gebhart/patrepeval huggingface dataset:
Structure-Function Analysis of the p35 Subunit of Mouse Interleukin 12 (1995)

Mouse IL-12 acts on both mouse and human cells; human IL-12 acts only on human cells. This species specificity is determined by the p35 subunit of the IL-12 heterodimer. Since mouse and human p35 sequences are 60% identical, the determinants for the species specificity most likely residue in the nonhomologous sequences of mouse p35. To identify the regions on the p35 subunit interacting with the mouse IL-12 receptor, we constructed a series of chimeric mouse-human p35 molecules by replacing mouse sequences with the nonhomologous human counterparts. An IL-12 heterodimer containing a mouse-human p35 chimera with five residues changed in three discontinuous sites had drastically reduced (750-3000-fold) bioactivities on mouse cells. However, the competitive binding activity of the same mutant IL-12 heterodimer on mouse cells was only reduced 30-fold relative to wild-type IL-12. These findings therefore suggest that 1) the mouse p35 subunit participates in both receptor binding and signaling, 2) the mutations introduced into p35 affect signaling to a much greater extent than receptor binding, and 3) the five residues identified on p35 are required for interacting with the mouse, but not with the human IL-12 receptor and as such contribute extensively to the observed species specificity of IL-12.
Engineering and characterization of a bispecific HER2 × EGFR‐binding affibody molecule (2009)

HER2 (human epidermal-growth-factor receptor-2; ErbB2) and EGFR (epidermal-growth-factor receptor) are overexpressed in various forms of cancer, and the co-expression of both HER2 and EGFR has been reported in a number of studies. The simultaneous targeting of HER2 and EGFR has been discussed as a strategy with which to potentially increase efficiency and selectivity in molecular imaging and therapy of certain cancers. In an effort to generate a molecule capable of bispecifically targeting HER2 and EGFR, a gene fragment encoding a bivalent HER2-binding affibody molecule was genetically fused in-frame with a bivalent EGFR-binding affibody molecule via a (G4S)3 [(Gly4-Ser)3]-encoding gene fragment. The encoded 30 kDa affibody construct (ZHER2)2-(G4S)3-(ZEGFR)2, with potential for bs (bispecific) binding to HER2 and EGFR, was expressed in Escherichia coli and characterized in terms of its binding capabilities. The retained ability to bind HER2 and EGFR separately was demonstrated using both biosensor technology and flow-cytometric analysis, the latter using HER2- and EGFR-overexpressing cells. Furthermore, simultaneous binding to HER2 and EGFR was demonstrated in: (i) a sandwich format employing real-time biospecific interaction analysis where the bs affibody molecule bound immobilized EGFR and soluble HER2; (ii) immunofluorescence microscopy, where the bs affibody molecule bound EGFR-overexpressing cells and soluble HER2; and (iii) a cell-cell interaction analysis where the bs affibody molecule bound HER2-overexpressing SKBR-3 cells and EGFR-overexpressing A-431 cells. This is, to our knowledge, the first reported bs affinity protein with potential ability for the simultaneous targeting of HER2 and EGFR. The potential future use of this and similar constructs, capable of bs targeting of receptors to increase the efficacy and selectivity in imaging and therapy, is discussed.
Best Practices for Data Centers: Lessons Learned from Benchmarking 22 Data Centers (2006)

Over the past few years, the authors benchmarked 22 data center buildings. From this effort, we have determined that data centers can be over 40 times as energy intensive as conventional office buildings. Studying the more efficient of these facilities enabled us to compile a set of “best-practice ” technologies for energy efficiency. These best practices include: improved air management, emphasizing control and isolation of hot and cold air streams; rightsizing central plants and ventilation systems to operate efficiently both at inception and as the data center load increases over time; optimized central chiller plants, designed and controlled to maximize overall cooling plant efficiency, central air-handling units, in lieu of distributed units; “free cooling ” from either air-side or water-side economizers; alternative humidity control, including elimination of control conflicts and the use of direct evaporative cooling; improved uninterruptible power supplies; high-efficiency computer power supplies; on-site generation combined with special chillers for cooling using the waste heat; direct liquid cooling of racks or computers; and lowering the standby losses of standby generation systems. Other benchmarking findings include power densities from 5 to nearly 100 Watts per
Solute diffusion in swollen membranes. IX. Scaling laws for solute diffusion in gels (1988)

Abstract A scaling law was developed for the diffusion coefficient of spheroidal and ellipsoidal solutes in nonporous, equilibrium‐swollen hydrogels. The law relates the solute diffusion coefficient to the solute size, the gel mesh size, and the gel equilibrium volume degree of swelling. The law was verified by appropriate data of low and high molecular weight solute diffusion through hydrogels such as swollen networks of poly(vinyl alcohol), poly(2‐hydroxyethyl methacrylate), cellulose, and others. An additional scaling law was developed which relates the rate of release of a small or large molecule from an equilibrium swollen hydrogel with time and with morphological characteristics of the polymeric network.
The structure of cloned DNA complementary to catfish pancreatic somatostatin-14 messenger RNA. (1982)

