gebhart/patrepeval huggingface dataset:
Therapeutic Protein–Polymer Conjugates: Advancing Beyond PEGylation (2014)

Protein-polymer conjugates are widely used as therapeutics. All Food and Drug Administration (FDA)-approved protein conjugates are covalently linked to poly(ethylene glycol) (PEG). These PEGylated drugs have longer half-lives in the bloodstream, leading to less frequent dosing, which is a significant advantage for patients. However, there are some potential drawbacks to PEG that are driving the development of alternatives. Polymers that display enhanced pharmacokinetic properties along with additional advantages such as improved stability or degradability will be important to advance the field of protein therapeutics. This perspective presents a summary of protein-PEG conjugates for therapeutic use and alternative technologies in various stages of development as well as suggestions for future directions. Established methods of producing protein-PEG conjugates and new approaches utilizing controlled radical polymerization are also covered.
Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia (2008)

Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3-independent growth in Ba/F3 cells and/or IL-9-independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.
Alteration of Fatty Acid Profiles in Different Pulmonary Surfactant Phospholipids in Acute Respiratory Distress Syndrome and Severe Pneumonia (2001)

Impairment of alveolar surfactant function has been documented in the acute respiratory distress syndrome (ARDS) and in severe pneumonia (PNEU); however, the underlying mechanisms are not completely understood. In the current report we present a detailed analysis of fatty acid (FA) profiles of different surfactant phospholipid (PL) classes isolated from bronchoalveolar lavage fluids (BALF) and large surfactant aggregates (LSA) from mechanically ventilated patients with ARDS (n = 8), ARDS associated with lung infection (ARDS + PNEU, n = 9), and PNEU (n = 22). Healthy volunteers served as control subjects (n = 8). PLs were isolated by thin-layer chromatography, and the FA profile of each PL class was assessed by gas chromatography. In addition, the minimal surface tension (gamma min) of untreated LSA and of LSA after supplementation with additional dipalmitoylated phosphatidylcholine (DPPC) was analyzed (pulsating bubble surfactometer). As compared with control LSA, the percentage of palmitic acid in phosphatidylcholine (PC) was significantly decreased in all patient groups (ARDS 63.0 +/- 2.0%, ARDS + PNEU 64.6 +/- 4.9%, PNEU 65.6 +/- 1.5%, control subjects 80.1 +/- 1.7%), whereas the relative amount of unsaturated species in PC increased significantly in all groups. Phosphatidylglycerol (PG) and phosphatidylinositol (PI) presented similar FA profiles in control subjects, but differed in the patients. The FA pattern of sphingomyelin (SPH) and phosphatidylethanolamine (PE) displayed only minor changes under conditions of respiratory failure. As compared with control subjects a highly significant increase of gamma min from near zero to approximately 16 mN/m was observed in all patients and was found to be inversely correlated to the percentage of palmitic acid in PC of LSA or BALF. Accordingly, values for gamma min were significantly improved upon secondary supplementation of LSA with DPPC up to control values. We conclude that marked changes in the FA composition of the predominant surfactant PL classes occur, both in ARDS triggered by nonpulmonary events and PNEU. The marked reduction of palmitic acid in the PC fraction may be related to changes in surfactant function under these conditions.
Synthesis of 5‐trifluoromethyl‐5,8‐dideazafolic acid and 5‐trifluoromethyl‐5,8‐dideazaisofolic acid (1990)

Abstract The target folate analogue 5‐trifluoromethyl‐5,8‐dideazafolic acid has been elaborated in a seven‐step reaction sequence beginning with 2‐fluoro‐6‐trifluoromethylbenzonitrile. The bridge‐reversed isomer 5‐trifluoromethyl‐5,8‐dideazaisofolic acid was prepared in six steps using the common intermediate 2,6‐diamino‐3,4‐dihydro‐4‐oxo‐5‐trifluoromethylquinazoline. The key intermediate 2‐amino‐3,4‐dihydro‐4‐oxo‐5‐trifluoromethyl‐quinazoline was prepared using two distinct synthetic routes and the resulting products were found to be identical.
Identification of potential cell‐surface proteins in Candida albicans and investigation of the role of a putative cell‐surface glycosidase in adhesion and virulence (2004)

