gebhart/patrepeval huggingface dataset:
Neuropathology of Human Spinal Cord Injury Sustained in Sports-related Activities (1997)

The neuropathology of 20 cases of traumatic human spinal injury is described. Cases were classified as having "complete" or "incomplete" spinal cord injuries based upon the neuropathological findings. Special attention was directed to those cases with neuropathological evidence of continuity of long tract axons across the lesion but that were obtained from individuals with clinically complete sensory and motor loss. Clinical and neuropathological data were obtained from the Western Australian Spinal Cord Injury Database and were selected from those cases involving sports-related injuries. From the total of 20 cases of spinal injury, 6 exhibited neuropathologically and clinically complete cord injuries, 4 were neuropathologically incomplete yet clinically complete, and 4 were neuropathologically and clinically incomplete (one being motor complete yet sensory incomplete). The clinical/neuropathological correlation was indeterminate in 6 cases because of death at or shortly after the accident. The neuropathological findings varied with the severity of trauma and the length of survival. In those cases examined less than 3 months postinjury, there was typically swelling of the cord from vasogenic edema with petechial hemorrhage and myelomalacia. Central hemorrhagic necrosis was common as was hyperemia with free red cells present among disrupted tissue. Activated astrocytes and polymorphs or macrophages were observed and early stages of glial cell scar formation were evident. Wallerian degeneration was evident in motor tracts caudal to the level of insult and in sensory tracts rostral to the lesion. Cases examined 3-6 months postinjury often revealed multilocular cysts with gliotic walls often extending several millimeters above and below the primary locus of injury. In the "chronic" cases (i.e., those surviving more than 6 months), there was evidence of varying degrees of preserved long tract parenchyma, nerve root regeneration, and Schwann cell remyelination of long tract axons. The degree of sparing of long motor and sensory tract parenchyma generally correlated well with the clinical observations of residual function. In four cases, however, there was a residuum of motor or sensory tract axons that appeared to have been spared injury, but the clinical data reported chronically complete sensory and motor loss. The presence of clinically complete yet neuropathologically incomplete injury was more often associated with crush or flexion injuries than with extension or compression trauma. The preserved parenchyma in these types of lesion may provide the anatomical substrate for restorative intervention.
G-protein coupled CB2 receptor: Method development for membrane protein NMR (2004)

The experiment-based three-dimensional structures of G protein coupled receptors (GPCRs) would have greatly aided the understanding of their structure-function relationships, thus facilitating rational ligand design for these biologically and therapeutically important integral membrane proteins. In considering the difficulties to study the GPCR structures by conventional approaches, a “NMR structure from building blocks to 3D assemblies” strategy was proposed and investigated. In order to validate and apply this approach, a comprehensive method development was conducted. ^ The scope of the research work described in this thesis was mainly focused on the method development of GPCR segments expression, purification, and sample preparation. To achieve this objective, cannabinoid receptor subtype CB2 was chosen as a target molecule. Transmembrane helices and multi-helix bundles from CB2 were expressed in E. coli in a high yield, followed by multi-step purification procedures. Expression and purification protocols were developed, including usage of fusion protein over-expression systems, nickel affinity chromatography, chemical or enzymatic cleavage, and reverse phase HPLC. These processes were monitored by electrophoresis, HPLC, mass spectrometry, and circular dichroism spectroscopy. The final products were analyzed and validated by these analytical methods as well. Preliminary NMR studies characterized the prepared CB2 segments, and thus validated the developed methods. ^ With the developed expression and purification schemes, milligrams of uniformly isotope-labeled membrane protein samples were prepared and purified. The samples were sufficient and qualified for membrane protein NMR studies and structure determinations as other continuing projects. The developed methods were standardized, and will be adapted to produce other transmembrane helices and helix bundles of CB2, and those from other GPCRs, for their membrane protein NMR studies and other biophysical studies in the future. ^
The Position of the α and β Subunits in a Single Chain Variant of Human Chorionic Gonadotropin Affects the Heterodimeric Interaction of the Subunits and Receptor-binding Epitopes (2001)

