Biology subjects

Huang, C.-C.

Publications and source records attributed to Huang, C.-C..

30 records · Page 2Linked to original sources

bioRxiv2020

Zinc oxide nanoparticles modulate the gene expression of ZnT1 and ZIP8 to manipulate zinc homeostasis and stress-induced cytotoxicity in human neuroblastoma SH-SY5Y cells

Zinc ions (Zn2+) are important messenger molecules involved in various physiological functions. To maintain the homeostasis of cytosolic Zn2+ concentration ([Zn2+]c), Zrt/Irt-related proteins (ZIPs) and Zn2+ transporters (ZnTs) are the two families of proteins responsible for decreasing and increasing the [Zn2+]c, respectively, by fluxing Zn2+ across the membranes of the cell and intracellular compartments in opposite directions. Most studies focus on the cytotoxicity incurred by a high concentration of [Zn2+]c and less investigate the [Zn2+]c at physiological levels. Zinc oxide-nanoparticle (ZnO-NP) is blood brain barrier-permeable and elevates the [Zn2+]c to different levels according to the concentrations of ZnO-NP applied. In this study, we mildly elevated the [Zn2+]c by zinc oxide-nanoparticles (ZnO-NP) at concentrations below 1 g/ml, which had little cytotoxicity, in cultured human neuroblastoma SH-SY5Y cells and characterized the importance of Zn2+ transporters in 6-hydroxy dopamine (6-OHDA)-induced cell death. The results show that ZnO-NP at low concentrations elevated the [Zn2+]c transiently in 6 hr, then declined gradually to a basal level in 24 hr. Knocking down the expression levels of ZnT1 (mostly at the plasma membrane) and ZIP8 (present in endosomes and lysosomes) increased and decreased the ZnO-NP-induced elevation of [Zn2+]c, respectively. ZnO-NP treatment reduced the basal levels of reactive oxygen species and Bax/Bcl-2 mRNA ratios; in addition, ZnO-NP decreased the 6-OHDA-induced ROS production, p53 expression, and cell death. Therefore, mild elevations in [Zn2+]c induced by ZnO-NP activate beneficial effects in reducing the 6-OHDA-induced cytotoxic effects. Therefore, brain-delivery of ZnO-NP can be regarded as a potential therapy for neurological disease.

neuroscience↗

bioRxiv2020

An aptamer-based magnetic flow cytometer using matched filtering

Facing unprecedented population-ageing, the management of noncommunicable diseases (NCDs) urgently needs a point-of-care (PoC) testing infrastructure. Magnetic flow cytometers are one such solution for rapid cancer cellular detection in a PoC setting. In this work, we report a giant magnetoresistive spin-valve (GMR SV) biosensor array with a multi-stripe sensor geometry and matched filtering to improve detection accuracy without compromising throughput. The carefully designed sensor geometry generates a characteristic signature when cells labeled with magnetic nanoparticles (MNPs) pass by thus enabling multi-parametric measurement like optical flow cytometers (FCMs). Enumeration and multi-parametric information were successfully measured across two decades of throughput. 10-{micro}m polymer microspheres were used as a biomimetic model where MNPs and MNP-decorated polymer conjugates were flown over the GMR SV sensor array and detected with a signal-to-noise ratio (SNR) as low as 2.5 dB due to the processing gain afforded by the matched filtering. The performance was compared against optical observation, exhibiting a 92% detection efficiency. The system achieved a 95% counting accuracy for biomimetic models and 98% for aptamer-based pancreatic cancer cell detection. This system demonstrates the ability to perform reliable PoC diagnostics towards the benefit for NCD control plans.

bioengineering↗

bioRxiv2020

Predicting molecular subtypes of breast cancer using pathological images by deep convolutional neural network from public dataset

Breast cancer is a heterogeneously complex disease. A number of molecular subtypes with distinct biological features lead to different treatment responses and clinical outcomes. Traditionally, breast cancer is classified into subtypes based on gene expression profiles; these subtypes include luminal A, luminal B, basal like, HER2-enriched, and normal-like breast cancer. This molecular taxonomy, however, could only be appraised through transcriptome analyses. Our study applies deep convolutional neural networks and transfer learning from three pre-trained models, namely ResNet50, InceptionV3 and VGG16, for classifying molecular subtypes of breast cancer using TCGA-BRCA dataset. We used 20 whole slide pathological images for each breast cancer subtype. The results showed that our scale training reached about 78% of accuracy for validation. This outcomes suggested that classification of molecular subtypes of breast cancer by pathological images are feasible and could provide reliable results

bioinformatics↗

bioRxiv2019

Cerebellar-recipient motor thalamus drives behavioral context-specific movement initiation

