100 research outputs found
Contribution of protein phosphorylation to binding-induced folding of the SLBP–histone mRNA complex probed by phosphorus-31 NMR
No full textAbstractPhosphorus-31 (31P) NMR can be used to characterize the structure and dynamics of phosphorylated proteins. Here, I use 31P NMR to report on the chemical nature of a phosphothreonine that lies in the RNA binding domain of SLBP (stem-loop binding protein). SLBP is an intrinsically disordered protein and phosphorylation at this threonine promotes the assembly of the SLBP–RNA complex. The data show that the 31P chemical shift can be a good spectroscopic probe for phosphate-coupled folding and binding processes in intrinsically disordered proteins, particularly where the phosphate exhibits torsional strain and is involved in a network of hydrogen-bonding interactions
The People’s Justice: Clarence Thomas and the Constitutional Stories that Define Him
No full textEvent Description
For thirty years, Clarence Thomas has been denounced as the “cruelest justice,” a betrayer of his race, an ideologue, and the enemy of the little guy. In this compelling study of the man and the jurist, Amul Thapar demolishes that caricature.
Every day, Americans go to court. Invoking the Constitution, they fight for their homes, for a better education for their children, and to save their cities from violence. Recounting the stories of a handful of these ordinary Americans whose struggles for justice reached the Supreme Court, Thapar shines new light on the heart and mind of Clarence Thomas.
A woman in debilitating pain whose only effective medication has been taken away by the government, the motherless children of a slain police officer, victims of sexual assault— read their eye-opening stories, stripped of legalese, and decide for yourself whether Thomas’s originalist jurisprudence delivers equal justice under law.
“Finding the right answer,” Justice Thomas has observed, “is often the least difficult problem.” What is needed is “the courage to assert that answer and stand firm in the face of the constant winds of protest and criticism.”
That courage—along with wisdom and compassion—shines out from every page of The People’s Justice. At the heart of this book is the question: Would you want to live in Justice Thomas’s America? After reading these stories, even his critics might be surprised by their answer. Speaker Bio
Amul R. Thapar serves as a judge on the United States Court of Appeals for the Sixth Circuit. His judicial career began in 2007 when President George W. Bush nominated him to serve on the Eastern District of Kentucky, making him the first South Asian Article III judge in American history. In 2017, he became President Donald J. Trump’s first appellate court nominee.
Before joining the bench, Thapar served as the United States Attorney for the Eastern District of Kentucky. While United States Attorney, Thapar worked on the Attorney General’s Advisory Committee (“AGAC”) and chaired the AGAC’s Controlled Substances and Asset Forfeiture subcommittee. He also served on the Terrorism and National Security subcommittee, the Violent Crime subcommittee, and the Child Exploitation working group. Thapar has worked in private practice, at Williams & Connolly in Washington, D.C., and Squire, Sanders & Dempsey in Cincinnati, Ohio. He also served as an Assistant United States Attorney in both the Southern District of Ohio and the District of Columbia.
Thapar received his undergraduate degree from Boston College and his law degree from the University of California, Berkeley. After graduating, Thapar worked as a law clerk to the Honorable S. Arthur Spiegel of the United States District Court for the Southern District of Ohio and the Honorable Nathaniel R. Jones of the United States Court of Appeals for the Sixth Circuit.
