gebhart/patrepeval huggingface dataset:
PROSITE, a protein domain database for functional characterization and annotation (2009)

PROSITE consists of documentation entries describing protein domains, families and functional sites, as well as associated patterns and profiles to identify them. It is complemented by ProRule, a collection of rules based on profiles and patterns, which increases the discriminatory power of these profiles and patterns by providing additional information about functionally and/or structurally critical amino acids. PROSITE is largely used for the annotation of domain features of UniProtKB/Swiss-Prot entries. Among the 983 (DNA-binding) domains, repeats and zinc fingers present in Swiss-Prot (release 57.8 of 22 September 2009), 696 ( approximately 70%) are annotated with PROSITE descriptors using information from ProRule. In order to allow better functional characterization of domains, PROSITE developments focus on subfamily specific profiles and a new profile building method giving more weight to functionally important residues. Here, we describe AMSA, an annotated multiple sequence alignment format used to build a new generation of generalized profiles, the migration of ScanProsite to Vital-IT, a cluster of 633 CPUs, and the adoption of the Distributed Annotation System (DAS) to facilitate PROSITE data integration and interchange with other sources. The latest version of PROSITE (release 20.54, of 22 September 2009) contains 1308 patterns, 863 profiles and 869 ProRules. PROSITE is accessible at: http://www.expasy.org/prosite/.
Preoperative Radiation and Chemotherapy in the Treatment of Adenocarcinoma of the Rectum (1995)

This therapeutic regimen has provided enhanced local control and decreased metastases. Furthermore, the marked degree of tumor downstaging, as seen by a 27% incidence of sterile pathologic specimens and a low rate of positive lymph nodes in this group with initially advanced lesions, strongly suggest that less radical surgery and sphincter preservation may be used with increasing frequency.
Cannabinoid receptor antagonist SR141716A decreases operant ethanol self administration in rats exposed to ethanol-vapor chambers. (1999)

To study the potential role of dependence status on CB1-mediated blockade of ethanol self-administration.We examined the effects of the cannabinoid antagonist SR141716A (0, 0.03, 0.3, and 3 mg/kg) on operant ethanol (10% v/v) self-administration in male Wistar rats that were made ethanol-dependent by chronic (14 d) exposure to ethanol vapor-chambers or exposed to air in identical vapor chambers.Dependent animals responded more for ethanol than did air control nondependent rats. The acute administration of a 3 mg/kg dose of SR141716A almost suppressed ethanol self-administration only in ethanol dependent animals. However, operant responses for food were not affected by the administration of SR141716A.These results further support that cannabinoid CB1 receptor blockade may have a potential utility for the treatment of alcoholism.
Synthetic clay nanocomposite‐based coatings prepared by UV‐cure photopolymerization (2004)

Abstract The effect of synthetic clay on the photopolymerization kinetics and coating properties of methyl α‐hydroxymethylacrylate (MHMA) systems in the presence of novel hydroxylated dimethacrylate crosslinkers is reported. In the presence of clay earlier onset of autoacceleration was observed, high rates of polymerization were achieved, and high final overall conversions were reached. Higher rates and increase in conversions were also observed as the clay content increased in the medium. To increase compatibility between clay and polymer matrix the use of Jeffamines as polymer/clay compatibilizers, based on ion–dipole interactions between ethylene oxide units and clay ions, was also investigated. Nanocomposite‐based films by photopolymerization of the mixtures coated on glass microscope slides were prepared and evaluated using X‐ray and TEM. The absence of Bragg diffraction peaks in all nanocomposite films indicated loss of organization of the clay layers and formation of well‐dispersed, exfoliated systems was confirmed by TEM. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1252–1263, 2004
TMC125, a Novel Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor Active against Nonnucleoside Reverse Transcriptase Inhibitor-Resistant Human Immunodeficiency Virus Type 1 (2004)