Pancreatic poly(A) RNA isolated from the channel catfish (Ictalurus punctatus) was enriched for sequences corresponding to somatostatin mRNA on isokinetic sucrose gradients. Double-stranded cDNA was synthesized and inserted into the Pst I site pBR322 via the poly(dG) . poly(dC) tailing method. Escherichia coli was transformed with this DNA, and colonies containing somatostatin cDNA sequences were identified by hybridization using a primer-extended somatostatin cDNA. The somatostatin cDNA was obtained by extending a 5'-labeled undecanucleotide primer complementary to somatostatin mRNA with reverse transcriptase using catfish poly(A) RNA as a template. The synthetic primer d(T-T-C-C-A-G-A-A-G-A-A) was deduced from the amino acid sequence Phe-Phe-Trp-Lys present in somatostatin-14. Twenty positive colonies were obtained upon screening 2000 transformants. The restriction maps of the plasmid DNA obtained from the positive colonies were examined. Nineteen of these plasmids contained sequences corresponding to somatostatin-14, while one contained a sequence corresponding to somatostatin-22. The nucleotide sequence of pancreatic somatostatin-14 is reported here. The cDNA contains 350 nucleotides in the 3' noncoding region, 345 nucleotides in the coding region, and 104 nucleotides in the 5'-untranslated region. The mRNA codes for a precursor to somatostatin which is 114 amino acids in length. The preprosomatostatin has a sequence of hydrophobic amino acids at the NH2 terminus, followed by a connecting peptide of approximately 75 amino acids. The sequence Arg-Lys precedes somatostatin-14. Analysis of genomic DNA from the channel catfish reveals that somatostatin-14 and somatostatin-22 are present on different restriction fragments.
Angiostasis as a way to improve immunotherapy (2009)

Tumours express tumour-associated antigens that are recognised as self-antigens precluding the induction of effective anti-tumour immune responses. Inflammatory conditions which facilitate appropriate antigen presentation and reduce the immuno-suppressive micro-milieu may break tolerance. However, tumours have evolved mechanisms to escape cytotoxic T-cell attack by expressing inhibitory molecules on their surface, secreting suppressive factors, attracting regulatory T cells to the tumour environment or downregulating MHC molecules. Induction of angiogenesis by tumours may represent another mechanism by which tumours escape from immune attack. It provides an anti-inflammatory milieu that will prevent appropriate activation and maturation of antigen presenting cells, allow tumours to secrete suppressive factors and inhibit expression of tumour endothelial adhesion receptors, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin, needed for appropriate interactions with immune cells. Inhibition of angiogenesis may, apart from its direct detrimental effects on the tumour, reverse these processes and contribute to anti-tumour immune reactivity. Without trying to give a complete overview of the field, this paper reviews insights on angiogenesis inhibition in relation to tumour immune responsiveness, mainly based on the Maastricht-Amsterdam experience. This review adds to the hypothesis of improvement of immuno-directed therapies for cancer by angiostasis.
Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases. (1996)

Energy metabolism of human colon cancer in vivo relies predominantly on glucose. Although studies have revealed increased expression of Glut1 mRNA in colon cancer, Glut1 protein (Glut1) expression in the large intestine and its significance are still unknown. The objective of this work was to determine whether Glut1 is present in human colorectal neoplasms and whether that presence is of biological significance. Formalin-fixed, paraffin-embedded tissue sections of 53 colonic adenocarcinomas, 82 adenomas, 46 hyperplastic polyps, and 38 normal colon samples were immunostained with the anti-Glut1 antibody MYM. The localization was carried out using the avidin-biotin immunoperoxidase technique. No Glut1 immunoreactivity was present in normal colonic mucosa or in hyperplastic polyps, whereas 8 (10%) of 82 adenomas showed such immunoreactivity. The frequency of Glut1 expression in adenomas increased with villous morphology and with the size of the adenoma. Forty-four (83%) of 53 colorectal adenocarcinomas expressed Glut1, and, of these, tumors in which >50% of the cancer cells expressed Glut1 had a significantly higher incidence of metastasis to the lymph nodes (P = 0.0001). It is concluded that (a) Glut1 is expressed as a late event in the carcinogenesis process in human colorectal cancer, and (b) expression of Glut1 in a high proportion of cancer cells is associated with a high incidence of lymph node metastases.
Characterization of various zinc oxide catalysts and their activity in the dehydration-dehydrogenation of isobutanol (2008)