The glycoprotein hormone family represents a class of heterodimers, which include the placental hormone human chorionic gonadotropin (CG) and the anterior pituitary hormones follitropin, lutropin, and thyrotropin. They are composed of common alpha subunit and a hormone-specific beta subunit. Based on the CG crystal structure, it was suggested that the quaternary subunit interactions are crucial for biological activity. However, recent observations using single chain glycoprotein hormone analogs, where the beta and alpha subunits are linked (NH(2)-CGbeta-alpha; CGbetaalpha orientation), implied that the heterodimeric-like quaternary configuration is not a prerequisite for receptor binding/signal transduction. To study the heterodimeric alignment of the two subunit domains in a single chain and its role in the intracellular behavior and biological action of the hormone, a single chain CG variant was constructed in which the carboxyl terminus of alpha was fused to the CGbeta amino terminus (NH(2)-alpha-CGbeta; alphaCGbeta orientation). The secretion rate of alphaCGbeta from transfected Chinese hamster ovary cells was less than that seen for CGbetaalpha. The alphaCGbeta tether was not recognized by dimer-specific monoclonal antibodies and did not bind to lutropin/CG receptor. To define if one or both subunit domains were modified in alphaCGbeta, it was co-transfected with a monomeric alpha or CGbeta gene. In each case, alphaCGbeta/alpha and alphaCGbeta/CGbeta complexes were formed indicating that CG dimer-specific epitopes were established. The alphaCGbeta/alpha complex bound to receptor indicating that the beta domain in the alphaCGbeta tether was still functional. In contrast, no significant receptor binding of alphaCGbeta/CGbeta was observed indicating a major perturbation in the alpha domain. These results suggest that although dimeric-like determinants are present in both alphaCGbeta/alpha and alphaCGbeta/CGbeta complexes, the receptor binding determinants in the alpha domain of the tether are absent. These results show that generating heterodimeric determinants do not necessarily result in a bioactive molecule. Our data also indicate that the determinants for biological activity are distinct from those associated with intracellular behavior.
European randomized study of prostate cancer screening: first-year results of the Finnish trial (1999)

Approximately 20000 men 55-67 years of age from two areas in Finland were identified from the Population Registry and randomized either to the screening arm (1/3) or the control arm (2/3) of a prostate cancer screening trial. In the first round, the participation rate in the screening arm was 69%. Of the 5053 screened participants, 428 (8.5%) had a serum prostate-specific antigen (PSA) concentration of 4.0 ng/ml or higher, and diagnostic examinations were performed on 399 of them. A total of 106 cancers were detected among them corresponding to a positive predictive value of 27%, which is comparable with mammography screening for breast cancer. The prostate cancer detection rate based on a serum PSA concentration of 4.0 ng ml(-1) or higher was 2.1%. Approximately nine out of ten screen-detected prostate cancers were localized (85% clinical stage T1-T2) and well or moderately differentiated (42% World Health Organization (WHO) grade I and 50% grade II), which suggests a higher proportion of curable cancers compared with cases detected by other means.
Molecular Basis of Bacterial Outer Membrane Permeability Revisited (2003)

Gram-negative bacteria characteristically are surrounded by an additional membrane layer, the outer membrane. Although outer membrane components often play important roles in the interaction of symbiotic or pathogenic bacteria with their host organisms, the major role of this membrane must usually be to serve as a permeability barrier to prevent the entry of noxious compounds and at the same time to allow the influx of nutrient molecules. This review summarizes the development in the field since our previous review (H. Nikaido and M. Vaara, Microbiol. Rev. 49:1-32, 1985) was published. With the discovery of protein channels, structural knowledge enables us to understand in molecular detail how porins, specific channels, TonB-linked receptors, and other proteins function. We are now beginning to see how the export of large proteins occurs across the outer membrane. With our knowledge of the lipopolysaccharide-phospholipid asymmetric bilayer of the outer membrane, we are finally beginning to understand how this bilayer can retard the entry of lipophilic compounds, owing to our increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopolysaccharide structure is modified by environmental conditions.
Dendritic cell-based immunotherapy of cancer with carcinoembryonic antigen-derived, HLA-A24-restricted CTL epitope: Clinical outcomes of 18 patients with metastatic gastrointestinal or lung adenocarcinomas (2004)

We conducted a clinical study of cancer vaccine therapy with dendritic cells (DCs) and HLA-A24-restricted carcinoembryonic antigen (CEA)-derived peptide to assess the feasibility and efficacy of such therapy. Eighteen patients with CEA-expressing metastatic gastrointestinal or lung adenocarcinomas who were positive for human leukocyte antigen (HLA)-A24 were enrolled. DCs were generated from the patients' autologous monocyte-enriched fractions of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4. The generated DCs were pulsed with CEA-derived, HLA-A24-restricted 9-mer peptide (CEA652) and injected into the patients intradermally and subcutaneously every 2 weeks. Toxicity and clinical and immunological responses were closely monitored in each patient. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. Although no definite tumor shrinkage occurred in any patient, long-term stable disease or marked decreases in the serum CEA level were observed in some patients after therapy. Most of the patients in whom treatment was clinically effective showed a positive skin response to CEA652-pulsed DCs (delayed-type hypersensitivity skin test) and a positive in vitro CTL response to CEA652 peptide after therapy. We conclude that active specific immunotherapy using DCs pulsed with CEA652 is a safe and feasible treatment that is clinically effective in some patients with metastatic gastrointestinal or lung adenocarcinomas. Our results will hopefully encourage further refinement and development of DC-based immunotherapy with HLA-A24-restricted CEA-derived peptide for refractory solid cancers that express CEA.
Antivector and antitransgene host responses in gene therapy. (2000)

