gebhart/patrepeval huggingface dataset:
The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor (2001)

The mammalian hairless (hr) gene plays a critical role in the maintenance of hair growth. Although the hr gene has been identified, the biochemical function of its encoded protein (Hr) has remained obscure. Here, we show that Hr functions as a transcriptional corepressor for thyroid hormone receptors (TRs). We find that two independent regions of Hr mediate TR binding and that interaction requires a cluster of hydrophobic residues similar to the binding motifs proposed for nuclear receptor corepressors (N-CoR and SMRT). Similarly, we show that Hr binds to the same region of TR as known corepressors. We show that Hr interacts with histone deacetylases (HDACs) and is localized to matrix-associated deacetylase (MAD) bodies, indicating that the mechanism of Hr-mediated repression is likely through associated HDAC activity. Thus, Hr is a component of the corepressor machinery, and despite its lack of sequence identity with previously described corepressors, its mode of action is remarkably conserved. On the basis of its thyroid hormone-inducible and tissue- and developmental-specific expression, Hr likely defines a new class of nuclear receptor corepressors that serve a more specialized role than ubiquitous corepressors. The discovery that Hr is a corepressor provides a molecular basis for specific hair loss syndromes in both humans and mice.
The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family (2017)

Interferons (IFNs) are a broad class of cytokines elicited on challenge to the host defense and are essential for mobilizing immune responses to pathogens. Divided into three classes, type I, type II, and type III, all IFNs share in common the ability to evoke antiviral activities initiated by the interaction with their cognate receptors. The nine-member IFN regulatory factor (IRF) family, first discovered in the context of transcriptional regulation of type I IFN genes following viral infection, are pivotal for the regulation of the IFN responses. In this review, we briefly describe cardinal features of the three types of IFNs and then focus on the role of the IRF family members in the regulation of each IFN system.
Transformation of cereals via Agrobacterium and the pollen pathway: a critical assessment (1992)

Summary It has been proposed that transgenic plants of cereals can be generated by inoculating florets with Agrobacterium at or near anthesis. This procedure is shown to lead to the production of embryos of wheat and barley with enhanced resistance to antibiotic selection. It has also been possible to recover plants of wheat, barley and maize that gave positive hybridization signals with probes produced from within the T‐DNA of the Agrobacterium vector. However, no evidence was found for transmission of the bands detected by hybridization in the progeny of the putative transgenic plants nor could enzyme activity associated with the resistance genes be found in plant extracts. Furthermore, undigested genomic DNA from the plants that were positive when probed with the T‐DNA, showed hybridization to bands smaller than the genomic DNA. It is suggested that the apparent transformation is an artifact of the procedure and does not reflect transformation of the plant nuclear genome.
Staphylococcal alpha-toxin: oligomerization of hydrophilic monomers to form amphiphilic hexamers induced through contact with deoxycholate detergent micelles. (1981)

Native staphylococcus aureus alpha-toxin is secreted as a hydrophilic polypeptide chain of Mr 34,000. The presence of deoxycholate above the critical micellar concentration induced the toxin monomers to self-associate, forming ring or cylindrical oligomers. The oligomers were amphiphilic and bound detergent. In deoxycholate solution, the protein-detergent complexes exhibited a sedimentation coefficient of 10.4 S. A Mr of 238,700 was determined by ultracentrifugation analyses at sedimentation equilibrium. Because quantitative detergent-binding studies indicated a protein/detergent ratio of approximately 5:1 (wt/wt), the protein moiety in each protein-detergent complex was determined to be approximately Mr 200000, corresponding to a hexamer of the native molecule. The amphiphilic toxin hexamers were ultrastructurally indistinguishable from the cytolytic, annular toxin complexes that form on and in biological target membranes. They bound lipid and could be incorporated into artificial lecithin lipid vesicles. The transition of toxin protein molecules from a hydrophilic monomer to an amphiphilic oligomer through self-association has thus been shown to be inducible solely through contact of the native protein molecules with an appropriate amphiphilic substrate.
A Chest‐Laminated Ultrathin and Stretchable E‐Tattoo for the Measurement of Electrocardiogram, Seismocardiogram, and Cardiac Time Intervals (2019)

