gebhart/patrepeval huggingface dataset:
Alcohol: the ubiquitous risk factor (2000)

Alcohol: the ubiquitous risk factorThis issue includes four papers that draw attention to one of the most important causes of injury in all age groups and in every part of the world-alcohol.In particular, the papers address impaired drivers.The first is an original article pointing to the benefits of laws that penalize drivers whose blood alcohol content (BAC) exceeds 0.08% by weight (p 109).In view of the growing evidence to which this paper adds substantially, it is diYcult to understand why so many constituencies tolerate higher limits.It is even more diYcult to fathom why, whatever the limits, more impaired drivers are not apprehended or, when they are, why they are not punished more severely.These issues are addressed in the second paper-one that we hope will be the first of many written by from a lawyer's perspective (p 96).The senior author, Robert Solomon, is the legal advisor to the Canadian branch of Mothers Against Drunk Driving (MADD).Although the statistics in this paper only reflect the experience in one province, my guess is that the issues these data point to are commonplace, not only elsewhere in Canada but also world wide.In spite of limitations in the data system itself, the findings clearly point to serious flaws in how both the police and the legal system address impaired driving.Set aside the legal subtleties and look at the larger picture the findings present.As someone who has been spared personal experience with drunk driving, I find the results extremely disturbing.Imagine, then, how the families of victims must feel about this "system" that is supposed to deter.Because most injury prevention initiatives depend on lay persons for their success, I asked the vice president of MADD in the US, Wendy Hamilton, to present it as a Featured Program (p 90).Anyone familiar with this amazing program is bound to be impressed with its many accomplishments.Sadly, its origins and continued strength derive almost entirely from needless personal tragedies.There are many such programs in other countries and each deserves similar recognition.Finally, because impaired driving is dealt with so diVerently from one country to another, I asked Kathryn Stewart of the Pacific Institute for Research and Evaluation to write a guest editorial on this issue (p 80).She graciously agreed.Her superb contribution draws attention to how international the eVort has been to conquer this problem.Not surprisingly, perhaps, the country with the lowest tolerated level is Sweden, 0.02%.Stewart's editorial also
IMPACT: a high-level synthesis system for low power control-flow intensive circuits (1998)

In this paper, we present a comprehensive high-level synthesis system that is geared towards reducing power consumption in control-flow intensive circuits. An iterative improvement algorithm is at the heart of the system. The algorithm searches the design space by handling scheduling, module selection, resource sharing and multiplexer network restructuring simultaneously. The scheduler performs concurrent loop optimization and implicit loop unrolling. It minimizes the expected number of cycles of the schedule without compromising on the minimum and maximum schedule lengths. A fast simulation technique based on trace manipulation aids power estimation in driving synthesis in the right direction. Experimental results demonstrate power reduction of up to 85% with minimal overhead in area over area-optimized designs operating at 5 V.
VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization (2006)

There are growing data to suggest that tissue hypoxia represents a critical force that drives adult vasculogenesis. Vascular endothelial growth factor (VEGF) expression is dramatically up-regulated by hypoxia and results in enhanced neovascularization. Although the role of VEGF in angiogenesis has been well characterized, its role in adult vasculogenesis remains poorly understood. We used two distinct murine bone marrow transplantation (BMT) models to demonstrate that increased VEGF levels at the site of tumor growth promoted vasculogenesis in vivo. This effect of VEGF was downstream of its effect to enhance either mobilization or survival of circulating endothelial progenitor cells (EPCs). Both VEGFR1 (flt1) and VEGFR2 (flk1) are expressed on culture expanded human EPCs. Previous studies suggest that the effect of VEGF on endothelial cell migration is primarily mediated via VEGFR2; however, VEGF-induced EPC migration in vitro was mediated by both receptors, suggesting that VEGF-VEGFR1 interactions in EPCs are distinct from differentiated endothelial cells. We used specific blocking antibodies to these receptors to demonstrate that VEGFR1 plays an important role in human EPC recruitment to tumors. These findings were further supported by our finding that tumor-associated placental growth factor (PlGF), a VEGFR1-specific agonist, increased tumor vasculogenesis in a murine BMT model. We further showed that both VEGF receptors were necessary for the formation of functional vessels derived from exogenously administered human ex vivo expanded EPCs. Our data suggest local VEGF and/or PlGF expression promote vasculogenesis; VEGF plays a role in EPC recruitment and subsequent formation of functional vessels.
Pseudomonas aeruginosa alginate in cystic fibrosis sputum and the inflammatory response (1990)