Current viral gene therapy vectors effectively transfer genes in vivo at the price of eliciting innate and acquired host responses against the vector and/or transgene. Antigens present in the viral vector and the expression of the transgene both cause cellular and humoral immune responses dependent on the viral vector, the route of administration, and the genotype and infection history of the host. In general, adenoviral vectors cause strong immune responses, which result in only transient expression of the therapeutic gene. Adeno-associated virus and retrovirus vectors elicit weaker immune responses and can therefore result in long-term gene transfer and expression. Methods to avoid host responses, including modification of viral vector and immunosuppression of the host, can increase the longevity and efficiency of gene transfer.
Lack of reduction in racial disparities in cancer‐specific mortality over a 20‐year period (2014)

The survival gap for African Americans has not closed over time. Race-based differences in outcome persist independent of stage of disease and treatment, suggesting that additional strategies beyond screening and improving access to care, such as further research into tumor biologies disproportionately affecting African Americans, are needed to improve survival for African American patients with cancer.
Decreasing stearoyl‐CoA desaturase‐1 expression inhibits β‐catenin signaling in breast cancer cells (2012)

Stearoyl-CoA desaturase-1 (SCD1) is an endoplasmic reticulum anchored enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly palmytoleyl-CoA and oleyl-CoA. Recent studies have revealed a function for SCD1 in the modulation of signaling processes related to cell proliferation, survival and transformation to cancer. We used MCF7 and MDA-MB-231 cells to analyze the role of SCD1 in the metastatic acquisition of breast cancer cells. Silencing SCD1 expression in breast cancer cells has no effect on cell viability but the levels of cell proliferation, cell cycle genes' expressions and the phosphorylation state of ERK1/2 MAPK are significantly reduced. Decreasing SCD1 expression also reduces the level of GSK3 phosphorylation, indicating higher activity of the kinase. Using cells fractionation, immunofluorescence and a β-catenin/TCF-responsive reporter construct, we demonstrate that lowering SCD1 expression leads to a decrease of β-catenin amounts within the nucleus and to inhibition of its transactivation capacity. Moreover, MDA-MB-231 cells transfected with the SCD1 siRNA show a lower invasive potential than the control cells. Taken together, our data demonstrate that low SCD1 expression is associated with a decrease in the proliferation rate of breast cancer cells associated with a decrease in ERK1/2 activation. SCD1 silencing also inhibits GSK3 phosphorylation, lowering β-catenin translocation to the nucleus, and, subsequently, its transactivation capacity and the expression of its target genes. Finally, we show that silencing SCD1 impairs the epithelial to mesenchymal transition-like behavior of the cells, a characteristic of metastatic breast cancer.
Mechanisms of in Situ Activation for DNA-Targeting Antitumor Agents (2002)

ADVERTISEMENT RETURN TO ISSUEArticleNEXTMechanisms of in Situ Activation for DNA-Targeting Antitumor AgentsScott E. Wolkenberg and Dale L. BogerView Author Information Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 Cite this: Chem. Rev. 2002, 102, 7, 2477–2496Publication Date (Web):May 15, 2002Publication History Received3 January 2002Published online15 May 2002Published inissue 1 July 2002https://pubs.acs.org/doi/10.1021/cr010046qhttps://doi.org/10.1021/cr010046qresearch-articleACS PublicationsCopyright © 2002 American Chemical SocietyRequest reuse permissionsArticle Views2617Altmetric-Citations307LEARN 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 SUBJECTS:Alcohols,Crystal cleavage,Genetics,Nucleic acid structure,Post-translational modification Get e-Alerts
Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer (2011)

Delivery of macromolecules into cells and tissues such as skin is a major challenge. This obstacle poses a particular challenge for the delivery of siRNA where cellular and tissue level transport barriers need to be overcome. siRNAs are potential therapeutics for various dermatological diseases including psoriasis, atopic dermatitis, and cancer; however, their utility is limited by their low absorption across the stratum corneum (SC) and into viable cells of skin. Here, we address this challenge using a peptide identified by phage display termed skin penetrating and cell entering (SPACE) peptide. In vitro studies indicated that the SPACE peptide, when conjugated to cargoes such as small molecules and proteins, was able to facilitate their penetration across the SC into epidermis and dermis. The peptide also exhibited increased penetration into various cells including keratinocytes, fibroblasts, and endothelial cells, likely through a macropinocytosis pathway. The ability of SPACE peptide to deliver siRNA was tested in vivo using two targets, interleukin-10 and GAPDH. Conjugation of the peptide to siRNA led to their enhanced absorption into skin and knockdown of corresponding protein targets.
Structure of Kre2p/Mnt1p (2004)

