gebhart/patrepeval huggingface dataset:
Generation of protein carbonyls by glycoxidation and lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids (1998)

Accumulation of carbonyl derivatives of proteins (protein carbonyl) is taken as a biomarker of oxidative protein damage in aging and in various diseases. We detected protein carbonyls in situ in human diabetic arteriosclerotic tissues and characterized the formation of protein carbonyls. Protein carbonyls were identified in the thickened intima of arterial walls and co-localized with protein adducts formed by carbonyl amine chemistry between protein and carbonyl compounds derived from autoxidation of carbohydrates, lipids, and ascorbate, i.e. advanced glycation end products or glycoxidation products, such as carboxymethyllysine (CML) and pentosidine, and lipoxidation products, such as malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE). In vitro incubation of proteins with ascorbic acid accelerated the production of protein carbonyls as well as CML and pentosidine, and incubation with arachidonate accelerated the production of protein carbonyls as well as CML, MDA, and HNE. By contrast, incubation of proteins with glucose resulted in the production of CML and pentosidine, but not protein carbonyls. Schiff base inhibitors, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylace tanilide and aminoguanidine, inhibited the production of protein carbonyls after incubation with ascorbate and arachidonate. The present study suggests that ascorbate and polyunsaturated fatty acids, but not glucose, represent potential sources of protein carbonyls, and that both the glycoxidation and lipoxidation reactions contribute to protein carbonyl formation in aging and various diseases.
Generating Genome-Scale Candidate Gene Lists for Pharmacogenomics (2009)

A critical task in pharmacogenomics is identifying genes that may be important modulators of drug response. High-throughput experimental methods are often plagued by false positives and do not take advantage of existing knowledge. Candidate gene lists can usefully summarize existing knowledge, but they are expensive to generate manually and may therefore have incomplete coverage. We have developed a method that ranks 12,460 genes in the human genome on the basis of their potential relevance to a specific query drug and its putative indications. Our method uses known gene-drug interactions, networks of gene-gene interactions, and available measures of drug-drug similarity. It ranks genes by building a local network of known interactions and assessing the similarity of the query drug (by both structure and indication) with drugs that interact with gene products in the local network. In a comprehensive benchmark, our method achieves an overall area under the curve of 0.82. To showcase our method, we found novel gene candidates for warfarin, gefitinib, carboplatin, and gemcitabine, and we provide the molecular hypotheses for these predictions.
MobileNetV2: Inverted Residuals and Linear Bottlenecks (2018)

In this paper we describe a new mobile architecture, MobileNetV2, that improves the state of the art performance of mobile models on multiple tasks and benchmarks as well as across a spectrum of different model sizes. We also describe efficient ways of applying these mobile models to object detection in a novel framework we call SSDLite. Additionally, we demonstrate how to build mobile semantic segmentation models through a reduced form of DeepLabv3 which we call Mobile DeepLabv3. The MobileNetV2 architecture is based on an inverted residual structure where the input and output of the residual block are thin bottleneck layers opposite to traditional residual models which use expanded representations in the input an MobileNetV2 uses lightweight depthwise convolutions to filter features in the intermediate expansion layer. Additionally, we find that it is important to remove non-linearities in the narrow layers in order to maintain representational power. We demonstrate that this improves performance and provide an intuition that led to this design. Finally, our approach allows decoupling of the input/output domains from the expressiveness of the transformation, which provides a convenient framework for further analysis. We measure our performance on Imagenet classification, COCO object detection, VOC image segmentation. We evaluate the trade-offs between accuracy, and number of operations measured by multiply-adds (MAdd), as well as the number of parameters
Biomarkers for Anti-Angiogenic Therapy in Cancer (2013)

Angiogenesis, the development of new vessels from existing vasculature, plays a central role in tumor growth, survival, and progression. On the molecular level it is controlled by a number of pro- and anti-angiogenic cytokines, among which the vascular endothelial growth factors (VEGFs), together with their related VEGF-receptors, have an exceptional position. Therefore, the blockade of VEGF signaling in order to inhibit angiogenesis was deemed an attractive approach for cancer therapy and drugs interfering with the VEGF-ligands, the VEGF receptors, and the intracellular VEGF-mediated signal transduction were developed. Although promising in pre-clinical trials, VEGF-inhibition proved to be problematic in the clinical context. One major drawback was the generally high variability in patient response to anti-angiogenic drugs and the rapid development of therapy resistance, so that, in total, only moderate effects on progression-free and overall survival were observed. Biomarkers predicting the response to VEGF-inhibition might attenuate this problem and help to further individualize drug and dosage determination. Although up to now no definitive biomarker has been identified for this purpose, several candidates are currently under investigation. This review aims to give an overview of the recent developments in this field, focusing on the most prevalent tumor species.
Human immunodeficiency virus causes mononuclear phagocyte dysfunction. (1990)

