Biology subjects

Han, F.

Publications and source records attributed to Han, F..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Predictive Systems Biology Modeling: Unraveling Host Metabolic Disruptions and Potential Drug Targets in SARS-CoV-2 and Its Variants

BackgroundHost response is critical to the onset, progression, and outcome of viral infections. Since viruses hijack the host cellular metabolism for their replications, we hypothesized that restoring host cell metabolism can efficiently reduce viral production. ResultsHere, we present a viral-host Metabolic Modeling (vhMM) method to systematically evaluate the disturbances in host metabolism in viral infection and computationally identify targets for modulation by integrating genome-wide precision metabolic modeling and cheminformatics. We applied vhMM to SARS-CoV-2 infections and identified consistent changes in host metabolism and gene and endogenous metabolite targets between the original SARS-COV-2 and different variants (Alpha, Delta, and Omicron). Among six compounds predicted for repurposing, methotrexate, cinnamaldehyde, and deferiprone were tested in vitro and effective in inhibiting viral production with IC50 less than 4uM. Further, an analysis of real-world patient data showed that cinnamon usage significantly reduced the SARS-CoV-2 infection rate with an odds ratio of 0.65 [95%CI: 0.55[~]0.75]. ConclusionsThese results demonstrated that vhMM is an efficient method for predicting targets and drugs for viral infections.

systems biology↗

bioRxiv2023

Mechanism of ozone alleviation of malignant ascites in hepatocellular carcinoma through inhibition of NETs

Malignant ascites in hepatocellular carcinoma is usually a sign of advanced disease and poor prognosis and is also thought to be associated with chronic inflammation mediated by neutrophil extracellular trap networks (NETs). Whereas ozone, a strong oxidant, has significant antibacterial and anti-inflammatory effects, its effectiveness in treating malignant liver ascites is unclear.cOzone showed significant anti-peritoneal fluid production properties in H22 tumor-bearing mice, and ozone reduced peritoneal fluid production by activating AMPK and up-regulating SR-A phagocytosis damage-associated molecular patterns (DAMPs) to reduce the production of NETs. This suggests that ozone could be used as a new drug for the treatment of malignant ascites in hepatocellular carcinoma.

cancer biology↗

bioRxiv2023

Sex-specific age-related changes in glymphatic function assessed by resting-state functional magnetic resonance imaging

The glymphatic system that clears out brain wastes, such as amyloid-{beta} (A{beta}) and tau, through cerebrospinal fluid (CSF) flow may play an important role in aging and dementias. However, a lack of non-invasive tools to assess the glymphatic function in humans hindered the understanding of the glymphatic changes in healthy aging. The global infra-slow (<0.1 Hz) brain activity measured by the global mean resting-state fMRI signal (gBOLD) was recently found to be coupled by large CSF movements. This coupling has been used to measure the glymphatic process and found to correlate with various pathologies of Alzheimers disease (AD), including A{beta} pathology. Using resting-state fMRI data from a large group of 719 healthy aging participants, we examined the sex-specific changes of the gBOLD-CSF coupling, as a measure of glymphatic function, over a wide age range between 36-100 years old. We found that this coupling index remains stable before around age 55 and then starts to decline afterward, particularly in females. Menopause may contribute to the accelerated decline in females.

neuroscience↗

bioRxiv2022

SARS-CoV-2 Omicron boosting induces de novo B cell response in humans

The primary two-dose SARS-CoV-2 mRNA vaccine series are strongly immunogenic in humans, but the emergence of highly infectious variants necessitated additional doses of these vaccines and the development of new variant-derived ones1-4. SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells (MBCs)5-9. It remains unclear, however, whether the additional doses induce germinal centre (GC) reactions where reengaged B cells can further mature and whether variant-derived vaccines can elicit responses to novel epitopes specific to such variants. Here, we show that boosting with the original SARS- CoV-2 spike vaccine (mRNA-1273) or a B.1.351/B.1.617.2 (Beta/Delta) bivalent vaccine (mRNA-1273.213) induces robust spike-specific GC B cell responses in humans. The GC response persisted for at least eight weeks, leading to significantly more mutated antigen-specific MBC and bone marrow plasma cell compartments. Interrogation of MBC-derived spike-binding monoclonal antibodies (mAbs) isolated from individuals boosted with either mRNA-1273, mRNA-1273.213, or a monovalent Omicron BA.1-based vaccine (mRNA-1273.529) revealed a striking imprinting effect by the primary vaccination series, with all mAbs (n=769) recognizing the original SARS-CoV-2 spike protein. Nonetheless, using a more targeted approach, we isolated mAbs that recognized the spike protein of the SARS-CoV-2 Omicron (BA.1) but not the original SARS-CoV-2 spike from the mRNA-1273.529 boosted individuals. The latter mAbs were less mutated and recognized novel epitopes within the spike protein, suggesting a naive B cell origin. Thus, SARS-CoV-2 boosting in humans induce robust GC B cell responses, and immunization with an antigenically distant spike can overcome the antigenic imprinting by the primary vaccination series.