Kre2p/Mnt1p is a Golgi alpha1,2-mannosyltransferase involved in the biosynthesis of Saccharomyces cerevisiae cell wall glycoproteins. The protein belongs to glycosyltransferase family 15, a member of which has been implicated in virulence of Candida albicans. We present the 2.0 A crystal structures of the catalytic domain of Kre2p/Mnt1p and its binary and ternary complexes with GDP/Mn(2+) and GDP/Mn(2+)/acceptor methyl-alpha-mannoside. The protein has a mixed alpha/beta fold similar to the glycosyltransferase-A (GT-A) fold. Although the GDP-mannose donor was used in the crystallization experiments and the GDP moiety is bound tightly to the active site, the mannose is not visible in the electron density. The manganese is coordinated by a modified DXD motif (EPD), with only the first glutamate involved in a direct interaction. The position of the donor mannose was modeled using the binary and ternary complexes of other GT-A enzymes. The C1" of the modeled donor mannose is within hydrogen-bonding distance of both the hydroxyl of Tyr(220) and the O2 of the acceptor mannose. The O2 of the acceptor mannose is also within hydrogen bond distance of the hydroxyl of Tyr(220). The structures, modeling, site-directed mutagenesis, and kinetic analysis suggest two possible catalytic mechanisms. Either a double-displacement mechanism with the hydroxyl of Tyr(220) as the potential nucleophile or alternatively, an S(N)i-like mechanism with Tyr(220) positioning the substrates for catalysis. The importance of Tyr(220) in both mechanisms is highlighted by a 3000-fold reduction in k(cat) in the Y220F mutant.
Heterodimerization of Calcium Sensing Receptors with Metabotropic Glutamate Receptors in Neurons (2001)

Calcium sensing (CaR) and Group I metabotropic glutamate receptors exhibit overlapping expression patterns in brain, and share common signal transduction pathways. To determine whether CaR and Group I metabotropic glutamate receptors (mGluRs) (mGluR1alpha and mGluR5) can form heterodimers, we immunoprecipitated CaR from bovine brain and observed co-precipitation of mGluR1alpha. CaR and mGluR1alpha co-localize in hippocampal and cerebellar neurons, but are expressed separately in other brain regions. In vitro transfection studies in HEK-293 cells established the specificity and disulfide-linked nature of the CaR:mGluR1alpha (CaR:mGluR5) interactions. CaR:mGluR1alpha (CaR:mGluR5) heterodimers exhibit altered trafficking via Homer 1c when compared with CaR:CaR homodimers. CaR becomes sensitive to glutamate-mediated internalization when present in CaR:mGluR1alpha heterodimers. These results demonstrate cross-family covalent heterodimerization of CaR with Group I mGluRs, and increase the potential role(s) for CaR in modulating neuronal function.
A Fluidic Actuator for Active Combustion Control (2008)

In this work the performance of a fluidic actuator in an active combustion control scheme is demonstrated. The actuator was tested in two different burner configurations, a bluff body burner and a generic swirl-stabilized burner, where it modulated parts of the fuel flow. The oscillation frequency was controlled by varying the inlet mass flow of the actuator. Fluidic actuators are of special interest for fuel-based active control schemes featuring high frequency fuel flow modulation, as they are much more durable then conventional valves due to the absence of fast moving parts. Hot wire measurements were performed to investigate the fluidic actuator’s oscillation characteristics without combustion. The actuator was then incorporated into a bluff body burner and a swirl-stabilized burner, respectively, where it modulated parts of the fuel flow blended with nitrogen. Pressure and heat release fluctuations in the combustor were recorded and images of the flame were taken. For both burners the heat release response of the flame to fuel flow modulation was first studied during stable combustion. The spectra of the heat release signals showed a clear peak corresponding to the fluidics’ oscillation frequency, thus validating the ability of the actuator to influence the combustion process. As the next step, each of the two combustors was operated at conditions that featured a strong low-frequency combustion instability when no fuel was modulated. In case of the bluff body burner applying fuel modulation resulted in attenuation of the combustion instability for some oscillation frequencies. The attenuation was highest when modulating the fuel flow in between the fundamental instability frequency and its subharmonic. Modulating the fuel flow at the subharmonic, however, resulted in an amplification of the instable mode. Also when applied to the swirl burner, the fludics’ fuel flow modulation caused a significant reduction of the pressure oscillations, although the actuator could only be operated at oscillation frequencies much lower than the instability frequency due to the attached tubes. The results obtained in this work show that the fluidic actuator in use allows for fuel modulation and hence combustion control without the need for complex and fast moving parts, thus ensuring a long actuator lifetime. This makes the fluidic actuator highly appropriate for application in industrial gas turbines.