Alginate, a viscous polysaccharide from mucoid Pseudomonas aeruginosa, may interfere with the host defenses in patients with cystic fibrosis and chronic P. aeruginosa lung infection. The alginate concentration in the sol phase of expectorated sputum was quantitated by a biochemical method and a newly developed enzyme-linked immunosorbent assay. There was a high degree of correlation between the methods, and the concentration of alginate ranged from 4 to 101 micrograms/ml with a median of 35.5 micrograms/ml when measured by enzyme-linked immunosorbent assay. Alginate could not be detected in the bronchial secretions from patients without P. aeruginosa infection. In vitro investigation of alginate did not show any activation of the alternative pathway of complement, as determined by a hemolytic kinetic assay and by testing for neutrophil chemotaxis. At a high concentration, P. aeruginosa alginate caused a slight activation of the classical pathway of complement. Alginate did not cause neutrophil chemotaxis by itself but was able to reduce the neutrophil chemotactic response to N-formylmethionylleucylphenylalanine and for zymosan-activated serum. P. aeruginosa and seaweed alginates were able to prime neutrophils for increased N-formylmethionylleucylphenylalanine-induced neutrophil oxidative burst, as determined by chemiluminescence. Because of its ability to prevent attraction of neutrophils to the site of infection, lack of complement activation, and ability to enhance neutrophil oxidative burst, alginate from P. aeruginosa may contribute to the persistence and pathogenesis of chronic P. aeruginosa infection in cystic fibrosis.
Elimination of Hepatic Metastases of Colon Cancer Cells via p53-Independent Cross-Talk between Irinotecan and Apo2 Ligand/TRAIL (2004)

The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their p53 status, we demonstrate that loss of p53 renders tumor cells relatively resistant to the topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits JAK2-STAT3/5-dependent expression of survival proteins (Bcl-x(L) and XIAP) and cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer cells. Whereas xenografts of p53-deficient colon cancer cells are relatively resistant to irinotecan compared with their p53-proficient counterparts, combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases of both p53-proficient and p53-deficient cancer cells in vivo and significantly improves the survival of animals relative to treatment with either agent alone. Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to p53, our data demonstrate that irinotecan enhances Apo2L/TRAIL-induced apoptosis of tumor cells via a distinct p53-independent mechanism involving inhibition of JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan against both p53-proficient and p53-deficient colorectal cancers, including those that have metastasized to the liver.
Antibodies That Promote Thyroid Growth (1983)

We used a strain of differentiated rat-thyroid cells in continuous culture (the FRTL-5 strain) to detect the presence of growth-promoting antibodies in serum samples from patients with autoimmune thyroid disease. We found that IgG preparations from 17 of 20 patients (85 per cent) with active Graves' disease and two of five patients (40 per cent) with Hashimoto's thyroiditis could augment thyroid-cell growth. In parallel with IgG-induced elevations in intracellular cyclic AMP levels in the same cell line, all 20 of the patients with active Graves' disease had thyroid-stimulatory antibodies. Patients' IgG preparations fell into three subclasses: those with both potent cyclic AMP stimulation and potent growth-promoting activity; those with potent cyclic AMP stimulation but low-level growth promotion; and those with potent growth promotion and low-level cyclic AMP action. Growth-promoting antibodies were not detected in patients with Graves' disease in remission (seven patients), nodular goiter (seven), subacute thyroiditis (five), or atrophic thyroiditis (one). Simultaneous assays of growth promotion and cyclic AMP stimulation may be useful in the care of patients with autoimmune thyroid disease.
Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways (2007)

