gebhart/patrepeval huggingface dataset:
Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1G93A mouse model of ALS (2008)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motoneuron degeneration, resulting in muscle paralysis and death, typically within 1-5 years of diagnosis. Although the pathogenesis of ALS remains unclear, there is evidence for the involvement of proteasome dysfunction and heat shock proteins in the disease. We have previously shown that treatment with a co-inducer of the heat shock response called arimoclomol is effective in the SOD(G93A) mouse model of ALS, delaying disease progression and extending the lifespan of SOD(G93A) mice (Kieran et al. 2004). However, this previous study only examined the effects arimoclomol when treatment was initiated in pre- or early symptomatic stages of the disease. Clearly, to be of benefit to the majority of ALS patients, any therapy must be effective after symptom onset. In order to establish whether post-symptomatic treatment with arimoclomol is effective, in this study we carried out a systematic assessment of different treatment regimes in SOD(G93A) mice. Treatment with arimoclomol from early (75 days) or late (90 days) symptomatic stages significantly improved muscle function. Treatment from 75 days also significantly increased the lifespan of SOD(G93A) mice, although treatment from 90 days has no significant effect on lifespan. The mechanism of action of arimoclomol involves potentiation of the heat shock response, and treatment with arimoclomol increased Hsp70 expression. Interestingly, this up-regulation in Hsp70 was accompanied by a decrease in the number of ubiquitin-positive aggregates in the spinal cord of treated SOD(G93A) mice, suggesting that arimoclomol directly effects protein aggregation and degradation.
Elevation of membrane tyrosine phosphatase activity in density-dependent growth-arrested fibroblasts. (1991)

Swiss 3T3 cells harvested at high density contain a membrane protein-tyrosine-phosphatase (EC 3.1.3.48) whose specific activity is on average 8-fold higher than that of cells harvested at low or medium densities. Investigation of the conditions affecting this elevation of specific activity suggests that it is associated with density-dependent growth arrest. Fibroblasts in the exponentially doubling phase have a relatively low level of membrane phosphatase specific activity, which rises only as the rate of cell proliferation decreases and is maximal when cell growth is contact inhibited. These observations have been extended to BALB/c 3T3 fibroblasts and normal human diploid fibroblasts. The increase in membrane tyrosine phosphatase activity is coupled to density arrest and not to cellular quiescence in general, as no increase in phosphatase specific activity is detected when non-contact-inhibited cells are induced to arrest their growth through serum deprivation. The observed alterations in specific activity are attributable to a tyrosine phosphatase of Mr 37,000 that was purified and characterized from solubilized membrane fractions of Swiss 3T3 cells. A regulatory mechanism controlling tyrosine phosphatase activity may play a role in cell proliferation and growth arrest caused by cell contact.
Appreciating HIV Type 1 Diversity: Subtype Differences in Env (2009)

Human immunodeficiency virus type 1 (HIV-1) group M is responsible for the current AIDS pandemic and exhibits exceedingly high levels of viral genetic diversity around the world, necessitating categorization of viruses into distinct lineages, or subtypes. These subtypes can differ by around 35% in the envelope (Env) glycoproteins of the virus, which are displayed on the surface of the virion and are targets for both neutralizing antibody and cell-mediated immune responses. This diversity reflects the remarkable ability of the virus to adapt to selective pressures, the bulk of which is applied by the host immune response, and represents a serious obstacle for developing an effective vaccine with broad coverage. Thus, it is important to understand the underlying biological consequences of intersubtype diversity. Recent studies have revealed that some of the HIV-1 subtypes exhibit phenotypic differences stemming from subtle changes in Env structure, particularly within the highly immunogenic V3 domain, which participates directly in viral entry. This review will therefore explore current research that describes subtype differences in Env at the genetic and phenotypic level, focusing in particular on V3, and highlighting recent discoveries about the unique features of subtype C Env, which is the most globally prevalent subtype.
Influence of Mastication on Gastric Emptying (2002)