To initiate goal-directed behavior, animals must transform sensory cues into motor commands that generate appropriately timed actions. Sensorimotor transformations along the cerebellar-thalamocortical pathway are thought to shape motor cortical output and movement timing, but whether this pathway initiates goal-directed movement remains poorly understood. Here, we recorded and perturbed activity in cerebellar-recipient regions of motor thalamus (dentate / interpositus nucleus-recipient regions, MThDN/IPN) and primary motor cortex (M1) in mice trained to execute a cued forelimb lever push task for reward. MThDN/IPN population responses were dominated by a time-locked increase in activity immediately prior to movement that was temporally uncoupled from cue presentation, providing a fixed latency feedforward motor timing signal to M1FL. Blocking MThDN/IPN output suppressed cued movement initiation. Stimulating the MThDN/IPN thalamocortical pathway in the absence of the cue recapitulated cue-evoked M1 membrane potential dynamics and forelimb behavior in the learned behavioral context, but generated semi-random movements in an altered behavioral context. Thus, cerebellar-recipient motor thalamocortical input to M1 is indispensable for the generation of motor commands that initiate goal-directed movement, refining our understanding of how the cerebellar-thalamocortical pathway contributes to movement timing.

neuroscience↗

bioRxiv2018

Isoniazid preventive therapy protects against tuberculosis among household contacts of isoniazid-resistant patients.

BackgroundThe World Health Organization recommends the use of isoniazid (INH) alone or combination INH and rifapentine therapy to treat latent tuberculosis infection (LTBI) in groups at high risk of tuberculosis (TB) progression. The recent rise of INH- and multi-drug resistant (MDR) TB has complicated the choice of LTBI treatment regimen. We examine the risk of TB disease among household contacts (HHCs) who received INH after being exposed to patients with drug-sensitive, INH-resistant, or MDR tuberculosis. MethodsIn this prospective cohort study conducted Between September 2009 and August 2012 in Lima, Peru, we identified 4,500 index TB patients and measured incident TB disease in their 14,044 HHCs over a one-year follow-up period. HHCs under 19 years of age were offered INH preventive therapy (IPT). We used a Cox frailty proportional hazards model to evaluate whether the effect of IPT on incident TB disease varied by the resistance profile of the index case. We repeated the analyses in a second independent dataset. FindingsAmong 4,216 HHCs under 19 years of age, 2,106 (50%) initiated IPT at enrolment. The protective effect of INH was more extreme in HHCs exposed to drug-sensitive (Hazard Ratio [95% confidence interval]=0{middle dot}2[0{middle dot}20-0{middle dot}50]) and to MDR-TB (0{middle dot}26[0{middle dot}08-0{middle dot}77]) compared to those exposed to mono-INH-resistant (0{middle dot}80[0{middle dot}23 to 2{middle dot}79]). Among those who received at least three months of INH, effectiveness increased across all three groups (INH-sensitive:0{middle dot}20 [0{middle dot}10 to 040]; MDR:0{middle dot}16 [0 02-127]; mono-INH-resistant:0{middle dot}72 [0{middle dot}16-3{middle dot}16]). In the second independent study, TB occurred in none of the 76 HHCs who received IPT compared to 3% (8/273) of those who did not. InterpretationWe found that IPT use is associated with reduced incidence of TB disease among contacts of MDR-TB patients. This finding suggests that INH may have role in the management of MDR-LTBI. FundingNational Institutes of Health and the National Institute of Allergy and Infectious Diseases CETR (U19AI109755) and TBRU (U19AI111224)

epidemiology↗

bioRxiv2018

Vitamin D status and risk of incident tuberculosis disease: a systematic review and individual participant data meta-analysis

