Cysteine Modifiers Suggest an Allosteric Inhibitory Site on the CAL PDZ Domain

Protein–protein interactions have become attractive targets for both experimental and therapeutic interventions. The PSD-95/Dlg1/ZO-1 (PDZ) domain is found in a large family of eukaryotic scaffold proteins that plays important roles in intracellular trafficking and localization of many target proteins. Here, we seek inhibitors of the PDZ protein that facilitates post-endocytic degradation of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR): the CFTR-associated ligand (CAL). We develop and validate biochemical screens and identify methyl-3,4-dephostatin (MD) and its analog ethyl-3,4-dephostatin (ED) as CAL PDZ inhibitors. Depending on conditions, MD can bind either covalently or non-covalently. Crystallographic and NMR data confirm that MD attacks a pocket at a site distinct from the canonical peptide-binding groove, and suggests an allosteric connection between target residue Cys319 and the conserved Leu291 in the GLGI motif. MD and ED thus appear to represent the first examples of small-molecule allosteric regulation of PDZ:peptide affinity. Their mechanism of action may exploit the known conformational plasticity of the PDZ domains and suggests that allosteric modulation may represent a strategy for targeting of this family of protein–protein binding modules

Complex thermal expansion properties in a molecular honeycomb lattice

[FeL3][BF4]2·xH2O (L = 3-(pyrazinyl)-1H-pyrazole) shows negative thermal expansion between 150–240 K but positive thermal expansion at 240–300 K, linked to rearrangement of anions and water molecules within pores in the lattice.</p

Discovery of Novel, Orally Bioavailable, Antileishmanial Compounds Using Phenotypic Screening

Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug

Seismic imaging in Long Valley, California, by surface and borehole techniques: An investigation of active tectonics

The search for silicic magma in the upper crust is converging on the Long Valley Caldera of eastern California, where several lines of geophysical evidence show that an active magma chamber exists at mid‐to lower‐crustal depths. There are also other strong indications that magma may be present at depths no greater than about 5 km below the surface. In this paper, we review the history of the search for magma at Long Valley. We also present the preliminary results from a coordinated suite of seismic experiments, conducted by a consortium of institutions in the summer and fall of 1984, that were designed to refine our knowledge of the upper extent of the magma chamber. Major funding for the experiments was provided by the Geothermal Research Program of the U.S. Geological Survey (USGS) and by the Magma Energy Technology Program of the U.S. Department of Energy (DOE), a program to develop the technology necessary to extract energy directly from crustal magma. Additional funding came from DOE's Office of Basic Energy Sciences and the National Science Foundation (NSF). Also, because extensive use was made of a 0.9‐km‐deep well lent to us by Santa Fe Geothermal, Inc., the project was conducted partly under the auspices of the Continental Scientific Drilling Program (CSDP). As an integrated seismic study of the crust within the caldera that involved the close cooperation of a large number of institutions, the project was moreover viewed as a prototype for future scientific experiments to be conducted under the Program for Array Seismic Studies of the Continental Lithosphere (PASSCAL). The experiment thus represented a unique blend of CSDP and PASSCAL methods, and achieved goals consistent with both programs

PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function

1960: Abilene Christian College Lectures - Full Text

Table of Contents: Theme Speeches: Christian Faith in the Modern World Basis of Faith - Leonard Mullens - 9 Authority in Christianity - John T. Smithson, Jr. - 27 Origin and Preservation of the Bible - Neil R. Lightfoot - 44 Alleged Discrepancies of the Bible - David H. Bobo - 62 The Unity of the Bible - Jack Meyer - 91 Faith and Reason - Joe Sanders - 115 The Reasonableness of Supernaturalism - Virgil Trout - 126 The Present Statue of the Doctrine of Organic Evolution - J.D. Thomas - 146 The Nature of Man - Roy F. Osborne, Jr. - 181 Modern Challenges to Christian Morals - Carl Spain - 199 The Christ, Whose Son is He? - Gordon Teel - 232 Special Speeches Teaching the Word of God in Korea - L. Haskell Chessfire - 255 The Influence of Christian Education - Judge Jack Pope - 276 Mission Opportunities in the Far East - Harry Robert Fox - 288 Mission Work in Austria - Robert Skelton - 303 Report from Switzerland - Heinrich Blum - 313 The Work in Nigeria - Rees Byrant - 320 The Training of Evangelists in Foreign Fields - Reiner Kallus - 331 Christian Scholarships - Everett Ferguson - 340 Evangelizing the World - A.R. Holton - 349 Panel Discussions The Significance of the Dead Sea Scrolls The Scrolls and the Text of the Bible - Paul Rotenberry - 357 The Relation between the Religion of the Essenes and that of Early Christians - Jay Smith - 366 Biblical Interpretation Expediency and Pattern Authority - J.W. Roberts - 381 Examples in Pattern Authority - Thomas B. Warren - 392 Mental Health and Sin The Present State of Mental Health Knowledge - Donald R. Sime - 409 The Relationship of Mental Health Problems to Sin - Paul Easley - 421 The Teenager The Problems of Youth - Mack Wayne Craig - 432 Influences for Good - Wyatt Sawyer - 443 The Benefits of Abilene Christian College To the Church - Hulen Jackson - 451 To The Home - Robert S. Bell - 459 \u27To the Community - Louie Welch - 465 Expenses At Abilene Christian College - James C. Kerr - 469 The Graduate School at Abilene Christian College What I Am Getting Now in the ACC Graduate Program - Harold Vanderpool - 475 How the ACC Graduate Program Has Stood Up - Everett Ferguson - 481 What the ACC Graduate Program Ought To Be - Frank Pack - 486 The Importance to the Church of the ACC Graduate Program A.R. Holton - 490 Beware: Large File Size Uploaded by Jackson Hage