There is compelling clinical evidence for dysfunction of the mononuclear phagocyte system in patients with AIDS, which is believed due in part to loss of T-cell cooperativity. The direct consequences of human immunodeficiency virus infection on macrophage function are unknown. To address this question we infected normal human macrophages in vitro with a monocytotropic strain of human immunodeficiency virus and performed assays to quantify their extra- and intracellular killing ability. Human immunodeficiency virus-infected macrophages were significantly less effective than control cells in mediating antibody-dependent cell-mediated cytotoxicity against leukemic cell targets and intracellular killing of Candida pseudotropicalis. The functional defects were profound, related temporarily to active virus production by the macrophages, and could not be overcome by granulocyte-macrophage colony-stimulating factor. Treatment of macrophages with 3'-azido-3'-deoxythymidine (AZT) 6 days after infection caused a marked decrease in virus production and prevented development of the intracellular killing functional defect. The results suggest that early antiviral therapy may be useful in preventing or mitigating some virus-induced mononuclear phagocyte dysfunction.
Minimally oxidised LDL as estimated by a new method increase in plasma of type 2 diabetic patients with atherosclerosis or nephropathy. (1996)

A new sensitive and reproducible method was used to assess LDL oxidative status in Type 2 diabetic patients and control subjects, and the relationships between LDL oxidation and atherosclerosis or nephropathy were determined. LDL oxidation was measured in 35 patients with Type 2 diabetes and 15 control subjects 40 to 60 years of age. Atherosclerosis was assessed by clinical examination, vascular ultrasound, and measurement of intima-media thickness (IMT). Twenty-four hour urinary albumin excretion measurements were performed. Although no differences in lipid values were found between the 22 diabetic patients with atherosclerosis (ATS+) and the 13 without (ATS-), LDL oxidation was significantly higher in ATS+ than ATS- patients (p = 0.009) or control subjects (p = 0.007). LDL oxidation was also increased in the 15 patients with nephropathy (p = 0.003). Oxidation was correlated with IMT in patients with normal to moderately increased IMT ( < or = 1.05 mm). Determination of LDL oxidative status could thus be very helpful in assessing cardiovascular risk, especially in high-risk subjects such as patients with diabetes mellitus.
Modulation of the immune response by anaphylatoxin in the microenvironment of the interacting cells. (1982)

It was shown that the anaphylatoxins C3a and C5a can modulate in vitro immunological reactivities. C3a suppresses both the in vitro polyclonal antibody response and the specific antibody response to sheep red blood cells (SRBC) of both mouse spleen cells and human peripheral blood cells. The target cell in the mouse for C3a appears to be an Lyt-1+2- suppressor-inducer cell and macrophages appear not to be required. In contrast to C3a, C5a enhances in vitro responses of mice. Both the response to SRBC and the mixed lymphocyte reaction are enhanced by C5a. This enhancement appears to be through an Ia- macrophage that contains receptors for C5a. It appears that enhancement may be brought about by interleukin 1, which is released when Ia- macrophages are pulsed with C5a. It is suggested that these anaphylatoxins, when present in high concentrations in the microenvironment of the interacting cells of the immune system, play a dynamic role in the regulation of the immune response. Peptide fragments cleaved from the Fc portion of antibody, complexed with antigen in this microenvironment, may have a similar regulating role.
A hierarchical “nesting” approach to describe the stability of alpha helices with side‐chain interactions (1990)

A straightforward hierarchical statistical-mechanical approach is shown to enable one to describe the stability of the alpha helix in the presence of side-chain interactions. The formulation can be used with even the simple nearest-neighbor models and it is demonstrated explicitly with the popular 2 x 2 Zimm-Bragg model [B. H. Zimm and J. K. Bragg (1959) J. Chem. Physics 31, 526-535]. It involves a conceptual dissection of the polypeptide chain into interacting blocks; the behavior of any block with side-chain interactions is treated then with conventional binding polynomial techniques. This dissection is a manifestation of "nesting," which is a hierarchical framework for the description of the behavior of complex macromolecules [C. H. Robert, H. Decker, B. Richey, S. J. Gill, and J. Wyman (1987) Proc. Natl. Acad. Sci. 84, 1891-1895]. The method is demonstrated through applications to existing, detailed data for the pH and salt dependences of the helix-coil transition in the S peptide and in synthetic peptides.
Matching conceptual graphs as an aid to requirements re-use (2002)

