gebhart/patrepeval huggingface dataset:
Using virtual lines to enhance locality exploitation (1994)

Because the spatial locality of numerical codes is significant, the potential for performance improvements is important. However, large cache lines cannot be used in current on-chip data caches because of the important pollution they breed. In this paper, we propose a hardware design, called the Virtual Line Scheme, that allows the utilization of large virtual cache lines when fetching data from memory for better exploitation of spatial locality, while the actual physical cache line is smaller than currently found cache lines for better exploitation of temporal locality. Simulations show that a 17% to 64% reduction of the average memory access time can be obtained for a 20-cycle memory latency. It is also shown how simple software informations can be used to significantly decrease memory traffic, a flaw associated with the utilization of large cache lines.
Ubiquitin extension proteins of Arabidopsis thaliana. Structure, localization, and expression of their promoters in transgenic tobacco. (1990)

The highly conserved protein ubiquitin is synthesized in eukaryotes as two types of protein fusions from which active ubiquitin is derived by proteolytic processing. We report here the isolation and characterization of multiple genes from one type that encode ubiquitin extension proteins from the higher plant, Arabidopsis thaliana (L.). Two genes with 90% nucleotide identity in their exons encode ubiquitin and identical 52-amino acid (aa) extension proteins with 85 and 79% aa identity to 52-aa extension proteins from humans and yeast, respectively. Two other genes with 90% nucleotide identity encode ubiquitin and 81-aa extension proteins that differ by 4 amino acids from each other and are approximately 70% identical to the 76- and the 80-aa extension proteins from yeast and humans, respectively. Antibodies recognizing the 52- and 81-aa Arabidopsis extension proteins identify them as constituents of ribosomes. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the 52- and 81-aa extension proteins migrate at 6.8 and 11.5 kDa, respectively, and neither cross-reacts with anti-ubiquitin antibodies, indicating that extension proteins are cleaved from ubiquitin following translation. Ubiquitin extension protein genes encode the smallest transcript size class of ubiquitin mRNAs in Arabidopsis. The 5'-flanking regions of both UBQ1 and UBQ6, genes representative of the both extension proteins, direct the expression of readily detectable levels of the marker enzyme beta-glucuronidase in transgenic tobacco, suggesting the utility of these promoters for expression of foreign genes in higher plants.
Donepezil in Alzheimer's disease: From conventional trials to pharmacogenetics. (2007)

Donepezil is the leading compound for the treatment of Alzheimer's disease (AD) in more than 50 countries. As compared with other conventional acetylcholinesterase inhibitors (AChEIs), donepezil is a highly selective and reversible piperidine derivative with AChEI activity that exhibits the best pharmacological profile in terms of cognitive improvement, responders rate (40%-58%), dropout cases (5%-13%), and side-effects (6%-13%) in AD. Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and activities of the daily living in both moderate and severe AD, contributing to slow down disease progression and, to a lesser exetnt, to delay institutionalization. Patients with vascular dementia might also benefit from donepezil in a similar fashion to AD patients. Some potential effects of donepezil on the AD brain, leading to reduced cortico-hippocampal atrophy, include the following: AChE inhibition, enhancement of cholinergic neurotransmission and putative modulation of other neurotransmitter systems, protection against glutamate-induced excitotoxicity, activation of neurotrophic mechanisms, promotion of non-amyloidodgenic pathways for APP processing, and indirect effects on cerebrovascular function improving brain perfusion. Recent studies demonstrate that the therapeutic response in AD is genotype-specific. Donepezil is metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. Approximately, 15%-20% of the AD population may exhibit an abnormal metabolism of AChEIs; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of AChEIs to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including donepezil, the best responders are the CYP2D6-related extensive (EM)(*1/*1, *1/*10) (57.47%) and intermediate metabolizers (IM)(*1/*3, *1/*5, *1/*6, *7/*10) (25.29%), and the worst responders are the poor (PM) (*4/*4)(9.20%) and ultra-rapid metabolizers (UM) (*1xN/*1) (8.04%). Pharmacogenetic and pharmacogenomic factors may account for 75%-85% of the therapeutic response in AD patients treated with donepezil and other AChEIs metabolized via enzymes of the CYP family. The implementation of pharmacogenetic protocols can optimize AD therapeutics.
Mucin utilisation and host interactions of the novel intestinal microbe Akkermansia muciniphila (2007)

