gebhart/patrepeval huggingface dataset:
Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia (1996)

Respiratory infections with Pseudomonas aeruginosa and Burkholderia cepacia play a major role in the pathogenesis of cystic fibrosis (CF). This review summarizes the latest advances in understanding host-pathogen interactions in CF with an emphasis on the role and control of conversion to mucoidy in P. aeruginosa, a phenomenon epitomizing the adaptation of this opportunistic pathogen to the chronic chourse of infection in CF, and on the innate resistance to antibiotics of B. cepacia, person-to-person spread, and sometimes rapidly fatal disease caused by this organism. While understanding the mechanism of conversion to mucoidy in P. aeruginosa has progressed to the point where this phenomenon has evolved into a model system for studying bacterial stress response in microbial pathogenesis, the more recent challenge with B. cepacia, which has emerged as a potent bona fide CF pathogen, is discussed in the context of clinical issues, taxonomy, transmission, and potential modes of pathogenicity.
The pleiotypic response to amino acid deprivation is the result of interactions between components of the glycolysis and protein synthesis pathways (1992)

Several diverse metabolic events become compromised when mammalian cells are made deficient in essential amino acids or when charging of their tRNA is blocked by amino acid analogs. This rapid general demise of cell function can be due to inhibition of phosphofructokinase (PFK) by uncharged tRNA. It has now been demonstrated that when tRNA is added to PFK in an assay dependent upon the reassociation of inactive, dissociated enzyme subunits, nanomolar concentrations cause complete inhibition. The model for control suggests that charged tRNA becomes associated with EF-1, which is specific for aminoacyl-tRNAs and is present in sufficiently high concentrations in cells to sequester that charged forms from an inhibitory role. Support for this model include: (1) the rapid onset of inhibition of glycolysis and glucose uptake upon amino acid deficiency; (2) the unique role of the product of PFK activity, fructose-1,6-diphosphate, in reactions of peptide chain initiation, particularly its role as a co-factor for purified eIF-2B, the GDP/GTP exchange factor; (3) the correlations of this interaction with the cellular and molecular lesions of insulin insufficiency; (4) the recognition that the anomalous role of high concentrations of cAMP as a stimulant of peptide chain initiation in energy depleted or gel-filtered cell lysates correlates with its stimulatory action on PFK as an analog for the positive effector, adenosine-5'-monophosphate; and (5) the role of fructose-1,6-diphosphate in the formation of glyceraldehyde-3-phosphate, a substrate for synthesis of ribose-5-phosphate via the non-oxidative portion of the pentose phosphate pathway, which, as a precursor of phosphoribosylpyrophosphate, is essential for nucleic acid synthesis.
Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone (2011)

Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2-plus-gD-2 combination had robust CD4+ T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4+ T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation.
Lysosomal Degradation of α-Synuclein in Vivo (2010)

Pathologic accumulation of alpha-synuclein is a feature of human parkinsonism and other neurodegenerative diseases. This accumulation may be counteracted by mechanisms of protein degradation that have been investigated in vitro but remain to be elucidated in animal models. In this study, lysosomal clearance of alpha-synuclein in vivo was indicated by the detection of alpha-synuclein in the lumen of lysosomes isolated from the mouse midbrain. When neuronal alpha-synuclein expression was enhanced as a result of toxic injury (i.e. treatment of mice with the herbicide paraquat) or transgenic protein overexpression, the intralysosomal content of alpha-synuclein was also significantly increased. This effect was paralleled by a marked elevation of the lysosome-associated membrane protein type 2A (LAMP-2A) and the lysosomal heat shock cognate protein of 70 kDa (hsc70), two essential components of chaperone-mediated autophagy (CMA). Immunofluorescence microscopy revealed an increase in punctate (lysosomal) LAMP-2A staining that co-localized with alpha-synuclein within nigral dopaminergic neurons of paraquat-treated and alpha-synuclein-overexpressing animals. The data provide in vivo evidence of lysosomal degradation of alpha-synuclein under normal conditions and, quite importantly, under conditions of enhanced protein burden. In the latter, increased lysosomal clearance of alpha-synuclein was mediated, at least in part, by CMA induction. It is conceivable that these neuronal mechanisms of protein clearance play an important role in neurodegenerative processes characterized by abnormal alpha-synuclein buildup.
Substances that can trigger activation of the alternative pathway of complement have anti‐melanoma activity in mice (1984)

