Biology subjects

Duan, W.

Publications and source records attributed to Duan, W..

31 records · Page 2Linked to original sources

bioRxiv2023

A resource for probing influences of perinatal factors on neurodevelopment in 3-10-years-old Chinese children

Adverse perinatal factors can disrupt the normal development of the brain, with potential long-term impacts on childrens overall development. Currently, the neuropathological mechanisms by which these factors lead to various neurodevelopmental disorders (NDDs) remain largely unknown. An open resource that integrate perinatal factors with brain and mental health development is essential for investigating NDD-related aetiology. In this Data Descriptor, we introduce a multicentre database containing information on perinatal factors that influence childrens brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors associated with a high incidence of NDDs at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development among children aged 3-10 years are associated with perinatal factors. Ultimately, our goal was to develop an early prediction and screening model for NDDs that leverages normative data to facilitate NDD aetiology research. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD and present preliminary brain-mind associations.

neuroscience↗

bioRxiv2023

Distinct Microstructural Heterogeneities Underpin Specific Micromechanical Properties in Human ACL Femoral and Tibial Entheses

The anterior cruciate ligament (ACL) is anchored to the femur and tibia by a specialized interface tissue called the enthesis, which transfers forces in multiple directions and magnitudes without accruing fatigue damage during loading cycles over a lifetime. However, the precise structural and mechanical characteristics of the ACL femoral enthesis (FE) and tibial enthesis (TE) and their intricate interplay are unknown. In this study, we identified two ultrathin-graded mineralization regions in the FE ([~]21 m) and TE ([~]14 m), both of which exhibited distinct biomolecular compositions and mineral assembly patterns. FE interface exhibited progressively maturing hydroxyapatites (HAps), whereas minerals at the TE interface region changed from an amorphous phase (ACP) to HAps with increasing crystallinity. The LC-MS/MS results revealed that MGP protein uniquely enriched at the TE interface may be favorable for stabilizing ACP, while CLEC11A enriched at the FE interface could facilitate osteogenesis of the interface. The finite element analysis results indicated that the FE model was more resistant to shearing, while the TE model facilitated tensile resistance. It suggested that the great discrepancy in biomolecular expression and the corresponding mineral assembling heterogeneities together contributed to the superior mechanical properties of both the FE and TE models. These findings provide new perspectives regarding the management of ACL injury and the development of high-performance interface materials.

bioengineering↗

bioRxiv2023

Interrogation of dynamic glucose-enhanced MRI and fluorescence-based imaging reveals a perturbed glymphatic network in Huntington disease

Huntingtons disease (HD) is a neurodegenerative disorder that presents with progressive motor, mental, and cognitive impairment leading to early disability and mortality. The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of HD. The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance including abnormal proteins from mammalian brains. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to assess CSF clearance capacity to predict glymphatic function in a mouse model of HD. Our results demonstrate significantly diminished CSF clearance efficiency in premanifest zQ175 HD mice. The impairment of CSF clearance of D-glucose, measured by DGE MRI, worsened with disease progression. These DGE MRI findings in compromised glymphatic function in HD mice were further confirmed with fluorescence-based imaging of glymphatic CSF tracer influx, suggesting an impaired glymphatic function in premanifest stage of HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain as well as postmortem human HD brain. Our data, acquired using a clinically translatable MRI approach, indicate a perturbed glymphatic network in the HD brain as early as in the premanifest stage. Further validation of these findings in clinical studies should provide insights into potential of glymphatic clearance as a HD biomarker and for glymphatic functioning as a disease-modifying therapeutic target for HD.