immunology↗

bioRxiv2022

A new species of Nanhsiungchelys (Testudines: Cryptodira: Nanhsiungchelyidae) from the Upper Cretaceous of Nanxiong Basin, China, and the role of anterolateral processes on the carapace in drag reduction

Nanhsiungchelyidae are a group of large turtles that lived in Asia and North America during the Cretaceous. Here we report a new species of nanhsiungchelyid, Nanhsiungchelys yangi sp. nov., from the Upper Cretaceous of Nanxiong Basin, China. This is the second valid species of Nanhsiungchelys, and the holotype consists of a well-preserved skull and lower jaw, as well as the anterior parts of the carapace and plastron. The diagnostic features of Nanhsiungchelys include a huge estimated body size (~55.5 cm), a special network of sculptures on the surface of the skull and shell, weak cheek emargination and temporal emargination, deep nuchal emargination, and a pair of anterolateral processes on the carapace. However, Nanhsiungchelys yangi differs from the other species of Nanhsiungchelys in having a triangular-shaped snout and wide anterolateral processes. A phylogenetic analysis of nanhsiungchelyids places Nanhsiungchelys yangi and Nanhsiungchelys wuchingensis as sister taxa. Some nanhsiungchelyids bear special anterolateral processes on the carapace, which are unknown in extant turtles. Here we test the function of these processes in Nanhsiungchelys yangi using computational fluid dynamics, and the results suggest these processes could enhance locomotory performance by remarkably reducing drag force when the animal was swimming through water.

paleontology↗

bioRxiv2022

Early β-amyloid accumulation and hypoconnectivity in the default mode network are related to its disengagement from global brain activity

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSImportanceC_ST_ABSThe specific pattern/trajectory of {beta}-amyloid (A{beta}) pathology spreading in Alzheimers disease (AD), from default mode network (DMN) regions to sensory-motor areas, is well known, but poorly understood. ObjectiveTo determine if resting-state global brain activity is linked to early A{beta} deposition in the DMN. DesignThis is a retrospect analysis of multi-modal and longitudinal data from the Alzheimers disease Neuroimaging Initiative (ADNI) cohort. SettingThe ADNI was a multicenter project involving 63 research centers. ParticipantsThe study included 144 participants (72.6 {+/-} 7.5 years; 73 females) of whom 28 were controls, 21 had significant memory concerns, 72 had cognitive impairment (N=72), and 23 had AD. There were both baseline and 2-year follow-up data for A{beta}-PET for 112 of the subjects. They were classified into following stages based on the CSF A{beta}42 (CSF+: <192 ng/L) and cortical A{beta} (PET+: >0.872 SUVR) levels: non-A{beta}-accumulators (CSF-/PET-); early-A{beta}-accumulators (CSF+/PET-); and late-A{beta}-accumulators (CSF+/PET+). ExposureResting-state brain activity was assessed by functional magnetic resonance imaging (rsfMRI), whereas glymphatic function was estimated by the coupling between fMRI blood-oxygen-level-dependent (BOLD) signals and CSF movements. Main Outcomes and MeasuresCortical A{beta} accumulation measured by 18F-AV45 amyloid-positron emission tomography (PET), CSF A{beta}42, and total and phosphorylated tau protein levels in all participants. ResultsGlymphatic function assessed by fMRI was strongly ({rho} > 0.43, P < 0.042) associated with various markers of protein aggregation in early A{beta} accumulators in whom A{beta} just begins to accumulate cortically in the DMN. Among these early accumulators, the preferential A{beta} accumulation in the DMN regions in the subsequent two years was correlated with lower gBOLD signal ({rho} = 0.51, P = 0.027) and lower local glymphatic function ({rho} = 0.48, P = 0.041) in the same regions at baseline. Conclusions and RelevanceResting-state global brain activity and related glymphatic function are linked to A{beta} pathology, particularly its preferential deposition in the DMN at the earliest AD stages. This suggests potential novel early therapeutic directions that might provide disease modification. KO_SCPLOWEYC_SCPLOW PO_SCPLOWOINTSC_SCPLOWO_ST_ABSQuestionC_ST_ABSWhy does the {beta}-amyloid (A{beta}) plaque deposit preferentially in the default mode network (DMN) regions at early preclinical stages of Alzheimers disease? FindingsIn this analytic observational cohort study with 144 subjects, we found that the preferential reduction of global resting-state brain activity in the DMN, as well as its coupling with cerebrospinal fluid movement, was significantly correlated with the preferential A{beta} accumulation in these DMN regions among 19 subjects with early A{beta} accumulation. MeaningResting-state global brain activity plays a role in the early A{beta} accumulation in the DMN, presumably due to its involvement in glymphatic clearance.

