Biology subjects

Jiang, T.

Publications and source records attributed to Jiang, T..

At least 127 records · Page 7Linked to original sources

bioRxiv2021

Emergence of a smooth interface from growth of a dendritic network against a mechanosensitive contractile material

Structures and machines require smoothening of raw materials. Self-organized smoothening guides cell and tissue morphogenesis, and is relevant to advanced manufacturing. Across the syncytial Drosophila embryo surface, smooth interfaces form between expanding Arp2/3-based actin caps and surrounding actomyosin networks, demarcating the circumferences of nascent dome-like compartments used for pseudo-cleavage. We found that smoothening of the actomyosin interfaces requires Arp2/3 in vivo. To dissect the physical basis of this requirement, we reconstituted the interacting networks using node-based models. When actomyosin networks were simulated with clearances instead of Arp2/3 networks, rough boundaries persisted with low levels of myosin contractility. With addition of expanding Arp2/3 networks, network-network interfaces failed to smoothen, but accumulated myosin nodes and tension. After incorporating actomyosin mechanosensitivity, Arp2/3 network growth induced local contractility and smoothening of the interfaces, effects also evident in vivo. In this way, a smooth structure can emerge from the lateral interaction of irregular starting materials.

cell biology↗

bioRxiv2021

Divergent Connectional Asymmetries of the Inferior Parietal Lobule Shape Hemispheric Specialization in Humans, Chimpanzees, and Macaque Monkeys

The inferior parietal lobule (IPL) is one of the most expanded cortical regions in humans relative to other primates. It is also among the most structurally and functionally asymmetric regions in the human cerebral cortex. Whether the structural and connectional asymmetries of IPL subdivisions differ across primate species and how this relates to functional asymmetries remain unclear. We identified IPL subregions that exhibited positive allometric in both hemispheres, scaling across rhesus macaque monkeys, chimpanzees, and humans. The patterns of IPL subregions asymmetry were similar in chimpanzees and humans, but no IPL asymmetries were evident in macaques. Among the comparative sample of primates, humans showed the most widespread asymmetric connections in the frontal, parietal, and temporal cortices, constituting leftward asymmetric networks that may provide an anatomical basis for language and tool use. Unique human asymmetric connectivity between the IPL and primary motor cortex might be related to handedness. These findings suggest that structural and connectional asymmetries may underlie hemispheric specialization of the human brain.

neuroscience↗

bioRxiv2021

Analysis of Spleen Histopathology, Splenocyte composition and Hematological Parameters in Mice Infected with Plasmodium berghei K173

Malaria is a fatal disease that presents clinically as a continuum of symptoms and severity, which are determined by complex host-parasite interactions. Clearance of infection is believed to be accomplished by the spleen and mononuclear phagocytic system (MPS), both in the presence and absence of artemisinin treatment. The spleen filters infected RBCs from circulation through immune-mediated recognition of the infected RBCs followed by phagocytosis. Using different strains of mice infected with P. berghei K173 (PbK173), the mechanisms leading to splenomegaly, histopathology, splenocyte activation and proliferation, and their relationship to control of parasitemia and host mortality were examined. Survival time of mice infected with PbK173 varied, although the infection was uniformly lethal. Mice of the C57BL/6 strain were the most resistant, while mice of the strain ICR were the most susceptible. BALB/c and KM mice were intermediate. In the course of PbK173 infection, both strains of mice experienced significant splenomegaly. Parasites were observed in the red pulp at 3 days post infection in all animals. All spleens retained late trophozoite stages as well as a fraction of earlier ring-stage parasites. The percentages of macrophages in infected C57BL/6 and KM mice were higher than uninfected mice on 8 dpi. Spleens of infected ICR and KM mice exhibited structural disorganization and remodeling. Furthermore, parasitemia was significantly higher in KM versus C57BL/6 mice at 8 dpi. The percentages of macrophages in ICR infected mice were lower than uninfected mice, and the parasitemia was higher than other strains. The results presented here demonstrate the rate of splenic mechanical filtration and the splenic macrophages likely contribute to an individuals total parasite burden. This in turn can influence the pathogenesis of malaria. Finally, different genetic backgrounds of mice have different splenic mechanisms for controlling malaria infection.

