Biology subjects

Li, C.

Publications and source records attributed to Li, C..

At least 577 records · Page 32Linked to original sources

bioRxiv2023

RCoV19: A One-stop Hub for SARS-CoV-2 Genome Data Integration, Variants Monitoring, and Risk Pre-warning

The Resource for Coronavirus 2019 (RCoV19, https://ngdc.cncb.ac.cn/ncov/) is an open-access information resource dedicated to providing valuable data on the genomes, mutations, and variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this updated implementation of RCoV19, we have made significant improvements and advancements over the previous version. Firstly, we have implemented a highly refined genome data curation model. This model now features an automated integration pipeline and optimized curation rules, enabling efficient daily updates of data in RCoV19. Secondly, we have developed a global and regional lineage evolution monitoring platform, alongside an outbreak risk pre-warning system. These additions provide a comprehensive understanding of SARS-CoV-2 evolution and transmission patterns, enabling better preparedness and response strategies. Thirdly, we have developed a powerful interactive mutation spectrum comparison module. This module allows users to compare and analyze mutation patterns, assisting in the detection of potential new lineages. Furthermore, we have incorporated a comprehensive knowledgebase on mutation effects. This knowledgebase serves as a valuable resource for retrieving information on the functional implications of specific mutations. In summary, RCoV19 serves as a vital scientific resource, providing access to valuable data, relevant information, and technical support in the global fight against COVID-19.

bioinformatics↗

bioRxiv2023

Adaptive Functions of Structural Variants in Human Brain Development

Quantifying the structural variants (SVs) in nonhuman primates could provide a niche to clarify the genetic backgrounds underlying human-specific traits, but such resource is largely lacking. Here, we report an accurate SV atlas in a population of 562 rhesus macaques, verified by two public SV benchmarks, an inhouse benchmark of eight macaque genomes with long-read sequencing and another inhouse benchmark of one macaque genome with whole-genome assembly. This accurate, quantitative SV map indicates stronger purifying selection on inversions, one type of poorly-clarified SVs to date, especially for those located on regulatory regions, suggesting a strategy for prioritizing inversions with the most important functions. Based on the distribution and the evolutionary features of these inversions in macaque population, we then identified 75 human-specific inversions, clarified their functional effects and prioritized them. Notably, the top-ranked inversions have substantially shaped the human transcriptome, through their dual-effects of reconfiguring the ancestral genomic architecture and introducing regional mutation hotspots at the inverted regions. As a proof-of-concept, we linked APCDD1, located on one of these inversions with the highest rank score and downregulated in human brains, to neuronal maturation. The accumulation of human-specific mutations on its promoter region, accelerated by the formation of the inversion, contributed to the decreased expression in humans. Notably, the overexpression of APCDD1 could accelerate the neuronal maturation, while its depletion in mice delays the neuronal maturation. This study thus highlights the contribution of SVs, especially the inversions, to the distinct features in human brain development.

evolutionary biology↗

bioRxiv2023

Class A capsid assembly modulator apoptotic elimination of hepatocytes with high HBV core antigen level in vivo is dependent on de novo core protein translation