Cell-surface proteins are attractive targets for the development of novel antifungals as they are more accessible to drugs than are intracellular targets. By using a computational biology approach, we identified 180 potential cell-surface proteins in Candida albicans, including the known cell-surface adhesin Als1 and other cell-surface antigens, such as Pra1 and Csa1. Six proteins (named Csf1-6 for cell-surface factors) were selected for further biological characterization. First, we verified that the selected CSF genes are expressed in the yeast and/or hyphal form and then we investigated the effect of the loss of each CSF gene on cell-wall integrity, filamentation, adhesion to mammalian cells and virulence. As a result, we identified Csf4, a putative glycosidase with an apparent orthologue in Saccharomyces cerevisiae (Utr2), as an important factor for cell-wall integrity and maintenance. Interestingly, deletion of CSF4 also resulted in a defect in filamentation, a reduction in adherence to mammalian cells in an in vitro adhesion assay, and a prolongation of survival in an immunocompetent mouse model of disseminated candidiasis. A delay in colonization of key organs (e.g. kidney) was also observed, which is consistent with a reduction in virulence of the csf4-deletion strain. These data indicate a key role for extracellular glycosidases in fungal pathogenesis and represent a new site for therapeutic intervention to cure and prevent fungal disease.
Inflammatory status as a main determinant of outcome in patients with unstable angina, independent of coagulation activation and endothelial cell function (1999)

We found that in a clinically well-defined study population of patients with severe unstable angina, a proinflammatory state is an important and independent determinant of short-term outcome. The data strengthen the importance of inflammation in this syndrome.
Therapeutic Modulation of DMD Splicing by Blocking Exonic Splicing Enhancer Sites with Antisense Oligonucleotides (2006)

Antisense oligonucleotides (AONs) can be used to correct the disrupted reading frame of Duchenne muscular dystophy patients (DMD). We have a collection of 121 AONs, of which 79 are effective in inducing the specific skipping of 38 out of the 79 different DMD exons. All AONs are located within exons and were hypothesized to act by steric hindrance of serine-arginine rich (SR) protein binding to exonic splicing enhancer (ESE) sites. Indeed, retrospective in silico analysis of effective versus ineffective AONs revealed that the efficacy of AONs is correlated to the presence of putative ESE sites (as predicted by the ESEfinder and RESCUE-ESE software). ESE predicting software programs are thus valuable tools for the optimization of exon-internal antisense target sequences.
Therapeutic Potential of Group III Metabotropic Glutamate Receptors (2008)

Metabotropic glutamate (mGlu) receptors have received much attention, driven by a strong belief in the potential of these modulatory glutamate receptors as drug targets. So far, major drug discovery programs have largely focused on group I (mGlu1 and 5) and II (mGlu2 and 3) mGlu receptors, which have been implicated in neuropathological and various psychiatric disorders. The four group III representatives (mGlu4, mGlu6, mGlu7 and mGlu8) are less understood, mainly due to the paucity of specific compounds. Recent advances in the identification of selective or specific compounds, and the generation of transgenic animals have, however, revealed important insights into the potential role of group III receptors in the pathophysiology of neurological and mood disorders. Activation of the mGlu4 receptor seems to be beneficial for treating Parkinson-like symptoms and a potential role in the treatment of mood disorders is slowly growing. Similarly, genetic inactivation studies and usage of relatively selective agonists strongly support the involvement of the mGlu8 receptor for anxiety disorders. In contrast, controversial data have been obtained for the mGlu7 receptor. While mGlu7 receptor-deficient animals show an anxiolytic profile in several in vivo readouts, the first selective allosteric agonist AMN082 has also been reported to improve anxiety-like behaviour despite activating the stress axis. The least investigated receptor remains the mGlu6 receptor, which is mostly based on its predominant expression in the retina.
Inhibition of Histone Deacetylation Induces Constitutive Derepression of the Beta Interferon Promoter and Confers Antiviral Activity (2001)

The induction of alpha/beta interferon (IFN-alpha/beta) genes constitutes one of the first responses of the cell to virus infection. The IFN-beta gene is constitutively repressed in uninfected cells and is transiently activated after virus infection. In this work we demonstrate that histone deacetylation regulates the silent state of the murine IFN-beta gene. Using chromatin immunoprecipitation (ChIP) assays, we show a direct in vivo correlation between the transcriptionally silent state and a state of hypoacetylation of histone H4 on the IFN-beta promoter region. Trichostatin A (TSA), a specific inhibitor of histone deacetylases, induced strong, constitutive derepression of the murine IFN-beta promoter stably integrated into a chromatin context, as well as the hyperacetylation of histone H4, without requiring de novo protein synthesis. We also show in this work that TSA treatment strongly enhances the endogenous IFN level and confers an antiviral state to murine fibroblastic L929 cells. Inhibition of histone deacetylation with TSA protected the cells against the lost of viability induced by vesicular stomatitis virus (VSV) and inhibited VSV multiplication. Using antibodies neutralizing IFN-alpha/beta, we show that the antiviral state induced by TSA is due to TSA-induced IFN production. The demonstration of the predominant role of histone deacetylation during the regulation of the constitutive repressed state of the IFN-beta promoter constitutes an interesting advance on the understanding of the negative regulation of this gene and opens up the possibility of new therapeutic perspectives.
Templated synthesis of ZnSe nanostructures using lyotropic liquid crystals (2005)