microbiology↗

bioRxiv2021

Targeting EGFR in glioblastoma with a novel brain-penetrant small molecule EGFR-TKI

Epidermal growth factor receptor (EGFR) is mutated or amplified in a majority of glioblastoma (GBM), and its mutation and focal amplification correlate with a more aggressive disease course. However, EGFR-directed tyrosine kinase inhibitors (TKIs) tested to date have yielded minimal clinical benefit. Here, we report a novel covalent-binding EGFR-TKI, CM93, as a potential drug to target adult GBMs with aberrant EGFR. CM93 has extraordinary brain exposure, with a brain-to-plasma ratio greater than 20-fold at estimated steady state. While all approved EGFR-TKIs are subject to extensive efflux transporter activity, CM93 does not inhibit the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters in Caco-2 cells at expected clinically relevant plasma concentrations. Equally, CM93 demonstrates moderate absorption and permeation in Caco-2 cell monolayers with efflux ratios < 2, suggesting that it is not likely a substrate of an efflux transporter. Collectively, these in vitro data may account for the dramatic increase in brain exposure over plasma as noted above. Pre-clinical efficacy studies showed that CM93 is more effective than other EGFR-TKIs in blocking the proliferation of GBM tumor cells from both patient-derived and cultured human GBM cell lines with EGFR amplification and/or EGFRvIII mutation. In addition, CM93 administered as a single agent was able to attenuate the growth of orthotopic U251-EGFRvIII xenografts and extend the survival of tumor-bearing mice in a dose-dependent manner. Moreover, CM93 inhibited EGFR phosphorylation in GBM tumors derived from a novel genetically-engineered mouse (GEM) model of GBM with EGFRvIII expression both in vitro and in vivo. CM93 also extended the survival of mice bearing orthotopic allografts of GBM. Notably, mice maintained stable body weight during treatments with increasing doses of CM93 up to 75 mg/kg per day. Together, these data suggest that CM93 is a potential EGFR-TKI well suited for the treatment of adult GBM with mutant EGFR.

cancer biology↗

bioRxiv2021

Recognition of a Tandem Lesion by DNA Glycosylases Explored Combining Molecular Dynamics and Machine Learning

The combination of several closely spaced DNA lesions, which can be induced by a single radical hit, constitutes a hallmark in the DNA damage landscape and radiation chemistry. The occurrence of such tandem base lesions give rise to a strong coupling with the double helix degrees of freedom and induce important structural deformations, in contrast to DNA strands containing a single oxidized nucleobase. Although such complex lesions are known to be refractory to repair by DNA glycosylases, there is still a lack of structural evidence to rationalize these phenomena. In this contribution, we explore, by numerical modeling and molecular simulations, the behavior of the bacterial glycosylase responsible for base excision repair (MutM), specialized in excising oxidatively-damaged defects such as 7,8-dihydro-8-oxoguanine (8-oxoG). The difference in lesion recognition between a simple damage and a tandem lesions featuring an additional abasic site is assessed at atomistic resolution owing to microsecond molecular dynamics simulation and machine learning postprocessing, allowing to extensively pinpoint crucial differences in the interaction patterns of the damaged bases. This work advocates for the use of such high throughput numerical simulations for exploring the complex combinatorial chemistry of tandem DNA lesions repair and more generally multiple damaged sites of the utmost significance in radiation chemistry.

biochemistry↗

bioRxiv2020

Whole-brain connectivity atlas of glutamatergic and GABAergic neurons in mouse dorsal and median raphe nucleus

The dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons regulating diverse behavioral functions. Their whole-brain input-output circuits remain incompletely understood. We used viral tracing combined with fluorescence micro-optical sectioning tomography to generate a comprehensive whole-brain atlas of inputs and outputs of glutamatergic and GABAergic neurons in the DR and MR. We discovered that these neurons receive inputs from similar upstream brain regions. The glutamatergic and GABAergic neurons in the same raphe nucleus have divergent projection patterns with differences in critical brain regions. Specifically, MR glutamatergic neurons project to the lateral habenula via multiple pathways. Correlation and cluster analysis indicated that glutamatergic and GABAergic neurons in the same raphe nucleus receive inputs from heterogeneous neurons in upstream brain regions and send different collateral projections. This connectivity atlas provides insights into the cell heterogeneity, anatomical connectivity and behavioral functions of the raphe nucleus.