neuroscience↗

bioRxiv2022

Shell Microelectrode Arrays (MEAs) for brain organoids

Brain organoids are important models for mimicking some three-dimensional (3D) cytoarchitectural and functional aspects of the brain. Multielectrode arrays (MEAs) that enable recording and stimulation of activity from electrogenic cells are widely utilized in biomedical engineering. However, conventional MEAs, initially designed for monolayer cultures, offer limited recording contact area restricted to the bottom of the 3D organoids. Inspired by the shape of electroencephalography (EEG) caps, we developed miniaturized chip-integrated MEA caps for organoids. The optically transparent shells are composed of self-folding polymer leaflets with conductive polymer-coated metal electrodes. Tunable folding of the minicaps polymer leaflets guided by mechanics simulations enables versatile recording from organoids of different sizes and we validate the feasibility of electrophysiology recording from 400-600 {micro}m sized organoids for up to four weeks and in response to glutamate stimulation. Our studies suggest that 3D shell MEAs offer significant potential for high signal-to-noise and 3D spatiotemporal brain organoid recording.

bioengineering↗

bioRxiv2022

The specific roles of renal macrophages in monitoring and clearing off intratubular particles

During the filtrate of the glomerulus flows though the renal tubular system, a variety of microscopic sediment particles, including mineral crystals resulting from urine concentration, are generated. Dislodging these particles in the intratubular compartment is critical to ensure free flow of filtrate and the final formation of urine. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we uncovered that the juxtatubular macrophages in the medulla constitutively formed transepithelial protrusions and were "sampling" urine contents. These behaviors were strengthened in the development of nephrolithiasis. In particular, the juxtatubular macrophages were efficient in sequestering and phagocytosing intraluminal sediment particles, and occasionally making transmigration to the tubule lumen to escort the excretion of urine particles. Specific depletion of renal macrophages precipitated kidney stone formation and aggravated the accompanied inflammation upon hyperoxaluria challenge. Thus, renal macrophages undertake a specific role in maintaining the tubular system unobstructed.

immunology↗

bioRxiv2022

Characteristics of N6-methyladenosine modification during sexual reproduction of Chlamydomonas reinhardtii

The unicellular green alga Chlamydomonas reinhardtii (referred to as Chlamydomonas throughout) is an ideal model organism which possesses both plant and animal attribute for studying the fundamental processes such as photosynthesis, sexual reproduction and life cycle etc. N6-methyladenosine (m6A) is the most prevalent mRNA modification and plays important roles during sexual reproduction in animals and plants. However, the pattern and function of m6A modification during Chlamydomonas sexual reproduction is still unknown. Here, we performed transcriptome and MeRIP sequencing on the six samples from different stages during sexual reproduction of Chlamydomonas life cycle. The results showed that m6A occurs widely at the main motif of UGKAM (K= U/G, M= A/C) in Chlamydomonas mRNA. Moreover, m6A peak in Chlamydomonas mRNA is mainly enriched in the 3UTR region and negatively correlated with the abundance of the transcripts at each stage. Especially, genes in microtubule-associated pathway showed a significant negative correlation between gene expression level and m6A level, indicating the influences of m6A modification on sexual reproduction and life cycle of Chlamydomonas through regulating microtubule-based movement. In summary, our findings first demonstrate the distributions and the functions of m6A modification in Chlamydomonas and provide new insights into the understandings of m6A modification in the process of sexual reproduction in other plant organisms evolutionarily.

