gebhart/patrepeval huggingface dataset:
Toll-like receptors: emerging targets of immunomodulation (2004)

Toll-like receptors (TLRs) were shown to play a critical role in the recognition and activation of pathogens by the innate immune system. Pathogen engagement of the TLR–myeloid differentiation protein 88 (MyD88) pathway favours the development of a protective T-helper (TH)1-biased T cell response. Interruption of TLR recognition or signalling has profound effects on protective immunity and enhances a TH2-biased immune response. Agonists or antagonists of specific TLRs have effects beyond infectious control and may represent a novel therapeutic for immunostimulation in vaccines, cancer, inflammatory disorders and allergy.
The Biological Activity of Human CD20 Monoclonal Antibodies Is Linked to Unique Epitopes on CD20 (2006)

We have previously defined a panel of fully human CD20 mAb. Most of these were unexpectedly efficient in their ability to recruit C1q to the surface of CD20-positive cells and mediate tumor lysis via activation of the classical pathway of complement. This complement-dependent cytotoxicity (CDC) potency appeared to relate to the unusually slow off-rate of these human Abs. However, we now present epitope-mapping data, which indicates that all human mAb bind a novel region of CD20 that may influence CDC potency. Epitope mapping, using both mutagenesis studies and overlapping 15-mer peptides of the extracellular loops of CD20, defined the amino acids required for binding by an extensive panel of mouse and human mAb. Binding by rituximab and mouse CD20 mAb, had an absolute requirement for alanine and proline at positions 170 and 172, respectively, within the large extracellular loop of CD20. Surprisingly, however, all of the human CD20 mAb recognize a completely novel epitope located N-terminally of this motif, also including the small extracellular loop of CD20. Thus, although off-rate may influence biological activity of mAb, another critical factor for determining CDC potency by CD20 mAb appears to be the region of the target molecule they recognize. We conclude that recognition of the novel epitope cooperates with slow off-rate in determining the activity of CD20 Ab in activation of complement and induction of tumor cell lysis.
Pathogenesis of Avian Influenza A (H5N1) Viruses in Ferrets (2002)

Highly pathogenic avian influenza A H5N1 viruses caused outbreaks of disease in domestic poultry and humans in Hong Kong in 1997. Direct transmission of the H5N1 viruses from birds to humans resulted in 18 documented cases of respiratory illness, including six deaths. Here we evaluated two of the avian H5N1 viruses isolated from humans for their ability to replicate and cause disease in outbred ferrets. A/Hong Kong/483/97 virus was isolated from a fatal case and was highly pathogenic in the BALB/c mouse model, whereas A/Hong Kong/486/97 virus was isolated from a case with mild illness and exhibited a low-pathogenicity phenotype in mice. Ferrets infected intranasally with 10(7) 50% egg infectious doses (EID(50)) of either H5N1 virus exhibited severe lethargy, fever, weight loss, transient lymphopenia, and replication in the upper and lower respiratory tract, as well as multiple systemic organs, including the brain. Gastrointestinal symptoms were seen in some animals. In contrast, weight loss and severe lethargy were not noted in ferrets infected with 10(7) EID(50) of two recent human H3N2 viruses, although these viruses were also isolated from the brains, but not other extrapulmonary organs, of infected animals. The results demonstrate that both H5N1 viruses were highly virulent in the outbred ferret model, unlike the differential pathogenicity documented in inbred BALB/c mice. We propose the ferret as an alternative model system for the study of these highly pathogenic avian viruses.
Multifunctional Asymmetric Catalysis. (2001)