Keywords .Mucin, A. muciniphila , mucin degradation, molecular techniques, host responseMucins are the major organic components of the defence barrier, known as mucus, covering epithelial cells in many organs, including the entire gastrointestinal (GI) tract. Microbes that can associate with mucins benefit from this interaction since they can access nutrients. Mucin-degrading bacteria are therefore an important community that have not been extensively studied as the substrate itself, mucin, is a complex and high molecular weight glycoprotein.The work presented here is focused on the identification and isolation of mucin-degrading bacteria from the GI tract, their degradation of mucin and their interaction with the host.Mucin-degrading bacteria were analysed by combining molecular- and cultivation-based approaches. The faecal mucin-degrading bacterial community was found to be highly diverse and host-specific. A novel isolate, representing a novel genus, was cultured from the highest dilution of the enrichment of a single individual. This intestinal isolate, Akkermansia muciniphila, was found to grow to a limited extent on a very limited amount of substrates but grew efficiently on mucin. Phylogenetic analysis based on 16S rRNA sequences indicated that A. muciniphila belonged to the phylum Verrucomicrobia, which was not known to contain intestinal members. Moreover, 16S rRNA genes from A. muciniphila have been retrieved in several clone libraries derived from either faecal or biopsy samples from human and mice. In addition, A. muciniphila was found to be rather abundant in the GI tract. Based on fluorescent in situ hybridisation and quantitative PCR, A. muciniphila was found to represent an average of 10 9 cells / g faecal sample. A negative correlation between the concentration of faecal mucin and the number of A. muciniphila was observed, suggesting it to be involved in mucin degradation in vivo . Several specific enzymes, mostly glycosidases were found to be secreted during its growth on mucin that was degraded for a major part (85%). Hence, the specific impact of A. muciniphila on the host was investigated in germ-free mice and compared to that of the non mucin-degrading bacterium L. plantarum . Transcriptomic microarray analysis showed that both A. muciniphila and L. plantarum modulated a similar number of genes but that host response was found to be highly specific for each bacterium, depending on the anatomical location. Amongst the major responses, we could detect for A. muciniphila a regulation of the immune response, cell proliferation, cell adhesion and apoptosis, and for L. plantarum a regulation of the lipid metabolism.Overall, this work has brought new insights into the mucin-degrading community of bacteria, and in particular the role of A. muciniphila,an abundant human mucin-degrading bacterium.
TYK2 and JAK2 Are Substrates of Protein-tyrosine Phosphatase 1B (2001)

The reversible tyrosine phosphorylation of proteins, modulated by the coordinated actions of protein-tyrosine kinases and protein-tyrosine phosphatases (PTPs), regulates the cellular response to a wide variety of stimuli. It is established that protein kinases possess discrete sets of substrates and that substrate recognition is often dictated by the presence of consensus phosphorylation sites. Here, we have extended this concept to the PTPs and demonstrated that (E/D)-pY-pY-(R/K) is a consensus substrate recognition motif for PTP1B. We have shown that JAK2 and TYK2 are substrates of PTP1B and that the substrate recognition site within theses kinases is similar to the site of dephosphorylation previously identified within the insulin receptor. A substrate-trapping mutant of PTP1B formed a stable interaction with JAK2 and TYK2 in response to interferon stimulation. Expression of wild type or substrate-trapping mutant PTP1B inhibited interferon-dependent transcriptional activation. Finally, mouse embryo fibroblasts deficient in PTP1B displayed subtle changes in tyrosine phosphorylation, including hyperphosphorylation of JAK2. The closely related JAK family member, JAK1, which does not match the consensus dephosphorylation site, was not recognized as a substrate. These data illustrate that PTP1B may be an important physiological regulator of cytokine signaling and that it may be possible to derive consensus substrate recognition motifs for other members of the PTP family, which may then be used to predict novel physiological substrates.
Typhoid and Paratyphoid Fever in 192 Hospitalized Children in Thailand (1987)