Mono and bifunctional zinc oxide catalysts were prepared to study their activity in the catalytic conversion of isobutanol. The prepared catalysts were characterized by X-ray diffraction analysis and nitrogen adsorption measurements. The conversion of isobutanol was taken as a model reaction to measure the catalytic activity of the prepared oxide catalysts. The overall conversion yield of competitive dehydration-dehydrogenation reactions of isobutanol was found to be higher over the binary oxide catalysts than over the single oxide one at all reaction temperature within the range 250-400?C. The binary oxide catalysts were more selective for isobutene, as the predominant dehydrated product. The single oxide catalyst exhibited higher selectivity towards isobutyraldehyde as the dehydrogenated product, and the selectivity increased with increasing reaction temperature.
Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers (2001)

Both (Li(+)) and valproic acid (VPA) are effective in treating bipolar disorder, but the pathway by which either works, and whether it is common to both drugs, is not agreed upon. We recently reported, using an in vivo fatty acid model, that Li(+) reduces the turnover rate of the second messenger arachidonic acid (AA) by 80% in brain phospholipids of the awake rat, without changing turnover rates of docosahexaenoic or palmitic acid. Reduced AA turnover was accompanied by down-regulation of gene expression and protein levels of an AA-specific cytosolic phospholipase A(2) (cPLA(2)). To see if VPA had the same effect on AA turnover, we used our in vivo fatty acid model in rats chronically administered VPA (200 mg/kg, i.p. for 30 days). Like Li(+), VPA treatment significantly decreased AA turnover within brain phospholipids (by 28-33%), although it had no effect on cPLA(2) protein levels. Thus, both mood stabilizers, Li(+) and VPA have a common action in reducing AA turnover in brain phospholipids, albeit by different mechanisms.
The platelet endothelial cell adhesion molecule‐1 (PECAM1) contributes to endothelial barrier function (1995)

In this study we have analyzed the role of the platelet-endothelial cell adhesion molecule-1 (PECAM1) in vascular barrier function. PECAM1 is an immunoglobulin gene superfamily member expressed by endothelial cells at the cell boundaries. Macromolecule permeability assays performed on cell monolayers that express native or transfected PECAM1, indicated that the molecule participates in the establishment and maintenance of vascular barrier function in vitro. This hypothesis was confirmed by the finding that in vivo injection of the specific monoclonal antibody directed against the murine vascular PECAM1 led to a detectable leakage of hepatic and renal blood vessels.
A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause (2011)

These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.
Sub-10 nm diameter InGaAs vertical nanowire MOSFETs (2017)

We present the first sub-10 nm diameter vertical nanowire transistors of any kind in any semiconductor system. These devices are InGaAs MOSFETs fabricated by a top-down approach using reactive ion etching, alcohol-based digital etch and Ni alloyed contacts. A record I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">on</sub> of 350 μA/μm at I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</sub> = 100 nA/μm and V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">dd</sub> = 0.5 V is obtained in a 7 nm diameter device. The same device exhibits a peak transconductance (g <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m, pk</sub> ) of 1.7 mS/μm and minimal subthreshold swing (S) of 90 mV/dec at V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">ds</sub> = 0.5 V, achieving the highest quality factor (defined as the ratio g <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m, pk</sub> /S) of 19 reported in vertical nanowire transistors. Excellent scaling behavior is observed with g <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m, pk</sub> and I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">on</sub> increasing as the diameter is shrunk down to 7 nm.
Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells (2008)

IL-17 and IL-22 are typical cytokines produced by the Th17 T cell subset, but it is unclear if Th17 cytokines can be produced by other cell types. We demonstrate that IL-10-deficient and IL-10R-deficient macrophages stimulated with lipopolysaccharide produce high levels of IL-17 and IL-22. Addition of exogenous IL-10 to IL-10-deficient macrophages abolished IL-17 production. When IL-10-deficient and IL-10R-deficient splenocytes were cultured under Th17 polarizing conditions, the population of IL-17-producing cells was increased and the cultures produced significantly higher levels of IL-17 and IL-22. The addition of recombinant IL-10 to IL-10-deficient splenocytes significantly decreased the percentage of IL-17-producing CD4(+) T cells. Finally, the mRNA for the Th17 transcription factor retinoic acid-related orphan receptor (ROR)gammat was significantly elevated in IL-10-deficient spleen cells and macrophages. These data demonstrate that Th17 cytokines and RORgammat are also expressed in macrophages and that IL-10 negatively regulates the expression of Th17 cytokines and RORgammat by both macrophages and T cells.
Fluorinated Compounds in Medicinal Chemistry: Recent Applications, Synthetic Advances and Matched-Pair Analyses (2014)

