10 assembled endogenous virus-like particles with genetically encoded neoantigen peptides for cancer vaccination

Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we firstly designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation.

cancer biology↗

bioRxiv2024

Genome-Wide Association Study Reveals Influence of Cell-specific Gene Networks on Soybean Root System Architecture

Root system architecture (RSA) describes the shape and arrangement of a plants roots in the soil including the angle, rate of growth, and type of individual roots, which facilitates the uptake of nutrients and water. In crop improvement efforts, RSA has been less well studied due to the technical challenges associated with phenotyping roots as well as a focus on above-ground traits such as yield. We developed a gel-based root phenotyping system called RADICYL (Root Architecture 3D Cylinder), which is a non-invasive, high-throughput approach that enabled us to measure 15 RSA traits. We leveraged RADICYL to perform a comprehensive genome-wide association study (GWAS) with a panel of 371 diverse soybean elite lines, cultivars, landraces, and closely related species to identify gene networks underlying RSA. We identified 54 significant single nucleotide polymorphisms (SNPs) in our GWAS, some of which were shared across multiple RSA traits while others were specific to a given trait. We generated a single cell atlas of the soybean root using single nuclei RNA sequencing (snRNAseq) to explore the associated genes in the context of root tissues. Using gene co-expression network (GCN) analyses applied to RNA-seq of soybean root tissues, we identified network-level associations of genes predominantly expressed in endodermis with root width, and of those expressed in metaphloem with lateral root length. Our results suggest that pathways active in the endodermis and metaphloem cell-types influence soybean root system architecture.

plant biology↗

bioRxiv2023

Direct Pacbio sequencing methods and applications for different types of DNA sequences

The development of Sanger sequencing and next-generation sequencing methods within the past few years have assisted investigators profile the diversity and relative abundances of heterogenous species in vector preparations. Especially Recombinant adeno-associated viruses (rAAVs), genome editing, and mRNA related research are currently the most prominently investigated platform in different area and essentially use for synthetic biology, gene and cell therapy, food industrial and medicinal pharmer etc. area. However, these types of research related constructs always contain high GC sequences, poly structure, long-length DNA sequences and ITR repeats sequences. Unfortunately, Sanger sequencing and NGS platforms may be inaccessible to investigators with limited resources, require large amounts of input material, or may require long wait times for sequencing and analyses. Recent advances with PacBio sequencing have helped to bridge the gap for quick and relatively inexpensive long-read sequencing needs. Specifically, long-read sequencing methods, like single molecule real-time (SMRT) sequencing, have been used to uncover truncations, chimeric genomes, and inverted terminal repeat (ITR) mutations in vectors. Recombinant adeno-associated virus (raav) is the most prominent platform in the field of current research, and its sequence is characterized by high GC, multi-structure, long sequence, genome, and repeat sequence. Sanger sequencing has certain defects in the detection of recombinant adeno-associated viruses. Meanwhile, Sanger needs to design sequencing primers based on known sequences to determine whether the sequences are correct. When sequence information is incomplete, it can only randomly design primers, obtain a sequence by luck, and then conduct the next round of sequencing. However, PacBios limitations and sample biases are not well-defined for sequencing. And sometimes the accuracy for base calling was low, resulting in a high degree of miscalled bases and false indels. These false indels led to read-length compression; thus, assessing heterogeneity based on read length is not advisable with current PacBio technologies. In this study, we explored the capacity for PacBio sequencing to directly interrogate content to obtain full-length resolution of encapsulated genomes. We found that the PacBio platform can cover the entirety of different type sequences like poly structure, long-length DNA fragment, high GC sequences and repeat sequences, especially the rAAV sequences from ITR to ITR without the need for pre-fragmentation. At the same time, the sequencing process was optimized to complete the sequencing of long difficult plasmids with the fewest plasmids and the fastest time. In summary, the optimization PacBio sequencing and novel bioinformation (BI) analysis method are able to correctly identify truncation hotspots in single-strand and self-complementary vectors using by SMRT sequencing and can serve as a rapid and low-cost alternative for proofing different type of sequences.

molecular biology↗

bioRxiv2023

Guild-Level Gut Microbial Alterations Associate with Non-hepatitis Virus related Hepatocellular Carcinoma