neuroscience↗

bioRxiv2022

Induction of Autophagy Prevents Mutant SOD1G93A Related Neurotoxicity in Experimental Models of Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting from the progressive loss of both upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord. Currently, there are only two drugs, Riluzole (Rilutek) and Edaravone (Radicava), approved by FDA for ALS treatment. These two drugs are very expensive with only a few months of life extension. So far, there is no cure for ALS. Aberrant protein aggregation in motor neurons is an intracellular hallmark of ALS. The disturbance in protein homeostasis may contribute to the onset and progression of ALS. Autophagy plays an important role in degrading misfolded proteins, thereby preventing their aggregation. Pharmacological manipulation of autophagy has been proposed as a new therapeutic approach for treating ALS. IADB, a novel indole alkaloid derivative, has been reported to exert mitochondrial protection and cardioprotection through its autophagy-modulating potential. Our present study attempted to examine whether IADB has therapeutic potential in SOD1G93A-associated experimental models of ALS. We found that IADB could promote the clearance of SOD1G93A aggregates and reduce the overproduction of mitochondrial reactive oxygen species (mtROS) in motor neuron-like NSC-34 cells transfected with SOD1G93A. We further examined the IADB in a SOD1-G93A mouse model of ALS. Administration of IADB started at the age of 55 days until the end stage of the disease. IADB treatment significantly increased LC3-II levels and decreased human SOD1 levels and p62 expression in the spinal cords of SOD1G93A mice, suggesting that IADB treatment could induce autophagy activation and promote clearance of mutant SOD1 aggregates in this mouse model of ALS. Moreover, IADB treatment could alleviate the activation of microglia and astrocytes and reduce mitochondrial oxidative damage in the spinal cord of SOD1G93A mice. Finally, we demonstrated that IADB treatment could improve motor performance and delay the onset and progression of the disease in a mouse model of ALS. The neuroprotective effects of IADB may mainly originate from its autophagy-promoting property.

neuroscience↗

bioRxiv2022

RNA-Targeting CRISPR/Cas13d System Eliminates Disease-Related Phenotypes in Pre-clinical Models of Huntington's Disease.

Huntingtons disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Although the pathogenesis of HD remains complex, the CAG-expanded (CAGEX) HTT mRNA and protein ultimately causes disease through a toxic gain-of-function mechanism. As the reduction of pathogenic mutant HTT mRNA is beneficial as a treatment, we developed a CAGEX RNA-eliminating CRISPR-Cas13d system (Cas13d/CAGEX) that binds and eliminates toxic CAGEX RNA in HD patient iPSC-derived striatal neurons. We show that intrastriatal delivery of Cas13d/CAGEX via a single adeno-associated viral vector, serotype 9 (AAV9) mediates significant and selective reduction of mutant HTT mRNA and protein levels within the striatum of heterozygous zQ175 mice, an established mouse model of HD. Moreover, the reduction of mutant HTT mRNA renders a sustained reversal of HD phenotypes, including improved motor coordination, attenuated striatal atrophy, and reduction of mutant HTT protein aggregates. Importantly, phenotypic improvements were durable for at least 8 months without gross or behavioral adverse effects, and with minimal off-target interactions of Cas13d/CAGEX in the mouse transcriptome. Taken together, we demonstrate a proof-of-principle of an RNA-targeting CRISPR/Cas13d system as a therapeutic approach for HD, a strategy with broad implications for the treatment of other dominantly inherited neurodegenerative disorders.

neuroscience↗

bioRxiv2021

High Resolution Nanostructure with Two-stages of Exponential Energy Dissipation at the Ultrathin Osteochondral Interface Tissue of Human Knee Joint

Cartilage adheres to subchondral bone via a specific osteochondral interface tissue where forces are transferred from soft cartilage to hard bone without fatigue damage over a lifetime of load cycles. However, the fine structure and mechanical properties of osteochondral interface tissue remain unclear. Here, we identified an ultrathin [~]20-30 m calcified region with two-layered micro-nano structures of osteochondral interface tissue in human knee joint, which exhibited characteristic biomolecular compositions and complex nanocrystals assembly. Within this region, an exponential increase of modulus (3 orders of magnitude) was conducive to the force transmission which was verified by finite element simulations. The nanoscale heterogeneity of hydroxyapatite, along with enrichment of elastic-responsive protein-titin which is usually present in muscle, endowed the osteochondral tissue with excellent energy dissipation and fatigue resistance properties. Our results provide potential design for high-performance interface materials for osteochondral interface regeneration and functional coatings.