Background and aimsCapsid assembly (CA) is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the viral core protein. CA is the target for various new anti-viral candidate therapeutics known as capsid assembly modulators (CAMs) of which the CAM-aberrant (CAM-A) class induces aberrant shaped core protein structures and lead to hepatocyte cell death. The aim of the studies was to identify the mechanism of action of the CAM-A modulators leading to HBV infected hepatocyte elimination. MethodsThe CAM-A mediated mechanism of HBsAg reduction was evaluated in vitro in a stable HBV replicating cell line and in vivo in AAV-HBV transduced C57BL/6, C57BL/6 SCID and HBV-infected chimeric mice with humanized livers. ResultsIn vivo treatment with CAM-A modulators induced pronounced reductions in HBe- and HBsAg which were associated with a transient increase in ALT. Both HBs- and HBeAg reduction and ALT increase were delayed in C57BL/6 SCID and chimeric mice, suggesting that adaptive immune responses may indirectly contribute to this phenotype. However, depletion of CD8+ T-cells in transduced wild-type mice did not have a negative impact on antigen reduction, indicating that CD8+ T-cell responses are not essential. Coinciding with the transient ALT elevation in AAV-HBV transduced mice, we observed a transient increase in markers related to endoplasmic reticulum stress and apoptosis as well as cytokines related to apoptosis pathways, followed by the detection of a proliferation marker. Pathway enrichment analysis of microarray data revealed that antigen presentation pathway (MHC-I) was upregulated, overlapping with observed apoptosis. Combination treatment with HBV-specific siRNA demonstrated that CAM-A mediated HBsAg reduction is dependent on de novo core protein translation and that the effect is dependent on high levels of core protein expression, which will likely focus the CHB sub-population that could respond. ConclusionCAM-A treatment eradicates HBV infected hepatocytes with high core protein levels through the induction of apoptosis a promising approach as part of a regimen to achieve functional cure. Lay summaryTreatment with hepatitis B virus (HBV) capsid assembly modulators that induce the formation of aberrant HBV core protein structures (CAM-A) leads to programmed cell death, apoptosis, of HBV-infected hepatocytes and subsequent reduction of HBV antigens, which differentiates CAM-A from other CAMs. The effect is dependent on the de novo synthesis and high levels of core protein.

microbiology↗

bioRxiv2023

Geranylgeranyl pyrophosphate (GGPP) is associated with hepatic lipid accumulation and insulin resistance in MAO by prenylating Perilipin4

Metabolically Abnormal Obesity (MAO) is characterized by hepatic steatosis and type 2 diabetes (T2D), in contrast to Metabolically Healthy Obesity (MHO). In this study, we investigated the role of hepatic geranylgeranyl pyrophosphate (GGPP), a metabolite of the mevalonate (MVA) pathway, in regulating the differences in lipid metabolism between MAO and MHO. Our findings revealed that GGPP levels were significantly elevated in individuals with MAO, and deficiency of GGPP in the liver ameliorated the defects associated with MAO. Furthermore, we discovered that the prenylation of the lipid droplet-associated protein Perilipin 4 by GGPP enhances the formation of large lipid droplets, thereby exacerbating hepatic lipid accumulation and insulin resistance. Notably, the inhibitor DGBP, targeting the GGPP synthase Ggpps, effectively attenuated the traits of MAO, offering novel insights into the treatment of this condition.

pathology↗

bioRxiv2023

Exploring Degradation of Intrinsically Disordered Protein YAP induced by PROTACs

Yes-associated protein (YAP), a potent oncogene and a key player in the Hippo tumor suppression pathway, has long been considered challenging to target due to its partially intrinsically disordered nature. However, recent advances in High-throughput Screening (HTS) have led to the discovery of a few YAP binders. Building upon this progress, a novel approach utilizing Proteolysis-Targeting Chimera (PROTAC) technology was employed to design and synthesize a series of YAP degraders. Here, our degraders were created by linking NSC682769, a previously reported YAP binder, with either VHL ligand 2 or pomalidomide using various linkers of different lengths and types. The most promising degrader YZ-6 recruits the E3 ligase VHL, inducing rapid and sustained YAP degradation leading to suppression of YAP/TEAD-led transcription in both YAP-dependent NCI-H226 and Huh7 cancer cell lines. In addition to its degradation capabilities, YZ-6 also exhibited potent antiproliferative activity in both cell lines. Importantly, YZ-6 efficiently suppresses tumor development in the Huh7 xenograft mouse model without adverse effects on the mice. These findings highlight the potential of PROTAC-mediated degradation as a viable strategy for reducing oncogenic YAP levels and attenuating downstream signaling in cancer cells. Moreover, the development of PROTACs based on NSC672869 holds promise for treating YAP-driven malignancies.

cancer biology↗

bioRxiv2023

Label-free, real-time monitoring of membrane binding events at zeptomolar concentrations using frequency-locked optical microresonators