Two types of general and practical enantioselective catalysts, namely, bimetallic complexes and Lewis acid-Lewis base bifunctional catalysts were developed based on the concept of multifunctional catalysis. In the first part of this review, the first example of a catalytic enatioselective nitro-Mannich reaction as well as a direct catalytic enantioselective aldol reaction of 2-hydroxyacetophenone using bimetallic complexes is discussed. The new complex, composed of ytterbium, potassium, and BINOL in a ratio of 1:1:3, promoted the nitro-Mannich reaction of nitromethane with up to 91% ee. On the other hand, second generation ALB catalyzed an enantioselective and diastereoselective nitro-Mannich reaction of nitroalkanes in up to 83% ee with a diastereomeric ratio up to 7:1. Moreover, the reaction of aldehydes with 2-hydroxyacetophenone in the presence of LLB, KHMDS, and H2O selectively gave the corresponding anti-alpha,beta-dihydroxy ketones in up to 95% ee and, in the presence of the catalyst prepared from linked-BINOL and 2 eq of Et2Zn, selectively afforded the syn-alpha,beta-dihydroxy ketones in up to 86% ee. In the second part, the development of new catalysts displaying a Lewis acidity and a Lewis basicity is described. The Lewis acid of the catalyst activates aldehydes, imines, acyl quinoliniums, and ketones. At the same time, the Lewis base activates the nucleophile (TMSCN). Catalysts of this type produced a highly enantioselective cyanation of these electrophiles. Application of the catalytic enantioselective cyanosilylation of aldehydes to a total synthesis of epothilones is also described.
Identification of neoxanthin synthase as a carotenoid cyclase paralog (2000)

Neoxanthin, a precursor of the plant hormone abscisic acid, is an allenic xanthophyll recognized as the last product of carotenoid synthesis in green plants. A cDNA for neoxanthin synthase (NSY) was isolated from tomato using a molecular approach based on the mechanistic and structural similarities of NSY to two other closely related carotenogenic enzymes, lycopene cyclase (LCY) and capsanthin-capsorubin synthase (CCS). The identified tomato NSY cDNA (T.NSY) encodes a 56-kDa plastid-targeted protein that when expressed in Escherichia coli, catalyzes the conversion of violaxanthin to neoxanthin. In tobacco leaves that transiently express T.NSY, an increase in neoxanthin content with a concomitant decrease in violaxanthin is observed. NSY is structurally similar to LCY and CCS. However, in Cyanobacteria, the generally accepted progenitor of plastids, both CCS and NSY are absent while LCY is present. LCY catalyzes a simplified version of the reaction catalyzed by NSY and CCS suggesting that these two enzymes were remodeled from LCY during higher plant evolution to create new forms of oxidized carotenoids.
Automatic generation of gene finders for eukaryotic species (2006)

Acyclic discrete phase type distributions are well suited to model sequence length distributions. The performance of each individual gene predictor on each individual genome is comparable to the best of the manually optimised species-specific gene finders. It is shown that species-specific gene finders are superior to gene finders trained on other species.
Theory of photoinduced changes in refractive index and spontaneous polarization (1978)

Changes in the refractive index n and spontaneous polarization Ps associated with lattice reordering in the vicinity of ionized or excited shallow and deep impurity centres are considered. Distortions corresponding to both the nonpolar and ferroelectric phonon soft branches are taken into account in continuum approximation. The changes of n and Ps due to excited deep and shallow impurity centres are shown to differ, as a rule, only in sign. The temperature dependence of the refractive index change is ascertained to be different for ferro- and non-ferroelectrics.
A novel approach for inhibiting growth factor signalling in murine tooth development: Inhibition of FGF's (1998)

Growth factors belonging to the FGF and TGF-beta families, together with other secreted factors such as Sonic hedgehog, have been shown to be spatially and temporally regulated during tooth development. Providing evidence of the functions of these molecules has, however, proved difficult. We have developed a novel strategy for investigating the role of secreted molecules in tooth development using soluble forms of membrane bound receptors to sequester ligands. Chimeric fusion proteins of receptor extracellular domains were cloned into the eukaryotic expression vector pIG-1 and transfected into COS cells. Fusion proteins secreted by the COS cells were purified using Protein A Sepharose. A soluble form of the FGF receptor FGF-1IIIc, which preferentially binds FGF-2 and FGF-4, was produced using this technique and added to mouse mandible cultures. Addition of the soluble receptors to E13 cultures resulted in down-regulation of Sonic hedgehog expression in molar enamel knots, consistent with inhibition of FGF-4 signalling.
Aspects of the Metabolism of the Epidermal Growth Factor Receptor in A431 Human Epidermoid Carcinoma Cells (1984)

The biosynthesis and posttranslational metabolism of the epidermal growth factor (EGF) receptor were examined in the A431 human epidermoid carcinoma cell line. Polyclonal antibody against the receptor specifically immunoprecipitated two [35S]methionine-labeled proteins of Mr = 160,000 and 170,000. Pulse chase experiments showed the Mr = 160,000 protein to be a precursor of the Mr = 170,000 protein. Preincubation with tunicamycin resulted in immunoprecipitation of a single band of Mr = 130,000, whereas monensin inhibited maturation to the Mr = 170,000 form. Digestion of the Mr = 160,000 and 170,000 proteins with endoglycosidase H resulted in the appearance of Mr = 130,000 and 165,000 proteins, respectively. Prolonged pulse-chase experiments indicated that the half-life of the receptor is ca. 20 h in the absence of EGF and 5 h in the presence of EGF. Approximately three- to five-fold more phosphate is incorporated into the mature receptor upon addition of EGF, due primarily to increases in levels of phosphotyrosine and phosphoserine. Phosphate was also present on the Mr = 160,000 protein and the Mr = 130,000 protein found in the presence of tunicamycin.
Beyond Borders: Web Globalization Strategies (2002)

From the Publisher:
Web globalization isn't just about expanding into new markets; it's about surviving in changing markets -- and it isn't easy. Beyond Borders: Web Globalization Strategies helps you hit the ground running. It offers great tips and hands-on strategies for setting up your site to go global and helps you avoid common mistakes that even Fortune 500 companies have made along the way. In the end, you will have guidelines and suggestions for bridging the borders between languages, cultures, countries, and -- ultimately -- people.
Variational Network Quantization (2018)

In this paper, the preparation of a neural network for pruning and few-bit quantization is formulated as a variational inference problem. To this end a quantizing prior that leads to a multi-modal, sparse posterior distribution over weights is introduced and a differentiable Kullback-Leibler divergence approximation for this prior is derived. After training with Variational Network Quantization, weights can be replaced by deterministic quantization values with small to negligible loss of task accuracy (including pruning by setting weights to 0). The method does not require fine-tuning after quantization. Results are shown for ternary quantization on LeNet-5 (MNIST) and DenseNet-121 (CIFAR-10).
Anatomy of the Concussion: More Serious than Meets the Eye? (2011)

Sports-related concussions have unique features that distinguish them from those mild traumatic brain injuries (MTBI’s) caused by other mechanisms. Sports-related MTBI’s may result from relatively lower-velocity impacts as compared with high-speed motor vehicle collisions, and are thought to cause different neurophysiologic injury. A survey of youth coaches revealed 42% believed a concussion only occurs when an athlete loses consciousness, and 25% would allow the athlete to return to play despite showing symptoms of concussion. Concussions occur not only in youth sports but also at the collegiate and professional levels. It is believed that, post-concussion, an athlete has diminished reaction time, thus increasing the risk of further injury. MTBI tends to occur again in patients with single MTBI. This review of concussion research aims to study the functional effects of MTBI on the brain. Ultimately, investigations should extend towards establishing increased public awareness of concussions with corresponding standardized care criteria.
Design of Novel Conformational and Genotype-Specific Antigens for Improving Sensitivity of Immunoassays for Hepatitis C Virus-Specific Antibodies (2005)

The current commercially licensed enzyme-linked immunosorbent assays (ELISAs) for hepatitis C virus (HCV) mainly use recombinant proteins containing linear epitopes. There is evidence, however, that conformational epitopes of HCV are more immunoreactive. Thus, we have designed an HCV antibody assay that employs a conformational protein, NS3NS4a PI (with functional protease and helicase activities), and a linear fusion protein, multiple-epitope fusion antigen 7.1 (MEFA 7.1) or MEFA 7.2. We have shown that NS3NS4a PI detects early-seroconversion conformation-sensitive antibodies better than c33c antigen. The correct conformation of NS3NS4a PI also cross-reacts with different genotype samples better than the c33c antigen. MEFA 7.1 and MEFA 7.2 incorporate all the major immunodominant and genotype-specific epitopes of HCV core, E1, E2 hypervariable region 1 (HVR1), E2 HVR1-plus-HVR2 consensus, NS3, NS4, and NS5. Since MEFA 7.1 is degraded by the active NS3NS4a PI protease, we designed a second MEFA 7.2 construct in which the six protease cleavage sites found in MEFA 7.1 were eliminated by amino acid mutation. We demonstrate here that MEFA 7.2 remains intact in the presence of NS3NS4a PI and preserves the epitopes present in MEFA 7.1. Compared to currently licensed assays, an ELISA incorporating a combination of the two antigens NS3NS4a PI and MEFA 7.1 or 7.2 demonstrates better serotype sensitivity and detects seroconversion earlier in many commercially available panels. We believe that an assay using NS3NS4a PI and MEFA 7.1 or 7.2 may have the potential to replace current HCV immunoassays for better sensitivity.
Gastric electrical stimulation for gastroparesis: A goal greatly pursued, but not yet attained (2011)

The lack of an effective medical treatment for gastroparesis has pushed the research of new techniques of gastric electrical stimulation (GES) for nearly half a century of experimentation with a large variety of electrical stimuli delivered to the gastric wall of animals and patients with gastroparesis. Three principal methods are currently available: gastric low-frequency/high-energy GES with long pulse stimulation, high-frequency/low-energy GES with short pulse stimulation and neural sequential GES. The first method aims to reset a regular slow wave rhythm, but has variable effects on contractions and requires devices with large and heavy batteries unsuitable for implantation. High-frequency/low-energy GES, although inadequate to restore a normal gastric electro-mechanical activity, improves dyspeptic symptoms, such as nausea and vomiting, giving patients a better quality of life together with a more satisfactory nutritional status and is suitable for implantation. Unfortunately, the numerous clinical studies using this type of GES, with the exception of two, were not controlled and there is a need for definitive verification of the effectiveness of this technique to justify the cost and the risks of this procedure. The last method, which is neural sequential GES, consists of a microprocessor-controlled sequential activation of a series of annular electrodes along the distal two thirds of the stomach and is able to induce propagated contractions causing forceful emptying of the gastric content. The latter method is the most promising, but has been used only in animals and needs to be tested in patients with gastroparesis before it is regarded as a solution for this disease.
Structure-function relationship in the IL-1 family (1996)

The interleukin 1 (IL-1) family is a group of related cytokines including two agonist proteins (IL-1alpha and IL-1beta), each derived by enzymatic cleavage of precursor proteins (pro-IL-1alpha and pro-IL-1beta), and three forms of an antagonist protein (IL-1ra, icIL-1raI, icIL-1raII). IL-1 plays a key role in the onset and development of the host reaction to invasion, being an important factor in the initiation of the inflammatory response and in the triggering of immune functions. Due to its pleiotropic activity and to the high potency of its inflammatory effects, IL-1 activity is tightly regulated in the body by a complex network of control systems. These include the presence of two types of inhibitors, the receptor antagonist IL-1ra and the second type of IL-1 receptor (IL-1RI), which is a natural scavenger of IL-1. Furthermore, regulation of IL-1 activity is attained by a strict hierarchy of binding affinity of the two receptors (the activating IL-1RI and the inhibitory IL-1RII) for the various members of the IL-1 family. Additional levels of control are represented by the presence of soluble forms of both receptors and of immature pro-IL-1 forms with different characteristics of activity and receptor binding capacity. To clarify the features of reciprocal interaction among ligands and receptors, in the attempt to understand the rules regulating the IL-1 system and its effectiveness, a deep analysis of the relationship between structure and function in the proteins of the IL-1 family becomes of key importance. Information on this line has been provided by several groups mainly with studies of mutagenesis of IL-1alpha, IL-1beta and IL-1ra in parallel with biological assays of activity. In this review, a survey of the available data is provided, in order to construct a hypothetical model of the functional structure of IL-1 proteins as a basis for future therapeutic interventions based on genetic and protein engineering.
Unlocking Organizational Potential: A Computational Platform for Investigating Structural Interdependence in Design (2009)

