264 research outputs found
A study of the design and real-time implementation of a semi-generic integer-to-integer discrete wavelet transform
Genome-Wide Requirements for Resistance to Functionally Distinct DNA-Damaging Agents
The mechanistic and therapeutic differences in the cellular response to DNA-damaging compounds are not completely understood, despite intense study. To expand our knowledge of DNA damage, we assayed the effects of 12 closely related DNA-damaging agents on the complete pool of ~4,700 barcoded homozygous deletion strains of Saccharomyces cerevisiae. In our protocol, deletion strains are pooled together and grown competitively in the presence of compound. Relative strain sensitivity is determined by hybridization of PCR-amplified barcodes to an oligonucleotide array carrying the barcode complements. These screens identified genes in well-characterized DNA-damage-response pathways as well as genes whose role in the DNA-damage response had not been previously established. High-throughput individual growth analysis was used to independently confirm microarray results. Each compound produced a unique genome-wide profile. Analysis of these data allowed us to determine the relative importance of DNA-repair modules for resistance to each of the 12 profiled compounds. Clustering the data for 12 distinct compounds uncovered both known and novel functional interactions that comprise the DNA-damage response and allowed us to define the genetic determinants required for repair of interstrand cross-links. Further genetic analysis allowed determination of epistasis for one of these functional groups
Interrogating a Hexokinase-Selected Small-Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase
This is the published version.Parasites in the genus Plasmodium cause disease throughout the tropic and subtropical regions of the world. P. falciparum, one of the deadliest species of the parasite, relies on glycolysis for the generation of ATP while it inhabits the mammalian red blood cell. The first step in glycolysis is catalyzed by hexokinase (HK). While the 55.3-kDa P. falciparum HK (PfHK) shares several biochemical characteristics with mammalian HKs, including being inhibited by its products, it has limited amino acid identity (âź26%) to the human HKs, suggesting that enzyme-specific therapeutics could be generated. To that end, interrogation of a selected small-molecule library of HK inhibitors has identified a class of PfHK inhibitors, isobenzothiazolinones, some of which have 50% inhibitory concentrations (IC50s) of <1 ÎźM. Inhibition was reversible by dilution but not by treatment with a reducing agent, suggesting that the basis for enzyme inactivation was not covalent association with the inhibitor. Lastly, six of these compounds and the related molecule ebselen inhibited P. falciparum growth in vitro (50% effective concentration [EC50] of âĽ0.6 and <6.8 ÎźM). These findings suggest that the chemotypes identified here could represent leads for future development of therapeutics against P. falciparum
Copper (I) SNS Pincer Complexes: Impact of Ligand Design and Solvent Coordination on Conformer Interconversion from Spectroscopic and Computational Studies
The syntheses and detailed characterizations (X-ray crystallography, NMR spectroscopy, cyclic voltammetry, infrared spectroscopy, electrospray mass spectrometry, and elemental analyses) of two new Cu(I) pincer complexes are reported. The pincer ligand coordinates through one nitrogen and two sulfur donor atoms and is based on bis-imidazole or bis-triazole precursors. These tridentate SNS ligands incorporate pyridine and thione-substituted imidazole or triazole functionalities with connecting methylene units that provide flexibility to the ligand backbone and enable high bite-angle binding. Variable temperature 1H NMR analysis of these complexes and of a similar zinc(II) SNS system shows that all are fluxional in solution and permits the determination of ÎGexp⥠and ÎSexpâĄ. DFT calculations are used to model the fluxionality of these complexes and indicate that a coordinating solvent molecule can promote hemilability of the SNS ligand by lowering the energy barrier involved in the partial rotation of the methylene units
Benign perimesencephalic hemorrhage occurring after previous aneurysmal subarachnoid hemorrhage: a case report
<p>Abstract</p> <p>Introduction</p> <p>Both aneurysmal subarachnoid hemorrhage and benign perimesencephalic hemorrhage are well-described causes of spontaneous subarachnoid hemorrhage that arise as a result of different pathologic processes. To the best of the authors' knowledge, there have been no reports of both vascular pathologies occurring in the same individual.</p> <p>Case presentation</p> <p>A 51-year-old Caucasian woman with a history of aneurysmal subarachnoid hemorrhage presented five years after her initial treatment with ictal headache, meningismus, nausea and emesis similar to her previous bleeding event. Computed tomographic imaging revealed perimesencephalic bleeding remote from her previously coiled anterior communicating artery aneurysm. Both immediate and delayed diagnostic angiography revealed no residual filling of the previously coiled aneurysm and no other vascular anomalies, consistent with benign perimesencephalic hemorrhage. The patient had an uneventful hospital course and was discharged to home in good condition.</p> <p>Conclusions</p> <p>This report for the first time identifies benign perimesencephalic hemorrhage occurring in the setting of previous aneurysmal subarachnoid hemorrhage. The presence of a previously treated aneurysm can complicate the process of diagnosing benign perimesencephalic hemorrhage. Fortunately, in this case, the previously treated anterior communicating artery aneurysm was remote from the perimesencephalic hemorrhage and could be ruled out as a source. The patient's prior aneurysmal subarachnoid hemorrhage did not worsen the anticipated good outcome associated with benign perimesencephalic hemorrhage.</p
Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure
Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a âMITFâhighâ phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance âAXLâhighâ phenotype. > 50% of melanomas progress with enriched âAXLâhighâ populations, and because AXL is linked to deâdifferentiation and invasiveness avoiding an âAXLâhigh relapseâ is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITFâinduced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK reâactivation in a paracrine manner. Most importantly, EDN1 not only supports MITFâhigh populations through the endothelin receptor B (EDNRB), but also AXLâhigh populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXLâhighâexpressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXLâhigh cells
Academic Cancer Center Phase I Program Development
Multiple factors critical to the effectiveness of academic phase I cancer programs were assessed among 16 academic centers in the U.S. Successful cancer centers were defined as having broad phase I and I/II clinical trial portfolios, multiple investigatorâinitiated studies, and correlative science. The most significant elements were institutional philanthropic support, experienced clinical research managers, robust institutional basic research, institutional administrative efforts to reduce bureaucratic regulatory delays, phase I navigators to inform patients and physicians of new studies, and a large cancer center patient base. New programs may benefit from a separate standâalone operation, but mature phase I programs work well when many of the activities are transferred to diseaseâoriented teams. The metrics may be useful as a rubric for new and established academic phase I programs.This commentary assesses the factors necessary for the effectiveness of academic phase I cancer programs. The metrics presented here may be useful as a rubric for new and established programs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139928/1/onco12106-sup-0001-suppinfo1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139928/2/onco12106.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139928/3/onco12106-sup-0002-suppinfo2.pd
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