Binding events to elements of the cell membrane act as receptors which regulate cellular function and communication and are the targets of many small molecule drug discovery efforts for agonists and antagonists. Conventional techniques to probe these interactions generally require labels and large amounts of receptor to achieve satisfactory sensitivity. Whispering gallery mode microtoroid optical resonators have demonstrated sensitivity to detect single-molecule binding events. Here, we demonstrate the use of frequency-locked optical microtoroids for characterization of membrane interactions in vitro at zeptomolar concentrations using a supported biomimetic membrane. Arrays of microtoroids were produced using photolithography and subsequently modified with a biomimetic membrane, providing high quality (Q) factors (>106) in aqueous environments. Fluorescent recovery after photobleaching (FRAP) experiments confirmed the retained fluidity of the microtoroid supported-lipid membrane with a diffusion coefficient of 3.38 {+/-} 0.26 m2 {middle dot}s-1. Utilizing this frequency-locked membrane-on-a-chip model combined with auto-balanced detection and non-linear post-processing techniques, we demonstrate zeptomolar detection levels The binding of Cholera Toxin B-monosialotetrahexosyl ganglioside (GM1) was monitored in real-time, with an apparent equilibrium dissociation constant (kd) = 1.53 nM. The measured affiny of the agonist dynorphin A 1-13 to the {kappa}-opioid receptor revealed a kd = 3.1 nM using the same approach. Radioligand binding competition with dynorphin A 1-13 revealed a Kd in agreement (1.1 nM) with the unlabeled method. The biosensing platform reported herein provides a highly sensitive real-time characterization of membrane embedded protein binding kinetics, that is rapid and label-free, for toxin screening and drug discovery, among other applications.

biophysics↗

bioRxiv2023

Chemical proteomic approach for in-depth glycosylation profiling of plasma carcinoembryonic antigen in cancer patients

Carcinoembryonic antigen (CEA) of human plasma is a biomarker of many cancer diseases, and its N-glycosylation accounts for 60% of molecular mass. It is highly desirable to characterize its glycoforms for providing additional dimension of features to increase its performance in prognosis and diagnosis of cancers. However, to systematically characterize its site-specific glycosylation is challenging due to its low abundance. Here, we developed a highly sensitive strategy for in-depth glycosylation profiling of plasma CEA through chemical proteomics combined with multi-enzymatic digestion. A trifunctional probe was utilized to generate covalent bond of plasma CEA and its antibody upon UV irradiation. As low as 1 ng/mL CEA in plasma could be captured and digested with trypsin and chymotrypsin for intact glycopeptide characterization. Twenty six out of 28 potential N-glycosylation sites were well identified, which were the most comprehensive N-glycosylation site characterization of CEA on intact glycopeptide level as far as we known. Importantly, this strategy was applied to the glycosylation analysis of plasma CEA in cancer patients. Differential site-specific glycoforms of plasma CEA were observed in patients with colorectal carcinomas (CRC) and lung cancer. The distributions of site-specific glycoforms were different as the progression of CRC, and most site-specific glycoforms were overexpressed in stage II of CRC. Overall, we established a highly sensitive chemical proteomic method to profile site-specific glycosylation of plasma CEA, which should generally applicable to other well-established cancer glycoprotein biomarkers for improving their cancer diagnosis and monitoring performance. In BriefA chemical proteomic approach for glycosylation profiling of proteins was established for glycosylation characterization of plasma CEA with low abundance. Although CEA has been widely used in diagnosis and prognosis of many cancers, it lacks specificity and sensitivity. We found that the glycosylation of CEA on intact glycopeptide level provided additional dimension of molecular features to improve the performance of CEA in cancer diagnosis and progression. HighlightsO_LIA chemical proteomic approach for glycosylation profiling of proteins with low abundance C_LIO_LIGlycosylation identification of plasma CEA on intact glycopeptide level with high sensitivity and reproducibility C_LIO_LIGlycosylation features of plasma CEA in cancer patients with CRC and lung cancer and in CRC patients at different progression stages C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/558933v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@73b539org.highwire.dtl.DTLVardef@7ed658org.highwire.dtl.DTLVardef@12a3e20org.highwire.dtl.DTLVardef@54a87f_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Comparative single-cell regulome reveals evolutionary innovations in neural progenitor cells during primate corticogenesis