Intraperitoneal (i.p.) injection of substances that can ignite the alternative pathway of complement, namely isolated human C3b or C3(H2O), guinea-pig C3(H2O) or cobra venom factor, or conventionally prepared zymosan, will reproducibly and very significantly increase the mean survival time of C57BL mice previously inoculated i.p. with melanoma cells. The effect is greater at higher doses and earlier post-inoculation (p.i.) administration, but the substances are active at low doses (30-100 micrograms/mouse) if given early enough. It is likely that C3b or C3(H2O) was the previously unidentified anti-tumour factor activated in serum by S. aureus treatment or serum fractionation and described elsewhere. Activation of the alternative pathway of complement appears to have potential interest for cancer therapy.
Update on the current status of cytomegalovirus vaccines (2010)

Human cytomegalovirus (HCMV) is ubiquitous in all populations, and is the most commonly recognized cause of congenital viral infection in developed countries. On the basis of the economic costs saved and the improvement in quality of life that could potentially be conferred by a successful vaccine for prevention of congenital HCMV infection, the Institute of Medicine has identified HCMV vaccine development as a major public health priority. An effective vaccine could potentially also be beneficial in preventing or ameliorating HCMV disease in immunocompromised individuals. Although there are no licensed HCMV vaccines currently available, enormous progress has been made in the last decade, as evidenced by the recently reported results of a Phase II trial of a glycoprotein B vaccine for the prevention of HCMV infection in seronegative women of childbearing age. HCMV vaccines currently in clinical trials include: glycoprotein B subunit vaccines; alphavirus replicon particle vaccines; DNA vaccines; and live-attenuated vaccines. A variety of vaccine strategies are also being examined in preclinical systems and animal models of infection. These include: recombinant vesicular stomatitis virus vaccines; recombinant modified vaccinia virus Ankara; replication-deficient adenovirus-vectored vaccines; and recombinant live-attenuated virus vaccines generated by mutagenesis of cloned rodent CMV genomes maintained as bacterial artificial chromosomes in Escherichia coli. In this article, we provide an overview of the current state of clinical trials and preclinical development of vaccines against HCMV, with an emphasis on studies that have been conducted in the past 5 years. We also summarize a number of recent advances in the study of the biology of HCMV, particularly with respect to epithelial and endothelial cell entry of the virus, which have implications for future vaccine design.
Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice (2009)

Type 1 diabetes (T1D) is an autoimmune disease that is caused by the destruction of insulin-producing beta cells. Viral infections induce immune responses that can damage beta cells and promote T1D or on the other hand prevent the development of the disease. However, the opposing roles of viral infections in T1D are not understood mechanistically. We report here that viruses that do not inflict damage on beta cells provided protection from T1D by triggering immunoregulatory mechanisms. Infection of prediabetic NOD mice with Coxsackie virus B3 or lymphocytic choriomeningitis virus (LCMV) delayed diabetes onset and reduced disease incidence. Delayed T1D onset was due to transient upregulation of programmed cell death-1 ligand 1 (PD-L1) on lymphoid cells, which prevented the expansion of diabetogenic CD8+ T cells expressing programmed cell death-1 (PD-1). Reduced T1D incidence was caused by increased numbers of invigorated CD4+CD25+ Tregs, which produced TGF-beta and maintained long-term tolerance. Full protection from T1D resulted from synergy between PD-L1 and CD4+CD25+ Tregs. Our results provide what we believe to be novel mechanistic insight into the role of viruses in T1D and should be valuable for prospective studies in humans.
Cochlear Base-Apex Differences in Cell-Death Pathways Following Exposure to Low-Frequency Noise (2008)

To determine what death pathways are followed by noise-damaged outer hair cells (OHCs).
Clinical applications of a novel sustained-release injectable drug delivery system: DepoFoam technology. (2001)