neuroscience↗

bioRxiv2020

Prokaryotic virus Host Predictor: a Gaussian model for host prediction of prokaryotic viruses in metagenomics

BackgroundViruses are ubiquitous biological entities, estimated to be the largest reservoirs of unexplored genetic diversity on Earth. Full functional characterization and annotation of newly-discovered viruses requires tools to enable taxonomic assignment, the range of hosts, and biological properties of the virus. Here we focus on prokaryotic viruses, which include phages and archaeal viruses, and for which identifying the viral host is an essential step in characterizing the virus, as the virus relies on the host for survival. Currently, the method for determining the viral host is either to culture the virus, which is low-throughput, time-consuming, and expensive, or to computationally predict the viral hosts, which needs improvements at both accuracy and usability. Here we develop a Gaussian model to predict hosts for prokaryotic viruses with better performances than previous computational methods. ResultsWe present here Prokaryotic virus Host Predictor (PHP), a software tool using a Gaussian model, to predict hosts for prokaryotic viruses using the differences of Ae-mer frequencies between viral and host genomic sequences as features. PHP gave a host prediction accuracy of 34% (genus level) on the VirHostMatcher benchmark dataset and a host prediction accuracy of 35% (genus level) on a new dataset containing 671 viruses and 60,105 prokaryotic genomes. The prediction accuracy exceeded that of two alignment-free methods (VirHostMatcher and WIsH, 28%-34%, genus level). PHP also outperformed these two alignment-free methods much (24%-38%vs 18%-20%, genus level) when predicting hosts for prokaryotic viruses which cannot be predicted by the BLAST-based or the CRISPR-spacer-based methods alone. Requiring a minimal score for making predictions (thresholding) and taking the consensus of the top 30 predictions further improved the host prediction accuracy of PHP. ConclusionsThe Prokaryotic virus Host Predictor software tool provides an intuitive and user-friendly API for the Gaussian model described herein. This work will facilitate the rapid identification of hosts for newly-identified prokaryotic viruses in metagenomic studies. Author SummaryProkaryotic viruses which include phages and archaeal viruses play an important role in balancing the global ecosystem by regulating the composition of bacteria and archaea in water and soil. Identifying the viral host is essential for characterizing the virus, as the virus relies on the host for survival. Currently, the method for determining the viral host is either to culture the virus which is low-throughput, time-consuming, and expensive, or to computationally predict the viral hosts which needs improvements at both accuracy and usability. This study developed a Gaussian model to predict hosts for prokaryotic viruses with better performances than previous computational methods. It will contribute to the rapid identification of hosts for prokaryotic viruses in metagenomic studies, and will extend our knowledge of virus-host interactions.

bioinformatics↗

bioRxiv2020

Reproducible abnormalities of functional gradient reliably predict clinical and cognitive symptoms in schizophrenia