Thapar is the author of The People’s Justice: Clarence Thomas and the Constitutional Stories that Define Him. He has also published law review articles in the Yale Law Journal, Michigan Law Review and Catholic University Law Review. He teaches courses on originalism, the Federalists and Anti-Federalists, habeas corpus and legal writing at Notre Dame Law School, the University of Virginia School of Law and Vanderbilt Law School. Event Locatio
Regulation of DNA Double-Strand Break Repair by Non-Coding RNAs
No full textDNA double-strand breaks (DSBs) are deleterious lesions that are generated in response to ionizing radiation or replication fork collapse that can lead to genomic instability and cancer. Eukaryotes have evolved two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DSBs. Whereas the roles of protein-DNA interactions in HR and NHEJ have been fairly well defined, the functions of small and long non-coding RNAs and RNA-DNA hybrids in the DNA damage response is just beginning to be elucidated. This review summarizes recent discoveries on the identification of non-coding RNAs and RNA-mediated regulation of DSB repair
Roles of Prolyl Isomerases in RNA-Mediated Gene Expression
No full textThe peptidyl-prolyl cis-trans isomerases (PPIases) that include immunophilins (cyclophilins and FKBPs) and parvulins (Pin1, Par14, Par17) participate in cell signaling, transcription, pre-mRNA processing and mRNA decay. The human genome encodes 19 cyclophilins, 18 FKBPs and three parvulins. Immunophilins are receptors for the immunosuppressive drugs cyclosporin A, FK506, and rapamycin that are used in organ transplantation. Pin1 has also been targeted in the treatment of Alzheimer’s disease, asthma, and a number of cancers. While these PPIases are characterized as molecular chaperones, they also act in a nonchaperone manner to promote protein-protein interactions using surfaces outside their active sites. The immunosuppressive drugs act by a gain-of-function mechanism by promoting protein-protein interactions in vivo. Several immunophilins have been identified as components of the spliceosome and are essential for alternative splicing. Pin1 plays roles in transcription and RNA processing by catalyzing conformational changes in the RNA Pol II C-terminal domain. Pin1 also binds several RNA binding proteins such as AUF1, KSRP, HuR, and SLBP that regulate mRNA decay by remodeling mRNP complexes. The functions of ribonucleoprotein associated PPIases are largely unknown. This review highlights PPIases that play roles in RNA-mediated gene expression, providing insight into their structures, functions and mechanisms of action in mRNP remodeling in vivo
Isolation and characterisation of mouse intestinal mesoangioblasts
No full textAIMS AND OBJECTIVES: Children suffering from intestinal failure (IF) endure considerable morbidity and overall have poor survival rates, complicated by the shortage of organs available for transplantation. Therefore, new therapeutic approaches are pivotal if outcomes are to be improved. Over the past years, tissue engineering (TE) has emerged as a possible alternative treatment for many congenital and acquired conditions. TE aims at creating bioengineered organs by means of combining scaffolds with appropriate cell types, which in the intestine are organised within a multilayer structure. In order to generate functional intestine, this cellular diversity and organisation will need to be recreated. While the cells for the epithelial, neural and vascular compartments have been well defined, so far, less attention has been put on the muscular compartment. More recently, mesoangioblasts (MABs) have been identified as a novel source for tissue regeneration since they are able to give rise to vascular and other mesodermal derivatives. To date MABs have not been successfully isolated from intestinal tissue. Therefore, our aim was to demonstrate the possibility of isolating MABs from adult mouse small intestine. MATERIALS AND METHODS: All experiments were carried out using small intestinal tissues from C57BL/6J mice. We applied an established protocol for MAB isolation from the isolated neuromuscular layer of the small intestine. Cultured cells were stained for Ki67 to assess proliferation rates as well as for a panel of pericyte markers to determine their phenotype. RESULTS: Cells were successfully isolated from gut biopsies. Cultured cells showed good proliferative capacity and positivity for at least three pericytes markers found in vessels of the gut neuromuscular wall: neuron-glial antigen 2, alkaline phosphatase and platelet-derived growth factor β. CONCLUSION: This proof-of-principle study lays the foundation for further characterization of MABs as a possible cell source for intestinal smooth muscle regeneration and TE.sponsorship: The authors would like to acknowledge the NIHR Great Ormond Street Hospital Biomedical Research Centre which supports all research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Additional support for this project was provided by Horizon 2020 INTENS funding. NT is supported by Great Ormond Street Hospital Children's Charity. SP's PhD studentship is funded through a GOSHCC grant awarded to NT. CM is supported by Guts UK (Derek Butler Fellowship). PDC is supported by National Institute for Health Research (NIHR-RP-2014-04-046). (NIHR Great Ormond Street Hospital Biomedical Research Centre, Horizon 2020 INTENS funding, Great Ormond Street Hospital Children's Charity, GOSHCC, Guts UK (Derek Butler Fellowship), National Institute for Health Research|NIHR-RP-2014-04-046)status: Publishe