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1); however, currently marketed NNRTIs rapidly select resistant virus, and cross-resistance within the class is extensive. A parallel screening strategy was applied to test candidates from a series of diarylpyrimidines against wild-type and resistant HIV strains carrying clinically relevant mutations. Serum protein binding and metabolic stability were addressed early in the selection process. The emerging clinical candidate, TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC50] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC50 = 3.5 microM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group O virus. Incubation of TMC125 with human liver microsomal fractions suggested good metabolic stability (15% decrease in drug concentration and 7% decrease in antiviral activity after 120 min). Although TMC125 is highly protein bound, its antiviral effect was not reduced by the presence of 45 mg of human serum albumin/ml, 1 mg of alpha1-acid glycoprotein/ml, or 50% human serum. In an initial screen for activity against a panel of 25 viruses carrying single and double reverse transcriptase amino acid substitutions associated with NNRTI resistance, the EC50 of TMC125 was <5 nM for 19 viruses, including the double mutants K101E+K103N and K103N+Y181C. TMC125 also retained activity (EC50 < 100 nM) against 97% of 1,081 recent clinically derived recombinant viruses resistant to at least one of the currently marketed NNRTIs. TMC125 is a potent next generation NNRTI, with the potential for use in individuals infected with NNRTI-resistant virus.
Single Molecule Profiling of Alternative Pre-mRNA Splicing (2003)

Alternative pre-messenger RNA splicing is an important mechanism for generating protein diversity and may explain in part how mammalian complexity arises from a surprisingly small complement of genes. Here, we describe "digital polony exon profiling,"a single molecule-based technology for studying complex alternative pre-messenger RNA splicing. This technology allows researchers to monitor the combinatorial diversity of exon inclusion in individual transcripts. A minisequencing strategy provides single nucleotide resolution, and the digital nature of the technology allows quantitation of individual splicing variants. Digital polony exon profiling can be used to investigate the physiological and pathological roles of alternately spliced messenger RNAs, as well as the mechanisms by which these messenger RNAs are produced.
Nature of the bifunctional chelating agent used for radioimmunotherapy with yttrium-90 monoclonal antibodies: critical factors in determining in vivo survival and organ toxicity. (1989)

One factor that is critical to the potential effectiveness of radioimmunotherapy is the design of radiometal-chelated antibodies that will be stable in vivo. Stability in vivo depends on the condition that both the chelate linkage and radiolabeling procedures not alter antibody specificity and biodistribution. In addition, synthesis and selection of the chelating agent is critical for each radiometal in order to prevent inappropriate release of the radiometal in vivo. In the present study, we compare the in vivo stability of seven radioimmunoconjugates that use different polyaminocarboxylate chelating agents to complex yttrium-88 to the mouse anti-human interleukin-2 receptor monoclonal antibody, anti-Tac. Chelate linkage and radiolabeling procedures did not alter the immunospecificity of anti-Tac. In order to assess whether yttrium was inappropriately released from the chelate-coupled antibody in vivo, iodine-131-labeled and yttrium-88 chelate-coupled antibodies were simultaneously administered to the same animals to correlate the decline in yttrium and radioiodinated antibody activity. The four stable yttrium-88 chelate-coupled antibodies studied displayed similar iodine-131 and yttrium-88 activity, indicating minimal elution of yttrium-88 from the complex. In contrast, the unstable yttrium-88 chelate-coupled antibodies had serum yttrium-88 activities that declined much more rapidly than their iodine-131 activities, suggesting loss of the radiolabel yttrium-88 from the chelate. Furthermore, high rates of yttrium-88 elution correlated with deposition in bone. Four chelating agents emerged as promising immunotherapeutic reagents: isothiocyanate benzyl DTPA and its derivatives 1B3M, MX, and 1M3B. All four isothiocyanate agents showed prolonged yttrium-88 vascular survival which was essentially identical to that of their iodine-131 activity with only minimum accumulation (1.4-1.8%/g) of the yttrium-88 injected dose into bone. Thus, these four chelating agents were very stable in vivo and suitable for yttrium-monoclonal antibody radioimmunotherapy.
Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells. (1996)