BackgroundSchizophrenia (SZ) typically manifests heterogeneous phenotypes involving positive, negative and cognitive symptoms. However, the underlying neural mechanisms of these symptoms keep unclear. Functional gradient is a fascinating measure to characterize continuous, hierarchical organization of brain. MethodsWe aimed to investigate whether reproducible disruptions of functional gradient existed in SZ compared to normal controls (NC), and these abnormalities were associated with severity of clinical and cognitive symptoms in SZ. All analyses were implemented in two independent large-sample multi-site datasets (discovery dataset, 400 SZ and 336 NC; replication dataset, 279 SZ and 262 NC). First, functional gradient across cerebral cortex was calculated in each subject. Second, vertex-wise comparisons of cortical gradient between SZ and NC groups were performed to identify abnormalities in SZ. Meanwhile, reproducible and robustness analyses were implemented to validate these abnormalities. Finally, regression analyses were performed using generalized additive models to link these abnormalities to severity of clinical and cognitive symptoms in SZ. ResultsWe found an abnormal gradient map in SZ in the discovery dataset, which was reproducible in the replication dataset. The abnormal gradient pattern was also robust when performing methodological alternatives and control analyses. Further, these reproducible abnormalities can reliably predict symptoms of clinical and cognitive domains across the two independent datasets. ConclusionThese findings demonstrated that alterations in functional gradient can provide a reliable signature of SZ, characterizing the heterogenous symptoms of clinical or cognitive domains, and may be further investigated to understand the neurobiological mechanisms of these symptoms. Impact StatementIn our study, using functional gradient measure and statistical learning technology and two independent multi-site case-control resting-state fMRI datasets (discovery dataset: 736 subjects; replication dataset: 541 subjects), we comprehensively investigated functional hierarchical organization in the cerebral cortex of SZ and its association with interindividual severity of symptoms. We found reproducible and robust abnormalities of functional gradient existed in SZ, which provided a reliable signature to characterize negative and general psychopathology symptoms, as well as cognitive deficits. Our findings can provide new insights to understand the neurobiological mechanisms of clinical and cognitive symptoms in SZ.

neuroscience↗

bioRxiv2020

Extensive MET alterations confer clinical response to MET inhibitors in gliomas

Activating alterations of the MET gene are well-characterized oncogenic drivers, and MET inhibitors could successfully treat several tumor types with MET alterations, including gliomas with PTPRZ1-MET fusion. However, the full diversity and prevalence of MET alterations in gliomas are still lacking to accurately identify a subset of patients likely to benefit from MET inhibitor treatment. Here, we interrogated genomic profiles of 1,351 gliomas, and further identify 60 cases harboring MET alterations, including MET fusions and various MET exon skipping events. MET RNA alterations, but not MET amplification, are highly enriched in the secondary glioblastomas (sGBM) with significantly worse prognosis. Further molecular analysis has shown that MET RNA alterations acting an additive effects of MET overexpression are induced in the course of glioma evolution. In vitro and clinical studies indicate cells and patients harboring MET alterations have better response to MET inhibitors. Collectively, these data suggest that a subgroup of gliomas harboring MET alterations likely to have benefit from MET-targeted therapy.

neuroscience↗

bioRxiv2020

TruSight Oncology 500: Enabling Comprehensive Genomic Profiling and Biomarker Reporting with Targeted Sequencing

BackgroundAs knowledge of mechanisms that drive the development of cancer grows, there has been corresponding growth in therapies specific to a mechanism. While these therapies show improvements in patient outcomes, they can be expensive and are effective only for a subset of patients. These treatments drive interest in research focused on the assignment of cancer therapies based on aberrations in individual genes or biomarkers that assess the broader mutational landscape, including microsatellite instability (MSI) and tumor mutational burden (TMB). MethodsHere we describe the TruSight Oncology 500 (TSO500; Research Use Only) bioinformatics workflow. This tumor-only approach leverages the next-generation sequencing-based assay TSO500 to enable high fidelity determination of DNA variants across 523 cancer-relevant genes, as well as MSI status and TMB in formalin-fixed paraffin-embedded (FFPE) samples. ResultsThe TSO500 bioinformatic workflow integrates unique molecular identifier (UMI)-based error correction and a dual approach variant filtering strategy that combines statistical modeling of error rates and database annotations to achieve detection of variants with allele frequency approaching 5% with 99.9998% per base specificity and 99% sensitivity in FFPE samples representing a variety of tumor types. TMB determined using the tumor-only workflow of TSO500 correlated well with tumor-normal (N =170, adjusted R2=0.9945) and whole-exome sequencing (N=108, adjusted R2=0.933). Similarly, MSI status determined by TSO500 showed agreement (N=106, 98% agreement) with a MSI-PCR assay. ConclusionTSO500 is an accurate tumor-only workflow that enables researchers to systematically characterize tumors and identify the next generation of clinical biomarkers.