plant biology↗

bioRxiv2022

An orderly sequence of autonomic and neural events at transient arousal changes

Resting-state functional magnetic resonance imaging (rsfMRI) allows the study of functional brain connectivity based on spatially structured variations in neuronal activity. Proper evaluation of connectivity requires removal of non-neural contributions to the fMRI signal, in particular hemodynamic changes associated with autonomic variability. Regression analysis based on autonomic indicator signals has been used for this purpose, but may be inadequate if neuronal and autonomic activity covary. To investigate this potential co-variation, we performed rsfMRI experiments while concurrently acquiring electroencephalography and autonomic indicator signals, including heart rate, respiratory depth, and peripheral vascular tone. We identified a recurrent and systematic pattern of fMRI, EEG, and autonomic changes coincidental with intermittent arousal, suggesting arousal modulation. The temporal relationship between the various signals indicated combined neural and autonomic contribution to the fMRI signal, both of which involve widespread brain areas. The fMRI changes included brief signal reductions in salience and default-mode networks, and the thalamus, followed by a biphasic global change. These results suggest that proper measurement of functional connectivity with fMRI requires accounting for the full spectrum of autonomic and neural changes, as well as their co-variation during arousal state transitions.

neuroscience↗

bioRxiv2022

Computed tomographic analysis of the dental system of three Jurassic ceratopsians: implications for the evolution of the tooth replacement pattern and diet in early-diverging ceratopsians

The dental system of ceratopsids is among the most specialized structure in Dinosauria, and includes high angled wear surfaces, split tooth roots, and multiple teeth in each tooth family. However, the early evolution of this unique dental system is generally poorly understood due to a lack of knowledge of the dental morphology and development in early-diverging ceratopsians. Here we study the dental system of three of the earliest-diverging Chinese ceratopsians: Yinlong and Hualianceratops from the early Late Jurassic of Xinjiang, and Chaoyangsaurus from the Late Jurassic of Liaoning. By using micro-computed tomographic analyses, our study has revealed significant new information regarding the dental system of these early ceratopsians, including no more than five replacement teeth in each jaw quadrant; at most one generation of replacement teeth in each alveolus; nearly full resorption of the functional tooth root during tooth replacement; and occlusion with low-angled, concave wear facets that differs significantly from the shearing occlusal system seen in ceratopsids. Yinlong displays an increase in the number of maxillary tooth alveoli and a decrease in the number of replacement teeth during ontogeny as well as the retention of remnants of functional teeth in the largest individual. Early-diverging ceratopsians thus display a relatively slow tooth replacement rate compared to late-diverging ceratopsians. Combined with paleobotany and palaeoenvironment data, Yinlong likely uses gastroliths to triturate foodstuffs, and the difference in diet strategy might have influenced the pattern of tooth replacement in later-diverging ceratopsians.

paleontology↗

bioRxiv2021

Intranasal administration of a monoclonal neutralizing antibody protects mice against SARS-CoV-2 infection

Despite recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both, prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2 and retains activity against the variants of concern B.1.1.7 and B.1.351. Importantly, not only systemic but also intranasal application of DZIF-10c abolished presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies. Significance StatementMonoclonal neutralizing antibodies are important in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection. However, their intravenous application might lead to suboptimal bioavailability in the lung. We here precisely characterize a new monoclonal neutralizing antibody (DZIF-10c) that binds to the receptor binding domain of the spike protein of SARS-CoV-2. DZIF-10c neutralizes SARS-CoV-2 with exceptionally high potency and maintains activity against circulating variants of concern. The antibody has a favorable pharmacokinetic profile and protects mice from SARS-CoV-2 infection. Importantly, we show that intranasal administration of DZIF-10c generates protective efficacy. These results not only identify DZIF-10c as a novel highly potent neutralizing antibody, but further pave the way for a topical application of anti-SARS-CoV-2 antibodies.

microbiology↗

bioRxiv2021

Individual Level Differential Expression Analysis for Single Cell RNA-seq data

Bulk RNA-seq data quantify the expression of a gene in an individual by one number (e.g., fragment count). In contrast, single cell RNA-seq (scRNA-seq) data provide much richer information: the distribution of gene expression across many cells. To assess differential expression across individuals using scRNA-seq data, a straightforward solution is to create "pseudo" bulk RNA-seq data by adding up the fragment counts of a gene across cells for each individual, and then apply methods designed for differential expression using bulk RNA-seq data. This pseudo-bulk solution reduces the distribution of gene expression across cells to a single number and thus loses a good amount of information. We propose to assess differential expression using the gene expression distribution measured by cell level data. We find denoising cell level data can substantially improve the power of this approach. We apply our method, named IDEAS (Individual level Differential Expression Analysis for scRNA-seq), to study the gene expression difference between autism subjects and controls. We find neurogranin-expressing neurons harbor a high proportion of differentially expressed genes, and ERBB signals in microglia are associated with autism.