bioengineering↗

bioRxiv2021

A novel and accurate full-length HTT mouse model for Huntington's disease

Here we report the generation and characterization of a novel Huntingtons disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with [~]226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like mood and cognitive phenotypes at 2 months. From 3-4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibit neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers and testing gene-targeting therapeutic approaches for HD.

neuroscience↗

bioRxiv2020

HTT silencing delays onset and slows progression of Huntington disease like phenotype: Monitoring with a novel neurovascular biomarker

Huntingtons disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene, coding for pathologic mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic etiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest HD stage, when clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of manifest HD it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we have been developing more sensitive biomarkers such as functional neuroimaging with the goal of identifying noninvasive biomarkers that provide insight into the best time to introduce HTT-lowering treatment. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI technique in an HD mouse model. Significantly elevated CBVa was evident in premanifest zQ175 HD mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest HD. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study showed the potential of CBVa as a noninvasive fMRI biomarker for premanifest HD clinical trials and demonstrates long-term benefits of introducing an HTT lowering treatment in the premanifest HD.

neuroscience↗

bioRxiv2020

A valid protective immune response elicited in rhesus macaques by an inactivated vaccine is capable of defending against SARS-CoV-2 infection

With the relatively serious global epidemic outbreak of SARS-CoV-2 infection, public concerns focus on not only clinical therapeutic measures and public quarantine for this disease but also the development of vaccines. The technical design of our SARS-CoV-2 inactivated vaccine provides a viral antigen that enables the exposure of more than one structural protein based upon the antibody composition of COVID-19 patients convalescent serum. This design led to valid immunity with increasing neutralizing antibody titers and a CTL response detected post-immunization of this vaccine by two injections in rhesus macaques. Further, this elicited immunoprotection in macaques enables not only to restrain completely viral replication in tissues of immunized animals, compared to the adjuvant control and those immunized by an RBD peptide vaccine, but also to significantly alleviate inflammatory lesion in lung tissues in histo-pathologic detection, compared to the adjuvant control with developed interstitial pneumonia. The data obtained from these macaques immunized with the inactivated vaccine or RBD peptide vaccine suggest that immunity with a clinically protective effect against SARS-CoV-2 infection should include not only specific neutralizing antibodies but also specific CTL responses against at least the S and N antigens.

immunology↗

bioRxiv2019

The Influence of Blood Collection Tubes in Biomarkers Screening by Mass Spectrometry

BackgroundMass spectrometry (MS) is one of the rapidly developing bio-analytical techniques in recent years and have found many biomarkers of variety of disease. Whereas pre-analytical process is one of most crucial procedure which would significantly influence the results of biomarkers screening. In the current study, we conducted a pilot analysis of serum to determine the effects of blood collection tubes in biomarkers screening.\n\nMethodsMagnetic bead separation and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for qualitative analysis of healthy control and serum cancer patients. A total of 24 serum samples were analyzed in this study, of which were collected from patients or healthy control using non-additive tubes or coagulant activator tubes respectively. ClinProTools were used to compare the difference among the different groups.\n\nResultsThe results demonstrated that no matter for patients or normal people, the serum protein profile changed significantly when using coagulant tubes. We also found that the effect of coagulant on serum protein of patients was smaller than that of control group. There were significant differences among 27 peaks which were obtained in the control group and the control coagulant group. However, between patient group and patient coagulant group, only 1 differential peak were obtained. Coagulant changed the protein expression difference in the original serum, and the difference expanded, narrowed even reversed, most of which are small polypeptides (Mass<3000 Da), which significantly changed the results of biomarkers screening. The results showed that 19 potential biomarkers could be found with non-additive tubes and 16 potential biomarkers could be found with coagulate activator tubes, among which only 6 were the same.\n\nConclusionsThe choice of blood collection tube significantly influence the results of biomarkers screening by MS.