Lately, TNF alpha has been the focus of studies of autoimmunity; its role in the progression of autoimmune diabetes is, however, still unclear. To analyze the effects of TNF alpha in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNF alpha under the control of the rat insulin II promoter (RIP). In transgenic mice, TNF alpha expression on the islets resulted in massive insulitis, composed of CD4+ T cells, CD8+ T cells, and B cells. Despite infiltration of considerable number of lymphoid cells in islets, expression of TNF alpha protected NOD mice from IDDM. To determine the mechanism of TNF alpha action, splenic cells from control NOD and RIP-TNF alpha mice were adoptively transferred to NOD-SCID recipients. In contrast to the induction of diabetes by splenic cells from control NOD mice, splenic cells from RIP-TNF alpha transgenic mice did not induce diabetes in NOD-SCID recipients. Diabetes was induced however, in the RIP-TNF alpha transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNF alpha in islets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNF alpha action and provide evidence that local expression of TNF alpha protects NOD mice from autoimmune diabetes by preventing the development of autoreactive islet-specific T cells.
Interleukin-1 Gene Cluster Polymorphisms in Sarcoidosis and Idiopathic Pulmonary Fibrosis (2002)

Members of the interleukin-1 (IL-1) family are implicated in the pathogenesis of sarcoidosis and idiopathic pulmonary fibrosis (IPF). We have, therefore, performed a case-control study to investigate a plausible association between sarcoidosis and the polymorphisms in the IL-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1Ra) genes. Further, as a separate question, we explored whether the aforementioned genes of the IL-1 cluster are associated with IPF. Using PCR with sequence-specific primers, IL-1alpha -889, IL-1beta -511, IL-1beta +3953, and IL-1Ra intron 2 VNTR polymorphisms were determined in 348 white subjects of West Slavonic ancestry (95 patients with sarcoidosis, 54 patients with IPF, and 199 healthy control subjects). The IL-1alpha -889 1.1 genotype was significantly overrepresented in patients with sarcoidosis in comparison with control subjects (60.0 versus 44.2%, p = 0.012, p(corr) = 0.047). The distribution of IL-1beta -511, IL-1beta +3953, and IL-1Ra VNTR genotypes and alleles did not significantly differ between the cases and controls. No association between IPF and the investigated polymorphisms was found. Strong linkage disequilibrium between pairs of polymorphic loci was observed. Further population studies are warranted to confirm the observed association between sarcoidosis and the IL-1alpha polymorphism and also to explore mechanisms of IL-1alpha -889 participation in aberrant immune response in sarcoidosis.
STUDIES ON STREPTOCOCCAL BACTERIOPHAGES (1968)

Evidence has been presented that Group C bacteriophages differ as to their inactivating site on the streptococcal cell wall. While all three phages adsorb to isolated cell walls, only the C1 phage was inactivated by enzymatically prepared group-specific carbohydrate. None of the Group C phages were inactivated by chemically extracted group-specific carbohydrate. In contrast, all virulent Group A streptococcal bacteriophages adsorbed only to living Group A streptococci. However, Group A temperate phages were able to adsorb to isolated cell walls but not to group-specific carbohydrate. While it has not been possible to identify the specific inactivating substance for the Group A virulent phages, certain pieces of evidence indirectly implicate the group-specific carbohydrate, specifically the N-acetylglucosamine moiety. The fact that Group A virulent phages failed to adsorb to heat-killed Group A streptococcal cells suggests that additional factors produced by the living cell are needed for complete viral inactivation.
An Integrated 256-Channel Epiretinal Prosthesis (2010)

This paper reports an integrated 256-channel epiretinal prosthesis integrated circuit (IC). This epiretinal prosthesis system consists of a power telemetry subsystem to deliver 100 mW power, a data telemetry subsystem to transfer 2 Mbps data, digital controllers to decode stimulation patterns, and a 256-channel stimulator to generate user programmable bi-phasic current stimuli. In this study, dual-band telemetry is adopted to achieve both high power efficiency and high data rate. Frequencies of 2 and 22 MHz are chosen for power and data carrier frequencies, respectively. A mixed-mode and multiple-voltage design is applied to the stimulator for withstanding a high-compliance voltage of ± 10 V at the output stage as well as for reducing the area of each pixel. To add flexibility to the stimulator, each pixel has a local digital controller, which enables the stimulator IC to generate 256 parallel stimulations with various pulse widths and amplitudes. The chip is fabricated in TSMC 0.18 μm 32 V CMOS process with 256 area pads constructed above the stimulus current drivers.
Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. (2002)