The role of mastication on digestion efficiency remains to be demonstrated. This study investigates whether masticatory function influences gastric emptying rate. Twelve normal volunteers were studied on two occasions after ingestion of the same test meal containing ham cubes, crackers, and egg (mixed with 13C-octanoic acid), chewed, in random order, either with 50 masticatory cycles or with 25 cycles, swallowing ham cubes whole. Lag phase (Tlag) and gastric half-emptying time (T1/2) were measured by means of the 13C-octanoic acid breath test. Trituration performance was assessed by the sieve test, and was expressed as the percentage of ham particles < or = 1 mm after 50 masticatory cycles. Tlag and T1/2 were significantly shorter when the meal was chewed with 50 cycles than with 25 cycles (Tlag 25.9+/-3.8 vs. 36.4+/-4.1 min, p=0.017; T1/2 49.1+/-5.7 vs. 62.5+/-6 min, p=0.009). Trituration performance was inversely related to both Tlag (r=0.621, p=0.031) and T1/2 (r=0.699, p=0.012). Comminution of food influences significantly gastric emptying rates.
Methacholine Reactivity Predicts Changes in Lung Function Over Time in Smokers With Early Chronic Obstructive Pulmonary Disease. The Lung Health Study Research Group (1996)

As part of a clinical trial of early intervention in chronic obstructive pulmonary disease (COPD) (the Lung Health Study), 5,733 smokers with mild to moderate airflow obstruction underwent methacholine challenge tests at baseline. All participants were randomized to receive either usual care (no intervention) or special intervention, consisting of intensive smoking cessation counseling and the prescription of a metered-dose inhaler containing either ipratropium bromide or placebo (two inhalations three times daily). For this report, we analyzed the relationship between baseline methacholine reactivity and subsequent change in lung function. Methacholine reactivity was expressed as a logarithmic function of the two-point slope of percent decline in FEV1 over the concentration of methacholine (LMCR). Using a random effects linear model, LMCR was found to be a strong predictor of change in FEV1% predicted, after controlling for baseline lung function, age, sex, baseline smoking history, and changes in smoking status. Significant interactions were found between reactivity and smoking behavior. In the first year, participants who quit smoking showed improvement in FEV1, whereas continuing smokers showed worsening, and between Years 1 and 5, lung function declined to a greater extent in continuing smokers than in sustained quitters. For both time periods, these quitter/smoker differences increased as a function of airway reactivity. These findings indicate that methacholine reactivity is an important predictor of progression of airway obstruction in continuing smokers with early COPD, independent of the baseline level of obstruct.
The resolution and characterization of putative ubiquitin carrier protein isozymes from rabbit reticulocytes. (1988)

The covalent ligation of the 8.6-kDa polypeptide ubiquitin to various cellular target proteins is believed to represent a fundamental regulatory process. In this mechanism, the ATP-coupled activation and subsequent ligation of ubiquitin are catalyzed by separate enzymes (E1 and E3, respectively) functionally linked by ubiquitin carrier protein (E2). Carrier protein has been proposed to constitute a family of isozymes having molecular masses of 14, 17, 20, 24, and 32 kDa whose role is to shuttle activated polypeptide in the form of a high-energy thiol ester intermediate to the carboxyl terminus of ubiquitin. Using a combination of covalent affinity and high performance liquid chromatographic methods, the pututive E2 isozymes have been purified to apparent homogeneity. The E2(14kDa) isozyme resolved into two forms differing in net charge at pH 7.5. All of the E2 isozymes contained only one thiol ester site except for E2(17kDa) and E2(20kDa) which were capable of forming two such adducts per subunit. Thiol ester formation was rapid for the E2 isozymes and required the presence of activating enzyme. In contrast, the reverse reaction of thiol ester transfer from E2 to E1 was kinetically significant for only E2(14kDa), E2(20kDa), and E2(24kDa). The stability of E2(17kDa) and E2(32kDa) to such trapping may reflect a marked shift in binding affinity to E1 upon thiol ester formation. In addition, differential rates for thiol ester formation to each subunit of dimeric E2(14kDa) was also noted. The E2(14kDa) isoforms were approximately 10-fold more active in E3-dependent ubiquitin-protein ligation than either E2(20kDa) or E2(32kDa). Neither E2(17kDa) nor E2(24kDa) supported this reaction. In addition, the thiol ester formed to E2(14kDa) was inherently more reactive since its second order rate constant for the E3-independent transfer of ubiquitin to the small molecular weight nucleophile dithiothreitol was an order of magnitude greater than found for the other isozymes. If these proteins constitute a family of isozymes, they exhibit considerable catalytic diversity.
Interaction of pseudomonic acid A with Escherichia coli B isoleucyl-tRNA synthetase (1980)

