Biology subjects

Pham, V.

Publications and source records attributed to Pham, V..

3 recordsLinked to original sources

bioRxiv2020

Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type1 diabetes therapeutic reversal in preclinical models

In type 1 diabetes (T1D) immune-cell infiltration into the islets of Langerhans (insulitis) and {beta}-cell decline occurs many years before diabetes presents. Non-invasively detecting insulitis and {beta}-cell decline would allow diagnosis of eventual diabetes and provide a means to monitor the efficacy of therapeutic intervention. However, there is a lack of validated clinical approaches for non-invasively imaging disease progression leading to T1D. Islets have a dense microvasculature that reorganizes during diabetes. We previously demonstrated contrast-enhanced ultrasound measurements of pancreatic blood-flow dynamics could predict disease progression in T1D pre-clinical models. Here we test whether these measurements can predict successful therapeutic prevention of T1D. We performed destruction-reperfusion measurements using a small-animal ultrasound machine and size-isolated microbubbles, in NOD-scid mice receiving an adoptive transfer of diabetogenic splenocytes (AT mice). Mice received vehicle control or either of the following treatments: 1) antiCD4 to deplete CD4+ T cells; 2) antiCD3 to block T cell activation, 3) Verapamil to reduce {beta}-cell apoptosis and 4) TUDCA to reduce ER stress. We compared measurements of pancreas blood-flow dynamics with subsequent progression to diabetes. In AT mice blood-flow dynamics were altered >2 weeks after splenocyte transfer. AntiCD4, antiCD3 and verapamil provided a significant delay in diabetes development. Treated AT mice with delayed or absent diabetes development showed significantly altered blood flow dynamics compared to untreated AT mice. Conversely, treated AT mice that developed diabetes, despite therapy, showed similar blood-flow dynamics to untreated AT mice. Thus, contrast-enhanced ultrasound measurement of pancreas blood-flow dynamics can predict the successful or unsuccessful delay or prevention of diabetes upon therapeutic treatments that target both immune activity or {beta}-cell protection. This strategy may provide a clinically deployable predictive marker for disease progression and therapeutic reversal in asymptomatic T1D.

bioengineering↗

bioRxiv2019

Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis and beta-cell mass decline in mouse models of type 1 diabetes

Type 1 diabetes (T1D) is characterized by the infiltration of autoreactive T-cells into the islet of Langerhans, and depletion of insulin-secreting {beta}-cells. This immune cell infiltration (insulitis) first occurs during an asymptomatic phase of T1D that can take place many years prior to clinical diagnosis. Methods to diagnose insulitis and changes in {beta}-cell mass during this asymptomatic phase are limited, thus precluding early therapeutic intervention. While therapeutic treatments can delay T1D progression, treatment efficacy is limited and widely varying, and a method to track this efficacy is also lacking. During T1D progression, the islet microvasculature increases permeability as a result of insulitis, in both mouse models of T1D and humans with T1D. This increased permeability can allow nanoparticles, such as contrast agents for diagnostic imaging, to access the islet microenvironment. Contrast enhanced ultrasound (CEUS) uses shell-stabilized gas bubbles to provide high acoustic backscatter in vasculature and tissue and is clinically approved. A novel, sub-micron sized nanobubble (NB) ultrasound contrast agent has been developed and shown to extravasate and accumulate in tumors, where microvascular permeability is high. To test whether CEUS can be used to measure increased islet microvasculature permeability and indicate the asymptomatic phase of T1D, we applied CEUS measurements with NBs in pre-clinical T1D models. NOD mice and mice receiving an adoptive-transfer of diabetogenic splenocytes showed accumulation of NBs specifically within the pancreatic islets, and only in the presence of insulitis. This accumulation was measured by both ultrasound contrast and histological analysis, and accumulation only occurred for sub-micron sized bubbles. Importantly, accumulation was detected as early as 4w in NOD mice. Thus, CEUS with sub-micron sized NB contrast agent may provide a predicative marker for disease progression early in asymptomatic T1D, as well as monitoring of disease prevention or reversal.

bioengineering↗

bioRxiv2018

Molecular bases for the constitutive photomorphogenic phenotypes in Arabidopsis

Summary statementStrikingly similar morphological and gene expression phenotypes among cop1, spaQ and pifQ mutants suggest that the cop phenotype of the cop1 and spaQ mutants might be due in part to a reduced level of PIFs\n\nAbstractThe transition from skotomorphogenesis to photomorphogenesis is regulated in part by COP1/SPA complex and PIFs in Arabidopsis. The constitutive photomorphogenic (cop) phenotypes of the cop1 and spaQ mutants were shown to be due to a high abundance of the positively acting transcription factors. Here we show that the four major PIF proteins are unstable in cop1 mutant, and an overexpression of P1F1, P1F3, P1F4 and P1F5 suppresses the cop1 phenotypes in the dark. A comparison of the transcriptome data among cop1, spaQ and pifQ reveals remarkably overlapping gene expression profiles with a preferential regulation of the PIF direct target genes. Additionally, HFR1 strongly inhibits the in vivo binding and transcriptional activation activity of PIF1 in the dark. Taken together, these data suggest that the cop phenotypes of the cop1 and spaQ mutants might be due to a combination of the reduced level of PIFs, increased level of the positive factors (e.g., HY5/HFR1 and others), and the HFR1-mediated inhibition of PIF targeted gene expression in the dark.

plant biology↗