The signal transducers and activators of transcription (STAT)factors function as downstream effectors of cytokine and growth factor receptor signaling. Compared with normal cells and tissues, constitutively activated STATs have been detected in a wide variety of human cancer cell lines and primary tumors. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulated process. In tumor cells, constitutive activation of STATs is linked to persistent activity of tyrosine kinases, including Src, epidermal growth factor receptor, Janus kinases, Bcr-Abl, and many others. Such oncogenic tyrosine kinases are often activated as a consequence of permanent ligand/receptor engagement in autocrine or paracrine cytokine and growth factor signaling or represent autonomous constitutively active enzymes as a result of genetic alterations found in tumor but not normal cells. Persistent signaling of specific STATs, in particular Stat3 and Stat5, has been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis. STATs participate in oncogenesis through up-regulation of genes encoding apoptosis inhibitors and cell cycle regulators such as Bcl-x(L), Mcl-1, cyclins D1/D2, and c-Myc. Inhibition of constitutively active STAT signaling pathways has been shown repeatedly to inhibit tumor cell growth in vitro and in vivo and provides a novel means for therapeutic intervention in human cancer. In this review, we will: (a) explain the mechanisms of STAT activation in normal and malignant signaling; (b) summarize recent evidence for the critical role of constitutively activated Stat3 and Stat5 in oncogenesis; (c) identify candidate STAT target genes implicated in tumor progression; and (d) discuss molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in human cancer.
Bcl-2 on the endoplasmic reticulum: protecting the mitochondria from a distance (2003)

Bcl-2 has been described both as an inhibitor of programmed cell death and as an inhibitor of mitochondrial dysfunction during apoptosis. It is still not clear what biochemical activity of Bcl-2 is responsible for its function, but increasing evidence indicates that a functional activity of Bcl-2 on the endoplasmic reticulum (ER) protects mitochondria under diverse circumstances. Indeed, an emerging hypothesis is that, during apoptosis, the Bcl-2 family regulates ER-to-mitochondrion communication by BH3-only proteins and calcium ions and thereby triggers mitochondrial dysfunction and cell death.
Postnatal Passive Immunization of Neonatal Macaques with a Triple Combination of Human Monoclonal Antibodies against Oral Simian-Human Immunodeficiency Virus Challenge (2001)

To develop prophylaxis against mother-to-child human immunodeficiency virus (HIV) transmission, we established a simian-human immunodeficiency virus (SHIV) infection model in neonatal macaques that mimics intrapartum mucosal virus exposure (T. W. Baba et al., AIDS Res. Hum. Retroviruses 10:351-357, 1994). Using this model, neonates were protected from mucosal SHIV-vpu(+) challenge by pre- and postnatal treatment with a combination of three human neutralizing monoclonal antibodies (MAbs), F105, 2G12, and 2F5 (Baba et al., Nat. Med. 6:200-206, 2000). In the present study, we used this MAb combination only postnatally, thereby significantly reducing the quantity of antibodies necessary and rendering their potential use in humans more practical. We protected two neonates with this regimen against oral SHIV-vpu(+) challenge, while four untreated control animals became persistently infected. Thus, synergistic MAbs protect when used as immunoprophylaxis without the prenatal dose. We then determined in vitro the optimal MAb combination against the more pathogenic SHIV89.6P, a chimeric virus encoding env of the primary HIV89.6. Remarkably, the most potent combination included IgG1b12, which alone does not neutralize SHIV89.6P. We administered the combination of MAbs IgG1b12, 2F5, and 2G12 postnatally to four neonates. One of the four infants remained uninfected after oral challenge with SHIV89.6P, and two infants had no or a delayed CD4(+) T-cell decline. In contrast, all control animals had dramatic drops in their CD4(+) T cells by 2 weeks postexposure. We conclude that our triple MAb combination partially protected against mucosal challenge with the highly pathogenic SHIV89.6P. Thus, combination immunoprophylaxis with passively administered synergistic human MAbs may play a role in the clinical prevention of mother-to-infant transmission of HIV type 1.
Infectious RNA transcribed in vitro from a cDNA copy of the human coronavirus genome cloned in vaccinia virus (2001)