Methylene blue (MB) has been used clinically for about a century to treat numerous ailments. We show that MB and other diaminophenothiazines extend the life span of human IMR90 fibroblasts in tissue culture by >20 population doubling (PDLs). MB delays senescence at nM levels in IMR90 by enhancing mitochondrial function. MB increases mitochondrial complex IV by 30%, enhances cellular oxygen consumption by 37-70%, increases heme synthesis, and reverses premature senescence caused by H2O2 or cadmium. MB also induces phase-2 antioxidant enzymes in hepG2 cells. Flavin-dependent enzymes are known to use NAD(P)H to reduce MB to leucomethylene blue (MBH2), whereas cytochrome c reoxidizes MBH2 to MB. Experiments on lysates from rat liver mitochondria suggest the ratio MB/cytochrome c is important for the protective actions of MB. We propose that the cellular senescence delay caused by MB is due to cycling between MB and MBH2 in mitochondria, which may partly explain the increase in specific mitochondrial activities. Cycling of MB between oxidized and reduced forms may block oxidant production by mitochondria. Mitochondrial dysfunction and oxidative stress are thought to be key aberrations that lead to cellular senescence and aging. MB may be useful to delay mitochondrial dysfunction with aging and the decrease in complex IV in Alzheimer disease.
Prolactin mediates estradiol-induced inflammation in the lateral prostate of Wistar rats. (1993)

Inflammation was induced in the lateral prostate of castrated Wistar rats by exposure to a sc implant of estradiol-filled Silastic tubing, followed by the addition of a dihydrotestosterone implant to restore prostatic wet weight. The presence of inflammation was correlated with increased serum PRL, elevated pituitary weight, and a greater than 2-fold increase in the lateral prostate DNA concentration. The administration of bromocriptine (4 mg/kg.day) to these animals was effective in suppressing pituitary weight and hyperprolactinemia and mitigated the lateral prostate inflammatory response. Inflammation was restored in the bromocriptine-treated hormone-implanted rats by administering exogenous ovine PRL at a dose of 2 mg/kg twice a day. The results indicate that estradiol-induced inflammation in the rat lateral prostate is mediated at least in part by the release of PRL from the pituitary.
Type 1 T Regulatory Cells and Their Relationship with CD4 + CD25 + T Regulatory Cells (2003)

Suppression by T regulatory (T(reg)) cells is essential for the induction of peripheral tolerance. Several types of CD4+ T(reg) cells have been described in a number of systems. Although the precise mechanisms which mediate T(reg) cells effector activity remain to be defined, it is well established that they can suppress Immune responses via cell-cell interactions and/or the production of interleukin (IL)10 and transforming growth factor (TGF)beta. Type 1 T regulatory (T(reg)) cells are defined by their ability to produce high levels of IL10 and TGFbeta, and these cytokines mediate their ability to suppress pathological immune responses in the settings of transplantation, allergy, and autoimmune diseases. T(reg) cell activity is not necessarily beneficial, and they can also suppress immune responses to antigens from tumours and pathogens. The differentiation of T(reg) cells in vivo is likely controlled by certain dendritic cells that promote IL10 production and may express tolerogenic co-stimulatory molecules. Another subset of CD4+ T(reg) cells is defined by constitutive expression of CD25. Naturally occurring human CD4+CD25+ T(reg) cells are distinct from T(reg1) cells. Suppressive CD4+CD25+ T cell clones do not synthesize IL10 but produce TGFbeta which contributes to the suppression of proliferation mediated by these cells. However, CD4+CD25+ T(reg) cells may be involved in the process inducing the differentiation of T(reg1) cells. In conclusions, many questions on the basic biology of T(reg) cells remain to be answered, but the development of therapeutic strategies designed to harness their immunoregulatory effects can already be envisaged.
Molecular cloning of tomato fruit polygalacturonase: Analysis of polygalacturonase mRNA levels during ripening (1986)

