gebhart/patrepeval huggingface dataset:
Characterization of Adenosine-Induced Respiratory Depression in the Preterm Rabbit (1985)

The respiratory performance was studied after intraperitoneal administration of the adenosine agonists N6-phenyl-isopropyl-adenosine (PIA) and adenosine-5-ethylcarboxamide to preterm (gestational age 29-30 days) newborn halothane-anesthetized rabbits. Both agonists induced marked hypoventilation and irregular breathing by decreases in the breathing frequency as well as the tidal volume. Expiratory time was markedly prolonged, resulting in a decrease in the respiratory duty cycle (inspiratory time/total cycle duration). Analysis using the occluded-breath technique revealed that the adenosine analogues altered the time setting of the expiratory (inspiratory) neuronal circuits and lowered the inspiratory off-switch level, while inspiratory drive and the bulbopontine setting of the inspiratory phase were unaltered. The ventilatory response to CO2 was blunted after both adenosine analogues studied. Theophylline almost completely reversed the hypoventilation and irregular breathing seen after PIA injection. It is concluded that activation of central nervous adenosine receptors induced a marked respiratory depression in the preterm rabbit. Furthermore, our data imply that an overactivity of central adenosine mechanisms may have a pathophysiological significance for the irregular breathing or apnea of prematurity sometimes seen in the human neonate.
Potential of the conditionally replicative adenovirus Ad5-Delta24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy. (2002)

The use of replication-competent adenoviruses (Ads) for cancer therapy is receiving widespread attention, especially for the treatment of tumors refractory to current treatments such as glioblastoma. AdDelta24, which carries a 24-bp deletion in E1A and replicates in cells with a retinoblastoma-defective pathway, produced a strong antitumor effect in glioma. To improve infection efficiency of primary glioma cells, which express low levels of coxsackie adenovirus receptor (CAR), the tropism of AdDelta24 was expanded toward alphav integrins by insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob (Ad5-Delta24RGD). We show that Ad5-Delta24RGD had a stronger oncolytic effect than the non-RGD-expressing variant on a broad panel of primary glioma cells, in particular on those with low CAR expression. The effects of Ad5-Delta24RGD were also assessed on a panel of primary organotypic glioma spheroids. In all cases, Ad5-Delta24RGD strongly decreased the viability of these small tumor nodules in vitro. In s.c. glioblastoma xenografts expressing low levels of CAR, five intratumoral injections of 1 x 10(7) plaque-forming units Ad5-Delta24RGD resulted in complete tumor regression in 9 of 10 mice and long-term survival in all treated mice. Preclinical evaluations and clinical trials of replication-competent Ad have shown more promising results when combined with conventional therapeutics. Therefore, we assessed the effects of Ad5-Delta24RGD in combination with radiotherapy. Low-dose irradiation before Ad5-Delta24RGD infection decreased viability of glioma cells more effectively than Ad5-Delta24RGD alone with effects ranging from additive to supra-additive. In addition, combination treatment with Ad5-Delta24RGD and irradiation was studied in glioma xenografts. Five injections of 1 x 10(6) plaque-forming units Ad5-Delta24RGD induced significant tumor growth delay of >119 days compared with untreated controls and led to long-term survival in 6 of 9 mice. When viral treatment was combined with irradiation, tumor regression occurred in all mice resulting in long-term survival without evidence of tumor regrowth in 10 of 10 cases. This study thus provides evidence that Ad5-Delta24RGD has strong antitumor activity in malignant glioma, which can be additionally enhanced by irradiation such that the same therapeutic effect is achieved when a 10-fold lower viral dose is applied. These results support further development of Ad5-Delta24RGD in combination with radiation therapy for treatment of these highly malignant tumors.
Prevention of Heart Failure (2008)