The types of knowledge used during requirements acquisition are identified and a tool to aid in this process, the ReqColl (requirements collector), is introduced. The tool uses conceptual graphs to represent domain concepts, and attempts to recognize new concepts through the use of a matching facility. The overall approach to requirements capture is described and the approach to matching is illustrated informally. The detailed procedure for matching conceptual graphs is given. ReqColl is compared to similar work elsewhere, and some future research directions are indicated.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Styrene/Acrylic Acid Random Copolymers Synthesized by Nitroxide-Mediated Polymerization: Effect of Free Nitroxide on Kinetics and Copolymer Composition (2008)

Styrene/acrylic acid (S/AA) mixtures were copolymerized in concentrated 50 wt % 1,4-dioxane solutions at 120 °C at two ratios of additional free nitroxide mediator, N,N-tert-butyl-N-[1′-diethylphosphono-2,2′-dimethylpropyl] nitroxide (SG1), relative to 2-[N-tert-butyl-2,2-(dimethylpropyl)aminooxy]propionic acid (BlocBuilder, Arkema) alkoxyamine unimolecular initiator (4.5 and 9 mol % [SG1]/[BlocBuilder]). Without SG1 at initial acrylic acid monomer feed concentrations fAA,0 > 40 mol %, the apparent rate constants increased sharply, noticeable exotherms were observed, and polydispersities increased from 1.20 at fAA,0 = 0 mol % to 1.48 at fAA,0 = 80 mol %. With 4.5 mol % [SG1]/[BlocBuilder], polymerization rates were slower and not as strongly affected by fAA,0 although exotherms were still noticeable at high fAA,0. Polydispersities remained ∼1.3 and only increased to >1.4 at high conversions for fAA,0 = 80 mol %. Exotherms were rendered nearly negligible when 9 mol % [SG1]/[BlocBuilder] was used, leading to copolymers with much narrower molecular weight distributions and kpK values for comonomer mixtures bracketed between those of styrene and acrylic acid homopolymerizations at 120 °C (kp = propagation rate constant, K = equilibrium constant). Copolymer reactivity ratios estimated for samples produced using 9 mol % [SG1]/[BlocBuilder] by nonlinear least-squares minimization were rAA = 0.25 ± 0.11 and rS = 0.93 ± 0.37, in agreement with previous literature.
HER2 expression status in diverse cancers: review of results from 37,992 patients (2015)

Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/- amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.
Fischer Indole Synthesis in Brønsted Acidic Ionic Liquids: A Green, Mild, and Regiospecific Reaction System (2006)

Abstract A novel one‐pot Fischer indole synthesis approach has been developed by using Brønsted acidic ionic liquids as dual solvent‐catalysts. Yields of 83–97 % were obtained after reaction in BMImHSO 4 at 70–110 °C in 0.5–6 h, and exclusive formation of 2,3‐disubstituted indoles was observed in the reaction of alkyl methyl unsymmetrical ketones. The indoles produced could be conveniently separated from the reaction mixture without any volatile organic solvents, and the BMImHSO 4 could be readily reused without efficiency loss after simple treatment involving only 1 equiv. of HCl for neutralization followed by filtration.(© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2007)
[Anal incontinence--new methods of surgical treatment using artificial bowel sphincter and sacral nerve stimulation]. (2007)

Anal incontinence remains a largely hidden problem, with many patients which are long-term health and mobility problems. Anal incontinence is a symptom or sign rather than a disease, and that there are often multiple contributory factors. Anal incontinence affects both sexes and all age groups. Approximately 2% of the adult population have it on a frequent basis. Treatments include pelvic muscles training, drugs, surgery. Artificial bowel sphincters and sacral nerve stimulation (or neuromodulation) is a relatively new operative techniques for treating anal incontinence and are used in patients with an intact or repaired sphincter complex.
Air-stable Li3InCl6 electrolyte with high voltage compatibility for all-solid-state batteries (2019)

Ambient-air-stable Li<sub>3</sub>InCl<sub>6</sub> halide solid electrolyte, with high ionic conductivity of 1.49 × 10<sup>−3</sup> S cm<sup>−1</sup> at 25 °C, delivers essential advantages over commercial sulfide-based solid electrolyte.
Mice with an inactivation of the inducible nitric oxide synthase gene are susceptible to experimental autoimmune encephalomyelitis (1998)

Nitric oxide (NO) generated by the inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study mice genetically deficient for iNOS are shown to be susceptible to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG). In iNOS (-/-) mice the course of disease was earlier in onset and more aggressive compared to control animals. A disease-relevant compensatory up-regulation of neuronal (n)NOS and endothelial (e)NOS with increased production of NO in iNOS (-/-) mice is excluded by 1) the failure to detect increased nNOS and eNOS mRNA, 2) the absence of detection of nitrosylated tyrosine residues in EAE tissue indicating absence of NO-derived peroxynitrite, and 3) the lack of disease-preventing effects of NG-nitro-L-arginine methyl ester. In conclusion, these results do not support the hypothesis that NO is crucial for the development of EAE.
Regional Brain Volume in Depression and Anxiety Disorders (2010)

