1,181 research outputs found
Our Grandparents/æ§èŻ
A Theater and Performance senior project centering on the question of how can we be more connected to our grandparents through playing them in front of a camera on stage? Through exploring this question, the actor would present real stories about their grandparents on stage
Arylboronates as H2O2 or Photo-Inducible DNA Cross-Linking Agents: Design, Synthesis, Mechanism, and Anticancer Activity
Interest in the development of cancer therapies with improved selectivity and reduced host toxicity has been growing. In this thesis, we designed and synthesized a series of novel non-toxic arylboronic ester and biarylboronic ester derivatives that can be activated by hydrogen peroxide (H2O2) to induce DNA interstrand cross-link formation. The mechanism of DNA cross-linking induced by these arylboronates involves generation of phenol intermediates 1 followed by departure of leaving group (L) leading to quinone methides (QMs) 2, which directly cross-link DNA via alkylation. The QM formation is the rate-determining step for DNA cross-linking. The activity and selectivity of these compounds towards H2O2 were investigated and the activation mechanism was determined by NMR analysis and QM trapping experiments. The oxidative activation of these compounds by H2O2 produced an electron rich aromatic ring that facilitated QM formation and release of the leaving group.
We also evaluated the effects of the benzylic leaving groups (L), the core structures of the arylboronates, and the aromatic substituents (R) on H2O2-induced formation of bisquinone methides (bisQMs) for DNA interstrand cross-linking. A better leaving group (Br) and stepwise bisquinone methide formation increased interstrand cross-linking efficiency. The electron-donating groups (OMe or OH) on the aromatic ring greatly favored QM formation and improved interstrand cross-link (ICL) formation. An in vitro cytotoxicity assay showed that the arylboronic esters with OMe or OH at position 4 dramatically inhibited the growth of various cancer cell lines. These findings provide essential guidelines for designing novel anticancer prodrugs.
Furthermore, the photochemical reactivity of these arylboronates, including phenyl boronates and naphthalene boronates, towards DNA has been investigated. The results indicated that most arylboronates induced DNA ICL formation upon 350 nm irradiation. Two mechanisms were involved for photo-inducible DNA ICL formation: a) UV-irradiation of the arylboronates produced a methyl radical which was oxidized to a methyl cation capable of alkylating DNA; b) a methyl cation was directly generated by UV-irradiation of the arylboronates via heterolysis of CH2-L (L= Br or NMe3+Br-) bond. The activation mechanism was determined using the orthogonal traps, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and methoxyamine. The TEMPO reacts with free radicals while methoxyamine acts as a carbocation trap
Roles of perivascular adipose tissue and Kv7 voltageâdependent potassium channels in vascular tone
Hypertension is widely acknowledged as a major risk factor in the progression of many vascular diseases, especially for elderlies. The vascular tone plays a key role in several major areas of research.
The Kv7 voltage-dependent potassium channels (also known as Kv7 channels) are encoded by the KCNQ genes. The relationships between perivascular adipose tissue (PVAT) and Kv7 channels are still unclear. First, the role of PVAT in mouse mesenteric artery relaxation was examined. Aging, as well as other physiological changes, affects PVAT. Kv7 channels and the relative modulators are studied mainly on a mouse model in our research. Wire myography and membrane potential experiments were used to evaluate the vascular function in vitro. RNA sequencing experiments and q-PCR helped to reveal the roles of potential pathways influencing artery tone. The data indicates that the tone of the mesenteric artery is suppressed by the activation of Kv7 channels in young mouse. Kv7 channels participated in regulation not only through metabolic processes, but also through perivascular adipose tissue-derived relaxation factors. As a novel pharmacological vasodilator, QO58 can open the KCNQ channels in mouse mesenteric arteries, that reduced depolarization caused by α1 adrenoceptor agonist. This reduction was reversed by XE991, a Kv7 channel blocker. The results demonstrated studying aging and Kv7 voltage-dependent potassium channels might lead to innovative ways to treat vascular dysfunction. Ultimately, Kv7 channels indicate a prospective therapeutic in the field of aging research and hypertension treatment.Bluthochdruck ist ein Haupt-Risikofaktor fĂŒr die Entwicklung vieler Herz-Kreislauf-Erkrankungen, insbesondere im Alter. Dem GefĂ€Ătonus kommt eine wichtige Rolle in verschiedenen Hauptforschungsbereichen zu.