The increase in heart failure (HF) rates throughout the developed and developing regions of the world poses enormous challenges for caregivers, researchers, and policymakers. Therefore, prevention of this global scourge deserves high priority. Identifying and preventing the well-recognized illnesses that lead to HF, including hypertension and coronary heart disease, should be paramount among the approaches to prevent HF. Aggressive implementation of evidence-based management of risk factors for coronary heart disease should be at the core of HF prevention strategies. Questions currently in need of attention include how to identify and treat patients with asymptomatic left ventricular systolic dysfunction (Stage B HF) and how to prevent its development. The relationship of chronic kidney disease to HF and control of chronic kidney disease in prevention of HF need further investigation. Currently, we have limited understanding of the pathophysiological basis of HF in patients with preserved left ventricular systolic function and management techniques to prevent it. New developments in the field of biomarker identification have opened possibilities for the early detection of individuals at risk for developing HF (Stage A HF). Patient groups meriting special interest include the elderly, women, and ethnic/racial minorities. Future research ought to focus on obtaining a much better knowledge of genetics and HF, especially both genetic risk factors for development of HF and genetic markers as tools to guide prevention. Lastly, a national awareness campaign should be created and implemented to increase public awareness of HF and the importance of its prevention. Heightened public awareness will provide a platform for advocacy to create national research programs and healthcare policies dedicated to the prevention of HF.
Toward an Understanding of the Correlates of Protective Immunity to HIV Infection (1996)

Considerable progress has been made recently in understanding the genetic, immunologic and virologic factors in human immunodeficiency virus (HIV)-infected individuals who either rapidly progress or do not progress to acquired immunodeficiency syndrome (AIDS). In addition, detection of HIV-specific immune responses in HIV-negative individuals who have been exposed to the virus multiple times suggests that natural immune responses to HIV may be protective in rare individuals. Understanding the correlates of protective immunity to HIV infection is critical to efforts to develop preventive HIV vaccines as well as to determine the feasibility of treating HIV infection by boosting immunity to HIV.
Treatment and management of graft-versus-host disease: improving response and survival (2013)

Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogenic haematopoietic stem-cell transplantation and thus the focus of much ongoing research. Despite considerable advances in our understanding of the pathophysiology, diagnosis and predisposing factors for both acute and chronic forms of the disease, a standardised therapeutic strategy is still lacking. There is good evidence for initial treatment of both acute and chronic forms of the disease with corticosteroid therapy. However, the most effective approach to steroid-refractory disease remains controversial, with current practice based mainly on smaller studies and varying considerably between local institutions. Timely diagnosis, multidisciplinary working and good supportive care, including infection prophylaxis, are clearly important in optimizing response and survival in such patients. It is hoped that in the future systematic research strategies and the identification of novel therapeutic targets may improve outcome further. The following review aims to outline some of the existing options for the treatment and management of acute and chronic GVHD.
Direct modulation of tracheal Cl−-channel activity by 5,6- and 11,12-EET (1998)

Using microelectrode potential measurements, we tested the involvement of Cl- conductances in the hyperpolarization induced by 5,6- and 11,12-epoxyeicosatrienoic acid (EET) in airway smooth muscle (ASM) cells. 5,6-EET and 11,12-EET (0.75 microM) caused -5.4 +/- 1.1- and -3.34 +/- 0.95-mV hyperpolarizations, respectively, of rabbit tracheal cells (from a resting membrane potential of -53.25 +/- 0.44 mV), with significant residual repolarizations remaining after the Ca2+-activated K+ channels had been blocked by 10 nM iberiotoxin. In bilayer reconstitution experiments, we demonstrated that the EETs directly inhibit a Ca2+-insensitive Cl- channel from bovine ASM; 1 microM 5,6-EET and 1.5 microM 11,12-EET lowered the unitary current amplitude by 40 (n = 6 experiments) and 44.7% (n = 4 experiments), respectively. Concentration-dependent decreases in channel open probability were observed, with estimated IC50 values of 0.26 microM for 5,6- and 1.15 microM for 11,12-EET. Furthermore, pharmacomechanical tension measurements showed that both regioisomers induced significant bronchorelaxations in epithelium-denuded ASM strips. These results suggest that 5,6- and 11,12-EET can act in ASM as epithelium-derived hyperpolarizing factors.
Effectiveness of pilocarpine in postradiation xerostomia (1987)

Pilocarpine and placebo tablets were administered for 90 day periods in a double-blind, sequential crossover trial to 12 patients with postradiation xerostomia. Salivary flow was measured by two techniques, symptomatic change and adverse side effects were also recorded. Nine of the 12 patients showed marked improvement by two or more criteria while taking pilocarpine. None of the 12 patients showed meaningful improvement while on placebo. Side effects were minimal and easily controlled. These results show that pilocarpine is effective in relieving the signs and symptoms of postradiation xerostomia.
ANALYTIC SCORING OF TOEFL® CBT ESSAYS: SCORES FROM HUMANS AND E‐RATER® (2008)

