gebhart/patrepeval huggingface dataset:
Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation (2014)

Interactions between platelets, leukocytes, and activated endothelial cells are important during microvascular occlusion; however, the regulatory mechanisms of these heterotypic cell-cell interactions remain unclear. Here, using intravital microscopy to evaluate mice lacking specific isoforms of the serine/threonine kinase AKT and bone marrow chimeras, we found that hematopoietic cell-associated AKT2 is important for neutrophil adhesion and crawling and neutrophil-platelet interactions on activated endothelial cells during TNF-α-induced venular inflammation. Studies with an AKT2-specific inhibitor and cells isolated from WT and Akt KO mice revealed that platelet- and neutrophil-associated AKT2 regulates heterotypic neutrophil-platelet aggregation under shear conditions. In particular, neutrophil AKT2 was critical for membrane translocation of αMβ2 integrin, β2-talin1 interaction, and intracellular Ca2+ mobilization. We found that the basal phosphorylation levels of AKT isoforms were markedly increased in neutrophils and platelets isolated from patients with sickle cell disease (SCD), an inherited hematological disorder associated with vascular inflammation and occlusion. AKT2 inhibition reduced heterotypic aggregation of neutrophils and platelets isolated from SCD patients and diminished neutrophil adhesion and neutrophil-platelet aggregation in SCD mice, thereby improving blood flow rates. Our results provide evidence that neutrophil AKT2 regulates αMβ2 integrin function and suggest that AKT2 is important for neutrophil recruitment and neutrophil-platelet interactions under thromboinflammatory conditions such as SCD.
[Hypophosphatasia]. (2017)

Hypophosphatasia (HPP) is an inborn metabolic bone disorder caused by loss-of-function mutations in the gene encoding tissue nonspecific alkaline phosphatase (TNSALP). The adult form can be mistaken with common osteoporosis and/or present recurrent metatarsal fractures, skeletal and muscular pain. Subtrochanteric femoral pseudofractures resembling bisphosphonate-associated atypical femoral fractures can also be present, and Bps are therefore contraindicated in HPP. Early tooth loss and renal calcifications can orient towards the diagnosis. The diagnosis is based on low serum ALP levels (< 40 U/L) and high ALP substrate levels, such as vitamin B6 (pyridoxin), eventually on genetic testing. Recent development of an enzyme replacement therapy offers new therapeutic perspectives in severe cases.
Activation Systems for Latent Matrix Metalloproteinase-2 are Upregulated Immediately after Focal Cerebral Ischemia (2003)

During focal cerebral ischemia, matrix metalloproteinase-2 (MMP-2) can contribute to the loss of microvessel integrity within ischemic regions by degrading the basal lamina. MMP-2 is secreted in latent form (pro-MMP-2), but the activation of pro-MMP-2 in the ischemic territory has not been shown. Immunohistochemical and in situ hybridization studies of the expression of the direct activators of MMP-2, MT1-MMP and MT3-MMP, and the indirect activation system tissue plasminogen activator, urokinase (u-PA), its receptor (u-PAR), and its inhibitor PAI-1 after middle cerebral artery occlusion/reperfusion were undertaken in basal ganglia samples from 26 adolescent male baboons. The expressions of all three MMPs, u-PA, u-PAR, and PA1-1, but not tissue plasminogen activator, were increased from 1 hour after middle cerebral artery occlusion in the ischemic core. mRNA transcripts confirmed the increases in latent MMP-2, u-PA, u-PAR, and PAI-1 antigen very early after middle cerebral artery occlusion. The expression patterns are consistent with secretion of pro-MMP-2 and its activators in the ischemic core, perhaps from separate cell compartments. The rapid and coordinate appearance of pro-MMP-2 and its activation apparatus suggest that in the primate striatum this protease may participate in matrix injury during focal cerebral ischemia.
Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet (2013)