The therapeutic effectiveness of drugs is often limited by the inability to sustain therapeutic levels at the target site. Encapsulation of drugs in multivesicular lipid-based particles for sustained release is a novel approach to improving the pharmacokinetics of drug therapy. This paper reviews the preclinical and clinical literature on the applications and potential therapeutic benefits of DepoFoam technology, a novel sustained-release, injectable drug delivery system. DepoFoam formulations of drugs, including anticancer agents (cytarabine, methotrexate, bleomycin, recombinant interferon alfa, 5-fluorouridine-5'-monophosphate, and others), anti-infective agents (dideoxycytidine, 2'-norcyclic guanosine monophosphate, cidofovir, tobramycin, gentamicin, amikacin), analgesics (morphine, bupivacaine), and macromolecules (insulin, interleukin-2), delivered intrathecally, subcutaneously, intraperitoneally, or intralesionally, provide sustained therapeutic levels of drug at the intended target site and reduce systemic exposure and toxicity. Pharmacokinetic studies have demonstrated that DepoFoam particle encapsulation effectively extends the half-life of drugs, thus prolonging the duration of therapeutic drug concentrations in local tissues or in body spaces into which the encapsulated drug is injected. In the case of cell-cycle phase-specific chemotherapeutic agents, such formulations can improve efficacy and therapeutic ratio. DepoFoam is a promising drug delivery system for sustained release of hydrophilic injectable drugs that has a wide range of potential applications in oncology, infectious disease, analgesia, and other therapeutic areas.
Clostridium Difficile Colitis in the United States: A Decade of Trends, Outcomes, Risk Factors for Colectomy, and Mortality after Colectomy (2013)

Clostridium difficile colitis is increasing in the US, with an associated increase in total colectomies. Mortality rates after colectomy remain elevated. Progression to colectomy and mortality thereafter are associated with several patient and hospital factors. Knowledge of these risk factors may help in risk-stratification and counseling.
Progress toward the development of a viable BACE‐1 inhibitor (2009)

Abstract Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive formation of insoluble amyloid plaque and fibrillary tangles. Plaques are extracellular constructs consisting primarily of Aβ 42 derived from the catabolism of β‐amyloid precursor protein (APP). β‐Secretase (BACE‐1) is the enzyme responsible for the initiatory cleavage event in APP catabolism. The central role of BACE‐1 in the production of Aβ 42 has made it an attractive target for drug development. However, the development of BACE‐1 inhibitors has been hampered by difficulty in identifying inhibitors with acceptable pharmacokinetic and CNS penetration properties. The maturation of the BACE‐1 drug discovery effort from typical peptidomimetic inhibitors to more novel structural classes is reviewed. Drug Dev Res 70, 2009. © 2009 Wiley‐Liss, Inc.
Serine Phosphorylation of the Integrin β4 Subunit Is Necessary for Epidermal Growth Factor Receptor–induced Hemidesmosome Disruption (2007)

Hemidesmosomes (HDs) are multiprotein adhesion complexes that promote attachment of epithelial cells to the basement membrane. The binding of alpha6beta4 to plectin plays a central role in their assembly. We have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (S1356, S1360, and S1364), previously implicated in HD regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated. We have also established that epidermal growth factor receptor activation, which is known to function upstream of HD disassembly, results in the phosphorylation of only one or more of these three residues and the partial disassembly of HDs in keratinocytes. Additionally, we show that S1360 and S1364 of beta4 are the only residues phosphorylated by PKC and PKA in cells, respectively. Taken together, our studies indicate that multiple kinases act in concert to breakdown the structural integrity of HDs in keratinocytes, which is primarily achieved through the phosphorylation of S1356, S1360, and S1364 on the beta4 subunit.
The spectrum of fiber loss in a model of neuropathic pain in the rat: an electron microscopic study (1991)

Recently, Bennett and Xie reported that when the sciatic nerve of the rat is ligated loosely, the rat develops a pain syndrome with many features similar to those observed in neuropathic pain states in man. Anatomical and physiological studies to date indicate that the major pathology is a loss of large diameter myelinated fibers distal to the ligatures, with more subtle changes in small myelinated fibers. With a view to evaluating possible changes in the unmyelinated fibers, we have performed an electron microscopic analysis of the sciatic nerve 2 weeks after four ligatures were applied, at which time the animals displayed profound hyperalgesia and mechanical and thermal allodynia. Cross-sectional photomontages of regions proximal and distal to the ligatures were studied. Consistent with light microscopic and electrophysiological studies, we found a near complete loss of large myelinated fibers distal to the ligatures. Phagocytosis of large fibers was common. There was also considerable variation in the damage to small myelinated fibers. In some fascicles many small (less than 3 microns) myelinated axons remained; in other fascicles none could be detected. Importantly, we also found significant changes in the unmyelinated fiber spectrum. Counts of unmyelinated axons revealed a 34% and 71% decrease in the distal compared to the proximal nerve, in the two rats studied. The large clusters of unmyelinated axons that characterize normal nerve (and the nerve proximal to the ligatures) were rarely found distally. Rather, many of the unmyelinated axons coursed singly or in very loose bundles. Many of the surviving axons were shrunken and distorted, although still in contact with Schwann cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Tagging alcohols with cyclic carbonate: a versatile equivalent of (meth)acrylate for ring-opening polymerization (2007)