BackgroundFew studies have evaluated the association between pre-existing vitamin D deficiency (VDD) and incident TB. We assessed the impact of baseline vitamin D on TB risk. MethodsWe assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6751 household contacts of TB patients in Peru. We also conducted a one-stage individual participant data meta-analysis searching PubMed and Embase for studies of vitamin D and TB until December 31, 2017. We included studies that assessed vitamin D before TB diagnosis. We defined VDD as 25-(OH)D <50 nmol/L, insufficiency as 50-75 nmol/L and sufficiency as >75nmol/L. We estimated the association between vitamin D and incident TB using conditional logistic regression in the Peru cohort and generalized linear mixed models in the meta-analysis. FindingsIn Peru, baseline VDD was associated with a statistically insignificant increase in incident TB (aOR 1{middle dot}70, 95% CI 0{middle dot}84-3{middle dot}46; p=0{middle dot}14). We identified seven studies for the meta-analysis and analyzed 3544 participants. Individuals with VDD and very low vitamin D (<25nmol/L) had increased TB risk (aOR 1{middle dot}48, 95% CI 1{middle dot}04-210;p=0{middle dot} 03 and aOR 2 08, 95% CI 0{middle dot}88-4{middle dot}92; p trend=002 respectively). Among HIV-positive patients, VDD and very low vitamin D conferred a 2-fold (aOR 2.18, 95% CI 1{middle dot} 22-3{middle dot}90; p=0{middle dot} 01) and 4-fold (aOR 4{middle dot}28, 95% CI 0{middle dot}85-21{middle dot}44; p trend=0{middle dot}01) increased risk of TB respectively. InterpretationOur findings suggest vitamin D predicts TB risk in a dose-dependent manner and vitamin D supplementation may play a role in TB prevention. FundingNational Institute of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Dental and Craniofacial Research (NIDCR), Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Foundation, Ujala Foundation, Wyncote Foundation, NIH - Fogarty International Center Program of International Training Grants in Epidemiology Related to AIDS, NIAID Byramjee Jeejeebhoy Medical College HIV Clinical Trials Unit, NIAIDs Baltimore-Washington-India Clinical Trials Unit, National Commission on Biotechnology, the Higher Education Commission, International Research Support Initiative Program of the Higher Education Commission Government of Pakistan, the Bill and Melinda Gates Foundation, and the NIH Fogarty International Center. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSNumerous studies have found lower serum vitamin D levels among patients with active TB disease compared to healthy controls. However, research has not clarified whether low vitamin D increases TB risk or whether TB disease leads to decreased vitamin D levels. We conducted PubMed and Medline searches for all studies available through December 31, 2017 on the association between vitamin D status and TB disease. We included the following keywords: "vitamin D," "vitamin D deficiency," "hypovitaminosis D," "25-hydroxyvitamin D," "1,25-dihydroxyvitamin D," "vitamin D2," "vitamin D3," "ergocalciferol," "cholecalciferol," and "tuberculosis." We found only seven studies had prospectively evaluated the impact of baseline vitamin D levels on risk of progression to TB disease. We report here the results of a case control study nested within a large prospective longitudinal cohort study of household contacts of TB cases and the results of an individual participant data (IPD) metaanalysis of available evidence on the association between vitamin D levels and incident TB disease. Added value of this studyWe demonstrated that low vitamin D levels predicts risk of future progression to TB disease in a dose-dependent manner. Implications of all the available evidenceThese findings suggest the possibility that vitamin D supplementation among individuals at high risk for developing TB disease might play a role in TB prevention efforts.

epidemiology↗

bioRxiv2018

RESISTANCE AT NO COST: THE TRANSMISSIBILITY AND POTENTIAL FOR DISEASE PROGRESSION OF DRUG-RESISTANT M. TUBERCULOSIS

BackgroundThe future trajectory of drug resistant tuberculosis strongly depends on the fitness costs of drug resistance mutations. Here, we measured the association of phenotypic drug resistance and the risk of TB infection and disease among household contacts (HHCs) of patients with pulmonary TB.\n\nMethodsWe evaluated 12767 HHCs of patients with drug sensitive and resistant pulmonary TB at baseline, two, six, and 12 months to ascertain infection status and to determine whether they developed tuberculosis disease. We also assessed the impact of drug resistance phenotype on the likelihood that a TB strain shared a genetic fingerprint with at least one other TB patient in the cohort.\n\nFindingsAmong 3339 TB patients for whom were DST available, 1274 (38%) had TB that was resistant to at least one drug and 478 (14*3%) had multi-drug resistant (MDR) TB, i.e. TB resistant to both INH and rifampicin. Compared to HHCs of drug sensitive TB patients, those exposed to a patient with MDR-TB had an 8% (95% CI: 4-13%) higher risk of infection by the end of follow up. We found no statistically significant difference in the relative hazard of incident TB disease among HHCs exposed to MDR-TB compared to DS-TB (Adjusted HR 1*28 [(95% CI: *9-1*83]). Patients with MDR-TB were more likely to be part of a genetic cluster than were DS-TB patients.\n\nInterpretationClinical strains of MDR M. tuberculosis are neither less transmissible than drug sensitive strains nor less likely to cause disease. (ClinicalTrials.gov number, NCT00676754)\n\nFundingNational Institutes of Health: NIH/NIAID CETR U19AI109755\n\nStatementAll authors have seen the manuscript and approved the manuscript.