From 1977 to 1984, Salmonella typhi was isolated from 85% and Salmonella paratyphl A was isolated from 15% of 192 Thai children with enteric fever at Children's Hospital, Bangkok. Children with enteric fever presented with sudden onset of fever and gastrointestinal symptoms. of fever presented with sudden onset Diarrhea occurred in 62% of children with paratyphoid fever and 36% of children with typhoid fever. Rose spots were seen in 15% of patients with typhoid and 7% of patients with paratyphoid fever. There were no deaths. Bronchitis and pneumonia occurring in 11% of patients were the most common complications. Acute hemolysis occurred in 3% of the patients with typhoid fever who had thalassemia or glucose-6-phosphate dehydrogenase deficiency. Chloramphenicol-resistant S typhi, which accounted for 70% of the isolates in 1977, has since 1982 accounted for less than 2% of isolates.
“Why Should I Trust You?”: Explaining the Predictions of Any Classifier (2016)

Despite widespread adoption in NLP, machine learning models remain mostly black boxes. Understanding the reasons behind predictions is, however, quite important in assessing trust in a model. Trust is fundamental if one plans to take action based on a prediction, or when choosing whether or not to deploy a new model. In this work, we describe LIME, a novel explanation technique that explains the predictions of any classifier in an interpretable and faithful manner. We further present a method to explain models by presenting representative individual predictions and their explanations in a non-redundant manner. We propose a demonstration of these ideas on different NLP tasks such as document classification, politeness detection, and sentiment analysis, with classifiers like neural networks and SVMs. The user interactions include explanations of free-form text, challenging users to identify the better classifier from a pair, and perform basic feature engineering to improve the classifiers.
Interleukin-1β Causes Pulmonary Inflammation, Emphysema, and Airway Remodeling in the Adult Murine Lung (2005)

The production of the inflammatory cytokine interleukin (IL)-1 is increased in lungs of patients with chronic obstructive pulmonary disease (COPD) or asthma. To characterize the in vivo actions of IL-1 in the lung, transgenic mice were generated in which human IL-1beta was expressed in the lung epithelium with a doxycycline-inducible system controlled by the rat Clara cell secretory protein (CCSP) promoter. Induction of IL-1beta expression in the lungs of adult mice caused pulmonary inflammation characterized by neutrophil and macrophage infiltrates. IL-1beta caused distal airspace enlargement, consistent with emphysema. IL-1beta caused disruption of elastin fibers in alveolar septa and fibrosis in airway walls and in the pleura. IL-1beta increased the thickness of conducting airways, enhanced mucin production, and caused lymphocytic aggregates in the airways. Decreased immunostaining for the winged helix transcription factor FOXA2 was associated with goblet cell hyperplasia in IL-1beta-expressing mice. The production of the neutrophil attractant CXC chemokines KC (CXCL1) and MIP-2 (CXCL2), and of matrix metalloproteases MMP-9 and MMP-12, was increased by IL-1beta. Chronic production of IL-1beta in respiratory epithelial cells of adult mice causes lung inflammation, enlargement of distal airspaces, mucus metaplasia, and airway fibrosis in the adult mouse.
Quantized resonator field coupled to a current-biased Josephson junction in circuit QED (2014)

A Lagrangian formalism is used toderive the Hamiltonian for a $\ensuremath{\lambda}$/4 resonator shunted by a current-biased Josephson junction. The eigenstates and the quantum dynamics of the system are analyzed numerically, and we show that this quantum system can function as an efficient detector of weak incident microwave fields.
The sphingosine kinase 1/sphingosine‐1‐phosphate pathway mediates COX‐2 induction and PGE 2 production in response to TNF‐α (2003)