Seismocardiography (SCG) is a measure of chest vibration associated with heartbeats. While skin soft electronic tattoos (e-tattoos) have been widely reported for electrocardiogram (ECG) sensing, wearable SCG sensors are still based on either rigid accelerometers or non-stretchable piezoelectric membranes. This work reports an ultrathin and stretchable SCG sensing e-tattoo based on the filamentary serpentine mesh of 28-µm-thick piezoelectric polymer, polyvinylidene fluoride (PVDF). 3D digital image correlation (DIC) is used to map chest vibration to identify the best location to mount the e-tattoo and to investigate the effects of substrate stiffness. As piezoelectric sensors easily suffer from motion artifacts, motion artifacts are effectively reduced by performing subtraction between a pair of identical SCG tattoos placed adjacent to each other. Integrating the soft SCG sensor with a pair of soft gold electrodes on a single e-tattoo platform forms a soft electro-mechano-acoustic cardiovascular (EMAC) sensing tattoo, which can perform synchronous ECG and SCG measurements and extract various cardiac time intervals including systolic time interval (STI). Using the EMAC tattoo, strong correlations between STI and the systolic/diastolic blood pressures, are found, which may provide a simple way to estimate blood pressure continuously and noninvasively using one chest-mounted e-tattoo.
Poly- -hydroxybutyrate/Calcium Polyphosphate Complexes in Eukaryotic Membranes (1989)

Poly-beta-hydroxybutyrate/calcium polyphosphate (PHB-CaPolyPi) complexes exist as labile quasi-crystalline structures in bacterial plasma membranes. The composition, structure, and distribution of the complex suggest it may play a role in the regulation of intracellular calcium and in calcium signaling. The importance of these functions led to this investigation of the occurrence of PHB-CaPolyPi complexes in eukaryotes. A variety of plant and animal systems were analyzed and all were found to contain PHB associated with CaPolyPi. The intracellular location of the complex in bovine liver was primarily the mitochondria and microsomes, with smaller amounts in the plasma membranes. Eukaryotic PHB had the same narrow range of chain lengths (120-200 subunits) as PHB in bacterial membranes, and was associated with PolyPi of somewhat greater length (170-220) than the bacterial counterpart (130-170).
Setting Objectives, Facing Trade-Offs (2011)

This chapter makes six points. First, policy makers have identified four key labor market policy objectives—create more jobs, raise the earnings of those working, increase social protection, and ensure that core labor standards are honored—and should keep all four in mind and not go after just one heedless of the other three. Second, while each of these four objectives is important in its own right, the overriding objective in the author's view is reducing poverty to the maximum extent possible. Third, policies aimed at helping advance one labor market policy objective may be harmful to another; tradeoffs on the policy side need to be faced explicitly. Fourth, resources always have alternative uses; tradeoffs on the budgetary side also need to be faced explicitly. Fifth, a good way to bring all of these considerations together is to ask about the size of the extra social benefits, the size of the extra social costs, and how they compare for one or more uses of a development budget; it is better to answer the right questions approximately than to answer the wrong questions precisely. And sixth, when the right questions are asked but the answers are not known, it would be good to carry out in-depth research to find out the answers; econometric studies and randomized experiments both have an important place in discovering what matters.
A proteome analysis of conditioned media from human neonatal fibroblasts used in the maintenance of human embryonic stem cells (2005)

The pathways involved in the maintenance of human embryonic stem (hES) cells remain largely unknown, although some signaling pathways have been identified in mouse embryonic stem (mES) cells. Fibroblast feeder layers are used to maintain the undifferentiated growth of hES cells and an examination of the conditioned media (CM) of human neonatal fibroblasts (HNFs) could provide insights into the maintenance of hES cells. The neonatal foreskin fibroblast line (HNF02) used in this study was shown to have a normal 2n = 46, XY chromosomal complement and to support the undifferentiated growth of the Embryonic Stem Cell International Pte. Ltd.-hES3 cell line. The CM of HNF02 was examined using two-dimensional liquid chromatography-tandem mass spectrometry (2-D LCMS) and two-dimensional electrophoresis (2-DE) followed by matrix-assisted laser desorption/ionization-time of flight tandem mass spectrometry (2-DE/MALDI). A total of 102 proteins were identified, 19 by 2-DE/MALDI, 53 by 2-D LCMS and 30 by both techniques. These proteins were classified into 15 functional groups. Proteins identified in the extracellular matrix and differentiation and growth factor functional categories were considered most likely to be involved in the maintenance of hES cell growth, differentiation and pluripotency as these groups contained proteins involved in a variety of events including cell adhesion, cell proliferation and inhibition of cell proliferation, Wnt signaling and inhibition of bone morphogenetic proteins.
Evidence supporting a physiological role for proANP-(1–30) in the regulation of renal excretion (2001)

The experiments, performed in pentobarbital sodium-anesthetized rats, consisted of a 1-h equilibration period followed by two 30-min control periods. Subsequently, synthetic rat pro atrial natriuretic peptide (ANP) [proANP-(1-30)] (n = 8) was given as a bolus of 10 microg in 1 ml of 0.9% saline followed by an infusion at 30 ng/min (20 microl/min) for six additional periods. Control rats (n = 6) received only 0.45% saline in the appropriate volumes. Mean arterial pressure, renal blood flow, and glomerular filtration rate did not change significantly in either group during the proANP-(1-30) infusion. Urine flow and potassium excretion increased approximately 50% in the proANP-(1-30)-infused group only (P < 0.05). Sodium excretion and fractional excretion of sodium, expressed as the change from their own baselines, were significantly increased by the proANP-(1-30) infusion (P < 0.05), whereas cGMP excretion was similar in both groups. These results suggest that the rat sequence of proANP-(1-30) produces a natriuresis in the rat independent of changes in hemodynamics and renal cGMP production. In a second study, rats (n = 8) were prepared as above and pretreated with 0.4 ml iv of rabbit serum containing an antibody directed against proANP-(1-30) (anti-proANP group). The rats were volume expanded with 3 ml of 6% albumin in Krebs and observed for 3 h to determine if the anti-proANP would attenuate the responses to volume expansion. Control rats (n = 7) received 0.4 ml of normal rabbit serum. The elevation in potassium excretion in response to volume expansion was significantly attenuated in the anti-proANP group (P < 0.05). Sodium excretion and urine flow responses also tended to be reduced but not significantly. These results suggest that in the rat, proANP-(1-30) plays a physiological role in regulating renal excretion.
Preclinical Evaluation of Novel Dendritic Cell-Based Prostate Cancer Vaccines (2008)

To enhance DC-based vaccines, we used the combination of a synthetic ligand-inducible CD40 receptor (iCD40) along with TLR-4 ligation in human monocyte-derived DCs. The iCD40 receptor permits targeted, reversible activation of CD40 in vivo, potentially bypassing the essential role of CD4+ T cells for activation of DCs. As a rigorous preclinical study of this approach, we evaluated key parameters of DC activation and function. While neither iCD40 nor TLR4 signaling alone led to high levels of IL-12p70 and IL-6, using iCD40 in combination with lipopolysaccharides (LPS) led to strongly synergistic production of both. Furthermore, this approach led to high expression of DC maturation markers, epitope-specific cytotoxic T cell and TH1 responses, as well as DC migration in vitro. Moreover, use of iCD40-modified and LPS-stimulated DCs led to targeted expansion of autologous T cells against the attractive tumor-associated antigen, prostate-specific membrane antigen (PSMA), supporting this technology as a potent strategy for DC-based prostate cancer immunotherapy.
A Series of Heterocyclic Inhibitors of Phenylalanyl‐tRNA Synthetases with Antibacterial Activity (2004)

Abstract For Abstract see ChemInform Abstract in Full Text.
Synthesis and Anticancer Evaluation of 4′-C-Methyl-2′-Fluoro Arabino Nucleosides (2009)

