Biology subjects

Nguyen, T. D.

Publications and source records attributed to Nguyen, T. D..

6 recordsLinked to original sources

bioRxiv2018

An aged human heart tissue model showing age-related molecular and functional deterioration resembling the native heart

Deaths attributed to ischemic heart disease increased by 41.7% from 1990 to 2013. This is primarily due to an increase in the aged population, however, research on cardiovascular disease (CVD) has been overlooking aging, a well-documented contributor to CVD. The field heavily depends on the use of young animals due to lower costs and ready availability, despite the prominent differences between young and aged heart structure and function. Here we present the first human induced pluripotent stem cell (hiPSC)-derived cardiomyocyte (iCM)-based, in vitro aged myocardial tissue model as an alternative research platform. Within 4 months, iCMs go through accelerated senescence and show cellular characteristics of aging. Furthermore, the model tissues fabricated using these aged iCMs, with stiffness resembling that of aged human heart, show functional and pharmacological deterioration specific to aged myocardium. Our novel tissue model with age-appropriate physiology and pathology presents a promising new platform for investigating CVD or other age-related diseases.

bioengineering↗

bioRxiv2018

Persistent cell motility requires transcriptional feedback of cytoskeletal - focal adhesion equilibrium by YAP/TAZ

Cell migration initiates by traction generation through reciprocal actomyosin tension and focal adhesion reinforcement, but continued motility requires adaptive cytoskeletal remodeling and adhesion release. Here, we asked whether de novo gene expression contributes to this cytoskeletal feedback. We found that global inhibition of transcription or translation does not impair initial cell polarization or migration initiation, but causes eventual migratory arrest through excessive cytoskeletal tension and over-maturation of focal adhesions, tethering cells to their matrix. The transcriptional co-activators YAP and TAZ mediate this feedback response, modulating cell mechanics by limiting cytoskeletal and focal adhesion maturation to enable persistent cell motility and 3D vasculogenesis. Motile arrest after YAP/TAZ ablation was partially rescued by depletion of the YAP/TAZ-dependent myosin phosphatase regulator, NUAK2, or by inhibition of Rho-ROCK-myosin II. Together, these data establish a transcriptional feedback axis necessary to maintain a responsive cytoskeletal equilibrium and persistent migration.

cell biology↗

bioRxiv2017

Enhanced Astrocyte Responses are Driven by a Genetic Risk Allele Associated with Multiple Sclerosis

Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-{kappa}B signaling and target gene expression driving lymphocyte recruitment in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates. In MS patients, the risk genotype was associated with increased lesion volumes on MRI. Thus, we established that the rs7665090G variant perturbs astrocyte function resulting in increased CNS access for peripheral immune cells. MS may thus result from variant-driven dysregulation of the peripheral immune system and the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.\n\nOne Sentence SummaryThe NF-{kappa}B relevant multiple sclerosis risk variant, rs7665090G, drives astrocyte responses that promote lesion formation.

neuroscience↗

bioRxiv2017

Four new induced pluripotent stem cell lines produced from northern white rhinoceros with non-integrating reprogramming factors

Since we first published methods for generation of induced pluripotent stem cells from endangered species1, we have developed improved non-integrating methods for reprogramming the functionally extinct northern white rhinoceros, and generated iPSCs from four more individuals. Our work is part of a long-term plan for assisted reproduction for conservation of endangered species.

developmental biology↗

bioRxiv2017

The decline of malaria in Vietnam, 1991-2014

A central component of malaria control initiatives throughout the world is the use of artemisinin-based combination therapies (ACTs) for treatment of uncomplicated P. falciparium malaria. Despite the well-documented clinical efficacy of ACTs, the population-level effects of ACT case management on malaria transmission have not been studied thoroughly until recently. An ideal case study for the population-level effects of artemisinin use can be found in Vietnam, where a major increase of malaria cases in the 1980s was followed by the gradual adoption of artemisinin-based clinical case management. We assembled annual data from Vietnams National Institutes for Malariology, Parasitology, and Entomology showing the degree to which artemisinin therapies were adopted in different provinces, the effort placed on vector control, and the funding available to provincial malaria control programs, from 1991 to 2014. Data on urbanization were also collected for this period. We found that a 10% increase in the artemisinin proportion of treatments procured by a provincial control program corresponded to a 32.8% (95% CI: 27.7 - 37.5%) decline in estimated malaria cases; the association persisted and the effect size was nearly unchanged if confirmed cases or suspected cases were used. There was no consistent effect of vector control on malaria cases in Vietnam as a whole, nor was any effect found when the data were broken up regionally. The association between urbanization and malaria was generally negative and sometimes statistically significant. This was most pronounced in the central region of Vietnam, where a 10% increase in urbanization corresponded to a 43.3% (95% CI: 21.6 - 58.9%) decrease in suspected malaria incidence; this association was not statistically significant if confirmed cases or estimated cases were used. The decline of malaria in Vietnam from 1991 to 2014 can largely be attributed to the rapid adoption of artemisinin-based drugs. Recent analyses of aggregated data from Africa have shown that insecticide-treated nets have had the greatest effect on lowering malaria prevalence over the past fifteen years, suggesting that the success of different types of malaria interventions is region specific. Continuing global efforts on malaria elimination should focus on both vector control measures and increased access to artemisinin-combination therapies.

epidemiology↗

bioRxiv2017

Non-annual seasonality of influenza-like illness in a tropical urban setting

In temperate countries, influenza and other viral respiratory diseases often have distinct seasonal peaks occurring during colder, wintertime months. However, little is known about the dynamics of influenza and viral respiratory disease dynamics in the tropics, despite high morbidity and a clear epidemiological link between tropical and temperate countries. In temperate countries, the dynamics of influenza and other respiratory diseases are often analyzed using syndromic surveillance data describing influenza-like illness (ILI) as ILI is highly correlated with virological surveillance for influenza. To obtain a detailed picture of respiratory disease incidence patterns in a large tropical city, we established an mHealth study in community outpatient clinics in Ho Chi Minh City, Vietnam (11N latitude). From August 2009 through December 2015, clinics reported daily case numbers of ILI using standard mobile-phone SMS messaging. A subset of these clinics performed molecular diagnostics for influenza A and B viruses. Unlike the annual patterns seen in temperate countries, ILI activity in Ho Chi Minh City exhibited strong non-annual periodicity and was not correlated with PCR-confirmed influenza. The dominant periodicity in the data was approximately 200 days. This was confirmed by a time series decomposition, a step-wise regression analysis on annual and non-annual covariates, and a forecasting exercise showing that forecasting was 30% to 40% more accurate when a 200-day non-annual cycle was included in the forecast. This suggests, for the first-time, that a non-annual cycle may be an essential driver of ILI dynamics in the tropics. This raises new questions about the seasonality and drivers of respiratory disease transmission in tropical countries.

epidemiology↗