We report a technique for controlled synthesis of zero-, one-, and two-dimensional compound semiconductor nanostructures by using cubic, hexagonal, and lamellar lyotropic liquid crystals as templates, respectively. The liquid crystals were formed by self-assembly in a ternary system consisting of a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) amphiphilic block copolymer as the surfactant, heptane as the non-polar dispersed phase, and formamide as the polar continuous phase. ZnSe quantum dots and nanowires with diameters smaller than 10 nm, as well as free-standing, disc-like quantum wells, were grown inside the spherical, cylindrical, and planar nanodomains, respectively, by reacting diethylzinc that was dissolved in the heptane domains with hydrogen selenide gas that was brought into contact with the liquid crystal in a sealed chamber at room temperature and atmospheric pressure. The shape and size of the resulting nanostructures can be manipulated by selecting the templating phase of the liquid crystal, the size of the dispersed nanodomains that is controlled by the composition of the template, and the concentration of diethylzinc in them.
Selective Patterned Growth of Silicide Nanowires without the Use of Metal Catalysts (2006)

Chemical vapor deposition of trans-Fe(SiCl3)2(CO)4 onto substrates with lithographically defined regions of thick (100 nm) and thin (1−2 nm) silicon oxides affords selective iron silicide nanowire growth only in those regions having thin silicon oxide. Bare silicon surfaces result in thin films of FeSi, whereas thick silicon oxide surfaces prohibit all deposition onto the substrate.
Laser scanning dental probe for endodontic root canal treatment (2011)

Complications that arise during endodontic procedures pose serious threats to the long-term integrity and health of the tooth. Potential complexities of root canals include residual pulpal tissue, cracks, mesial-buccal 2 and accessory canals. In the case of a failed root canal, a successful apicoectomy can be jeopardized by isthmuses, accessory canals, and root microfracture. Confirming diagnosis using a small imaging probe would allow proper treatment and prevent retreatment of endodontic procedures. An ultrathin and flexible laser scanning endoscope of 1.2 to 1.6mm outer diameter was used in vitro to image extracted teeth with varied root configurations. Teeth were opened using a conventional bur and high speed drill. Imaging within the opened access cavity clarified the location of the roots where canal filing would initiate. Although radiographs are commonly used to determine the root canal size, position, and shape, the limited 2D image perspective leaves ambiguity that could be clarified if used in conjunction with a direct visual imaging tool. Direct visualization may avoid difficulties in locating the root canal and reduce the number of radiographs needed. A transillumination imaging device with the separated illumination and light collection functions rendered cracks visible in the prepared teeth that were otherwise indiscernible using reflected visible light. Our work demonstrates that a small diameter endoscope with high spatial resolution may significantly increase the efficiency and success of endodontic procedures.
Increased cystatin C immunoreactivity in the skin in amyotrophic lateral sclerosis (2000)

These data suggest that a metabolic alteration of cystatin C may take place in the skin of ALS and the increased cystatin C in skin is likely to be related to the disease process in ALS.
Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia (2011)

B-cell chronic lymphocytic leukaemia (B-CLL) remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR) which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19(+) leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19(+) B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.
Cloning of eukaryotic gene and expression (2002)

Using T-A vector to constructeukaryotic gene recombinants is a rapid and convenient method. In this study, pcDNA3.1(+)/Cx26 was constructed by the method and transferred into nasopharyngeal carcinoma cell line HNE1. Cx26 protein was expressed in HNE1.
The PowerPC 604 microprocessor - multimedia ready (2002)

The PowerPC 604 microprocessor's implementation is described including its superscalar dispatch, branch prediction, speculative execution, special instructions, and caches. An example is given showing that the 604 is well suited to multimedia applications.
How Lasers Work (2008)

This chapter contains sections titled: Building a Laser Producing a Population Inversion Resonant Cavities Laser Beams and Resonance Wavelength Selection and Tuning Laser Excitation Techniques What Have We Learned?
Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro (2004)