As part of an ongoing program to develop novel antitumor agents over the years, we have synthesized and evaluated a number of 4'-C-substituted nucleosides. A few years ago, we reported the first synthesis of 4'-C-hydroxymethyl-2'-fluoro arabino nucleosides, which did not exhibit any cytotoxicity. In our exploration of related compounds, we synthesized and evaluated the 4'-C-methyl-2'-fluoro arabino nucleosides in both the purine and pyrimidine series. In the pyrimidine series, 1-(4-C-methyl-2-fluoro-beta-D-arabinofuranosyl) cytosine (13) was found to be highly cytotoxic and had significant antitumor activity in mice implanted with human tumor xenografts. The synthesis and anticancer activity of this series of nucleosides are reported.
Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor (1998)

A neurosecretory pathway regulates a reversible developmental arrest and metabolic shift at the Caenorhabditis elegans dauer larval stage. Defects in an insulin-like signaling pathway cause arrest at the dauer stage. We show here that two C. elegans Akt/PKB homologs, akt-1 and akt-2, transduce insulin receptor-like signals that inhibit dauer arrest and that AKT-1 and AKT-2 signaling are indispensable for insulin receptor-like signaling in C. elegans. A loss-of-function mutation in the Fork head transcription factor DAF-16 relieves the requirement for Akt/PKB signaling, which indicates that AKT-1 and AKT-2 function primarily to antagonize DAF-16. This is the first evidence that the major target of Akt/PKB signaling is a transcription factor. An activating mutation in akt-1, revealed by a genetic screen, as well as increased dosage of wild-type akt-1 relieves the requirement for signaling from AGE-1 PI3K, which acts downstream of the DAF-2 insulin/IGF-1 receptor homolog. This demonstrates that Akt/PKB activity is not necessarily dependent on AGE-1 PI3K activity. akt-1 and akt-2 are expressed in overlapping patterns in the nervous system and in tissues that are remodeled during dauer formation.
Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase (1995)

Regional variations in the expression of a striatal enriched protein tyrosine phosphatase called STEP were studied in the adult rat brain by a combination of immunocytochemistry, lesion studies, Western blotting, and in situ hybridization. Monoclonal antibodies generated against STEP identified multiple polypeptides of M(r) 46, 37, 33 and a doublet of M(r) 64-66 kDa on Western blots. Although the three STEP immunoreactive bands with lower molecular weights were enriched in cytosolic fractions, the 64-66 kDa doublet was enriched in membrane fractions. All of the immunoreactive forms were abundant in the caudate-putamen and were present in lower amounts or were undetectable in other brain regions. In substantia nigra, the M(r) 64-66 kDa doublet was not detected but bands with M(r) 46, 37, and 33 kDa were present. Immunocytochemical and lesion experiments demonstrated that the cytosolic STEP isoforms present in the substantia nigra are in presynaptic axons originating from the projection neurons of the caudate putamen, which innervate this structure. Additional in situ hybridization studies showed that STEP mRNA expression patterns correlate with the patterns of immunocytochemical staining. These findings indicate that there are multiple polypeptide isoforms of STEP enriched in the basal ganglia and related structures which differ in terms of their intracellular locations and functional roles.
Treatment of Acute Postoperative Anemia with Recombinant Human Erythropoietin (1989)