ABSTRACT The main purpose of the study was to investigate the distinctness and reliability of analytic (or multitrait) rating dimensions and their relationships to holistic scores and e‐rater ® essay feature variables in the context of the TOEFL ® computer‐based test (CBT) writing assessment. Data analyzed in the study were analytic and holistic essay scores provided by human raters and essay feature variable scores computed by e‐rater (version 2.0) for two TOEFL CBT writing prompts. It was found that (a) all of the six analytic scores were not only correlated among themselves but also correlated with the holistic scores, (b) high correlations obtained among holistic and analytic scores were largely attributable to the impact of essay length on both analytic and holistic scoring, (c) there may be some potential for profile scoring based on analytic scores, and (d) some strong associations were confirmed between several e‐rater variables and analytic ratings. Implications are discussed for improving the analytic scoring of essays, validating automated scores, and refining e‐rater essay feature variables.
ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload (2014)

Palmitate overload induces hepatic cell dysfunction characterized by enhanced apoptosis and altered citric acid cycle (CAC) metabolism; however, the mechanism of how this occurs is incompletely understood. We hypothesize that elevated doses of palmitate disrupt intracellular calcium homeostasis resulting in a net flux of calcium from the ER to mitochondria, activating aberrant oxidative metabolism. We treated primary hepatocytes and H4IIEC3 cells with palmitate and calcium chelators to identify the roles of intracellular calcium flux in lipotoxicity. We then applied (13)C metabolic flux analysis (MFA) to determine the impact of calcium in promoting palmitate-stimulated mitochondrial alterations. Co-treatment with the calcium-specific chelator BAPTA resulted in a suppression of markers for apoptosis and oxygen consumption. Additionally, (13)C MFA revealed that BAPTA co-treated cells had reduced CAC fluxes compared to cells treated with palmitate alone. Our results demonstrate that palmitate-induced lipoapoptosis is dependent on calcium-stimulated mitochondrial activation, which induces oxidative stress.
Edwardsiella ictaluri sp. nov., the Causative Agent of Enteric Septicemia of Catfish (1981)

We characterized 13 cultures of the enteric bacterium causing enteric septicemia of catfish by studying their biochemical reactions, deoxyribonucleic hybridizations, and deoxyribonucleic acid guanine-plus-cytosine contents. We confirmed that this bacterium is a new species, which is most closely related to Edwardsiella tarda of the family Enterobacteriaceae. Five strains of the bacterium causing enteric septicemia of catfish were 80% or more related to the type strain, SECFDL GA 77-52 (= CDC 1976-78 = ATCC 33202), in 60°C deoxyribonucleic acid homology reactions. Species level relatedness among the 13 strains which we studied was demonstrated by the more than 80% relatedness in 75°C reactions. The bacterium causing enteric septicemia of catfish was most closely related to E. tarda (56 to 62%) in 60°C reactions. The guanine-plus-cytosine was 53 mol%, as determined by buoyant density centrifugation. We propose the name Edwardsiella ictaluri sp. nov. for the bacterium causing enteric septicemia of catfish.
Flow Regulation of 72-kD Collagenase IV (MMP-2) After Experimental Arterial Injury (1998)

Hemodynamic forces such as low flow upregulate injury-induced MMP-2 mRNA and appear to be more important in regulating MMP-2 activity than injury alone. This may facilitate migration of the smooth muscle cells and subsequent development of intimal thickening.
An annotation language for optimizing software libraries (1999)

This paper introduces an annotation language and a compiler that together can customize a library implementation for specific application needs. Our approach is distinguished by its ability to exploit high level, domain-specific information in the customization process. In particular, the annotations provide semantic information that enables our compiler to analyze and optimize library operations as if they were primitives of a domain-specific language. Thus, our approach yields many of the performance benefits of domain-specific languages, without the effort of developing a new compiler for each domain.
Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite (2003)