The expression of a gene encoding the cell wall-degrading enzyme polygalacturonase [poly(1,4-alpha-D-galacturonide) glucanohydrolase, EC 3.2.1.15] was characterized during tomato fruit ripening. Polygalacturonase was purified from ripe tomato fruit and used to produce highly specific antiserum. Immunoblot analyses detected a 45- and a 46-kDa protein in ripe fruit but immunoprecipitation of in vitro translation products of mRNA from ripe tomato fruit yielded a single 54-kDa polypeptide, suggesting post-translational processing. A plasmid cDNA library was prepared from poly(A)(+) RNA isolated from ripe tomato fruit. The cDNA library was inserted into a lambda-based expression vector, and polygalacturonase cDNA clones were identified by immunological screening. Hybrid-select translation experiments indicated that the cDNAs encode a 54-kDa in vitro translation product that is specifically immunoprecipitated with polygalacturonase antiserum. RNA-blot analysis indicated that the 1.9-kilobase polygalacturonase mRNA was virtually absent from immature-green fruit, accumulated steadily during the ripening process, and was at its highest level in red-ripe fruit. There was at least a 2000-fold increase in the level of polygalacturonase mRNA between immature-green and red-ripe tomato fruit. These studies show that the levels of polygalacturonase mRNA are developmentally regulated during tomato fruit ripening.
Role of c-kit in mouse spermatogenesis: identification of spermatogonia as a specific site of c-kit expression and function (1991)

Recent studies have shown that the dominant white spotting (W) locus encodes the proto-oncogene c-kit, a member of the tyrosine kinase receptor family. One symptom of mice bearing mutation within this gene is sterility due to developmental failure of the primordial germ cells during early embryogenesis. To elucidate the role of the c-kit in gametogenesis, we used an anti-c-kit monoclonal antibody, ACK2, as an antagonistic blocker for c-kit function to interfere with the development of male and female germ cells during postnatal life. ACK2 enabled us to detect the expression of c-kit in the gonadal tissue and also to determine the functional status of c-kit, which is expressed on the surface of a particular cell lineage. Consistent with our immunohistochemical findings, the intravenous injection of ACK2 into adult mice caused a depletion in the differentiating type A spermatogonia from the testis during 24-36 h, while the undifferentiated type A spermatogonia were basically unaffected. Intraperitoneal injections of ACK2 into prepuberal mice could completely block the mitosis of mature (differentiating) type A spermatogonia, but not the mitosis of the gonocytes and primitive type A spermatogonia, or the meiosis of spermatocytes. Our results indicate that the survival and/or proliferation of the differentiating type A spermatogonia requires c-kit, but the primitive (undifferentiated) type A spermatogonia or spermatogenic stem cells are independent from c-kit. Moreover, the antibody administration had no significant effect on oocyte maturation despite its intense expression of c-kit.
Rates of formation and thermal stabilities of RNA:DNA and DNA:DNA duplexes at high concentrations of formamide (1977)

The thermal stabilities of RNA:DNA hybrids are substantially greater than those of DNA:DNA duplexes in aqueous electrolyte solutions containing high concentrations of formamide. Association rates to form DNA:DNA duplexes and DNA:RNA hybrids have been measured in these solvents. There is a temperature range in which DNA:DNA rates are negligible and RNA:DNA rates close to optimal.
Transient expression of FOXP3 in human activated nonregulatory CD4 + T cells (2006)