In recent years, several new fluorinated functional groups have been employed in medicinal chemistry. This review will highlight some recent developments in this area. We draw attention to useful synthetic advances for the installation of fluorine-containing groups. In addition, we examine the application of some fluorinated functional groups that have recently been gaining popularity in drug discovery. We use matched-pair analysis to assemble aggregate data on the impact on potency of one of these groups, pentafluorosulfanyl, as compared to trifluoromethyl. We further used matchedpair analysis to identify some interesting effects on in vitro ADME properties of replacing H by F on certain moieties.
Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides (2006)

Resorcylic acid lactones containing a cis-enone are susceptible to Michael addition reactions and are potent inhibitors of several protein kinases. A structural-bioinformatics analysis identified a conserved Cys residue in the ATP-binding site of the kinases reported to be inhibited by cis-enone resorcylic acid lactones but absent in those that are not. Mining of the kinome database revealed that a subset of some 46 kinases contained this Cys residue. Screening a panel of 124 kinases with the resorcylic acid lactone hypothemycin showed that 18 of 19 targets containing the conserved Cys were inhibited. Kinetic analyses showed time-dependent inhibition, a hallmark of covalent inactivation, and biochemical studies of the interaction of extracellular signal-regulated kinase (ERK)2 with hypothemycin confirmed covalent adduct formation. Resorcylic acid lactones are unique among kinase inhibitors in that they target mitogen-activated protein (MAP) kinase pathways at four levels: mitogen receptors, MAP kinase kinase (MEK)1/2 and ERK1/2, and certain downstream ERK substrates. Cell lines dependent on the activation of Tyr kinase mitogen receptor targets of the resorcylic acid lactones were unusually sensitive toward hypothemycin and showed the expected inhibition of kinase phosphorylation due to inhibition of the mitogen receptors and/or MEK1/2 and ERK1/2. Among cells without mitogen receptor targets, those harboring an ERK pathway-activating B-RAF V600E mutation were selectively and potently inhibited by hypothemycin. Hypothemycin also prevented stimulated activation of the p38 cascade through inhibition of the Cys-containing targets MEK3/6 and TGF-β-activated kinase 1 and of the JNK/SAPK (c-Jun N-terminal kinase/stress-activated protein kinase) cascade through inhibition of MEK4/7.
Intranasal Delivery of Caspase-9 Inhibitor Reduces Caspase-6-Dependent Axon/Neuron Loss and Improves Neurological Function after Stroke (2011)

Despite extensive research to develop an effective neuroprotective strategy for the treatment of ischemic stroke, therapeutic options remain limited. Although caspase-dependent death is thought to play a prominent role in neuronal injury, direct evidence of active initiator caspases in stroke and the functional relevance of this activity have not previously been shown. Using an unbiased caspase-trapping technique in vivo, we isolated active caspase-9 from ischemic rat brain within 1 h of reperfusion. Pathogenic relevance of active caspase-9 was shown by intranasal delivery of a novel cell membrane-penetrating highly specific inhibitor for active caspase-9 at 4 h postreperfusion (hpr). Caspase-9 inhibition provided neurofunctional protection and established caspase-6 as its downstream target. The temporal and spatial pattern of expression demonstrates that neuronal caspase-9 activity induces caspase-6 activation, mediating axonal loss by 12 hpr followed by neuronal death within 24 hpr. Collectively, these results support selective inhibition of these specific caspases as an effective therapeutic strategy for stroke.
The lectin‐like activity of human C1q and its implication in DNA and apoptotic cell recognition (2008)

C1q, the binding subunit of the C1 complex of complement, is an archetypal pattern recognition molecule known for its striking ability to recognize a wide variety of targets, ranging from pathogenic non self to altered self. DNA is one of the C1q ligands, but the precise region of C1q and the DNA motifs that support interaction have not been characterized yet. Here, we report for the first time that the peripheral globular region of the C1q molecule displays a lectin-like activity, which contributes to DNA binding through interaction with its deoxy-d-ribose moiety and may participate in apoptotic cell recognition.
Cutaneous Squamous-Cell Carcinoma in Patients Treated with PUVA (1984)

A 5.7-year prospective study of 1380 patients treated for psoriasis with oral methoxsalen (8-methoxypsoralen) and ultraviolet A photochemotherapy (PUVA) revealed that after adjustment for exposures to ionizing radiation and topical tar preparations, the risk that cutaneous squamous-cell carcinoma would develop at least 22 months after the first exposure to PUVA was 12.8 times higher in patients exposed to a high dose than in those exposed to a low dose (95 per cent confidence interval, 5.8 to 28.5). No substantial dose-related increase was noted for basal-cell carcinoma. The dose-dependent risk of cutaneous squamous-cell carcinoma suggests that PUVA can act as an independent carcinogen. In our study, morbidity associated with these tumors has been limited, but further follow-up is needed. Meanwhile, patients treated with PUVA should be followed closely for the possible development of cutaneous squamous-cell carcinoma.