Sodium pseudomonate was shown to be a powerful competitive inhibitor of Escherichia coli B isoleucyl-tRNA synthetase (Ile-tRNA synthetase). The antibiotic competitively inhibits (Ki 6 nM; cf. Km 6.3 microM), with respect top isoleucine, the formation of the enzyme . Ile approximately AMP complex as measured by the pyrophosphate-exchange reaction, and has no effect on the transfer of [14C]isoleucine from the enzyme . [14C]Ile approximately AMP complex to tRNAIle. The inhibitory constant for the pyrophosphate-exchange reaction was of the same order as that determined for the inhibition of the overall aminoacylation reaction (Ki 2.5 nM; cf. Km 11.1 microM). Sodium [9'-3H]pseudomonate forms a stable complex with Ile-tRNA synthetase. Gel-filtration and gel-electrophoresis studies showed that the antibiotic is only fully released from the complex by 5 M-urea treatment or boiling in 0.1% sodium dodecyl sulphate. The molar binding ratio of sodium [9'-3H]pseudomonate to Ile-tRNA synthetase was found to be 0.85:1 by equilibrium dialysis. Aminoacylation of yeast tRNAIle by rat liver Ile-tRNA synthetase was also competitively inhibited with respect to isoleucine, Ki 20 microM (cf. Km 5.4 microM). The Km values for the rat liver and E. coli B enzymes were of the same order, but the Ki for the rat liver enzyme was 8000 times the Ki for the E. coli B enzyme. This presumably explains the low toxicity of the antibiotic in mammals.
Mask assisted off-axis illumination technique for random logic (1993)

While off-axis illumination has been demonstrated to improve contrast and depth of focus for low k1, packed line–space (L/S) patterns [S. Asai, I. Hanyu, and K. Hikosaka, J. Vac. Sci. Technol. B 9, 2788 (1991); K. Kamon et al., Jpn. Appl. Phys. 30, 3021 (1991); K. Tounai et al., Proc. SPIE 1674, 753 (1992)], application of this approach to the more discordant patternings associated with random logic levels is suspect. We introduce a conventional mask ‘‘assist’’ feature technique that extends the off-axis L/S enhancements to more isolated features (both spaces and lines). It will be shown that the effective process window is substantially improved and exhibited proximity effects are mitigated for this technique. Also, a comparison to a phase-shifting mask solution for the patterning mix expected in random logic layouts is performed. Simulation results are verified on a 0.53 NA, DUV stepper.
Depressed Feeding by the Nematode Trichostrongylus colubriformis in Inoculated Goats (1986)

loc. cit.) that centrifugation alone may initiate migration of granules and surface lamination, but no further conversion to schistosomules occurs in water. It is possible that other kinds of agitation besides centrifugation may do the same thing. Cultivation in ELAC, saline and PBS at 37 C beyond 3 hr revealed that both saline and PBS organisms were slower than ELAC organisms in onset of esophageal gland granule migration (3 hr) and development of euchromatic nuclei (4872 hr). Even ELAC organisms lagged behind in in vivo schistosomules (Stirewalt et al., 1983, loc. cit.). Glycocalyx degradation, however, occurred at the same rate in all 3 types of incubation medium, but also was much slower than in vivo (Table II). These data demonstrate that conversion of cercariae to schistosomules can be brought about by the single simple procedure of cultivation of cercariae at 37 C in a medium such as ELAC, or even in saline or PBS. The changes occur more slowly in vitro than in vivo, and in saline and PBS than ELAC. Nevertheless, with this method of conversion, the large numbers of organisms required for preparation of a vaccine consisting of irradiated schistosomules, or for other immunological investigations, are easily obtainable. This study was supported by NIH Grant RR08005.
Helium: a transparent inter-kernel optimizer for OpenCL (2015)