Cyclic carbonate monomers based on a single biocompatible scaffold allow for incorporation of a wide range of functional groups into macromolecules via ring-opening polymerization.
The substrate specificity-determining amino acid code of 4-coumarate:CoA ligase (2003)

To reveal the structural principles determining substrate specificity of 4-coumarate:CoA ligase (4CL), the crystal structure of the phenylalanine activation domain of gramicidin S synthetase was used as a template for homology modeling. According to our model, 12 amino acid residues lining the Arabidopsis 4CL isoform 2 (At4CL2) substrate binding pocket (SBP) function as a signature motif generally determining 4CL substrate specificity. We used this substrate specificity code to create At4CL2 gain-of-function mutants. By increasing the space within the SBP we generated ferulic- and sinapic acid-activating At4CL2 variants. Increasing the hydrophobicity of the SBP resulted in At4CL2 variants with strongly enhanced conversion of cinnamic acid. These enzyme variants are suitable tools for investigating and influencing metabolic channeling mediated by 4CL. Knowledge of the 4CL specificity code will facilitate the prediction of substrate preference of numerous, still uncharacterized 4CL-like proteins.
A web-based platform for experimental investigation of electric power auctions (1999)

This paper describes the architecture and uses of an Internet-based software platform called PowerWeb. PowerWeb was designed and implemented as a simulation environment for evaluating various power exchange auction markets through experimental investigation. It is designed to host simulations of a competitive `day-ahead' electric energy market in which the participants interact by submitting bids or offers into a market via a web-based user interface. The PowerWeb environment is meant to be flexible so as to allow investigation of various market mechanisms. In this paper we describe its interactive, distributed and web-based character.
Primary structure of human lymphotoxin derived from 1788 lymphoblastoid cell line. (1985)

The amino acid sequence of human lymphotoxin derived from a 1788 lymphoblastoid cell line was determined. Peptide fragments obtained by trypsin, lysine-C peptidase, cyanogen bromide, and acetic acid cleavage of the intact protein were purified by reverse-phase high performance liquid chromatography and analyzed by amino acid composition and by automated Edman degradation. The protein is 171 amino acids long with a molecular weight of 18,664. It contains one asparagine-linked glycosylation site and lacks cysteine. The salient features of the amino acid sequence of lymphotoxin are described.
Subunit structure and amino acid composition of mouse submaxillary gland nerve growth factor (1971)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSubunit structure and amino acid composition of mouse submaxillary gland nerve growth factorRalph A. Bradshaw, R. A. Hogue Angeletti, and Roger D. WadeCite this: Biochemistry 1971, 10, 3, 463–469Publication Date (Print):February 1, 1971Publication History Published online1 May 2002Published inissue 1 February 1971https://pubs.acs.org/doi/10.1021/bi00779a018https://doi.org/10.1021/bi00779a018research-articleACS PublicationsRequest reuse permissionsArticle Views60Altmetric-Citations112LEARN 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-Alertsclose Get e-Alerts
Multiple Nucleosome Positioning Sites Regulate the CTCF-Mediated Insulator Function of the H19 Imprinting Control Region† (2002)

The 5' region of the H19 gene harbors a methylation-sensitive chromatin insulator within an imprinting control region (ICR). Insertional mutagenesis in combination with episomal assays identified nucleosome positioning sequences (NPSs) that set the stage for the remarkably precise distribution of the four target sites for the chromatin insulator protein CTCF to nucleosome linker sequences in the H19 ICR. Changing positions of the NPSs resulted in loss of both CTCF target site occupancy and insulator function, suggesting that the NPSs optimize the fidelity of the insulator function. We propose that the NPSs ensure the fidelity of the repressed status of the maternal Igf2 allele during development by constitutively maintaining availability of the CTCF target sites.
A Song of Sino-German People’s Friendship——On Prince Luitpold of Bavaria’s Visit to Jingdezhen (2013)

Exports of Chinese porcelain have long provided beautiful articles for daily use and collection for the people of the world, and the spread of porcelain production technology has promoted its development worldwide. Germany was the first European state to produce porcelain. In 1710, with the discovery of kaolin clay in Meissen, Dresden, porcelain articles imitating those of China were successfully