Foxp3 plays a key role in CD4+ CD25+ T(reg) cell function in mice and represents a specific marker for these cells. Despite the strong association between FOXP3 expression and regulatory function in fresh human T cells, little is known about the dynamics of endogenous FOXP3 expression and its relation to the suppressive function in activated human T cells. Here, we addressed the dynamics of FOXP3 expression during human CD4+ T cell activation by plate-bound anti-CD3 Ab as well as the relationship between its expression and regulatory function at the single-cell level. Our data show that FOXP3 is expressed in a high percentage of activated T cells after in vitro stimulation of human CD4+ CD25- cells. FOXP3 expression is strongly associated with hyporesponsiveness of activated T cells, but is not directly correlated with their suppressive capabilities, as we demonstrate that it is also expressed in activated nonsuppressive T cells. However, in this nonsuppressive T cell population, FOXP3 expression is transient, while it is stably expressed in activated T cells that do display suppressive function, and in natural CD4+ CD25++ T(reg) cells. These data indicate that expression of endogenous FOXP3, in humans, is not sufficient to induce regulatory T cell activity or to identify T(reg) cells.
Expression of Neisseria meningitidis iron-regulated outer membrane proteins, including a 70-kilodalton transferrin receptor, and their potential for use as vaccines (1990)

The iron-regulated proteins (IRPs) of five group B meningococcal strains expressing class 2 outer membrane proteins were compared with those of five strains expressing class 3 proteins. Three to four high-molecular-weight IRPs were expressed by each strain, but their molecular sizes varied between strains and were not related to class 2 or 3 protein expression. Transferrin and hemoglobin could be used as a sole iron source. By using anti-human transferrin antibodies, it was shown that meningococcal cells and purified outer membranes bound transferrin. Growth under conditions of iron limitation caused a several-fold increase in the amount of transferrin bound to the cell surface. The transferrin-binding protein was detergent solubilized from outer membranes and partially purified. The isolated protein bound human transferrin and had an apparent molecular mass of 70 kilodaltons. To evaluate the potential of vaccines containing IRPs, we prepared outer membrane vaccines from strains M986-NCV-1 (M986) (--:2a: P1.2) and 44/76-M25 (44/76) (--:15:P1.15) grown to fully express their IRPs. Both vaccines induced significant anti-IRP antibodies as measured by enzyme immunoassay and by Western immunoblot with both M986 and 44/76 outer membranes. By Western blot analysis, the M986 vaccine induced antibodies to two different IRPs, one of which was shared with 44/76. Since the IRPs are major in vivo-expressed outer membrane proteins and are required for survival in vivo, these proteins should be evaluated for their usefulness in a group B meningococcal vaccine.
ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK (2013)

ETC-1002 is an investigational drug currently in Phase 2 development for treatment of dyslipidemia and other cardiometabolic risk factors. In dyslipidemic subjects, ETC-1002 not only reduces plasma LDL cholesterol but also significantly attenuates levels of hsCRP, a clinical biomarker of inflammation. Anti-inflammatory properties of ETC-1002 were further investigated in primary human monocyte-derived macrophages and in in vivo models of inflammation. In cells treated with ETC-1002, increased levels of AMP-activated protein kinase (AMPK) phosphorylation coincided with reduced activity of MAP kinases and decreased production of proinflammatory cytokines and chemokines. AMPK phosphorylation and inhibitory effects of ETC-1002 on soluble mediators of inflammation were significantly abrogated by siRNA-mediated silencing of macrophage liver kinase B1 (LKB1), indicating that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. In vivo, ETC-1002 suppressed thioglycollate-induced homing of leukocytes into mouse peritoneal cavity. Similarly, in a mouse model of diet-induced obesity, ETC-1002 restored adipose AMPK activity, reduced JNK phosphorylation, and diminished expression of macrophage-specific marker 4F/80. These data were consistent with decreased epididymal fat-pad mass and interleukin (IL)-6 release by inflamed adipose tissue. Thus, ETC-1002 may provide further clinical benefits for patients with cardiometabolic risk factors by reducing systemic inflammation linked to insulin resistance and vascular complications of metabolic syndrome.