Seismic imaging in Long Valley, California, by surface and borehole techniques: An investigation of active tectonics

The search for silicic magma in the upper crust is converging on the Long Valley Caldera of eastern California, where several lines of geophysical evidence show that an active magma chamber exists at mid‐to lower‐crustal depths. There are also other strong indications that magma may be present at depths no greater than about 5 km below the surface. In this paper, we review the history of the search for magma at Long Valley. We also present the preliminary results from a coordinated suite of seismic experiments, conducted by a consortium of institutions in the summer and fall of 1984, that were designed to refine our knowledge of the upper extent of the magma chamber. Major funding for the experiments was provided by the Geothermal Research Program of the U.S. Geological Survey (USGS) and by the Magma Energy Technology Program of the U.S. Department of Energy (DOE), a program to develop the technology necessary to extract energy directly from crustal magma. Additional funding came from DOE's Office of Basic Energy Sciences and the National Science Foundation (NSF). Also, because extensive use was made of a 0.9‐km‐deep well lent to us by Santa Fe Geothermal, Inc., the project was conducted partly under the auspices of the Continental Scientific Drilling Program (CSDP). As an integrated seismic study of the crust within the caldera that involved the close cooperation of a large number of institutions, the project was moreover viewed as a prototype for future scientific experiments to be conducted under the Program for Array Seismic Studies of the Continental Lithosphere (PASSCAL). The experiment thus represented a unique blend of CSDP and PASSCAL methods, and achieved goals consistent with both programs

MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C)

Background Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. Methods This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. Findings Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. Interpretation A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. Funding This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists

Instruments to assess the perception of physicians in the decision-making process of specific clinical encounters: a systematic review

<p>Abstract</p> <p>Background</p> <p>The measurement of processes and outcomes that reflect the complexity of the decision-making process within specific clinical encounters is an important area of research to pursue. A systematic review was conducted to identify instruments that assess the perception physicians have of the decision-making process within specific clinical encounters.</p> <p>Methods</p> <p>For every year available up until April 2007, PubMed, PsycINFO, Current Contents, Dissertation Abstracts and Sociological Abstracts were searched for original studies in English or French. Reference lists from retrieved studies were also consulted. Studies were included if they reported a self-administered instrument evaluating physicians' perceptions of the decision-making process within specific clinical encounters, contained sufficient description to permit critical appraisal and presented quantitative results based on administering the instrument. Two individuals independently assessed the eligibility of the instruments and abstracted information on their conceptual underpinnings, main evaluation domain, development, format, reliability, validity and responsiveness. They also assessed the quality of the studies that reported on the development of the instruments with a modified version of STARD.</p> <p>Results</p> <p>Out of 3431 records identified and screened for evaluation, 26 potentially relevant instruments were assessed; 11 met the inclusion criteria. Five instruments were published before 1995. Among those published after 1995, five offered a corresponding patient version. Overall, the main evaluation domains were: satisfaction with the clinical encounter (n = 2), mutual understanding between health professional and patient (n = 2), mental workload (n = 1), frustration with the clinical encounter (n = 1), nurse-physician collaboration (n = 1), perceptions of communication competence (n = 2), degree of comfort with a decision (n = 1) and information on medication (n = 1). For most instruments (n = 10), some reliability and validity criteria were reported in French or English. Overall, the mean number of items on the modified version of STARD was 12.4 (range: 2 to 18).</p> <p>Conclusion</p> <p>This systematic review provides a critical appraisal and repository of instruments that assess the perception physicians have of the decision-making process within specific clinical encounters. More research is needed to pursue the validation of the existing instruments and the development of patient versions. This will help researchers capture the complexity of the decision-making process within specific clinical encounters.</p