The cellular and genetic mechanism underlying the human-specific features of cortex development remains unclear. We generated a cell-type resolved atlas of transcriptome and regulome of the developing macaque and mouse prefrontal cortex, and conducted evolutionary analyses with the published complementary human data. We discovered a primate-specific expansion of two neural progenitor subclasses, glia-committed radial glia (RG) and truncated RG. Specifically, the human neural progenitors show extensive transcriptional rewiring in the growth factor and extracellular matrix pathways. Expression of the human-specific progenitor marker ITGA2 in the cortex of fetal mouse promotes progenitor proliferation and an increased upper-layer neuron proportion. We demonstrate that these transcriptional divergences are primarily driven by the activity changes of the distal regulatory elements in the genome. Markedly, the chromatin regions with human-gained accessibility enrich the human-fixed sequence changes, as well as sequence polymorphisms associated with intelligence and neuropsychiatric disorders. Our results uncover evolutionary innovations in neural progenitors and gene regulatory mechanism during primate cortex evolution.

evolutionary biology↗

bioRxiv2023

Systems-wide analysis of the ROK-family regulatory gene rokL6 and the control of aminosugar toxicity in Streptomyces coelicolor

Streptomycetes are saprophytic bacteria that grow on complex polysaccharides, such as cellulose, starch, chitin and chitosan. For the monomeric building blocks glucose, maltose and N-acetylglucosamine (GlcNAc), the metabolic pathways are well documented, but that of glucosamine (GlcN) is largely unknown. Streptomyces nagB mutants, which lack glucosamine-6-phosphate deaminase activity, fail to grow in the presence of high concentrations of GlcN. Here we report that mutations in the gene for the ROK-family transcriptional regulator RokL6 relieve the toxicity of GlcN in nagB mutants, as a result of elevated expression of the Major Facilitator Superfamily (MFS) exporter SCO1448. Systems- wide analysis using RNA sequencing, ChIP-Seq, EMSAs, 5RACE, bioinformatics and genetics revealed that RokL6 is an autoregulator that represses transcription of sco1448 by binding to overlapping promoters in the rokL6-sco1448 intergenic region. RokL6-independent expression of sco1448 fully relieved toxicity of GlcN to nagB mutants. Taken together, our data show a novel system of RokL6 as a regulator that controls the expression of the MFS transporter SCO1448, which in turn protects cells against GlcN toxicity, most likely by exporting toxic metabolites out of the cell. IMPORTANCECentral metabolism plays a key role in the control of growth and antibiotic production in streptomycetes. Specifically, aminosugars act as signaling molecules that affect development and antibiotic production, via metabolic interference with the global repressor DasR. While aminosugar metabolism directly connects to other major metabolic routes such as glycolysis and cell wall synthesis, several important aspects of their metabolism are yet unresolved. Accumulation of N-acetylglucosamine 6-phosphate (GlcNAc-6P) or glucosamine 6-phosphate (GlcN-6P) is lethal to many bacteria, a yet unresolved phenomenon referred to as "aminosugar sensitivity". We made use of this concept by selecting for suppressors in genes related to GlcN toxicity in nagB mutants, which showed that the gene pair of rok-family regulatory gene rokL6 and MFS transporter gene sco1448 forms a cryptic rescue mechanism. Inactivation of rokL6 resulted in the expression of sco1448, which then prevents toxicity of amino sugar-derived metabolites in Streptomyces. The systems biology of RokL6 and its transcriptional control of sco1448 sheds new light on aminosugar metabolism in streptomycetes and on the response of bacteria to aminosugar toxicity.