bioinformatics↗

bioRxiv2021

Alien chromatin but not Fhb7 confers Fusarium head blight resistance in wheat breeding

The lack of resistance resources is a major bottleneck for wheat Fusarium head blight (FHB) resistance breeding. Three wheat-Th. elongatum FHB resistant translocation lines have been developed and used for wheat breeding without yield penalty. Transcriptomic analysis identified a derivative glutathione S-transferase transcript T26102, which was homologous to Fhb7 and induced dramatically by Fusarium graminearum. Unlike other studies, Fhb7 homologs were detected not only in Thinopyrum but also in Elymus, Leymus, Pseudoroegeria and Roegeria. We also found that several wheat-Th. ponticum derivatives carrying Fhb7 and its homologs were highly susceptible to FHB. Moreover, the transgenic plants expressing Fhb7 and its homolog on different backgrounds did not improve the FHB resistance. One Sentence SummaryThe GST-encoding Fhb7 candidate cannot improve Fusarium head blight resistance in wheat breeding.

genetics↗

bioRxiv2021

Decoupling of global brain activity and cerebrospinal fluid flow in Parkinson's cognitive decline

BackgroundDeposition and spreading of misfolded proteins (-synuclein and tau) have been linked to Parkinsons cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow that may reflect glymphatic function. ObjectiveTo determine if the decoupling of brain activity-CSF flow is linked to Parkinsons cognitive dysfunction. MethodsFunctional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment, MoCA) scores were collected from 60 Parkinsons and 58 control subjects. Parkinsons patients were subgrouped into those with (MoCA < 26; N = 29) and without (MoCA [≥] 26; N = 31) mild cognitive impairment (MCI). The coupling strength between the resting-state global blood-oxygen-level-dependent signal (gBOLD) and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. ResultsgBOLD-CSF coupling decreased significantly (p < 0.006) in Parkinsons patients showing MCI, compared to those without MCI and controls. Reduced gBOLD-CSF coupling was associated with decreased MoCA scores that was present in Parkinsons patients (p = 0.005) but not in controls (p = 0.65). Weaker gBOLD-CSF coupling in Parkinsons patients also was associated with a thinner right entorhinal cortex (Spearmans correlation = - 0.36; p = 0.012), an early structural change often seen in Alzheimers. ConclusionsThe decoupling between global brain activity and associated CSF flow is related to Parkinsons cognitive impairment.

neuroscience↗

bioRxiv2020

Reduction of neuronal activity mediated by blood-vessel regression in the brain

The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we reported that a substantial proportion of blood vessels in the adult brain sporadically occluded and regressed. Their regression proceeded through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels were found to be widespread in mouse, monkey and human brains. Both brief occlusions of the middle cerebral artery and lipopolysaccharide-mediated inflammation induced an increase of vessel regression. Blockage of leukocyte adhesion to endothelial cells alleviated LPS-induced vessel regression. We further revealed that blood vessel regression caused a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.

neuroscience↗

bioRxiv2020

Brain activity fluctuations propagate as waves traversing the cortical hierarchy

The brain exhibits highly organized patterns of spontaneous activity as measured by resting-state fMRI fluctuations that are being widely used to assess the brains functional connectivity. Some evidence suggests that spatiotemporally coherent waves are a core feature of spontaneous activity that shapes functional connectivity, though this has been difficult to establish using fMRI given the temporal constraints of the hemodynamic signal. Here we investigated the structure of spontaneous waves in human fMRI and monkey electrocorticography. In both species, we found clear, repeatable, and directionally constrained activity waves coursed along a spatial axis approximately representing cortical hierarchical organization. These cortical propagations were closely associated with activity changes in distinct subcortical structures, particularly those related to arousal regulation, and modulated across different states of vigilance. The findings demonstrate a neural origin of spatiotemporal fMRI wave propagation at rest and link it to the principal gradient of resting-state fMRI connectivity.

neuroscience↗

bioRxiv2020

The genetic architecture underlying ecological adaptation in Atlantic herring is not consistent with the infinitesimal model

Atlantic herring is widespread in North Atlantic and adjacent waters and is one of the most abundant vertebrates on earth. This species is well suited to explore genetic adaptation due to minute genetic differentiation at selectively neutral loci. Here we report hundreds of loci underlying ecological adaptation to different geographic areas and spawning conditions. Four of these represent megabase inversions confirmed by long read sequencing. The genetic architecture underlying ecological adaptation in the herring is in conflict with the infinitesimal model for complex traits because of the large shifts in allele frequencies at hundreds of loci under selection.

evolutionary biology↗