The gut microbiota of hepatocellular carcinoma (HCC) is different from that of cohort without HCC. However, the relationship between non-hepatitis virus related HCC and gut microbial alterations remains elusive. In this work, we studied the gut microbial data in Sequence Read Archive (SRA) database from 58 healthy controls (HC), 31 patients with nonalcoholic fatty liver disease (NAFLD), 206 patients with hepatitis B viruses, 35 patients with HBV related HCC (B-HCC), and 22 patients with non-HBV or non-HCV related HCC (NBNC-HCC). Depend on guild-based analysis, 27 gut bacterial co-abundance groups (CAGs) were established. By studying these CAGs, we found the gut microbial overall structure and composition differed among patients with NBNC-HCC, B-HCC, other liver diseases, and healthy cohort, such as members from Lachnospiraceae, Veillonellaceae, and Prevotella. The network calculated by these CAGs in patients with HCC showed less interactions than that in healthy cohort. The specific CAGs showed correlated to the development of HCC. In addition, gut bacterial dysbiosis index, which was calculated by significantly altered CAGs in patients with NBNC-HCC compared with healthy cohort, showed potential diagnostic power of NBNC-HCC. Therefore, this study shows a new way toward understanding the role of the gut microbiome in patients with non-hepatitis virus related HCC. IMPORTANCEGut microbiome may play an important role in the pathogenesis and development of hepatocellular carcinoma. However, the relationship between non-hepatitis virus related hepatocellular carcinoma and gut microbiome should be further understood. In the current work, we found the alterations of gut microbial structure, composition, and network robustness in these patients by guild-based data analysis. Specific gut bacteria in these patients were related to clinical parameters, such as blood biochemical indexes. More importantly, gut bacterial bio-markers, which can discriminate these patients and cohort without this disease, were showed in this study. Thus, our study suggests that these guild-level gut bacteria may contribute to the development of non-hepatitis virus related hepatocellular carcinoma. This provides a new direction for future studies, which aims to show the importance of the gut microbiome in hepatocellular carcinoma.

microbiology↗

bioRxiv2023

Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling

AbstractThe folding/misfolding and pharmacological rescue of multidomain ATP-binding cassette (ABC) C-subfamily transporters, essential for organismal health, remain incompletely understood. The ABCC transporters core consists of two nucleotide binding domains (NBD1,2) and transmembrane domains (TMD1,2). Using molecular dynamic simulations, biochemical and hydrogen deuterium exchange approaches, we show that the mutational uncoupling or stabilization of NBD1-TMD1/2 interfaces can compromise or facilitate the CFTR(ABCC7)-, MRP1(ABCC1)-, and ABCC6-transporters posttranslational coupled domain-folding in the endoplasmic reticulum. Allosteric or orthosteric binding of VX-809 and/or VX-445 folding correctors to TMD1/2 can rescue kinetically trapped CFTR post-translational folding intermediates of cystic fibrosis (CF) mutants of NBD1 or TMD1 by global rewiring inter-domain allosteric-networks. We propose that dynamic allosteric domain-domain communications not only regulate ABCC-transporters function but are indispensable to tune the folding landscape of their post-translational intermediates. These allosteric networks can be compromised by CF-mutations, and reinstated by correctors, offering a framework for mechanistic understanding of ABCC-transporters (mis)folding. One-Sentence SummaryAllosteric interdomain communication and its modulation are critical determinants of ABCC-transporters post-translational conformational biogenesis, misfolding, and pharmacological rescue.

biophysics↗

bioRxiv2023

Engineering Material Properties of Transcription Factor Condensates to Control Gene Expression in Mammalian Cells and Mice

Phase separation of biomolecules into condensates is a key mechanism in the spatiotemporal organization of biochemical processes in cells. However, the impact of the material properties of biomolecular condensates on important processes, such as the control of gene expression, remains largely elusive. Here, we systematically tune the material properties of optogenetically induced transcription factor condensates and probe their impact on the activation of target promoters. We demonstrate that transcription factors in rather liquid condensates correlate with increased gene expression levels, whereas stiffer transcription factor condensates correlate with the opposite effect, a reduced activation of gene expression. We demonstrate the broad nature of these findings in mammalian cells and mice, as well as by using different synthetic and natural transcription factors. We observe these effects for both transgenic and cell-endogenous promoters. Our findings provide a novel materials-based layer in the control of gene expression, which opens novel opportunities in optogenetic engineering and synthetic biology.

synthetic biology↗

bioRxiv2023

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer

Significance StatementONECUT2 (OC2) is a master transcription factor that alters lineage identity by activating gene networks associated with both neuroendocrine prostate cancer and prostate adenocarcinoma. A small molecule inhibitor of OC2 represses the lineage plasticity program activated by enzalutamide, suggesting OC2 inhibition as a novel therapeutic strategy to prevent emergence of treatment-resistant variants. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/560025v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@13278a4org.highwire.dtl.DTLVardef@8e82aeorg.highwire.dtl.DTLVardef@25a115org.highwire.dtl.DTLVardef@728eb4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic AbstractC_FLOATNO C_FIG Androgen receptor-(AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4, among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.

cancer biology↗

bioRxiv2023

Phase-Precession-Like Effects in the Anterior Insula Cortex during Reward Expectancy