epidemiology↗

bioRxiv2018

A nonsense mutant of the hepatitis B virus large S protein antagonizes multiple tumor suppressor pathways through c-Jun activation domain-binding protein1

Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Previous studies have identified recurrent nonsense mutations in the HBV large S (LHBs) gene from the liver from HBV core antigen-positive HCC patients. These nonsense mutants have been shown to be oncogenic in mouse xenograft models using a mouse embryonic fibroblast cell line. Here, we expressed in a liver cell line Huh-7 a carboxy terminally truncated protein from a nonsense mutant of the LHBs gene, sW182* (stop codon at tryptophane-182). Although the sW182* protein appeared not to be very stable in the cultured liver cells, we confirmed that the protein can be highly expressed and retained for a prolonged period of time in the hepatocytes in the mouse liver, indicating its stable nature in the physiological condition.\n\nIn the Huh-7 cells, the sW182* mutant downregulated tumor suppressors p53 and Smad4. This downregulation was reversed by a proteasome inhibitor MG132, implying the involvement of proteasome-based protein degradation in the observed regulation of the tumor suppressors. On the other hand, we found that c-Jun activation domain-binding protein 1 (Jab1) physically interacts with the sW182*, but not wild-type LHBs. RNA interference (RNAi) of Jab1 restored the levels of the downregulated p53 and Smad4. The sW182* mutant inhibited the promoter activity of downstream target genes of the tumor suppressors. Consistently, Jab1 RNAi reversed the inhibition.\n\nThese results suggest that the LHBs nonsense mutant antagonizes the tumor suppressor pathways through Jab1 in the liver contributing to HCC development.

molecular biology↗

bioRxiv2018

Chronic pain with use of analgesics and mortality in the home healthcare elderly: a nationwide population-based study

BackgroundChronic pain may cause increased complications and all-cause mortality. However, nationwide data on elderly patients receiving home healthcare (HHC) remain unknown. Therefore, we conducted this study to address this issue.\n\nMethodsWe identified elderly individuals ([≥] 65 years) with chronic pain receiving HCC between 2002 and 2013 in the Taiwan National Health Insurance Research Database. The comparisons of the causes of chronic pain, comorbidities, follow-up mortality, and the use of analgesics between two sexes and among three age subgroups were performed.\n\nResultsA total of 1435 participants were identified, with a mean age of 77.8 {+/-} 7.1 years and male percentage of 46.7%. The prevalence of chronic pain was 5.8%. Chronic pain was most prevalent in the 75-84 years age group (46.5%). Malignancy was the most common cause of chronic pain (94.2%), followed by peripheral vascular diseases (6.0%), osteoarthritis (4.3%), pressure ulcer (3.9%), spine diseases (3.1%), osteoporosis (1.3%), and headache (1.3%). The follow-up mortality was 32.8% within 6 month, 64.1% within 1 year, 79.9% within 2 years, and 84.3% within 3 years without difference in two sexes and age subgroups. Acetaminophen was found to be the most common analgesics, followed by non-steroidal anti-inflammatory drugs and opioids. Morphine was the most commonly used opioid.\n\nConclusionsThis study delineates the causes of chronic pain, use of analgesics, and follow-up mortality in the HHC elderly, clarifying the relationship between chronic pain and the HCC elderly. This will facilitate the further investigation of this issue in the future.

epidemiology↗

bioRxiv2018

Topographic diversity of structural connectivity in schizophrenia

The neurobiological heterogeneity of schizophrenia is widely accepted, but it is unclear how mechanistic differences converge to produce the observed phenotype. Establishing a pathophysiological model that accounts for both heterogeneity and phenotypic similarity is essential to inform stratified treatment approaches. In this cross-sectional diffusion tensor imaging (DTI) study, we recruited 77 healthy controls (HC), and 71 patients with DSM-IV diagnosis of schizophrenia (SCZ), and reconstructed the structural connectivity of 90 brain regions covering entire cerebral cortex. We first confirmed the heterogeneity in structural connectivity by showing a reduced inter-individual similarity in SCZ compared with HC. Moreover, we found it was not possible to cluster patients into subgroups with shared patterns of dysconnectivity, indicating a high degree of mechanistic divergence in schizophrenia. Instead of the strength of connectivity between any particular brain regions, we investigated the diversity (or statistically, the variance) of the topographic distribution of the strength was reduced. HC had higher topographic diversity in whole brain structural connectivity compared to the patient group\n\n(P = 2 x 10-6, T = 4.96, Cohen'S d = 0.87). In 62 of the 90 brain regions, the topographic diversity was significantly reduced in patients compared to controls after FDR correction (<0.05). When topographic diversity was used as a discriminant feature for classification between patients and controls, we significantly (P = 4.29 x 10-24) improved the classification accuracy to 79.6% (sensitivity 78.3%, specificity 81.3%). This finding suggests highly individualized pattern of structural dysconnectivity underlying the heterogeneity of schizophrenia converges to a convergent common pathway as reduced topographic diversity for the clinical construct of the disease.

