Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
15,255
result(s) for
"Michael, Laura"
Sort by:
Discovery of potent small-molecule inhibitors of lipoprotein(a) formation
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))
1
,
2
. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K
IV
) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs.
3
–
7
). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K
IV
7–8. We identify compounds that bind to apo(a) K
IV
7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a).
Biochemical screening and optimization identify small molecules that inhibit the formation of lipoprotein(a), and these inhibitors reduce the levels of Lp(a) in several animal models, suggesting that they could provide a therapeutic option in humans.
Journal Article
الطيارات تطير
\"الطيارات تطير\" كتاب يهديه مؤلفه إلى الأطفال الذين يعيشون على جانبي الجدار، جدار الفصل العنصري، والذين سيسقطونه على الأرض ذات يوم. تم تأليف هذا الكتاب بناء على طلب طفل فلسطيني يحلم أن يلعب بطائرته الورقية دونما خوف من الطائرات الحربية التي تلوث عالمه الجميل. تقوم القصة على محاورة بين أخين الأول وعمره 12 عاما والثاني وعمره 8 سنوات، يأتيه أخيه في الحلم، وليس في الواقع، ليلعب معه بطائرته الورقية، وأمل يحذوه بان ينتهي كابوس الإحتلال \"الأمر مثل النهار الذي لا يأتي إلا بعد ليل، لا يمكنك أن ترى أحدهما من دون الآخر، الضوء لا يكون ضوءا، كما قلت، \"إلا حينما ترى كم هو الظلام مظلم\"... احب أن تتكلم معي أحب كثيرا، هل ستطير معي طيارتي الورقية غدا، هل ستكون هناك تحت شجرة الطيارات ؟... يهدف هذا الكتاب إلى مساعدة الناشئة على فهم سبب وجود الصراع بين الفلسطينيين والإسرائيليين ولماذا لا ينتهي، ولذلك اختار المؤلف جل أبطاله من الاطفال مثل : سعيد ومحمود وغيرهم وهم في الواقع يلعبون بالطيارات الورقية في ساعات العصر الحارة في الطبقة الغربية، هؤلاء الأطفال يصنعون طياراتهم الورقية بأيديهم، من الجرائد والأكياس البلاستيكية المستعملة، إنهم يحولون ما قد يبدو كومة من القمامة إلى شيء جميل... \"الطيارات تطير\" قصة تكشف كيف يمكن لآمال الأطفال وأحلامهم أن تحلق أعلى من أي جدار.
Book
Concordant Changes of Plasma and Kidney MicroRNA in the Early Stages of Acute Kidney Injury: Time Course in a Mouse Model of Bilateral Renal Ischemia-Reperfusion
Acute kidney injury (AKI) is a syndrome characterized by the rapid loss of the kidney excretory function and is strongly associated with increased early and long-term patient morbidity and mortality. Early diagnosis of AKI is challenging; therefore we profiled plasma microRNA in an effort to identify potential diagnostic circulating markers of renal failure. The goal of the present study was to investigate the dynamic relationship of circulating and renal microRNA profiles within the first 24 hours after bilateral ischemia-reperfusion kidney injury in mice.
Bilateral renal ischemia was induced in C57Bl/6 mice (n = 10 per group) by clamping the renal pedicle for 27 min. Ischemia-reperfusion caused highly reproducible, progressive, concordant elevation of miR-714, miR-1188, miR-1897-3p, miR-877*, and miR-1224 in plasma and kidneys at 3, 6 and 24 hours after acute kidney injury compared to the sham-operated mice (n = 5). These dynamics correlated with histologic findings of kidney injury and with a conventional plasma marker of renal dysfunction (creatinine). Pathway analysis revealed close association between miR-1897-3p and Nucks1 gene expression, which putative downstream targets include genes linked to renal injury, inflammation and apoptosis.
Systematic profiling of renal and plasma microRNAs in the early stages of experimental AKI provides the first step in advancing circulating microRNAs to the level of promising novel biomarkers.
Journal Article
The Elgar companion to public choice
The Elgar Companion to Public Choice, Second Edition, brings together leading scholars in the field of political economy to introduce readers to the latest research in public choice. The Companion lays out a comprehensive history of the field and, in five additional parts, it explores public choice contributions to the study of the origins of the state, the organization of political activity, the analysis of decision-making in non-market institutions, the examination of tribal governance and to modeling and predicting the behavior of international organizations and transnational terrorism. Wit.