Protein, generally agreed to be the most satiating macronutrient, may differ in its effects on appetite depending on the protein source and variation in digestion and absorption. We investigated the effects of two milk protein types, casein and whey, on food intake and subjective ratings of hunger and fullness, and on postprandial metabolite and gastrointestinal hormone responses. Two studies were undertaken. The first study showed that energy intake from a buffet meal ad libitum was significantly less 90 min after a 1700 kJ liquid preload containing 48 g whey, compared with an equivalent casein preload (P<0.05). In the second study, the same whey preload led to a 28 % increase in postprandial plasma amino acid concentrations over 3 h compared with casein (incremental area under the curve (iAUC), P<0.05). Plasma cholecystokinin (CCK) was increased by 60 % (iAUC, P<0.005), glucagon-like peptide (GLP)-1 by 65 % (iAUC, P<0.05) and glucose-dependent insulinotropic polypeptide by 36 % (iAUC, P<0.01) following the whey preload compared with the casein. Gastric emptying was influenced by protein type as evidenced by differing plasma paracetamol profiles with the two preloads. Greater subjective satiety followed the whey test meal (P<0.05). These results implicate post-absorptive increases in plasma amino acids together with both CCK and GLP-1 as potential mediators of the increased satiety response to whey and emphasise the importance of considering the impact of protein type on the appetite response to a mixed meal.
Up-regulation of ephrin-a1 during melanoma progression (1999)

Ephrin-A1, formerly called B61, is a new melanoma growth factor; it is angiogenic and chemoattractant for endothelial cells. EPH-A2, or ECK (a receptor for ephrin-A1), is ectopically expressed in most melanoma cell lines; the pathology where this expression is first manifested and the possible role of the receptor in tumor progression are unknown. To determine these, we studied the expression of this ligand and receptor in biopsies of benign and malignant melanocytic lesions. EPH-A2 was not detected in normal melanocytes, benign compound nevi or advanced melanomas, though it was found in 2 of 9 biopsies of malignant melanoma in situ. Ephrin-A1 was present in occasional early lesions and in advanced primary melanomas (43%) and metastatic melanomas (67%). Expression of ephrin-A1 was induced in melanoma cells by pro-inflammatory cytokines. Our findings are consistent with 2 possible roles for ephrin-A1 in melanoma development: it may promote melanocytic cell growth or survival and induce vascularization in advanced melanomas. Both effects may be potentiated by inflammatory responses. Our data are consistent with earlier observations that an inflammatory infiltrate is associated with poor prognosis in thin primary melanomas.
Changes in Equivalent and Gradient Refractive Index of the Crystalline Lens with Accommodation (1997)

The ocular dimensions and refraction of the eye were measured for accommodation stimulus levels of 0.0, 1.5, 3.5, 5.5, and 8.0 D for 11 subjects aged 18 to 28 years, mean 21.2 +/- 2.62 years using keratometry, autorefraction, A-Scan ultrasonography, and video phakometry techniques. The subjects had refractive errors in the range + 0.50 to -4.25 D, mean -1.88 +/- 1.64 D. With the maximum level of accommodation the anterior chamber depth decreased by 0.23 +/- 0.09 mm, the lens thickness increased by 0.28 +/- 0.09 mm, and no significant differences were recorded in axial length or vitreous chamber depth. The radius of curvature of the anterior surface of the crystalline lens decreased from 11.54 +/- 1.27 to 6.59 +/- 0.97 mm and the posterior surface from -6.67 +/- 0.97 to -5.30 +/- 0.4 mm. We determined the equivalent refractive index to be 1.4277 +/- 0.0011, with no significant differences at different levels of accommodation. When the crystalline lens was modeled as a gradient refractive index (GRIN) structure with elliptical iso-indicial lines, the mean surface refractive index of the lens was 1.3859 +/- 0.0009 for an assumed central refractive index of 1.406. The power of the anterior surface of the lens increased from 4.38 +/- 0.49 to 7.59 +/- 0.34 D, the posterior surface increased from 7.67 +/- 1.28 to 9.32 +/- 0.64 D, and the GRIN power increased from 9.70 +/- 1.31 to 13.74 +/- 0.77 D for the maximum accommodative stimulus of 8.00 D. On the basis of the model used, a substantial part of the increase in power of the crystalline lens with accommodation resulted from the change in refractive index distribution within the lens.
Dissection of a Natural RNA Silencing Process in the Drosophila melanogaster Germ Line (2004)