microbiology↗

bioRxiv2023

PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency

HIV-1 latency results from tightly regulated molecular processes that act at distinct steps of HIV-1 gene expression. To elucidate the molecular players that govern latency, we previously performed a dCas9-chromatin immunoprecipitation coupled with mass spectrometry (Catchet-MS) and identified the interactome of the latent HIV-1 LTR. Here we characterize the Catchet-MS-identified PCI domain-containing 2 (PCID2) protein, a component of the TREX2 complex, to play a dual role in promoting HIV-1 latency by enforcing both transcriptional repression and post-transcriptional blocks to HIV-1 gene expression. PCID2 bound the latent HIV-1 LTR and repressed transcription initiation during latency. Depletion of PCID2 remodelled the chromatin landscape at the HIV-1 promoter and resulted in transcriptional activation and reversal of latency. Immunoprecipitation coupled to Mass Spectrometry identified PCID2-interacting proteins to include members of the spliceosome, including negative viral RNA (vRNA) alternative splicing regulators, and PCID2 depletion resulted in over-splicing of intron-containing vRNA and misregulated expression of vRNA splice variants. We demonstrate that MCM3AP and DSS1, two other RNA-binding TREX2 complex subunits that comprise the dock of the complex also inhibit transcription initiation and viral RNA alternative splicing during latency and similarly to PCID2 function as prominent latency associated repressors of HIV-1 gene expression. Thus, PCID2 is a novel HIV-1 latency-promoting factor, which in context of the TREX2 sub-complex PCID2-DSS1-MCM3AP blocks transcription and dysregulates vRNA processing.

microbiology↗

bioRxiv2023

Quantitative Learning of Cellular Features From Single-cell Transcriptomics Data Facilitates Effective Drug Repurposing

In this study, we have devised a computational framework SuperFeat that allows for the training of a machine learning model and evaluate the canonical cellular states/features in pathological tissues that underlie the progression of disease. This framework also enables the identification of potential drugs that target the presumed detrimental cellular features. This framework was constructed on the basis of an artificial neural network with the gene expression profiles serving as input nodes. The training data comprised single-cell RNA-seq datasets that encompassed the specific cell lineage during the developmental progression of cell features. A few models of the canonical cancer-involved cellular states/features were tested by such framework. Finally, we have illustrated the drug repurposing pipeline, utilizing the training parameters derived from the adverse cellular states/features, which has yielded successful validation results both in vitro and in vivo. SuperFeat is accessible at https://github.com/weilin-genomics/rSuperFeat.

cell biology↗

bioRxiv2023

A Novel Fluorogenic Spin Probe for Real-time Monitoring of Mitochondrial Reactive Oxygen Species (mROS) Generation in an in vitro Stroke Model

The extent of oxidative damage caused by a stroke can be assessed by monitoring mitochondrial reactive oxygen species (mROS), which can further aid in early diagnosis and evaluation of treatment efficacy. Mitochondrial ROS have been identified as a potential biomarker for stroke, as they are known to cause oxidative stress and mitochondrial dysfunction in brain tissue. However, monitoring reversible mROS levels has been challenging due to the lack of appropriate probes. In this study, we developed a fluorogenic spin probe, Mito-RT-ROS, based on the rhodamine skeleton, which demonstrated good sensitivity for reversible monitoring of mROS in a physiological environment such as starvation and recovery. We also evaluated the probes efficacy in an in vitro stroke model for real-time tracking of mROS generation in a pathological setting.

neuroscience↗

bioRxiv2023

Nuclear speckles regulate HIF-2α programs and correlate with patient survival in kidney cancer