In this study we addressed the role of sphingolipid metabolism in the inflammatory response. In a L929 fibroblast model, tumor necrosis factor-alpha (TNF) induced prostaglandin E2 (PGE2) production by 4 h and cyclooxygenase-2 (COX-2) induction as early as 2 h. This TNF-induced PGE2 production was inhibited by NS398, a COX-2 selective inhibitor. GC-MS analysis revealed that only COX-2-generated prostanoids were produced in response to TNF, thus providing further evidence of COX-2 selectivity. As sphingolipids have been implicated in mediating several actions of TNF, their role in COX-2 induction and PGE2 production was evaluated. Sphingosine-1-phosphate (S1P) induced both COX-2 and PGE2 in a dose-responsive manner with an apparent ED50 of 100-300 nM. The related sphingolipid sphingosine also induced PGE2, though with much less efficacy. TNF induced a 3.5-fold increase in sphingosine-1-phosphate levels at 10 min that rapidly returned to baseline by 40 min. Small interfering RNAs (siRNAs) directed against mouse SK1 decreased (typically by 80%) SK1 protein and inhibited TNF-induced SK activity. Treatment of cells with RNAi to SK1 but not SK2 almost completely abolished the ability of TNF to induce COX-2 or generate PGE2. By contrast, cells treated with RNAi to S1P lyase or S1P phosphatase enhanced COX-2 induction leading to enhanced generation of PGE2. Treatment with SK1 RNAi also abolished the effects of exogenous sphingosine and ceramide on PGE2, revealing that the action of sphingosine and ceramide are due to intracellular metabolism into S1P. Collectively, these results provide novel evidence that SK1 and S1P are necessary for TNF to induce COX-2 and PGE2 production. Based on these findings, this study indicates that SK1 and S1P could be implicated in pathological inflammatory disorders and cancer.
Allergic humans are hypo‐responsive to CXCR3 chemokines in a Th1 immunity‐promoting loop (2003)

CXCR3 binding chemokine CXCL10 (IP-10) markedly enhances antigen-specific Th1 recall responses in healthy humans, suggesting a role for this pathway in maintenance of clinical tolerance to environmental allergens as well as a potential therapeutic role for CXCR3 ligands in re-balancing the Th2-dominated responses that underlie generation and maintenance of allergic disorders. Here, we investigated the capacity of CXCR3 ligands to modulate allergen-driven IFNgamma production by healthy and allergic individuals characterized by Th1 and Th2 immunity-dominated allergen specific responses, respectively. Exogenous CXCR3 ligands up-regulated antigen-dependent IFNgamma production from healthy individuals' peripheral blood mononuclear cells up to 120-fold, a response neutralized by anti-CXCR3 treatment and not emulated by CCR5 ligands. In contrast, allergic individuals were strikingly hypo-responsive to CXCR3 ligands (P=0.0004). Chemokine-enhanced IFNgamma production correlated with T cell CXCR3 expression (r=0.736, P=0.0001) in vivo and was independent of Th2 cytokine levels. These findings demonstrate that CXCR3-ligation preferentially augments ongoing Th1 over Th2 responses and suggest that reduced capacity of allergic individuals to respond to CXCR3 ligands promotes the maintenance of human allergic disorders.
Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4+25+ T cells to allow an effective graft-versus-leukemia response (2003)

After allogeneic hematopoietic cell transplantation (HCT), the high inverse correlation between graft-versus-host disease (GVHD) and leukemic relapse requires that calculated measures be taken to reduce GVHD pathology while retaining the graft-versus-leukemia (GVL) effect. We sought to determine whether donor CD4(+)CD25(+) regulatory T cells could control ongoing GVHD, thereby providing an initial window of time in which the alloreactive anti-host response is permitted to begin, with the intent of most effectively eliminating residual leukemia cells. Prevention of lethal GVHD by infusion of donor CD4(+)CD25(+) cells early after HCT (day 2) was achieved across a major histocompatibility complex barrier in the haploidentical C3H-->(B6xC3H)F(1) model. However, in vitro expansion of donor CD4(+)CD25(+) T cells, stimulated by recipient cells in the presence of high-dose interleukin-2, was required for successful regulation. In contrast, in the major histocompatibility complex-matched, minor histocompatibility antigen-disparate, CD8-mediated B10.BR-->CBA GVHD model, lethal disease could be completely prevented by a single infusion of freshly isolated donor CD4(+)CD25(+) cells administered as late as 10 days after HCT. Of importance, this late regulatory effect required only a 3:1 ratio of effector CD8:CD4(+)CD25(+) T cells, indicating a strong potential for the delayed infusion of CD4(+)CD25(+) cells to control GVHD across minor histocompatibility antigen barriers. Furthermore, this regulation did not interfere with complete and lasting donor engraftment of the hematopoietic compartment. Of most significance, the day 10 infusion of donor CD4(+)CD25(+) cells into CBA HCT recipients that had been challenged with the MMCBA6 myeloid leukemia cell line did not block an effective GVL response, despite reducing lethal GVHD. These results suggest that donor CD4(+)CD25(+) T cells infused soon after transplantation can ameliorate the development of GVHD without sacrificing a sufficient GVL effect.
Ultracompact biochemical sensor built with two-dimensional photonic crystal microcavity (2004)