bioinformatics↗

bioRxiv2020

The mouse cortico-basal ganglia-thalamic network

The cortico-basal ganglia-thalamic loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behavior, and the natural history of many neurological and neuropsychiatric diseases. Classically, the basal ganglia is conceptualized to contain three primary information output channels: motor, limbic, and associative. However, given the roughly 65 cortical areas and two dozen thalamic nuclei that feed into the dorsal striatum, a three-channel view is overly simplistic for explaining the myriad functions of the basal ganglia. Recent works from our lab and others have subdivided the dorsal striatum into numerous functional domains based on convergent and divergent inputs from the cortex and thalamus. To complete this work, we generated a comprehensive data pool of [~]700 injections placed across the striatum, external globus pallidus (GPe), substantia nigra pars reticulata (SNr), thalamic nuclei, and cortex. We identify 14 domains of SNr, 36 in the GPe, and 6 in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify 6 parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information with complex patterns of convergence and divergence through every elemental node of the entire cortico-basal ganglia loop. These experiments reveal multiple important novel features of the cortico-basal ganglia network motif. The prototypical sub-network structure is characterized by a highly interconnected nature, with cortical information processing through one or more striatal nodes, which send a convergent output to the SNr and a more parallelized output to the GPe; the GPe output then converges with the SNr. A domain of the thalamus receives the nigral output, and is interconnected with both the striatal domains and the cortical areas that filter into its nigral input source. This study provides conceptual advancement of our understanding of the structural and functional organization of the classic cortico-basal ganglia network.

neuroscience↗

bioRxiv2020

The potential function of forehead gland secretions in conflict resolution of the male Great Himalayan leaf-nosed bats

Chemical communication is an important aspect of social behavior in almost all animals. Here, we used gas chromatography-mass spectrometry (GC-MS) to detect the chemical composition, and behavioral tests to evaluate the potential function of forehead gland secretions between adult male Great Himalayan leaf-nosed bats, Hipposideros armiger. Our results showed that the concentrations of compounds and their categories differed significantly among individuals, and behavioral studies indicated that males are capable of utilizing the secretions for individual discrimination. Moreover, paired males that were incapable of gland protrusion showed more physical contact and longer contest duration compared to pairs in which both males could protrude the gland. In trials where only one male could protrude the gland, males with gland protrusion were more likely to win in contests. These findings provide the first behavioral evidence that chemical communication plays a vital role in conflict resolution in non-human mammals.

ecology↗

bioRxiv2020

MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors

ObjectiveAlthogh Genome-wide association studies have identified >100 variants for rheumatoid arthritis (RA),the reported genetic variants only explain <40% of RA heritability. We conducted a systemic association study between common East-Asian miRNA SNPs with RA in a large Han Chinese cohort to explain missing heritability and identify miRNA epistatic interactions. Methods4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1 and TNFAIP3) and 225 common SNPs located in miRNA which might influence the miRNA target binding or pre-miRNA stability were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. A meta-analysis with previous GWAS studies (4,873 RA cases and 17,642 controls) was performed to discovery another novel miRNA RA-associated SNPs. Results2 novel SNPs including rs1414273 (miR-548ac, OR=0.84, P=8.26x10-4) and rs2620381 (miR-627, OR=0.77, P=2.55x10-3) conferred significant association with RA. Individuals carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, P<1.0x10-6) times more risk to be affected by RA. In addition, rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR=4.23, P=0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR=4.43, P=0.03). Finally, we demonstrated targets of the significant miRNAs showed enrichment in immune related genes (P=2.0x10-5) and FDA approved drug target genes (P=0.014). Conclusions6 novel miRNA SNPs including rs1414273 (miR-548ac, P=8.26x10-4), rs2620381 (miR-627, P=2.55x10-3), rs4285314 (miR-3135b, P=1.10x10-13), rs28477407 (miR-4308, P=3.44x10-5), rs5997893 (miR-3928, P=5.9x10-3) and rs45596840 (miR-4482, P=6.6x10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate the understanding of the pathogenesis and drug development for rheumatoid arthritis.

genetics↗

bioRxiv2020

Mapping Connectional Differences between Humans and Macaques in the Nucleus Accumbens Shell-Core Architecture

Two nucleus accumbens subregions, the shell and core, differ in the patterns whereby they integrate signals from prefrontal and limbic areas of the brain. In this study, we investigated whether the disproportionate volumetric differences of these brain areas, particularly the prefrontal cortex, between humans and macaques are accompanied by unique modifications of their macroscopic integrative connections with the shell and core. More specifically, we characterized the tractographic connectivity profiles of the human and macaque shell-core architecture and compared them between the two species. To make the cross-species comparisons more viable, we used the same whole-brain voxel-wise tractography-defined shell-like and core-like divisions in the two species as seeds and delineated pairs of interspecies connectionally comparable (ICC) target regions based on the similarity of the resting-state functional connectivity profiles for the two species, and finally used these seeds and ICC targets to establish a fingerprint-based common space for cross-species comparisons. Our results revealed that dissimilar structural connectivity profiles were found in the prefrontal but not the subcortical target group. We further localized this difference to specific targets to infer possible functional modifications between the two species.

neuroscience↗

bioRxiv2020

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

Precision medicine in oncology leverages clinical observations of exceptional response. Towards an understanding of the molecular features that define this response, we applied an integrated, multi-platform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted isoform of PI3K, PI3K{gamma}, by pharmacologic inhibition or genetic inactivation, disrupted this signaling axis by suppressing microglia/macrophage accumulation and associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3K{gamma} inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3K{gamma} in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3K{gamma} inhibition as a glioblastoma therapy. Significance StatementUnderstanding the basis for exceptional responders represents a key pillar in the framework of precision medicine. In this study, we utilized distinct informatics platforms to analyze the expression profiles of clinically annotated tumor specimens derived from patients afflicted with glioblastoma, the most common form of primary brain cancer. These analyses converged on prognostic contributions from glioblastoma-associated microglia/macrophages. Glioblastoma-associated microglia secreted interleukin 11 (IL11) to activate a STAT3-MYC signaling axis in glioblastoma cells, facilitating resistance to the standard-of-care chemotherapy, temozolomide. Microglia recruitment and IL11 secretion were dependent on the myeloid specific phosphoinositide-3-kinase gamma isoform (PI3K{gamma}). Inhibition or genetic inactivation of PI3K{gamma} in murine glioblastoma models recapitulated expression profiles observed in specimens derived from exceptional responders, suggesting potential for clinical translation.

cancer biology↗

bioRxiv2020

Pair-wise Interactions in Gene Expression Determine a Hierarchical Transcription Profile of the Human Brain

Orchestrated expressions of tens of thousands of genes give rise to the complexity of the brain. However, it is unclear what is the structure governing these myriads of gene-gene interactions. By analyzing the transcription data obtained from more than 3000 sites in human brains, we found that pair-wise interactions between genes are sufficient to accurately predict both the transcription pattern of the whole genome for individual brain areas and the transcription profile of the entire brain, suggesting a surprisingly simple interaction structure of the transcriptome itself. We further revealed that the strength of gene-gene interaction observed empirically allows the nearly maximal number of transcriptionally similar clusters of areas to form, which may account for the functional and structural richness of the brain. One Sentence SummaryPairwise interactions among genes shape the overall structure of human brain transcriptome.

genomics↗

bioRxiv2020

Clinical and biomarker changes in sporadic Alzheimer's disease: Amyloid-β not useful marker for disease onset or progression