Nuclear speckles are membrane-less bodies within the cell nucleus enriched in RNA biogenesis, processing, and export factors. In this study we investigated speckle phenotype variation in human cancer, finding a reproducible speckle signature, based on RNA expression of speckle-resident proteins, across >20 cancer types. Of these, clear cell renal cell carcinoma (ccRCC) exhibited a clear correlation between the presence of this speckle expression signature, imaging-based speckle phenotype, and clinical outcomes. ccRCC is typified by hyperactivation of the HIF-2 transcription factor, and we demonstrate here that HIF-2 drives physical association of a select subset of its target genes with nuclear speckles. Disruption of HIF-2-driven speckle association via deletion of its speckle targeting motifs (STMs)--defined in this study--led to defective induction of speckle-associating HIF-2 target genes without impacting non-speckle-associating HIF-2 target genes. We further identify the RNA export complex, TREX, as being specifically altered in speckle signature, and knockdown of key TREX component, ALYREF, also compromises speckle-associated gene expression. By integrating tissue culture functional studies with tumor genomic and imaging analysis, we show that HIF-2 gene regulatory programs are impacted by specific manipulation of speckle phenotype and by abrogation of speckle targeting abilities of HIF-2. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of a specific subset of HIF-2-regulated target genes that, in turn, influence patient outcomes. We also identify STMs in other transcription factors, suggesting that DNA-speckle targeting may be a general mechanism of gene regulation. HIGHLIGHTS- Nuclear speckles shown to reproducibly vary in cancer, predicting patient survival in ccRCC - HIF-2 drives DNA/gene-speckle contacts dependent on identified speckle targeting motifs within HIF-2 - Putative speckle targeting motifs are highly enriched among regulators of gene expression - Partitioning of transcription factor functional programs may be a major biological function of nuclear speckles

cancer biology↗

bioRxiv2023

Enhanced neutralization of SARS-CoV-2 XBB sub-lineages and BA.2.86 by a tetravalent COVID-19 vaccine booster

As the SARS-CoV-2 virus continues to evolve, novel XBB sub-lineages such as XBB.1.5, XBB.1.16, EG.5, HK.3 (FLip), and XBB.2.3, as well as the most recent BA.2.86, have been identified and aroused global concern. Understanding the efficacy of current vaccines and the immune systems response to these emerging variants is critical for global public health. In this study, we evaluated the neutralization activities of sera from participants who received COVID-19 inactivated vaccines, or a booster vaccination of the recently approved tetravalent protein vaccine in China (SCTV01E), or had contracted a breakthrough infection with BA.5/BF.7/XBB virus. Comparative analysis of their neutralization profiles against a broad panel of 30 SARS-CoV-2 sub-lineage viruses revealed that strains such as BQ.1.1, CH.1.1, and all the XBB sub-lineages exhibited heightened resistance to neutralization than previous variants, however, despite the extra mutations carried by emerging XBB sub-lineages and BA.2.86, they did not demonstrate significantly increased resistance to neutralization compared to XBB.1.5. Encouragingly, the SCTV01E booster vaccination consistently induced robust and considerably higher neutralizing titers against all these variants than breakthrough infection did. Cellular immunity assays also showed that the SCTV01E booster vaccination elicited a higher frequency of virus-specific memory B cells but not IFN-{gamma} secreting T cells. Our findings underline the importance of developing novel multivalent vaccines to more effectively combat future viral variants.

immunology↗

bioRxiv2023

Female baboon adrenal zona fasciculata and zona reticularis regulatory and functional proteins decrease across the life course

Debate exists on life-course adrenocortical zonal function trajectories. Rapid, phasic blood steroid concentration changes, such as circadian rhythms and acute stress responses, complicate quantification. To avoid pitfalls and account for life-stage changes in adrenocortical activity indices, we quantified zonae fasciculata (ZF) and reticularis (ZR) across the life-course, by immunohistochemistry of key regulatory and functional proteins. In 28 female baboon adrenals (7.5-22.1 years), we quantified 12 key proteins involved in cell metabolism, division, proliferation, steroidogenesis (including steroid acute regulatory protein, StAR), oxidative stress, and glucocorticoid and mitochondrial function. Life-course abundance of ten ZF proteins decreased with age. Cell cycle inhibitor and oxidative stress markers increased. Seven of the 12 proteins changed in the same direction for ZR and ZF. Importantly, ZF StAR decreased while ZR StAR was unchanged. Findings indicate ZF function decreased, and less markedly ZR function, with age. Causes and aging consequences of these changes remain to be determined.