The coronavirus genome is a positive-strand RNA of extraordinary size and complexity. It is composed of approximately 30000 nucleotides and it is the largest known autonomously replicating RNA. It is also remarkable in that more than two-thirds of the genome is devoted to encoding proteins involved in the replication and transcription of viral RNA. Here, a reverse-genetic system is described for the generation of recombinant coronaviruses. This system is based upon the in vitro transcription of infectious RNA from a cDNA copy of the human coronavirus 229E genome that has been cloned and propagated in vaccinia virus. This system is expected to provide new insights into the molecular biology and pathogenesis of coronaviruses and to serve as a paradigm for the genetic analysis of large RNA virus genomes. It also provides a starting point for the development of a new class of eukaryotic, multi-gene RNA vectors that are able to express several proteins simultaneously.
Neuroactive Chondroitin Sulfate Glycomimetics (2008)

We report the generation of chondroitin sulfate (CS) glycomimetics with tunable chemical and biological properties. Our approach greatly simplifies the synthesis of complex glycosaminoglycans, providing synthetically accessible, bioactive structures of programmable sulfation sequence. Using these glycopolymers, we demonstrate that multivalent interactions are critical for modulating CS activity and discover an unexpected tolerance for unnatural polymeric architectures. We envision that these glycomimetics will facilitate further explorations into the influence of macromolecular structure on glycosaminoglycan function and provide powerful tools for manipulating CS activity in vivo.
A Bayesian Approach to Filtering Junk E-Mail (1998)

In addressing the growing problem of junk E-mail on the Internet, we examine methods for the automated construction of filters to eliminate such unwanted messages from a user&amp;apos;s mail stream. By casting this problem in a decision theoretic framework, we are able to make use of probabilistic learning methods in conjunction with a notion of differential misclassification cost to produce filters which are especially appropriate for the nuances of this task. While this may appear, at first, to be a straight-forward text classification problem, we show that by considering domain-specific features of this problem in addition to the raw text of E-mail messages, we can produce much more accurate filters. Finally, we show the efficacy of such filters in a real world usage scenario, arguing that this technology is mature enough for deployment. Introduction As the number of users connected to the Internet continues to skyrocket, electronic mail (E-mail) is quickly becoming one of the fastest and m...
Interleukin‐6 regulates the phenotype of the immune response to a tuberculosis subunit vaccine (2001)

We investigated the role of interleukin-6 (IL-6) in the development of the immune response to a subunit vaccine against tuberculosis consisting of the culture filtrate proteins of Mycobacterium tuberculosis emulsified in the adjuvant dimethyldioctadecylammonium bromide (DDA). C57Bl/6 mice immunized with this vaccine developed a strong T helper 1 (Th1) response characterized by an increased production of interferon-gamma (IFN-gamma) secreted by CD4+ T cells. Neutralization of IL-6 during in vivo priming resulted in marked reduction in the ability of T cells to secrete IFN-gamma and IL-2 and to proliferate. IL-6 gene-disrupted mice primed with the vaccine showed a decrease in the number of IFN-gamma-producing cells and an increase in IL-4-secreting cells as compared to control mice. In contrast, neutralization of IL-6 during a boost of the vaccine in previously primed mice did not affect the development of IFN-gamma-producing cells but still increased the number of IL-4-producing cells. Our work shows that IL-6 plays a major role in the priming but not in the later expression of a Th1 response to a tuberculosis vaccine.