A team’s design—the structuring of its resources and flows of knowledge—is an important element determining its effectiveness. An essential element in achieving a team’s problem-solving potential is the role that interdependence, in both the task and the organization, plays in determining the dynamic and emergent system-level properties of the organization. In this paper, we present a computational platform for experimentally investigating the influence of informational dependencies found in the design of a complex system for exploring their role in determining system behaviors and performance. The approach presented in this paper is a multiagent simulation of the conceptual design of space mission plans by Team X, an advanced project design group at NASA’s Jet Propulsion Laboratory. The algorithm is composed of rich descriptive models of both the team-types and timing of interactions, collaborative methods, sequencing, rates of convergence- and the task-primary variables, their behaviors and relations, and the approaches used to resolve them. The objective is to create an environment of interaction representative of that found in actual design sessions. Better understanding how the dynamics arising from organizational and domain interdependencies impact an organization’s ability to effectively resolve its task should lead to the development of guidelines for better coping with task complexities, suggest ways to better design organizations, as well as suggest ways for improving the search for innovative solutions.
What’s the Harm in Having a “Harm Principle” Enshrined in Section 7 of the Charter? (2004)

To many, if not most, of us, it would seem like “common sense that you do not go to jail unless there is a potential that your activities will cause harm to others....” It has certainly long been accepted that government should not resort to the criminal law to control behaviour unless that behaviour creates a real risk of harm. But what if the government thought otherwise? What if the government decided to criminalize recreational activities that posed a neglible risk of harm to society? What if the government decided to criminalize conduct which, for the vast majority of the public who engage in that conduct, poses no real risk of harm? Does the Charter offer any protection against unnecessary criminal laws? Does section 7 of the Charter include a “harm principle” that restricts the imposition of criminal prohibitions to conduct that causes at least some measurable harm to society? in the recent trilogy of cases dealing with a section 7 Charter challenge to the criminal prohibition on marijuana, a majority of the Supreme Court of Canada decided that the “harm principle” was not a principle of fundamental justice. Despite the historical and widespread support for recognition of a “harm principle”, the majority’s decision wisely prevented the creation of a double-edged sword. In other words, constitutionalization of a “harm principle” could equally have led to challenges by public interest groups demanding that the government criminalize conduct that the group considers potentially injurious to society. Did we even need a “harm principle” to be enshrined within section 7 of the Charter? Ironically, prior to the majority’s decision in the trilogy of marijuana cases, the general balancing approach which the Supreme Court of Canada had recognized and applied, would have been reasonably well-suited to the task. Unfortunately, in the course of losing the battle to establish a firm footing for the “harm principle”, the appellants in the marijuana cases seem to also have severely narrowed the scope of substantive review afforded by previously decided cases.
Dissecting the heterogeneity of rheumatoid arthritis through linkage analysis of quantitative traits (2006)

Analysis of quantitative components of RA is a promising approach for dissecting the genetic heterogeneity of this complex disorder. These results highlight the potential importance of sex or other covariates that may modulate some of the genetic effects that influence the risk of specific disease manifestations.
Synthesis and pharmacological evaluation of 4,4-disubstituted piperidines (1989)

A new class of piperidine derivatives is added to the increasing family of compounds related to fentanyl and carfentanil. Herein, we describe the synthesis and pharmacology of a number of 1-(arylethyl)-4-(acylamino)-4-[(acyloxy)-methyl]piperidines such as 9, 15, and 23. As expected, many of these congeners of fentanyl are extremely potent narcotic agonists. The aim of the study was to identify short-acting analgesic agents (i.e. less than 6 min in the mouse hot-plate assay) for possible use in the surgical theater. Many of the drugs proved to be of intermediate and long duration (i.e. 6-15 min and greater than 15 min, respectively). In addition to analgesic activity, many of the compounds exhibited anesthetic properties as well. The structure-activity relationship for these entities is presented and discussed.