physiology↗

bioRxiv2023

Epigenetic Reshaping through Damage: Promoting Cell Fate Transition by BrdU and IdU Incorporation

Thymidine analogs have long been recognized for their ability to randomly incorporate into DNA. However, their significance in the chemical induction of pluripotency (CIP) remains unclear. Here, we investigated the impact of BrdU/IdU incorporation on the transition of cell fate through DNA damage repair (DDR). Our findings reveal a substantial upregulation of reprogramming mediator gene H3K27ac and H3K9ac, as well as global DNA demethylation in response to DDR. This process creates a hypomethylated environment that promotes cell fate transition. We term this mechanism as Epigenetic Reshaping through Damage (ERD). Overall, our study sheds light on the dynamic interplay between thymidine analogs, DDR, and epigenetic modifications, providing valuable insights into the mechanisms underlying cell fate transition.

cell biology↗

bioRxiv2023

Voxel-wise regression without intensity normalizationprovides better sensitivity when identifying injuryregions after stroke in FDG-PET images

BackgroundIn the analysis of brain fluorodeoxyglucose positron emission tomography (FDG-PET), intensity normalization is a necessary step to reduce inter-subject variability. However, the choice of an appropriate normalization method in stroke studies remains unclear, leading to inconsistent findings in the literature. Materials and methodsHere, we propose a regression-based and single-subject-based model for analyzing FDG-PET images without intensity normalization. Two independent data sets were collected before and after middle cerebral artery occlusion (MCAO), with one comprising 120 rats and the other comprising 96 rats. After data preprocessing, voxel intensities in the same region and hemisphere were paired before and after the MCAO scan. A linear regression model was applied to the paired data, and the coefficient of determination was calculated to measure the linearity. The results between the ipsilateral and contralateral hemispheres were compared, and significant regions were defined as those having reduced linearity. Our method was compared with existing intensity normalization methods and validated using the triphenyl tetrazolium chloride (TTC) staining data. ResultsThe proposed method detected more injury areas compared to existing approaches, as confirmed by the ground truth provided by TTC. The area under the curve (AUC) of the average receiver operating characteristic (ROC) curves using our method reached 0.84, whereas the AUCs using existing methods ranged from 0.77 [~] 0.79. The average false positive rate (FPR) and true positive rate (TPR) of the individual analysis results using our method (FPR = 0.06, TPR = 0.56) were better than the group-wise analysis results using t-tests (FPR = 0.10, TPR = 0.51). The identified injury regions were consistent in the two independent data sets. Some of them were confirmed by other publications. ConclusionsThe proposed method offers a new quantitative approach to analyzing FDG-PET images. The calculation does not involve intensity normalization and can be applied to a single subject. The method yields more sensitive results than existing intensity normalization methods.

neuroscience↗

bioRxiv2023

Multi-omics Analysis of Aging Liver Reveals Changes in Endoplasmic Stress and Degradation Pathways in Female Nonhuman Primates

The liver is critical for functions that support metabolism, immunity, digestion, detoxification, and vitamin storage. Aging is associated with severity and poor prognosis of various liver diseases such as nonalcoholic fatty liver disease (NAFLD). Previous studies have used multi-omic approaches to study liver diseases or to examine the effects of aging on the liver. However, to date, no studies have used an integrated omics approach to investigate aging-associated molecular changes in the livers of healthy female nonhuman primates. The goal of this study was to identify molecular changes associated with healthy aging in the livers of female baboons (Papio sp., n=35) by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. To integrate omics data, we performed unbiased weighted gene co-expression network analysis (WGCNA), and the results revealed 3 modules containing 3,149 genes and 33 proteins were positively correlated with age, and 2 modules containing 37 genes and 216 proteins were negatively correlated with age. Pathway enrichment analysis showed that unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were positively associated with age, whereas xenobiotic metabolism and melatonin and serotonin degradation pathways were negatively associated with age. The findings of our study suggest that UPR and a reduction in reactive oxygen species generated from serotonin degradation could protect the liver from oxidative stress during the aging process in healthy female baboons.

molecular biology↗