Our findings indicate that reduced volume of the rostral-dorsal anterior cingulate gyrus is a generic effect in depression and anxiety disorders, independent of illness severity, medication use, and sex. This generic effect supports the notion of a shared etiology and may reflect a common symptom dimension related to altered emotion processing. Specific involvement of the inferior frontal cortex in MDD and lateral temporal cortex in anxiety disorders without comorbid MDD, on the other hand, may reflect disorder-specific symptom clusters. Early onset of depression is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorder.
Efficient Isolation and Quantitative Proteomic Analysis of Cancer Cell Plasma Membrane Proteins for Identification of Metastasis-Associated Cell Surface Markers (2009)

Cell surface membrane proteins are involved in central processes such as cell signaling, cell-cell interactions, ion and solute transport, and they seem to play a pivotal role in several steps of the metastatic process of cancer cells. The low abundance and hydrophobic nature of cell surface membrane proteins complicate their purification and identification by MS. We used two isogenic cell lines with opposite metastatic capabilities in nude mice to optimize cell surface membrane protein purification and to identify potential novel markers of metastatic cancer. The cell surface membrane proteins were isolated by centrifugation/ultracentrifugation steps, followed by membrane separation using a Percoll/sucrose density gradient. The gradient fractions containing the cell surface membrane proteins were identified by enzymatic assays. Stable isotope labeling of the proteome of the metastatic cell line by SILAC followed by mass spectrometry analysis enabled identification and quantification of proteins that were differentially expressed in the two cell lines. Dual stable isotopic labels ((13)C-arginine and (13)C-lysine) instead of a single label ((13)C-arginine) increased the percentage of proteins that could be quantified from 40 to 93%. Repeated LC-MS/MS analyses (3-4 times) of each sample increased the number of identified proteins by 60%. The use of Percoll/sucrose density separation allowed subfractionation of membranes leading to enrichment of membrane proteins (66%) and reduction from 33% to only 16% of protein from other membranous organelles such as endoplasmatic reticulum, Golgi, and mitochondria. In total, our optimized methods resulted in 1919 protein identifications (corresponding to 826 at similarity level 80% (SL80); 1145 (509 at SL80) were identified by two or more peptides of which 622 (300 at SL80) were membrane proteins. The quantitative proteomic analysis identified 16 cell surface proteins as potential markers of the ability of breast cancer cells to form distant metastases.
The use of gene clusters to infer functional coupling (1999)

Previously, we presented evidence that it is possible to predict functional coupling between genes based on conservation of gene clusters between genomes. With the rapid increase in the availability of prokaryotic sequence data, it has become possible to verify and apply the technique. In this paper, we extend our characterization of the parameters that determine the utility of the approach, and we generalize the approach in a way that supports detection of common classes of functionally coupled genes (e.g., transport and signal transduction clusters). Now that the analysis includes over 30 complete or nearly complete genomes, it has become clear that this approach will play a significant role in supporting efforts to assign functionality to the remaining uncharacterized genes in sequenced genomes.
Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1 (2011)

Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by expressing four transcription factors: Oct4, Sox2, Klf4, and c-Myc. Here we report that enhancing RA signaling by expressing RA receptors (RARs) or by RA agonists profoundly promoted reprogramming, but inhibiting it using a RAR-α dominant-negative form completely blocked it. Coexpressing Rarg (RAR-γ) and Lrh-1 (liver receptor homologue 1; Nr5a2) with the four factors greatly accelerated reprogramming so that reprogramming of mouse embryonic fibroblast cells to ground-state iPSCs requires only 4 d induction of these six factors. The six-factor combination readily reprogrammed primary human neonatal and adult fibroblast cells to exogenous factor-independent iPSCs, which resembled ground-state mouse ES cells in growth properties, gene expression, and signaling dependency. Our findings demonstrate that signaling through RARs has critical roles in molecular reprogramming and that the synergistic interaction between Rarg and Lrh1 directs reprogramming toward ground-state pluripotency. The human iPSCs described here should facilitate functional analysis of the human genome.
PD-1 and PD-L1 antibodies for melanoma (2014)

Melanoma is the most serious form of skin cancer. Metastatic melanoma historically carries a poor prognosis and until recently there have been few effective agents available to treat widely disseminated disease. Recognition of the immunogenic nature of melanoma has resulted in the development of various immunotherapeutic approaches, especially with regards to the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1). Antibodies targeting the PD-1 axis have shown enormous potential in the treatment of metastatic melanoma. Here, we will review the immune basis for the disease and discuss approved immunotherapeutic options for advanced melanoma, as well as the current state of development of PD-1 and PD-L1 antibodies and their importance in shaping the future of melanoma treatment.