Book
Functional Characterization of VS-186B, a Novel HDAC Inhibitor with Anticancer Activity
Histone acetylation and deacetylation are key regulators of gene expression and are frequently dysregulated in cancer, contributing to tumorigenesis and drug resistance. Overexpression of histone deacetylases (HDACs) in many cancer types leads to silencing of tumor suppressor genes and uncontrolled proliferation. Tumors often rely on epigenetic mechanisms to escape therapy and develop resistance. This study aimed to identify novel compounds that selectively target cancer cells while minimizing toxicity to non-cancerous cell lines. A series of novel HDAC inhibitors was evaluated using the Differential Nuclear Staining (DNS) assay, flow cytometry, and HDAC inhibition assays. These assays assessed cytotoxicity, selectivity, and mechanisms of cell death. Among seven compounds tested, VS-186B exhibited the highest cytotoxicity and Selective Cytotoxicity Index (SCI), particularly against the human Jurkat T-cell leukemia cell line. Flow cytometry experiments (Annexin V-FITC, ROS, JC-1, and Caspase-3/7 assays) revealed that VS-186B induced apoptosis. VS-186B was more cytotoxic than Curcumin and Vorinostat across most of the cell lines tested and was more specific to hematological cells. Connectivity Map (CMap) analysis showed strong similarity to genes affected by known HDAC inhibitors. Subsequently, HDAC enzymatic assays confirmed that VS-186B inhibits Class I and II HDACs in a dose-dependent manner. VS-186B exhibits promising anticancer potential as a selective HDAC inhibitor since it induces apoptosis in cancer cells without significant cytotoxicity to non-cancerous lines with a similar gene expression profile to known HDAC inhibitors. These findings support further development of VS-186B as an epigenetic treatment for leukemia/lymphoma.
Journal Article
Disentangling the genetic overlap between cholesterol and suicide risk
Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2–189) 60% female; mean age = 42.58 years, range = 18–97 years, sd = 15.75 years] with no exclusion criteria for any given psychiatric disorder. We observed that total esterified cholesterol measured at the time of psychiatric assessment shared a significant genetic overlap with risk for suicide attempt (ρg = −0.64, p = 1.24 × 10−04). We also found that total unesterified cholesterol measured around 20 years prior to assessment varied as a function of genetic proximity to an affected individual (h2 = 0.21, se = 0.10, p = 8.73 × 10−04; βsuicide = −0.70, se = 0.25, p = 8.90 × 10−03). Finally, we found that the relationship between total unesterified cholesterol and suicide risk was significantly mediated by ABCA-1-specific cholesterol efflux capacity (βsuicide-efflux = −0.45, p = 0.039; βefflux-cholexterol = −0.34, p < 0.0001; βindirect = −0.15, p = 0.044). These findings suggest that the relatively well-delineated process of cholesterol metabolism and associated molecular pathways will be informative for understanding the neurobiological underpinnings of risk for suicide attempt.
Journal Article
Dream-along nursery rhymes
Includes three traditional nursery rhymes, illustrated by different people.
Book
A snapshot of the role of estrogen‐regulated divergent non‐coding transcripts
Recent high‐throughput sequencing technologies have discovered various polymerase II transcribed transcripts. The majority of them are non‐protein‐coding, understudied and poorly conserved. Non‐coding transcripts are categorised based on their location in the genome and the direction in which they are transcribed; these categories classify a non‐coding transcript as either antisense, intergenic or divergent. The RNAs belonging to divergent classes consist of two transcripts, transcribed in sense and antisense direction, generated from the same promoter or locus. Multiple environmental and genetic cues can determine the regulation of these transcripts. One of the well‐known signalling molecules, estrogen, has been shown to play a vital role in the activation and regulation of divergent transcripts by mediating effects through the estrogen receptors. Emerging studies have shown a strong causative effect between estrogen‐regulated divergent transcripts and diseases such as cancer. However, few, viz., lncRNA67, CUPID1 and CUPID2, show a causal relationship with estrogen‐dependent biology. This mini‐review summarises their role in estrogen‐dependent processes that may drive the research to identify novel estrogen‐signalling regulators. The expansion of genome‐wide studies has identified widespread transcription that may result in previously unstudied transcripts, such as divergent long non‐coding RNAs.
Journal Article