To date, few natural cases of RNA-silencing-mediated regulation have been described. Here, we analyzed repression of testis-expressed Stellate genes by the homologous Suppressors of Stellate [Su(Ste)] repeats that produce sense and antisense short RNAs. The Stellate promoter is dispensable for suppression, but local disturbance of complementarity between the Stellate transcript and the Su(Ste) repeats impairs silencing. Using in situ RNA hybridization, we found temporal control of the expression and spatial distribution of sense and antisense Stellate and Su(Ste) transcripts in germinal cells. Antisense Su(Ste) transcripts accumulate in the nuclei of early spermatocytes before the appearance of sense transcripts. The sense and antisense transcripts are colocalized in the nuclei of mature spermatocytes, placing the initial step of silencing in the nucleus and suggesting formation of double-stranded RNA. Mutations in the aubergine and spindle-E genes, members of the Argonaute and RNA helicase gene families, respectively, impair silencing by eliminating the short Su(Ste) RNA, but have no effect on microRNA production. Thus, different small RNA-containing complexes operate in the male germ line.
350. Toward Genosafe Endonuclease-Boosted Gene Targeting Using Breakthrough CRISPR/Cas9 for Next Generation Stem Cell Gene Therapy Culminating in Efficient Ex Vivo/In Vivo Gene Repair/Genomic Editing (2015)

Bacterial CRISPR-associated protein Cas9 acts as an in vitro programmable site-specific endonuclease directed to its DNA target by a 100-nt single-guide RNA (sgRNA) and drives a gene targeting breakthrough in human cells based on efficiency and easy cost-efficient sgRNA customization. Such a breakthrough substitutes simple digital RNA-DNA base-pairing for complex analogic protein-DNA binding of zinc-finger/TALE nucleases and is a key upgrade for the endonuclease-boosted gene targeting arm of our proposed 2006 Universal Stem Cell Gene Therapy Platform. However, Cas9 clinical translation is still pending on the final improvement of 1) DNA target specificity and 2) on-target genosafety. DNA TARGET SPECIFICITY of Cas9 relies on a 20-bp sequence complementary to the 5’-end of sgRNA and on adjacent 5’-NGG-3’ PAM recognized by Cas9 itself, thereby involving a DNA sequence longer than the 18-bp specificity reference for a human genome. However, Cas9 can accomodate up to 5 mismatches, mainly on the 5’-end of sgRNA, resulting in off-target genotoxic double-strand breaks (DSBs). Cas9 is thus subjected to strategic improvements including 1) truncation of 2/3 nt at the 5’-end of sgRNA and 2) use of single (nickase) and double (inactive dCas9) Cas9 mutants for DSB genesis by paired nickases and by dimers of FokI-dCas9 fusion protein. Another promising approch relies on the delivery of pre-assembled Cas9-sgRNA ribonucleoprotein (RNP) complexes using either nucleofection or ex vivo/in vivo cationic-lipid transfection. ON-TARGET GENOSAFETY is a major clinical concern. Gene targeting is boosted by site-specific endonucleases because it relies on homologous recombination, a DSB repair pathway mediating DNA exchanges between chromosomal and transfecting/transducing DNA, thereby providing the means to modify at will chromosomal DNA sequences (genomic editing) culminating in gene repair or targeted transgene integration. However, the aforedescribed homology-directed repair (HDR) pathway is challenged by non-homologous end-joining (NHEJ) DSB-repair leading to insertion/deletion mutations (indels): NHEJ prevails in the absence of homologous donor DNA (eg: off-target DSBs, targeted gene inactivation) and hampers on-target HDR while generating genotoxic indels. Therefore, under off-target-free condition, the on-target HDR/NHEJ ratio has to be increased to a clinical-trial genosafety level. We are thus resuming our former approach based on recombinase-DNA nucleoprotein filaments for the transfer of donor DNA in its active presynaptic state. Our approach is thus discussed in terms of ex vivo nucleofection and in vivo cationic-lipid transfection of nucleoprotein complexes comprising Cas9-sgRNA RNPs and donor-DNA presynaptic-filaments for efficient genosafe gene repair/genomic editing of Next Generation Stem Cell Gene Therapy focussed on hazard-free patient-specific iPS cells and expandable tissue-specific converted stem cells.