Die spannungsregulierten Kv7-Kalium-KanĂ€le (Kv7-KanĂ€le) werden durch KCNQ-Gene codiert. Die ZusammenhĂ€nge zwischen perivaskulĂ€rem Fettgewebe (perivascular adipose tissue, PVAT) und Kv7-KanĂ€len sind noch unklar. Zuerst wurde die Bedeutung von PVAT bei der Relaxation von Mesenterialarterien der Maus untersucht. Alter, ebenso wie weitere physiologische VerĂ€nderungen, beeinflusst PVAT. Kv7-KanĂ€le und ihre Modulatoren wurden hauptsĂ€chlich im Mausmodell studiert. Draht-Myographie und Membranpotential-Messungen wurden durchgefĂŒhrt, um die GefĂ€Ăfunktion in vitro zu beurteilen. RNA-Sequenzierung und q-PCR-Experimente unterstĂŒtzten das Aufdecken der Rolle möglicher Signalwege mit Einfluss auf den arteriellen GefĂ€Ătonus. Die Daten weisen darauf hin, dass der Tonus der Mesenterialarterien durch Aktivierung spannungsabhĂ€ngiger Kv7-Kalium-KanĂ€le bei jungen MĂ€usen vermindert wird. Kv7-KanĂ€le beeinflussen diese Regulation nicht nur durch metabolische Prozesse, sondern auch ĂŒber Faktoren aus dem perivaskulĂ€rem Fettgewebe. Als neuartiger pharmakologischer Vasodilatator kann QO58 die KCNQ-KanĂ€le in mesenterialen Arterien der Maus öffnen, wodurch die α-1-Adrenozeptor-Agonisten-vermittelte Depolarisation reduziert wurde. Diese Verringerung wurde durch den Kv7-Kanal-Blocker XE991 rĂŒckgĂ€ngig gemacht. Unsere Daten zeigen, dass die Untersuchung von Alterung und Kv7-KanĂ€len innovative Behandlungswege fĂŒr vaskulĂ€re Dysfunktion aufzeigen könnte. SchlieĂlich stellen Kv7-KanĂ€le ein vielversprechendes Ziel in der Altersforschung und der Behandlung von Bluthochdruck dar
Distributionally robust unsupervised domain adaptation and its applications in 2D and 3D image analysis
Obtaining ground-truth label information from real-world data along with uncertainty quantification can be challenging or even infeasible. In the absence of labeled data for a certain task, unsupervised domain adaptation (UDA) techniques have shown great accomplishment by learning transferable knowledge from labeled source domain data and adapting it to unlabeled target domain data, yet uncertainties are still a big concern under domain shifts. Distributionally robust learning (DRL) is emerging as a high-potential technique for building reliable learning systems that are robust to distribution shifts. In this research, a distributionally robust unsupervised domain adaptation (DRUDA) method is proposed to enhance the machine learning model generalization ability under input space perturbations. The DRL-based UDA learning scheme is formulated as a min-max optimization problem by optimizing worst-case perturbations of the training source data. Our Wasserstein distributionally robust framework can reduce the shifts in the joint distributions across domains. The proposed DRUDA method has been tested on various benchmark datasets. In addition, a gradient mapping-guided explainable network (GMGENet) is proposed to analyze 3D medical images for extracapsular extension (ECE) identification. DRUDA-enhanced GMGENet is evaluated, and experimental results demonstrate that the proposed DRUDA improves transfer performance on target domains for the 3D image analysis task successfully. This research enhances the understanding of distributionally robust optimization in domain adaptation and is expected to advance the current unsupervised machine learning techniques
A Path to Implement Precision Child Health Cardiovascular Medicine.
Congenital heart defects (CHDs) affect approximately 1% of live births and are a major source of childhood morbidity and mortality even in countries with advanced healthcare systems. Along with phenotypic heterogeneity, the underlying etiology of CHDs is multifactorial, involving genetic, epigenetic, and/or environmental contributors. Clear dissection of the underlying mechanism is a powerful step to establish individualized therapies. However, the majority of CHDs are yet to be clearly diagnosed for the underlying genetic and environmental factors, and even less with effective therapies. Although the survival rate for CHDs is steadily improving, there is still a significant unmet need for refining diagnostic precision and establishing targeted therapies to optimize life quality and to minimize future complications. In particular, proper identification of disease associated genetic variants in humans has been challenging, and this greatly impedes our ability to delineate gene-environment interactions that contribute to the pathogenesis of CHDs. Implementing a systematic multileveled approach can establish a continuum from phenotypic characterization in the clinic to molecular dissection using combined next-generation sequencing platforms and validation studies in suitable models at the bench. Key elements necessary to advance the field are: first, proper delineation of the phenotypic spectrum of CHDs; second, defining the molecular genotype/phenotype by combining whole-exome sequencing and transcriptome analysis; third, integration of phenotypic, genotypic, and molecular datasets to identify molecular network contributing to CHDs; fourth, generation of relevant disease models and multileveled experimental investigations. In order to achieve all these goals, access to high-quality biological specimens from well-defined patient cohorts is a crucial step. Therefore, establishing a CHD BioCore is an essential infrastructure and a critical step on the path toward precision child health cardiovascular medicine
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Epigenomic regulation of heart failure: integrating histone marks, long noncoding RNAs, and chromatin architecture.
Epigenetic processes are known to have powerful roles in organ development across biology. It has recently been found that some of the chromatin modulatory machinery essential for proper development plays a previously unappreciated role in the pathogenesis of cardiac disease in adults. Investigations using genetic and pharmacologic gain- and loss-of-function approaches have interrogated the function of distinct epigenetic regulators, while the increased deployment of the suite of next-generation sequencing technologies have fundamentally altered our understanding of the genomic targets of these chromatin modifiers. Here, we review recent developments in basic and translational research that have provided tantalizing clues that may be used to unlock the therapeutic potential of the epigenome in heart failure. Additionally, we provide a hypothesis to explain how signal-induced crosstalk between histone tail modifications and long non-coding RNAs triggers chromatin architectural remodeling and culminates in cardiac hypertrophy and fibrosis
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