cancer biology↗

bioRxiv2019

Performance of bitumen coating sheet using biomass pyrolysis oil

The \"green\" production of bitumen has raised increasing interest in recent years to reduce the environmental, energy and petro-based concerns. Bio-oil, prepared by biomass pyrolysis, can be used as substitute for petro-based bitumen in bitumen or bitumen-based coatings, for its similar properties of good adhesion and anti-corrosion characteristics. Although biomass is a renewable and widespread chemicals resource, its value-added utilization is still difficult. Several studies have qualitatively demonstrated the use of bio-bitumen in practical applications. The present study investigates the effects and properties and the incorporation of bio-bitumen shown to improve the performance of traditional petro-bitumen to some extent. Bio-bitumen was prepared from biomass pyrolysis oil and applied to self-adhesive and doped hot-melt sheets. Resulting physical properties demonstrate that bio-bitumen is a potential substitute in bitumen coating sheet.\n\nIMPLICATIONSThis paper is intended to verify the effect of pyrolyzed bio-oil from wheat straw on the performance of bitumen, as well as the feasibility of application in the coating sheet. Up to now, the research on bio-bitumen is mainly in pavement bitumen. In the present research, bio-bitumen was applied to the coating sheet in different proportions. Interestingly, the prepared coating sheet exhibited higher adhesion. Other performances, such as temperature stability, mechanical strength and temperature flexibility of coating sheet showed improvement in the presence of bio- oil, which indicated the suitability of bio-oil in coating sheet bitumen.

bioengineering↗

bioRxiv2018

Using composite phenotypes to reveal heterogeneity and model SpO2 of altitude acclimatization

Altitude acclimatization is the physiological process of the human body adjusting to the decreased availability of oxygen. Since several physiological processes are involved and the relation among them is complicated, analyses of single-traits is insufficient in revealing the complex mechanism of altitude acclimatization. In this study, we examined whether these physiological responses could be studied as composite phenotypes which are represented by a linear combination of physiological traits. We developed a strategy which combines both spectral clustering and PLSPM to define composite phenotypes. We captured 14 composite phenotypes from 28 physiological traits of altitude acclimatization. Using these composite phenotypes, we applied k-means to reveal hidden physiological heterogeneity in altitude acclimatization. Furthermore, we employed linear regression to systematically model oxygen saturation (SpO2) changes in altitude acclimatization and evaluated the model fitness performance. And composite phenotypes based Model 2 has better fitness than single-traits based Model 1 in all measurement indices. Therefore, this new strategy of defining and applying composite phenotypes can be considered as a general strategy of complex traits.

systems biology↗

bioRxiv2017

Predicting DNA Hybridization Kinetics from Sequence

Hybridization is a key molecular process in biology and biotechnology, but to date there is no predictive model for accurately determining hybridization rate constants based on sequence information. To approach this problem systematically, we first performed 210 fluorescence kinetics experiments to observe the hybridization kinetics of 100 different DNA target and probe pairs (subsequences of the CYCS and VEGF genes) at temperatures ranging from 28 {degrees}C to 55 {degrees}C. Next, we rationally designed 38 features computable based on sequence, each feature individually correlated with hybridization kinetics. These features are used in our implementation of a weighted neighbor voting (WNV) algorithm, in which the hybridization rate constant of an unknown sequence is predicted based on similarity reactions with known rate constants (a.k.a. labeled instances). Automated feature selection and weighting optimization resulted in a final 6-feature WNV model, which can predict hybridization rate constants of new sequences to within a factor of 2 with {approx}74% accuracy and within a factor of 3 with {approx}92% accuracy, based on leave-one-out cross-validation. Predictive understanding of hybridization kinetics allows more efficient design of nucleic acid probes, for example in allowing sparse hybrid-capture panels to more quickly and economically enrich desired regions from genomic DNA.

biophysics↗