IMPORTANCEThe dynamic changes of biomarkers and clinical profiles in sporadic Alzheimers disease (SAD) are poorly understood. OBJECTIVETo evaluate the impact of amyloid-{beta} (A{beta}) biomarkers on SAD by measuring the dynamic changes in biomarkers and clinical profiles in the progression of SAD. DESIGN AND SETTINGThis retrospective and longitudinal study analyzed clinical and biomarker data from 665 participants (mean follow-up 4.90 {+/-} 2.83 years) from a subset of the AD Neuroimaging Initiative (ADNI) participants collected from August 2005 to December 2018. By aligning the timing of the changes in the various biomarkers with the stable normal cognition (CN) baseline and mild cognitive impairment (MCI) or AD onset timepoints, we combined data from the stable CN, CN conversion to MCI (CN2MCI), and MCI conversion to AD (MCI2AD) groups to identify the trajectories associated with the progression of AD. PARTICIPANTSThe participants were 294 CN, 69 CN2MCI, 300 MCI2AD, and 24 who converted from CN to MCI to AD (CN2MCI2AD) (of whom 22 were also included in the CN2MCI). EXPOSURESAmyloid-{beta} measured by florbetapir positron emission tomography (PET) or cerebrospinal fluid assay of amyloid-{beta} (CSF A{beta}42). MAIN OUTCOMES AND MEASURESThe measures included the 13-item cognitive subscale of the AD Assessment Scale (ADAS13, as a clinical measure), hippocampal volume, and the fluorodeoxyglucose (FDG) PET standardized uptake value ratio (SUVR). RESULTSThe CN, CN2MCI, and MCI2AD subgroups median (interquartile range [IQR]) annual changes in ADAS13 were (0.388 [-0.278, 0.818], 1.000 [0.239, 2.330], and 3.388 [1.750, 6.169]). The annual changes in hippocampal volume for each group were (-0.005 %ICV [-0.011, -0.001], -0.006 %ICV [-0.012, -0.002], and -0.014 %ICV [-0.021, -0.009]). The annual changes in FDG PET SUVR for each group were (-0.011 [-0.030, 0.010], -0.027 [-0.056, -0.012], and -0.039 [-0.063, 0.014]). Changes in the amyloid biomarkers were inconsistent with clinical profile changes. The annual changes in CSF A{beta}42 for each group were (-1.500 pg/ml [-6.000, 4.000], -2.200 [-5.667, 4.000], and -2.000 [-7.000, 2.650]) and in A{beta} PET SUVR for each group were (0.004 [-0.002, 0.012], 0.004 [-0.001,0.011], and 0.005 [-0.006, 0.014]). During the stable CN and CN2MCI stages, subjects with elevated and those with normal amyloid showed no significant differences (likelihood ratio test, p < .01) in clinical measures, hippocampal volume, or FDG. CONCLUSIONS AND RELEVANCEHippocampal volume and FDG associated with clinical profiles impairment in the SAD progression. A{beta} alone is not associated with clinical profiles, hippocampal volume, and FDG impairment in the preclinical stage of SAD. Key PointsQuestion: What is the role of amyloid-{beta} in dynamic changes in biomarkers and clinical profiles in the progression of sporadic Alzheimers disease? Findings: The changes of the hippocampal volume and FDG that were consistent with the changes of the clinical profiles showed a non-linear change in the initial stage and an accelerated non-linear change during MCI2AD, changes in amyloid biomarkers were inconsistent with the clinical profile. Cognitively normal people with elevated or normal amyloid showed no significant differences in clinical measures, hippocampal volume, or FDG. Meaning: Amyloid-{beta} alone may not be used as the central index for defining the preclinical stage of SAD.

neuroscience↗

bioRxiv2020

Comparative transcriptome analysis reveals the intensive early-stage responses of host cells to SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a widespread outbreak of highly pathogenic COVID-19. It is therefore important and timely to characterize interactions between the virus and host cell at the molecular level to understand its disease pathogenesis. To gain insights, we performed high-throughput sequencing that generated time-series data simultaneously for bioinformatics analysis of virus genomes and host transcriptomes implicated in SARS-CoV-2 infection. Our analysis results showed that the rapid growth of the virus was accompanied by an early intensive response of host genes. We also systematically compared the molecular footprints of the host cells in response to SARS-CoV-2, SARS-CoV and MERS-CoV. Upon infection, SARS-CoV-2 induced hundreds of up-regulated host genes hallmarked by a significant cytokine production followed by virus-specific host antiviral responses. While the cytokine and antiviral responses triggered by SARS-CoV and MERS-CoV were only observed during the late stage of infection, the host antiviral responses during the SARS-CoV-2 infection were gradually enhanced lagging behind the production of cytokine. The early rapid host responses were potentially attributed to the high efficiency of SARS-CoV-2 entry into host cells, underscored by evidence of a remarkably up-regulated gene expression of TPRMSS2 soon after infection. Taken together, our findings provide novel molecular insights into the mechanisms underlying the infectivity and pathogenicity of SARS-CoV-2.

microbiology↗