State of the art automatic optimization of OpenCL applications focuses on improving the performance of individual compute kernels. Programmers address opportunities for inter-kernel optimization in specific applications by ad-hoc hand tuning: manually fusing kernels together. However, the complexity of interactions between host and kernel code makes this approach weak or even unviable for applications involving more than a small number of kernel invocations or a highly dynamic control flow, leaving substantial potential opportunities unexplored. It also leads to an over complex, hard to maintain code base. We present Helium, a transparent OpenCL overlay which discovers, manipulates and exploits opportunities for inter-and intra-kernel optimization. Helium is implemented as preloaded library and uses a delay-optimize-replay mechanism in which kernel calls are intercepted, collectively optimized, and then executed according to an improved execution plan. This allows us to benefit from composite optimizations, on large, dynamically complex applications, with no impact on the code base. Our results show that Helium obtains at least the same, and frequently even better performance, than carefully handtuned code. Helium outperforms hand-optimized code where the exact dynamic composition of compute kernel cannot be known statically. In these cases, we demonstrate speedups of up to 3x over unoptimized code and an average speedup of 1.4x over hand optimized code.
Prediction of chromosomal aneuploidy from gene expression data (2006)

Chromosomal aneuploidy is commonly observed in neoplastic diseases and is an important prognostic marker. Here we examine how gene expression profiles reflect aneuploidy and whether these profiles can be used to detect changes in chromosome copy number. We developed two methods for detecting such changes in the gene expression profile of a single sample. The first method, fold-change analysis, relies on the availability of gene expression data from a large cohort of patients with the same disease. The expression profile of the sample is compared with that of the dataset. The second method, chromosomal relative expression analysis, is more general and requires the expression data from the tested sample only. We found that the relative expression values are stable among different chromosomes and exhibit little variation between different normal tissues. We exploited this novel finding to establish the set of reference values needed to detect changes in the copy number of chromosomes in a single sample on the basis of gene expression levels. We measured the accuracy of the performance of each method by applying them to two independent leukemia datasets. The second method was also applied to two solid tumor datasets. We conclude that chromosomal aneuploidy can be detected and predicted by analysis of gene expression profiles. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
Mutagenesis of the DI/DIII Linker in Dengue Virus Envelope Protein Impairs Viral Particle Assembly (2012)

The dengue virus (DV) envelope (E) protein is important in mediating viral entry and assembly of progeny virus during cellular infection. Domains I and III (DI and DIII, respectively) of the DV E protein are connected by a highly conserved but poorly ordered region, the DI/DIII linker. Although the flexibility of the DI/DIII linker is thought to be important for accommodating the structural rearrangements undergone by the E protein during viral entry, the function of the linker in the DV infectious cycle is not well understood. In this study, we performed site-directed mutagenesis on conserved residues in the DI/DIII linker of the DV2 E protein and showed that the resulting mutations had little or no effect on the entry process but greatly affected virus assembly. Biochemical fractionation and immunofluorescence microscopy experiments performed on infectious virus as well as in a virus-like particle (VLP) system indicate that the DI/DIII linker mutants express the DV structural proteins at the sites of particle assembly near the ER but fail to form infectious particles. This defect is not due to disruption of E's interaction with prM and pr in immature and mature virions, respectively. Serial passaging of the DV2 mutant E-Y299F led to the identification of a mutation in the membrane-proximal stem region of E that fully compensates for the assembly defect of this DI/DIII linker mutant. Together, our results suggest a critical and previously unidentified role for the E protein DI/DIII linker region during the DV2 assembly process.
Combined 18F-FDG and 11C-methionine PET scans in patients with newly progressive metastatic prostate cancer. (2002)

These findings reflect the different biologic characteristics of the lesions in a heterogeneous tumor such as prostate cancer and suggest that a time-dependent metabolic cascade may occur in advanced prostate cancer, with initial uptake of 11C-methionine in dormant sites followed by increased uptake of 18F-FDG during progression of disease.
Rescue, expression, and analysis of a neutralizing human anti-hepatitis A virus monoclonal antibody. (1993)