Because the renin-angiotensin-aldosterone system has been implicated in the development of insulin resistance and promotion of fibrosis in some tissues, such as the vasculature, we examined the effect of eplerenone, a selective mineralocorticoid receptor (MR) antagonist, on nonalcoholic steatohepatitis (NASH) and metabolic phenotypes in a mouse model reflecting metabolic syndrome in humans. We adopted liver-specific transgenic (Tg) mice overexpressing the active form of sterol response element binding protein-1c (SREBP-1c) fed a high-fat and fructose diet (HFFD) as the animal model in the present study. When wild-type (WT) C57BL/6 and liver-specific SREBP-1c Tg mice grew while being fed HFFD for 12 wk, body weight and epididymal fat weight increased in both groups with an elevation in blood pressure and dyslipidemia. Glucose intolerance and insulin resistance were also observed. Adipose tissue hypertrophy and macrophage infiltration with crown-like structure formation were also noted in mice fed HFFD. Interestingly, the changes noted in both genotypes fed HFFD were significantly ameliorated with eplerenone. HFFD-fed Tg mice exhibited the histological features of NASH in the liver, including macrovesicular steatosis and fibrosis, whereas HFFD-fed WT mice had hepatic steatosis without apparent fibrotic changes. Eplerenone effectively ameliorated these histological abnormalities. Moreover, the direct suppressive effects of eplerenone on lipopolysaccharide-induced TNFα production in the presence and absence of aldosterone were observed in primary-cultured Kupffer cells and bone marrow-derived macrophages. These results indicated that eplerenone prevented the development of NASH and metabolic abnormalities in mice by inhibiting inflammatory responses in both Kupffer cells and macrophages.
BET Bromodomain Inhibition of MYC -Amplified Medulloblastoma (2013)

JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
Severe Burn Injuries and the Role of Elastin in the Design of Dermal Substitutes (2010)

Severe burn injuries are a major health problem as they can compromise whole body function and result in extensive emotional trauma exacerbated by prolonged hospital stay. Burn injury treatment has improved dramatically to increase the probability of survival, but burn survivors still suffer from excessive scarring and skin contractures, which substantially compromise their health and quality of life. Elastin is historically underrepresented in commercial dermal substitutes, yet deserves consideration because of its fundamental role in skin structure and function. Dermal elastic network is a strong determinant of skin resilience, texture, and quality but is not sufficiently regenerated following burn injury. In addition to its structural and mechanical roles, elastin has inherent cell signaling properties that promote a diverse range of cellular responses including chemotaxis, cell attachment, proliferation, and differentiation. Scaffold elasticity and regeneration of the elastic fiber system is now recognized as integral to the development of functional dermal substitutes. Dermal substitutes are intended to replace damaged dermal tissue in severe burn injuries. Elastin-based dermal substitutes have the potential to decrease wound contraction, improve scar appearance and functionality, and contribute to wound healing outcomes through a combination of elastin's mechanical and cell signaling properties.
Effect of antiviral drugs and hematopoietic growth factors on in vitro erythropoiesis. (1998)

Stem cell factor (SCF), hemin, and interleukin-3 (IL-3) increased colony growth in HIV+ and normal cultures. In control cultures, hematopoietic growth factors added singly increased growth 1.3- to 8-fold. Hematopoietic growth factors increased growth even in cultures containing antiviral drugs. In some instances growth factors restored growth to control levels. SCF, hemin, and IL-3 were most effective when combined.
Sequence requirements for synthetic peptide-mediated translocation to the nucleus. (1989)

The abilities of 18 synthetic peptides to target a carrier protein to the nucleus following microinjection into the cytoplasm of HeLa cells were determined. Eight of the sequences chosen for synthesis were based on published nuclear targeting regions as determined by gene fusion and deletion experiments. Six of these sequences were found to be effective when mimicked by a synthetic peptide and conjugated to a carrier protein. One additional peptide was based on a region of lamin L1, a nuclear protein from Xenopus laevis, in which the nuclear targeting region had not been previously investigated. This peptide was also able to target a carrier protein to the nucleus. Eight other peptides which resemble the known targeting signals had little or no nuclear targeting ability. Peptides which were able to target a carrier protein to the nucleus did so within 45 min of injection into the cytoplasm. Two peptides with little or no apparent nuclear targeting ability after 45 min were examined for longer times as well. No increase in nuclear accumulation was observed between 45 min and 4 h after cytoplasmic injection. Comparison of the sequences which were effective at nuclear targeting with those that were not revealed a possible consensus sequence for peptide-mediated nuclear transport.
Patient-controlled analgesic administration. A comparison of steady-state morphine infusions with bolus doses (1991)

The authors have shown previously that bone marrow transplant (BMT) patients who self-administered bolus doses of morphine gained equal oral mucositis pain relief while using less drug compared with similar patients receiving morphine by staff-controlled continuous infusion. In a follow-up study they compared the efficacy and side effects of morphine in two groups of marrow transplant patients who controlled their own analgesic administration either by conventional bolus-dose, patient-controlled analgesia (PCA) or by adjusting the rate of continuous morphine infusion to increase or decrease their plasma morphine concentration. Patients controlling their morphine infusion rates (pharmacokinetically based patient-controlled analgesia [PKPCA] group) obtained more relief from oral mucositis pain than did patients using conventional PCA. Patients in the PKPCA group used more morphine than PCA patients and achieved superior pain relief without significant increases in side effects (e.g., nausea, mood changes, sedation). The authors conclude that PKPCA improves the management of prolonged, severe pain in marrow transplant patients and that this approach to patient-controlled analgesia may be useful in other types of persistent pain.
Zika virus in the Americas: Early epidemiological and genetic findings (2016)

Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas.
Lysis of ras oncogene-transformed cells by specific cytotoxic T lymphocytes elicited by primary in vitro immunization with mutated ras peptide. (1994)

Ras protooncogenes are activated by characteristic point mutations in a wide variety of malignancies. The expressed p21ras proteins are oncogenic by virtue of single substituted amino acids, usually at position 12 or 61 of the 189-residue p21ras protein. In the current study, the ability of class I major histocompatibility complex (MHC)-restricted T cells to recognize the altered segment of a transforming p21ras protein and to lyse cells transformed by the corresponding ras oncogene was examined. Synthetic ras peptides encompassing the common activating substitution of leucine for glutamine at position 61 were constructed with an amino acid motif appropriate for binding to the H-2Kb murine class I MHC molecule. Cytotoxic T lymphocytes (CTL) specific for bound ras leucine 61 peptide were elicited by in vitro immunization of normal lymphocytes with synthetic peptides. The ras peptide-induced CTL specifically lysed syngeneic fibroblasts transformed by an activated ras gene encoding oncogenic p21ras protein containing the same single amino acid substitution. Thus, in some circumstances, mutated p21ras protein can serve as a tumor-specific antigen.
Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals (2014)

Nitrogen heterocycles are among the most significant structural components of pharmaceuticals. Analysis of our database of U.S. FDA approved drugs reveals that 59% of unique small-molecule drugs contain a nitrogen heterocycle. In this review we report on the top 25 most commonly utilized nitrogen heterocycles found in pharmaceuticals. The main part of our analysis is divided into seven sections: (1) three- and four-membered heterocycles, (2) five-, (3) six-, and (4) seven- and eight-membered heterocycles, as well as (5) fused, (6) bridged bicyclic, and (7) macrocyclic nitrogen heterocycles. Each section reveals the top nitrogen heterocyclic structures and their relative impact for that ring type. For the most commonly used nitrogen heterocycles, we report detailed substitution patterns, highlight common architectural cores, and discuss unusual or rare structures.
Noninvasive Raman Spectroscopy in Living Mice for Evaluation of Tumor Targeting with Carbon Nanotubes (2008)

An optimized noninvasive Raman microscope was used to evaluate tumor targeting and localization of single walled carbon nanotubes (SWNTs) in mice. Raman images were acquired in two groups of tumor-bearing mice. The control group received plain-SWNTs, whereas the experimental group received tumor targeting RGD-SWNTs intravenously. Raman imaging commenced over the next 72 h and revealed increased accumulation of RGD-SWNTs in tumor ( p < 0.05) as opposed to plain-SWNTs. These results support the development of a new preclinical Raman imager.
A Low-Loss Single-Pole-Double-Throw (SPDT) Switch Circuit (2007)

A low-loss single-pole-double-throw (SPDT) switch circuit using lateral RF MEMS switches has been developed on glass to operate from DC to 20 GHz. High compactness and low loss can be obtained by use of the lateral switches and coplanar waveguide (CPW) configuration. The circuit provides >24-dB isolation and <0.9-dB insertion loss up to 20 GHz. The pull-in voltage of the switch is only 12.4V, with a switching-on time of 35 μs and a switching-off time of 36 μs. A single-mask silicon-on-glass (SiOG) fabrication process has been developed to fabricate the SPDT switch circuit on glass, which has the advantages of low loss and high yield. The whole circuit has a size of 1.64mm × 1.3mm.
Molecular Recognition and Docking Algorithms (2003)

Molecular docking is an invaluable tool in modern drug discovery. This review focuses on methodological developments relevant to the field of molecular docking. The forces important in molecular recognition are reviewed and followed by a discussion of how different scoring functions account for these forces. More recent applications of computational chemistry tools involve library design and database screening. Last, we summarize several critical methodological issues that must be addressed in future developments.
Cytotoxicity Assay in Antibiotic-Associated Colitis (1979)

Journal Article Cytotoxicity Assay in Antibiotic-Associated Colitis Get access Te-Wen Chang, Te-Wen Chang Department of Medicine, New England Medical Center and Tufts University School of Medicine, Boston, MassachusettsDepartment of Medicine, Veterans Administration Hospital, Boston, Massachusetts Please address requests for reprints to Dr. Te-Wen Chang, New England Medical Center Hospital, 171 Harrison Avenue, Boston, Massachusetts 02111. Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Lauermann, Michael Lauermann Department of Medicine, New England Medical Center and Tufts University School of Medicine, Boston, MassachusettsDepartment of Medicine, Veterans Administration Hospital, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar John G. Bartlett John G. Bartlett Department of Medicine, New England Medical Center and Tufts University School of Medicine, Boston, MassachusettsDepartment of Medicine, Veterans Administration Hospital, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 140, Issue 5, December 1979, Pages 765–770, https://doi.org/10.1093/infdis/140.5.765 Published: 01 December 1979 Article history Revision received: 28 March 1979 Published: 01 December 1979 Received: 12 December 1979
Bapineuzumab (2010)