Author Response: Alex B. Munster, Angelo J. Franchini, Mahim I. Qureshi, Ankur Thapar, Alun H. Davies, London
No full textLetter to the Editor which raises questions for Catholic Priests
No full textThis letter deals with the problem of atheism and Catholicism. After mourning the loss of a Jesuit priest, the author turns to a previous issue of the paper. In that issue a prominent Jesuit administrator of the Calcutta Province of the Jesuits had praised Romila Thapar. This letter asks whether Thapar is acceptable to Catholic Christianity since she is avowedly an atheist. The Catholic priest in question did not reply and continues in his priestly office. The then editor of the Herald printed this letter in totality
Letter to the Editor which raises questions for Catholic Priests
No full textThis letter deals with the problem of atheism and Catholicism. After mourning the loss of a Jesuit priest, the author turns to a previous issue of the paper. In that issue a prominent Jesuit administrator of the Calcutta Province of the Jesuits had praised Romila Thapar. This letter asks whether Thapar is acceptable to Catholic Christianity since she is avowedly an atheist. The Catholic priest in question did not reply and continues in his priestly office. The then editor of the Herald printed this letter in totality
The prolyl isomerase pin1 regulates mRNA levels of genes with short half-lives by targeting specific RNA binding proteins.
No full textThe peptidyl-prolyl isomerase Pin1 is over-expressed in several cancer tissues is a potential prognostic marker in prostate cancer, and Pin1 ablation can suppress tumorigenesis in breast and prostate cancers. Pin1 can co-operate with activated ErbB2 or Ras to enhance tumorigenesis. It does so by regulating the activity of proteins that are essential for gene expression and cell proliferation. Several targets of Pin1 such as c-Myc, the Androgen Receptor, Estrogen Receptor-alpha, Cyclin D1, Cyclin E, p53, RAF kinase and NCOA3 are deregulated in cancer. At the posttranscriptional level, emerging evidence indicates that Pin1 also regulates mRNA decay of histone mRNAs, GM-CSF, Pth, and TGFβ mRNAs by interacting with the histone mRNA specific protein SLBP, and the ARE-binding proteins AUF1 and KSRP, respectively. To understand how Pin1 may affect mRNA abundance on a genome-wide scale in mammalian cells, we used RNAi along with DNA microarrays to identify genes whose abundance is significantly altered in response to a Pin1 knockdown. Functional scoring of differentially expressed genes showed that Pin1 gene targets control cell adhesion, leukocyte migration, the phosphatidylinositol signaling system and DNA replication. Several mRNAs whose abundance was significantly altered by Pin1 knockdown contained AU-rich element (ARE) sequences in their 3' untranslated regions. We identified HuR and AUF1 as Pin1 interacting ARE-binding proteins in vivo. Pin1 was also found to stabilize all core histone mRNAs in this study, thereby validating our results from a previously published study. Statistical analysis suggests that Pin1 may target the decay of essential mRNAs that are inherently unstable and have short to medium half-lives. Thus, this study shows that an important biological role of Pin1 is to regulate mRNA abundance and stability by interacting with specific RNA-binding proteins that may play a role in cancer progression
Modeling age-related differences in immediate memory using SIMPLE
No full textIn the SIMPLE model (Scale Invariant Memory and Perceptual Learning), performance on memory tasks is determined by the locations of items in multidimensional space, and better performance is associated with having fewer close neighbors. Unlike most previous simulations with SIMPLE, the ones reported here used measured, rather than assumed, dimensional values. The data to be modeled come from an experiment in which younger and older adults recalled lists of acoustically confusable and nonconfusable items. A multidimensional scaling solution based on the memory confusions was obtained. SIMPLE accounted for the overall difference in performance both between the two age groups and, within each age group, the overall difference between acoustically confusable and nonconfusable items in terms of the MDS coordinates. Moreover, the model accounted for the serial position functions and error gradients. Finally, the generality of the model’s account was examined by fitting data from an already published study. The data and the modeling support the hypothesis that older adults’ memory may be worse, in part, because of altered representations due to age-related auditory perceptual deficits
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