A human anti-hepatitis A virus mAb was rescued from a hybridoma cell line by conventional cDNA cloning, and expressed in CHO cells. The full nucleotide sequences of the mAb H and L chains were determined, revealing a VHI/V lambda II V region combination. Comparisons with germline V genes suggest that the V regions had undergone somatic mutations characteristic of an Ag-driven immune response. A comparison of the binding to hepatitis A virus between mAb derived from the CHO cells and the original hybridoma cell line using ELISA, radioimmunoprecipitation, and solid-phase competition RIA, indicated that the CHO cell-derived mAb fully retained the specificity of the mAb produced by hybridoma cells. Analysis of viral neutralization using a radioimmunofocus inhibition assay demonstrated the retention of antibody functionality after expression in CHO cells, demonstrating the use of this technique in the rescue and high level expression of unstable efficacious human mAb.
Interactions of cytokines, growth factors, and proteases in acute and chronic wounds (1996)

A healing wound represents a complex series of interactions between cells, soluble mediators, and extracellular matrix. Within this multifaceted environment, there are multiple regulatory points which control the ordered series of events that lead to normal tissue repair. An alteration in this physiologic network can lead to the development of a chronic wound. This article presents an update on the numerous mediators that exist within the wound environment in both acute normal healing and chronic nonhealing wounds. We also present a hypothesis which may provide a conceptual pathophysiologic mechanism with which to understand all chronic wounds.
The role of the tissue adhesive fibrin seal (FS) in esophageal anastomoses (1983)

Following surgical removal of esophageal tumors, leakage and mediastinitis is a frequent and often fatal complication. A new method has been developed to seal suture lines in the esophagus with preparations containing fibrinogen, cold insoluble globulin, factor XIII, antiplasmin, platelet growth factor, thrombin, and calcium chloride. In experimental animals operated on by standard methods, esophageal leakage developed in 50% of the animals and death in 40%. By contrast, in treated animals, esophageal leak and death developed in only 20%. More adhesions were found in treated animals than in control animals.
The impact of chronic disease (1981)

A large number of individuals with rheumatoid arthritis have been studied in order to better delineate the sociomedical problems experienced by patients with this chronic disease. Two hundred forty-five respondents were surveyed by use of a detailed questionnaire and interview, and the results indicate that major losses in the areas of work, finances, and family structure are extremely common. The majority of workers were totally disabled as a result of their disease. On the average, subjects in the group were earning only 50% of the income predicted for them had they not had arthritis. Sixty-three percent experienced a major change in their psychosocial status as a result of their disease. Work disability appears to be the most important sociomedical impact of rheumatoid arthritis since it is associated with significantly greater income and psychosocial losses. This evidence of numerous and serious sociomedical problems in persons with rheumatoid arthritis raises questions of emphasis and approach for physicians involved in the clinical care of chronic rheumatic disease patients.
Optical initiation of nanoporous energetic silicon for safing and arming technologies (2010)

Nanoporous silicon, commonly recognized for its photoluminescent properties, has gained attention as a new energetic material capable of energy density more than twice that of TNT. The addition of an oxidizer solution to inert nanoporous silicon results in an exothermic reaction when heat, friction, or focused light is supplied to the system. The energetic material can be integrated alongside microelectronics and micro-electro-mechanical systems (MEMS) for on-chip applications. This integration capability, along with the potential for large energetic yield, makes nanoporous energetic silicon a viable material for developing novel MEMS Safing and Arming (S&A) technologies. While ignition of nanoporous energetic silicon has been demonstrated for the purpose of propagation velocity measurements using a YAG laser, in this paper we show optical ignition for potential integration of the energetic with a miniaturized S&A device. Ignition is demonstrated using a 514nm laser at 37.7mW and a power density of 2.7kW/cm<sup>2</sup> at a stand-off distance of 23cm. Raman spectroscopy verifies that significant stress in porous silicon is produced by a laser operating near the power density observed to ignite porous silicon. Lastly, we integrate the nanoporous energetic silicon with a MEMS S&A, and demonstrate transfer to a firetrain consisting of one primary and one secondary explosive using a thermal initiator to ignite the nanoporous energetic silicon.