Risks inherent in the administration of blood products have increased efforts to avoid homologous transfusion. Although this has increased interest in autologous transfusion and intraoperative salvage, little attention has been focused on efforts to enhance endogenous erythropoiesis as a method of minimizing exposure to homologous blood. Recombinant human erythropoietin (rHuEPO) has been shown to enhance erythropoiesis. The purpose of this study is to evaluate the effect of rHuEPO, administered postoperatively, on a model of acute blood loss. Eleven adult male baboons were randomized into two groups. All animals underwent a laparotomy and an exchange transfusion, with 6% hetastarch, to a final hematocrit of 15%. Group I (N = 6) received 1,000 units/kg of recombinant human erythropoietin daily for the first 14 postoperative days. Group II (N = 5) received an equivalent volume of placebo. All animals were given supplemental vitamin B12, folate and 200% of shed iron, as iron dextran IV, after exchange transfusion. Response was observed for a period of 35 days. All animals survived the protocol. There were no adverse reactions to rHuEPO or surgical complications. The hematocrits were similar between groups at baseline and after exchange transfusion. The maximal rate of erythropoiesis was significantly faster in the rHuEPO group (2.1 vs. 1.3%/day; p less than 0.01). The time required to return to hematocrits of 30% (9.9 vs. 17.4 days, p less than 0.001) and to baseline hematocrits (11.9 vs. 32.1 days, p less than 0.01) were both significantly shorter in the rHuEPO group. The data show that rHuEPO accelerates the recovery from anemia in the postoperative setting. Acceleration of erythropoiesis represents another alternative to homologous transfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of cytokines on the liver (1991)

Cytokines are essential for the communication not only between the liver and extrahepatic sites but also within the liver itself. Cytokines regulate the intermediary metabolism of amino acids, proteins, carbohydrates, lipids and minerals. Cytokines partially interact with classical hormones such as glucocorticoids, resulting in a complex network of mutual control. Since many cytokines exert growth factor-like activities in addition to their specific proinflammatory effects, the distinction between cytokines and growth factors is somewhat artificial. The liver is an important site of synthesis and the major clearance organ for several cytokines. In liver disease, cytokines are involved in the onset of intrahepatic immune responses (e.g., during viral hepatitis), in liver regeneration (e.g., after partial hepatectomy) and in the fibrotic and cirrhotic transformation of the liver such as chronic chemical injury or viral infection. Further studies of cytokine actions may lead to a better understanding of liver diseases and to the development of new immunomodulating therapeutic options.
Capillary electrophoresis‐based separation of transferrin sialoforms in patients with carbohydrate‐deficient glycoprotein syndrome (1997)

The heterogeneity associated with protein glycoforms has been a challenge to analytical chemists and the subject of structure-function studies for biochemists since their presence in biological systems had been confirmed some three decades ago. Initial investigations led to discoveries of synthetic and degradative pathways, and brief forays into functional determination of the "glyco" portion on the protein activity in glycoproteins. Only recently has it come to our understanding that variations from the "normal" glycosylation patterns might be indicative of pathological states. The presence of certain transferrin (Tf) glycoforms in human serum has been shown to correlate with certain clinical syndromes. Hence, the ability to separate and quantitatively measure the various forms of human Tf has become increasingly important. It this study, we demonstrate that a simple method utilizing a DB-17-coated capillary to slow endoosmotic flow and a sieving buffer containing hydroxyethyl cellulose allows for the resolution of sialoforms of transferrin. An analysis time of less than eight minutes allows for baseline resolution of the lower sialoforms of Tf, presenting a simple, rapid test for carbohydrate-deficient transferrin (CDT). We demonstrate the utility of this methodology for the facile diagnosis of carbohydrate-deficient glycoprotein syndrome, and postulate that it may allow for the detection of other carbohydrate-deficient protein-related disease states.
IL-Converting Enzyme/Caspase-1 Inhibitor VX-765 Blocks the Hypersensitive Response to an Inflammatory Stimulus in Monocytes from Familial Cold Autoinflammatory Syndrome Patients (2005)

Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.
Why Dialysis Patients Need Combination Therapy with Both Cholecalciferol and A Calcitriol Analogs (2010)

The roles of vitamin D, mediated through its conversion to 1,25-dihydroxyvitamin D(3) (calcitriol), have been expanded recently through new knowledge about the range of tissues capable of activating it and the breadth of the genes under its regulatory control. This basic science together with the fact that numerous studies across North America are revealing that vitamin D insufficiency/deficiency (as defined by 25-OH-D levels <30 ng/ml) is extremely common (>80%) in dialysis patients are indicative that these patients have two vitamin D-related problems that require different treatment regimens. Combinations of vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol) and an active calcitriol analog should be used to treat their vitamin D deficiency and their calcitriol hormone insufficiency, respectively. This mini-review provides the case for combination therapy.