We report an experimental demonstration of an ultracompact biochemical sensor based on a two-dimensional photonic crystal microcavity. The microcavity, fabricated on a silicon-on-insulator substrate, is designed to have a resonant wavelength (lambda) near 1.5 microm. The transmission spectrum of the sensor is measured with different ambient refractive indices ranging from n = 1.0 to n = 1.5. From observation of the shift in resonant wavelength, a change in ambient refractive index of delta(n) = 0.002 is readily apparent. The correspondence between absolute refractive index and resonant wavelength agrees with numerical calculation to within 4% accuracy. The evaporation of water in a 5% glycerol mixture is also used to demonstrate the capability for in situ time-resolved sensing.
Antimalarial agents: Closing the gate on toll‐like receptors? (2006)

Antimalarial agents have a long history of efficacy in systemic lupus erythematosus (SLE). Initially understood to treat skin disease, they are known to also relieve arthritis and pleurisy. In addition to these therapeutic benefits, they likely have a role in prophylaxis of disease activation. Should all SLE patients be taking antimalarials? The answer to this requires more information regarding its prophylactic efficacy and is complicated by continuing concerns about retinal toxicity. The clinical use of antimalarial drugs might be significantly aided by better understanding of how they work. We will discuss here advances in several areas that provide a basis for understanding how antimalarials work in SLE and how they might be better utilized in the future. Over the last several years, a paradigm shift in understanding the importance of the innate immune system in SLE has been driven by the recognition that a class of pattern recognition receptors (PRRs), collectively known as Toll-like receptors (TLRs), likely contributes to pathogenesis. TLRs are best known for their ability to discriminate microbial macromolecules from host tissue and thereby rapidly activate the innate immune system. However, it has become increasingly apparent in recent years that select host molecules, especially nucleic acids, can serve as endogenous TLR ligands (for review, see refs. 1 and 2), perhaps promoting responses to damaged tissue (3). Notably, these receptors are harbored in intracellular compartments and therefore not normally accessible to circulating nucleic acids. However, receptors expressed by B cells (surface IgM), dendritic cells (DCs) (Fc receptor [FcR]), or other antigen-presenting cells can act as key intermedi
Reaction of dichloroketone with cyclic thioketals of .alpha.,.beta.-cycloalkenones: synthesis of 1,7-dithiacycloalk-5-en-2-one derivatives by a four-carbon cycloenlargement (1981)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTReaction of dichloroketone with cyclic thioketals of .alpha.,.beta.-cycloalkenones: synthesis of 1,7-dithiacycloalk-5-en-2-one derivatives by a four-carbon cycloenlargementGoffredo Rosini, Giancroce G. Spineti, Elisabetta Foresti, and Gabriele PradellaCite this: J. Org. Chem. 1981, 46, 11, 2228–2230Publication Date (Print):May 1, 1981Publication History Published online1 May 2002Published inissue 1 May 1981https://pubs.acs.org/doi/10.1021/jo00324a007https://doi.org/10.1021/jo00324a007research-articleACS PublicationsRequest reuse permissionsArticle Views214Altmetric-Citations31LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts