gebhart/patrepeval huggingface dataset:
Novel Protease Inhibitors (PIs) Containing Macrocyclic Components and 3( R ),3a( S ),6a( R )- bis -Tetrahydrofuranylurethane That Are Potent against Multi-PI-Resistant HIV-1 Variants In Vitro (2010)

Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
Mutations in Ribosomal Protein L16 and in 23S rRNA in Enterococcus Strains for Which Evernimicin MICs Differ (2002)

Mutations in ribosomal protein L16 and in 23S rRNA were investigated in 22 Enterococcus strains of different species and for which the MICs of evernimicin differ (MICs, 0.023 to 16 micro g/ml). Amino acid changes (Arg56His, Ile52Thr, or Arg51His) in protein L16 were found in seven strains, and a nucleotide G2535A mutation in 23S rRNA was found in 1 strain among 13 for which the MICs are > or =1 micro g/ml.
Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome (2001)

Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival after lung transplantation. Acute rejection, its main risk factor, is characterized by perivascular/bronchiolar leukocyte infiltration. BOS is characterized by persistent peribronchiolar leukocyte recruitment leading to airway fibrosis and obliteration. The specific mechanism(s) by which these leukocytes are recruited are unknown. Because MCP-1, acting through its receptor CCR2, is a potent mononuclear cell chemoattractant, we hypothesized that expression of this chemokine during an allogeneic-response promotes persistent recruitment of leukocytes and, ultimately, rejection. We found that elevated levels of biologically active MCP-1 in human bronchial lavage fluid (BALF) were associated with the continuum from acute to chronic allograft rejection. Translational studies in a murine model of BOS demonstrated increased MCP-1 expression paralleling mononuclear cell recruitment and CCR2 expression. Loss of MCP-1/CCR2 signaling, as seen in CCR2–/– mice or in WT mice treated with neutralizing antibodies to MCP-1, significantly reduced recruitment of mononuclear phagocytes following tracheal transplantation and led to attenuation of BOS. Lymphocyte infiltration was not reduced under these conditions. We suggest that MCP-1/CCR2 signaling plays an important role in recruitment of mononuclear phagocytes, a pivotal event in the pathogenesis of BOS.
Abstract 3719: Deletion of Angiotensin II type 2 Receptor Accelerates Adipogenesis in Murine Mesenchymal Stem Cells with Wnt 10b/beta-catenin Signaling: Potential Link to Obesity and Metabolic Syndrome (2008)

Recent evidence suggests that the reninangiotensin system (RAS) plays a vital role in adipocyte biology and the pathophysiology of metabolic syndrome. Obesity is a major risk factor and mesenchymal stem cells (MSCs) are suggested to be an important source of new fat cells. Previously we reported that MSCs have all the components of the RAS and that angiotensin II (Ang II) can influence adipocyte differentiation. However, the effect of Ang II type 2 receptor (AT2R) deletion on adipogenesis in mouse model is unknown. Accordingly, we employed AT2R-null mice and examined the role of AT2R in the differentiation of MSCs to adipocytes. Methods and Results: Murine MSCs were isolated from AT2R-null mice and wildtype littermates (WT). Confluent MSCs were differentiated into adipocytes by the established protocol. Adipogenesis was quantitated by assessing lipid droplet accumulation using 2 different methods. Using the fluorescent dye which binds to lipid droplets (AdipoRed), AT2R-null group showed significantly increased total fluorescence (261.6 ± 49.6 % vs. WT) on day 7. Oil red O staining, followed by extraction of the absorbed dye and measurement of the absorbance on day 14, also exhibited that AT2R-null group showed significantly increased lipid droplet accumulation (202.7 ± 14.1 % vs. WT). We next examined the expression of adipocyte-specific genes by real-time RT-PCR. AT2R-null group exhibited a significantly increased expression of PPARγ, fatty acid synthase, and adiponectin (vs. WT). Since Wnt 10b/beta-catenin signaling is reported to play an important role to inhibit adipogenesis, we further examined it by real-time RT-PCR and immunoblotting. The AT2R-null group exhibited significantly decreased Wnt 10b expression accompanied by a decrease of cellular beta-catenin (vs. WT). Conclusion: Our results demonstrate that the AT2 receptor has an inhibitory effect on adipogenic differentiation in murine mesenchymal stem cells. Moreover, this inhibitory effect is associated with Wnt 10b/beta-catenin signaling which plays an important role to inhibit adipogenesis. These results provide important insights into the pathophysiology of obesity and obesity related consequences such as metabolic syndrome and may identify potential therapeutic targets.
Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. (1987)

A previous report described the isolation of a directly transforming retrovirus, AKT8, from a spontaneous thymoma of an AKR mouse. The AKT8 provirus has now been molecularly cloned from a transformed, nonproducer cell line. The virus genome contains both viral and nonviral, cell-related sequences; the nonviral sequence has been designated v-akt, the presumed viral oncogene of the AKT8 virus. This gene lacks homology to the 16 other oncogenes tested. The cloned provirus has undergone a partial deletion, during cell passage in vitro, that prevents direct demonstration of the transforming ability of this molecular clone. Two human homologues of the v-akt oncogene, AKT1 and AKT2, were cloned. A survey of 225 human tumors for changes involving AKT1 led to the discovery of a 20-fold amplification of this gene in one of the five gastric adenocarcinomas tested. The results demonstrate that AKT8 has the characteristic structure of a directly transforming retrovirus and that it contains a gene derived from highly conserved cellular sequences that may be involved in the pathogenesis of some human malignancies.
[Toxoplasmic encephalitis in an HIV patient]. (2009)

Toxoplasmic encephalitis is considered one of the most frequent causes of death in HIV-positive patients. The article presents a case of a 40-year-old HIV-positive male hospitalized for surgical treatment of localized brain tumour verified by CT and MRI. Histopathologically, toxoplasmic aetiology was confirmed. Briefly, tissue toxoplasmosis represents a high risk among HIV-positive patients. Therefore, this disease must be considered in differential diagnosis of localized brain masses in HIV-positive patients.
Human Plasma Growth Hormone (GH)-Binding Proteins Are Regulated by GH and Testosterone* (1991)

Possible regulation of GH-binding proteins (GH-BPs) in human plasma was examined. Eight children with isolated GH deficiency had a very low level of plasma GH-binding activity (10.2 ± 1.1% of radioactivity). Under GH treatment the hormone binding to the high affinity BP (peak II-BP) increased in every patient to reach the mean value of 18.5 ± 1.4%. In one patient, Scatchard plot analysis indicated that this increase was related to a higher binding capacity without any significant change in the binding affinity. A positive correlation existed between the GH-binding activity and insulin-like growth factor-I plasma levels. In nine boys with pubertal delay, the GHspecific binding to peak II-BP was normal (30.6 ± 3.7% of radioactivity); it decreased significantly after testosterone treatment. In four boys with precocious puberty, the specific GH binding to peak II-BP was low (16.6 ± 1.1%). It increased significantly to 21.6 ± 1.1% of radioactivity after treatment with a LHRH analog. A negative correlation existed between plasma testosterone levels and GH binding to peak II-BP in boys presenting pubertal delay or precocious puberty. The high affinity GH-BP is regulated, and among the factors that play a role in this regulation, GH and testosterone have opposite effects.
A Fluorescence Turn-On Mechanism to Detect High Explosives RDX and PETN (2007)

A fluorescent chemosensor to detect saturated nitramine and nitrate ester explosives was devised based on a photochemical reduction reaction. 10-Methyl-9,10-dihydroacridine (AcrH2) was found to transfer a hydride ion equivalent to the high explosives RDX and PETN upon irradiation at 313 nm in degassed acetonitrile solutions. Mechanistic photophysical studies indicate that the photoreduction of RDX proceeds via a two-step electron−hydrogen atom transfer reaction, whereas PETN photoreduction proceeds via a three-step electron−proton−electron transfer sequence. A zinc analogue was synthesized and found to display an 80- or 25-fold increase in 480 nm emission intensity upon reaction with RDX or PETN, respectively. Moreover, the Zn analogue was found to be unresponsive to TNT and other common contaminants, in addition to being photostable under ambient conditions. On the basis of these characteristics, we report a powerful chemosensor that displays a direct fluorescent response to either RDX or PETN.
Activation of NF-E2–Related Factor-2 Reverses Biochemical Dysfunction of Endothelial Cells Induced by Hyperglycemia Linked to Vascular Disease (2008)

We conclude that activation of nrf2 may prevent biochemical dysfunction and related functional responses of endothelial cells induced by hyperglycemia in which increased expression of transketolase has a pivotal role.
Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants (2010)

Effective control of body weight and energy homeostasis requires stringent regulation of caloric intake and energy expenditure. Gut-brain interactions comprise a central axis for the control of energy homeostasis by integrating the intake of nutrients with an effective utilization of ingested calories either by storage or by expenditure as cellular fuel. Ghrelin, a stomach-derived peptide, is the only known circulating orexigenic hormone. It is acylated with a medium-chain fatty acid by the enzyme ghrelin O-acetyltransferase (GOAT) and displays a broad range of activity, from central control of food intake to peripheral functions such as gastric emptying and insulin secretion. PYY, a peptide produced by L cells of the small intestine and rectum, has been shown to inhibit gut motility and is proposed to stimulate a powerful central satiety response. In recent years, pharmacological studies in animals and clinical studies in humans have contributed to our knowledge of principal ghrelin and PYY actions. However, valuable findings from studies using ghrelin-deficient mice, ghrelin receptor [growth hormone secretagogue receptor-1a (GHSR1a)]-deficient mice, double-knockout mice (for ghrelin and GHSR), and GOAT-deficient or -overexpressor mice, as well as mice deficient for PYY or neuropeptide Y receptors have allowed better definition of the actual physiological functions of ghrelin and PYY. This review summarizes findings from mutant mouse studies with emphasis on respective gene knockout and transgenic animals and describes how these studies contribute to the current understanding of how endogenous ghrelin and PYY as two major representatives of endocrine gut-brain communications may regulate energy and glucose homeostasis.
S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas (2004)

S100A2 gene products were shown to be frequently and dramatically over-represented in non-small cell lung cancer (NSCLC) lesions over normal tissue by microarray analysis. We have now analysed an independent series of NSCLC tumours and multiple matched normal bronchial epithelial sites by RT-PCR and immunohistochemistry to investigate: whether this expression pattern can be confirmed and whether elevated expression is associated with tumour histology, clinical outcome or preneoplasia. In this second series, S100A2 was strongly expressed in 76% (35 out of 46) of tumours, more frequently in squamous cell than adenocarcinomas (P<0.002). This strong expression was not related to high-level gene amplification, but was associated in one of five informative cases with an allele-specific imbalance in transcript levels. Most tumours strongly expressed the DeltaNp63 transcript, the product of which is a putative regulator of S100A2 transcription and while all but one of the tumours positive for DeltaNp63 expressed S100A2, others negative for this regulator also expressed the gene. Contrary to the hypothesis that S100A2 is a tumour suppressor, no somatic mutations were identified in the coding sequence in 44 tumours. Furthermore, an examination of multiple tumour-free epithelial sites from 20 patients showed that strong expression was often associated with increasing levels of disorder in preinvasive bronchial lesions (P<0.0001).
Synthetic Applications of Nonpolymerizable Monomers in Living Cationic Polymerization: Functional Polyisobutylenes by End-Quenching (1995)

Abstract The chemistry and kinetics of 1,1-diphenylethylene (DPE) addition to living polyisobutylene was studied at -80°C in methyl chloride/n-hexanes or methylcyclohexane 40/60 v/v. Only monoaddition occurred even when large (9-fold) excess of 1,1-diphenylethylene was used. The kinetics of addition was established by 1H-NMR spectroscopy and by conductivity measurements. The methanol-quenched polymer of the DPE-capped PIB carried exclusively –OCH3 functionality, suggesting that all diphenyl alkyl chain-ends are ionized, which was confirmed by conductivity studies. It was determined that the diphenyl alkyl chain-ends are completely ionized when [TiCl4]/[chain end] ≥ 2 for chain-end concentrations ≥ 10−3 M. Close to quantitative end-quenching was achieved with 1-methoxy-1-(trimethylsiloxy)-2-methyl-1-propene and 1-cyclohexenyloxy-trimethylsilane.
MEASURING IN SITU MECHANICAL PROPERTIES OF PAVEMENT SUBGRADE SOILS (1999)

This synthesis report will be of interest to pavement and geotechnical design and research engineers, geologists and engineering geologists, and similar laboratory personnel. It describes the current practice for measuring the in situ mechanical properties of pavement subgrade soils. The tests conducted to estimate the mechanical properties of soil strength and stiffness are the primary topics, and these are discussed in the context of design procedures, factors affecting mechanical properties, and the variability of measurements. Information for the synthesis was collected by surveying U.S., Canadian, and selected European transportation agencies and by conducting a literature search. This report of the Transportation Research Board provides information on existing and emerging technologies for static and dynamic, and destructive and nondestructive testing for measuring in situ mechanical properties of pavement subgrade soils. Correlations between in situ and laboratory tests are presented. The effects of existing layers on the measurement of subgrade properties, and the subjects of soil spatial and seasonal variability are also discussed. Most importantly, the use of measured soil properties in pavement design and evaluation are explained. New applications or improvements to existing in situ test methods to support the use of mechanistic/stochastic-based pavement design procedures are also explained.
Antibody‐dependent cellular cytotoxicity in HIV infections (1996)

ADCC is an important immune effector mechanism against tumor and virus-infected cells that can be destroyed by the combined action of specific antibodies of IgG isotype against cell surface-associated antigens and effector cells, predominantly of the NK phenotype. ADCC has been shown to function in vivo in several systems. With regard to HIV, it can be readily demonstrated in vitro against the viral envelope proteins with serum and/or effector cells obtained from HIV-infected subjects. Several studies have demonstrated that the titers of the envy-specific ADCC-mediating antibodies decrease in the sera of HIV-infected individuals as the infection progresses toward AIDS. The cells that mediate ADCC also become functionally compromised in these individuals in early stages of the infection, thus depriving the host of the potential benefits of this process. Restoration of this process in the infected individuals by the administration of functionally competent effector cells (in vitro expanded and lymphokine-activated killer cells) and ADCC-mediating antibodies (hyperimmune serum or appropriate monoclonal antibodies), alone or in combination, may help slow the disease progress. Because of the multicomponent nature of the process, ADCC-mediating antibodies may prove a better correlate of protection and prognosis than the virus-specific neutralizing antibodies and cytotoxic T cells in assessing anti-HIV immunization and immunotherapy.
Discretely Tunable Optical Frequency Synthesizer Utilizing a Femtosecond Fiber Laser Injection-Locking Technique (2009)

In this letter, we propose a discretely tunable optical frequency synthesizer (DTOFS) based on distributed-feedback (DFB) lasers that can be selectively injection locked to a desired single mode of the femtosecond fiber laser comb. The methods for the injection locking, the monitoring of the lock status, and the selection of the desired comb mode are given. We demonstrate the discrete tunability of the DTOFS by constructing two frequency-stabilized DFB lasers, both of which are injection locked to a respective single mode of the fiber laser comb with the frequency difference, which is an exact multiple of the comb repetition frequency.
Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro (2013)

Extracellular vesicles (EVs) are small, double membrane vesicles derived from leukocytes, platelets, and cells of other tissues under physiological or pathological conditions. Generation of EVs in stored blood is thought to be associated with adverse effects and potentially immunosuppression in blood transfusion recipients. We measured the quantity and cells of origin for EVs isolated from stored red blood cell (RBC) units and tested whether they had any effects on T-cell-mediated immune responses. Mixing peripheral blood mononuclear cells (PBMCs) with EVs resulted in secretion of proinflammatory cytokines and chemokines and increased survival of unstimulated PBMCs. EVs augmented mitogen-induced CD4(+) and CD8(+) T-cell proliferation in an antigen-presenting cell (APC)-dependent manner. We demonstrated that EVs interacted primarily with monocytes and induced proinflammatory cytokine secretion. We also showed that the exosome fraction of EVs and not larger microvesicles was responsible for induction of TNF-α production by monocytes. Furthermore, blockade of CD40 or CD40L accessory molecules largely neutralized the EV augmentation of T-cell responses, implying a role for cell-cell interaction between T cells and EV-activated monocytes. Contrary to our hypothesis, the data demonstrate that EVs isolated from RBC units increase the potency of APCs and boost mitogen-driven T-cell proliferative responses.
Myogenic Differentiation by Human Processed Lipoaspirate Cells (2002)

The use of undifferentiated cells for cell-based tissue engineering and regeneration strategies represents a promising approach for skeletal muscle repair. For such strategies to succeed, a readily available source of myogenic precursor cells must be identified. We have previously shown that cells isolated from raw human lipoaspirates, called processed lipoaspirate cells, display multilineage mesodermal potential in vitro. Because human liposuctioned fat is available in large quantities and can be harvested with low morbidity, it may be an ideal source of stem cells for tissue-engineering applications. In this study, processed lipoaspirate cells were isolated from raw lipoaspirates harvested from eight patients who underwent cosmetic surgery. Processed lipoaspirate cells were placed in promyogenic conditions for up to 6 weeks, and the expression of the myogenic markers MyoD1 and myosin heavy chain was confirmed by using structure, histology, and reverse transcriptase-polymerase chain reaction. Histologic results were quantitated as an indicator or myogenic differentiation levels. We found that induced human processed lipoaspirate cells form multinucleated cells after 3 weeks of induction, indicative of the formation of myotubes. In addition, MyoD1 and skeletal muscle myosin heavy chain are expressed at distinct time points during differentiation with MyoD1 expression preceding expression of myosin. Finally, approximately 15 percent of human processed lipoaspirate cells can be induced toward myogenic differentiation 6 weeks after induction. In summary, our findings suggest that human processed lipoaspirate cells differentiate into myogenic cells. Furthermore, these cells may be a useful source for skeletal muscle engineering and repair.
Spatiotemporal Dynamics of Error Processing Dysfunctions in Major Depressive Disorder (2008)

Unmedicated patients with MDD showed reduced accuracy and potentiated error-related negativity immediately after committing errors, highlighting dysfunctions in the automatic detection of unfavorable performance outcomes. New analytic procedures allowed us to show that abnormal reaction to committing errors was accompanied by hyperactivation in rostral ACC and medial PFC regions 80 milliseconds after committing errors and a failure to recruit dorsolateral PFC-based cognitive control. Future studies are warranted to investigate whether these dysfunctions might foster the emergence and maintenance of negative processing biases and thus increase vulnerability to depression.
The Roman Fort at Lanchester, Co. Durham: a Geophysical Survey and Discussion of Garrisons (1992)

A geophysical survey of the whole of the auxiliary fort at Lanchester, Co. Durham, produced unprecedented images of individual buildings and the overall layout of the site interior. The combination of the detail of individual structures and the overall scope of the survey permit a discussion of the garrisons of the fort in the light of epigraphic and structural evidence. The composition of part-mounted units is discussed in relation to barrack accommodation and the date and status of Germanic units among garrisons in the area of Hadrian's Wall is considered.