Reward expectancy shapes behavioral performance by coordinating the allocation of cognitive resources, which incorporates the involvement of the anterior insular cortex (AIC). To investigate the electrophysiological mechanisms of the AIC during reward expectancy, we collected intracranial electroencephalographic data from epilepsy patients undergoing clinical monitoring. Subjects navigated a virtual T-maze containing rewards at three predetermined locations. We focused on the period immediately before entering the reward zone, termed the reward expectancy stage. During this stage, we identified the reward-specific brain patterns (RBPs) that were preactivated in the AIC. This pre-activation preceded the emergence of robust phase-amplitude coupling (PAC), where theta oscillations (5-7 Hz) modulated gamma activities (75-110 Hz). The PAC strength correlated positively with the pre-activation level of RBPs, implying the potential role of oscillatory coordination in amplifying preactivated reward representations. Strikingly, this PAC effect exhibited a specific temporal structure that peak gamma activity became progressively coupled to earlier theta phases as reward approached, mirroring the theta phase precession phenomenon previously observed in frontal and temporal lobes. We refer to this dynamic as phase-precession-like effect (PPLE). Moreover, subjects exhibiting PPLE in the AIC presented greater trial-by-trial improvements in response latency. Taken together, these findings shed light on the electrophysiological mechanisms of the AIC underlying reward expectancy.

neuroscience↗

bioRxiv2023

Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism

TMEM106B is an endolysosomal transmembrane protein not only associated with multiple neurological disorders including frontotemporal dementia, Alzheimers disease, and hypomyelinating leukodystrophy but also potentially involved in COVID-19. Additionally, recent studies have identified amyloid fibrils of C-terminal TMEM106B in both aged healthy and neurodegenerative brains. However, so far little is known about physiological functions of TMEM106B in the endolysosome and how TMEM106B is involved in a wide range of human conditions at molecular levels. Here, we performed lipidomic analysis of the brain of TMEM106B-deficient mice. We found that TMEM106B deficiency significantly decreases levels of two major classes of myelin lipids, galactosylceramide and its sulfated derivative sulfatide. Subsequent co-immunoprecipitation assay showed that TMEM106B physically interacts with galactosylceramidase. We also found that galactosyceramidase activity was significantly increased in TMEM106B-deficient brains. Thus, our results reveal a novel function of TMEM106B interacting with galactosyceramidase to regulate myelin lipid metabolism and have implications for TMEM106B-associated diseases.

neuroscience↗

bioRxiv2023

T2T-YAO: a Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese

Since its initial release in 2001, the human reference genome has been continuously improved in both continuity and accuracy, and the recently-released telomere-to-telomere version--T2T-CHM13--reaches its top quality after 20 years of effort. However, T2T-CHM13 does not represent an authentic diploid human genome, but rather one derived from a simplified, nearly homozygous genome of a hydatidiform mole cell line. To address this limitation and provide an alternative pertinent to the Chinese population, the largest ethnic group in the world, we have assembled a complete diploid human genome of a male Han Chinese, T2T-YAO, which includes telomere-to-telomere assemblies for all the 22+X+M and 22+Y chromosomes in his two haploids inherited separately from his parents. Both haplotypes contain no artificial sequences or model nucleotides and possess a high quality comparable to CHM13, with fewer than one error per [~]14 Mb. Derived from the individual who lives in the aboriginal region of Han Chinese, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors of the Han population. Each haplotype of T2T-YAO possesses [~]340 Mb exclusive sequences and [~]3100 unique genes as compared to CHM13, and their genome sequences show greater genetic distance to CHM13 than to each other in terms of nucleotide polymorphism and structural variations. The construction of T2T-YAO would serve as a high-quality diploid reference that enables precise delineation of genomic variations in a haplotype-sensitive manner, which could advance our understandings in human evolution, hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

genetics↗

bioRxiv2023

Degradation of amyloid beta species by multi-copper oxidases

Reduction of the production of amyloid beta (A{beta}) species has been intensively investigated as potential therapeutic approaches for Alzheimers disease (AD). However, the degradation of A{beta} species, another potential beneficial approach, has been far less explored. In this study, we discovered that ceruloplasmin (CP), an important multi-copper oxidase (MCO) in human blood, could degrade A{beta} peptides. We also found that the presence of Vitamin C could enhance the degrading effect in a concentration-dependent manner. We then validated the CP-A{beta} interaction using total internal reflection fluorescence (TIRF) microscopy, fluorescence photometer, and fluorescence polarization measurement. Based on the above discovery, we hypothesized that other MCOs had similar A{beta}-degrading functions. Indeed, we found that other MCOs could induce A{beta} degradation as well. Remarkably, we revealed that ascorbate oxidase (AO) had the strongest degrading effect among the tested MCOs. Using induced pluripotent stem (iPS) neuron cells, we observed that AO could rescue neuron toxicity which induced by A{beta} oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an A{beta}-induced deficit in synaptic transmission in the hippocampus. To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment.

neuroscience↗