Bapineuzumab appears capable of reducing the cerebral beta-amyloid peptide burden in patients with Alzheimer's disease. However, particularly in APOE 4 carriers, its ability to slow disease progression remains uncertain, and vasogenic edema - a dose-limiting and potentially severe adverse reaction - may limit its clinical applicability.
Benzyl Complexes of the Heavier Alkaline-Earth Metals:  The First Crystal Structure of a Dibenzylstrontium Complex (2001)

The first benzylstrontium complex, di(2-Me2N-α-Me3Si-benzyl)strontium, has been prepared via reaction of the benzylpotassium complex with SrI2. The crystal structure of the bis(THF)-solvate complex shows hexacoordination at Sr. Structural analyses and NMR analyses of the related Li, K, and Ca complexes reveal that the delocalization of the negative charge in the phenyl ring is metal dependent and decreases along the row K > Li ≥ Sr > Ca. The presented benzylstrontium complex contains two chiral benzylic centers and forms diastereomers. In apolar solvents at room temperature both diastereomers are observed. Either higher temperatures or extra added THF ligands result in fast inversion of the chiral benzylic carbanion. The process is concentration independent and follows a dissociative mechanism in which one of the Sr−Cα bonds is broken. The chiral benzylic carbon atom in the strontium complex shows faster inversion than that in the analogue benzylcalcium complex (Ca, 0.07 M, ΔG⧧(60 °C) = 16.8 kcal mol-1; Sr, 0.08 M, ΔG⧧(30 °C) = 15.0 kcal mol-1). The new benzylstrontium complex is an active initiator for the anionic living polymerization of styrene and is more reactive than its Ca analogue.
Tumor Necrosis Factor α-induced Phosphorylation of Insulin Receptor Substrate-1 (IRS-1) (1995)

Tumor necrosis factor-alpha (TNF) has been suggested to be the mediator of insulin resistance in infection, tumor cachexia, and obesity. We have previously shown that TNF diminishes insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1). The current work examines potential mechanisms that mediate this event. TNF effect on IRS-1 in Fao hepatoma cells was not associated with a significant reduction in insulin receptor tyrosine kinase activity as measured in vitro but impaired the association of IRS-1 with phosphatidylinositol 3-kinase, localizing TNF impact to IRS-1. TNF did not increase protein-tyrosine phosphatase activity and protein-tyrosine phosphatase inhibition by vanadate did not change TNF effect on IRS-1 tyrosine phosphorylation, suggesting that protein-tyrosine phosphatases are not involved in this TNF effect. In contrast, TNF increased IRS-1 phosphorylation on serine residues, leading to a decrease in its electrophoretic mobility. TNF effect on IRS-1 tyrosine phosphorylation was not abolished by inhibiting protein kinase C using staurosporine, while inactivation of Ser/Thr phosphatases by calyculin A and okadaic acid mimicked it. Our data suggest that TNF induces serine phosphorylation of IRS-1 through inhibition of serine phosphatases or activation of serine kinases other than protein kinase C. This increased serine phosphorylation interferes with insulin-induced tyrosine phosphorylation of IRS-1 and impairs insulin action.
Assessment of measurement errors for galvanic-resistivity electrodes of different composition (2008)

Abstract This research provides an empirical study of electrodes used to measure galvanic resistivity. The central element of this work is an estimation of errors in resistivity measurements that arise because of the type of electrode material used. Fourteen types of electrodes were tested including metal electrodes, metal-salt-compound (nonpolarizing) electrodes, and one nonmetal electrode, under conditions that are typical of those encountered during geophysical surveys. Measurement errors for resistance and chargeability were estimated using the reciprocity of data from an array of electrodes such as might be used for electric-resistance tomography. The same error analysis was applied to data from a network of high-precision resistors to separate instrument errors from electrode errors. Significant differences were observed in errors produced by different electrode materials. We conclude that the choice of electrode is very important for resistivity or chargeability surveys. Iron, steel (including rebar), lead, and phosphor bronze produced the smallest errors in resistance and chargeability. Aluminum, magnesium, titanium, copper, and zinc produced the largest errors. Stainless steel (alloy 316), tin, and brass performed reasonably well, as did carbon, which was the only nonmetal tested.