neuroscience↗

bioRxiv2017

Machine Learning of the Cardiac Phenome and Skin Transcriptome to Categorize Heart Disease in Systemic Sclerosis

BackgroundCardiac involvement is a leading cause of death in systemic sclerosis (SSc/scleroderma). The complexity of SSc cardiac manifestations is not fully captured by the current clinical SSc classification, which is based on extent of skin involvement and specific autoantibodies. Therefore, we sought to develop a clinically relevant SSc cardiac disease classification to improve clinical care and increase understanding of SSc cardiac disease pathobiology. We hypothesized that machine learning could identify novel SSc cardiac disease subgroups, and that gene expression assessment of skin could provide insights into molecular pathogenesis of these SSc pheno-groups.\n\nMethodsWe used unsupervised model-based clustering (phenomapping) of SSc patient echocardiographic and clinical data to identify clinically relevant SSc pheno-groups in a discovery cohort (n=316), and validated these findings in an external SSc validation cohort (n=67). Cox regression was used to evaluate survival differences among groups. Gene expression profiles from skin biopsies from a subset of SSc patients (n=68) and controls (n=18) were analyzed with weighted gene co-expression network analyses to identify gene modules that were associated with cardiac pheno-groups and echocardiographic parameters.\n\nResultsFour SSc cardiac pheno-groups were identified with distinct profiles. Pheno-group #1 displayed a predominant cutaneous phenotype without cardiac involvement; pheno-group #2 had long-standing SSc with limited skin and cardiac involvement; pheno-group #3 had diffuse skin involvement, a high frequency of interstitial lung disease (88%), and significant right heart remodeling/dysfunction; and pheno-group #4 had prolonged SSc disease duration, limited skin involvement, and marked biventricular cardiac involvement. After multivariable adjustment, pheno-group #3 (hazard ratio [HR] 7.8, 95% confidence interval [CI] 1.5-33.0) and pheno-group #4 (HR 10.5, 95% CI 2.1-52.7) remained associated with mortality (P<0.05). The addition of pheno-group classification was additive to conventional survival models (P<0.05 by likelihood ratio test for all models), a finding that was replicated in the validation cohort. Skin gene expression analysis identified 2 gene modules (representing fibrosis and skin integrity, respectively) that differed among the cardiac pheno-groups and were associated with specific echocardiographic parameters.\n\nConclusionsMachine learning of echocardiographic and skin gene expression data in SSc identifies clinically relevant subgroups with distinct cardiac phenotypes, survival, and associated molecular pathways in skin.

genomics↗

bioRxiv2017

The Impact of Vitamin A and Carotenoids on the Risk of Tuberculosis Progression

BackgroundLow and deficient levels of vitamin A are common in low and middle income countries where tuberculosis burden is high. We assessed the impact of baseline levels of vitamins A and carotenoids on TB disease risk.\n\nMethods and FindingsWe conducted a case-control study nested within a longitudinal cohort of household contacts of pulmonary TB cases in Lima, Peru. We screened all contacts for TB disease at 2, 6, and 12 months after enrollment. We defined cases as HIV-negative household contacts with blood samples who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected 4 controls from among contacts who did not develop TB disease, matching on gender and year of age. We used conditional logistic regression to estimate odds ratios (ORs) for incident TB disease by vitamin A and carotenoids levels, controlling for other nutritional and socioeconomic factors.\n\nAmong 6751 HIV-negative household contacts with baseline blood samples, 192 developed secondary TB disease during follow-up. We analyzed 180 cases with viable samples and 709 matched controls. After controlling for possible confounders, we found that baseline vitamin A deficiency was associated with a 10-fold increase in risk of TB disease among household contacts (aOR 10.42; 95% CI 4.01-27.05; p < 0.001). This association was dose-dependent with stepwise increases in TB disease risk with each decreasing quartile of vitamin A level. Carotenoid levels were also inversely associated with TB risk among adolescents.\n\nOur study is limited by the one year duration of follow up and by the relatively few blood samples available from household contacts under ten years of age.\n\nConclusionsVitamin A deficiency strongly predicted risk of incident TB disease among household contacts of TB patients. Vitamin A supplementation among individuals at high risk of TB may provide an effective means of preventing TB disease.

epidemiology↗