Pluripotent embryonic stem (ES) cells are capable of differentiating into all cell lineages, but the molecular mechanisms that regulate ES cell differentiation have not been sufficiently explored. In this study, we report that shear stress, a mechanical force generated by fluid flow, can induce ES cell differentiation. When Flk-1-positive (Flk-1(+)) mouse ES cells were subjected to shear stress, their cell density increased markedly, and a larger percentage of the cells were in the S and G(2)-M phases of the cell cycle than Flk-1(+) ES cells cultured under static conditions. Shear stress significantly increased the expression of the vascular endothelial cell-specific markers Flk-1, Flt-1, vascular endothelial cadherin, and PECAM-1 at both the protein level and the mRNA level, but it had no effect on expression of the mural cell marker smooth muscle alpha-actin, blood cell marker CD3, or the epithelial cell marker keratin. These findings indicate that shear stress selectively promotes the differentiation of Flk-1(+) ES cells into the endothelial cell lineage. The shear stressed Flk-1(+) ES cells formed tubelike structures in collagen gel and developed an extensive tubular network significantly faster than the static controls. Shear stress induced tyrosine phosphorylation of Flk-1 in Flk-1(+) ES cells that was blocked by a Flk-1 kinase inhibitor, SU1498, but not by a neutralizing antibody against VEGF. SU1498 also abolished the shear stress-induced proliferation and differentiation of Flk-1(+) ES cells, indicating that a ligand-independent activation of Flk-1 plays an important role in the shear stress-mediated proliferation and differentiation by Flk-1(+) ES cells.
Identification of vancomycin resistance protein VanA as a D-alanine:D-alanine ligase of altered substrate specificity (1991)

High-level glycopeptide resistance in Enterococcus faecium BM4147 is mediated by a 38-kDa protein VanA, whose amino acid sequence is related to Gram-negative D-alanine:D-alanine (D-Ala-D-Ala) ligases [Dutka-Malen, S., Molinas, C., Arthur, M., & Courvalin, P. (1990) Mol. Gen. Genet. 224, 364-372]. We report purification of VanA and demonstrate that it has D-Ala-D-Ala ligase activity but has substantially modified substrate specificity, compared with Gram-negative D-Ala-D-Ala ligases. VanA preferentially condenses D-Ala with D-Met or D-Phe, raising the possibility that its cellular role is to synthesize a modified cell-wall component, which is subsequently not recognized by vancomycin.
Phase II Study of Taxol, Merbarone, and Piroxantrone in Stage IV Non-Small-Cell Lung Cancer: The Eastern Cooperative Oncology Group Results (1993)

Further study of taxol is warranted. In future studies, taxol should be combined with other agents, and granulocyte colony-stimulating factor should be used to ameliorate myelosuppression.
Synaptic Plasticity and Memory: An Evaluation of the Hypothesis (2000)

Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.
Molecular environment of ZO‐1 in epithelial and non‐epithelial cells (1995)

We previously reported the expression of ZO-1 in cell types that do not form tight junctions. Here we compare the molecular environments of ZO-1 in epithelial cells, primary cultures of astrocytes and in the non-epithelial S180 sarcoma cell line. ZO-1 co-localizes with a subset of actin filaments in all cell types. In astrocytes, ZO-1 is found concentrated in discrete bands at points of cell-cell contact. Indirect immunofluorescent microscopy shows that these bands of ZO-1 co-localize with the adherens junction proteins vinculin and alpha-actinin, and with the antigen recognized by a pan-cadherin antibody. In contrast, ZO-1 in S180 cells, which exhibit limited cell-cell interactions, is diffusely distributed over the plasma membrane, with concentrations in lamellipodia where actin filaments accumulate. ZO-1 does not co-localize with vinculin at focal adhesions in this cell type. Analysis of ZO-1 immunoprecipitation profiles from different cell types, performed under conditions previously demonstrated to maintain interactions between ZO-1, ZO-2 and p130 from the MDCK epithelial cell line, show that the proteins which co-precipitate with ZO-1 vary with cell type. Precipitation of polypeptides at 165 kDa, potentially ZO-2, and 65 kDa occurs in both a mouse kidney tubule epithelial cell line and the non-epithelial S180 cells. No proteins specifically associate with ZO-1 immunoprecipitated from astrocytes. Spectrin, alpha-actinin, vinculin and cadherin are not detected in immunoblots of ZO-1 immunoprecipitates from any cell type.