gebhart/patrepeval huggingface dataset:
Identification of Functionally Important Residues of Human Thrombopoietin (1998)

Thrombopoietin (TPO) is a megakaryocyte growth and differentiation factor. It consists of a characteristic two domain structure. The amino-terminal domain of TPO has a sequence homology with erythropoietin and is required for the binding and activation of its receptor c-Mpl. To determine the functionally important regions interacting with its receptor, a series of site-directed mutants of TPO were constructed based on a three-dimensional model of the amino-terminal domain. Two strategies of mutagenesis were employed: 1) nonnative N-linked glycosylation scan of 12 residues predicted to be on the surface, and 2) alanine replacement scan of mostly charged 44 amino acid residues. Each TPO mutein was transiently expressed in COS7 cells, and the specific bioactivity of the TPO protein secreted into the culture medium was measured using a recombinant BaF3 cell line expressing human c-Mpl. Four alanine substitutions at Arg10, Pro42, Glu50, and Lys138 nearly or completely abolished the activity, whereas the mutation at Arg14 slightly decreased the activity, suggesting that these residues are functionally important in interacting with its receptor. These residues mapped to helix A, loop AB, and helix D. Sequence comparison between human TPO and other mammalian TPO showed that the identified residues are completely conserved among the species. However, unlike the recent report on the mutational analysis of TPO, alanine substitutions at Lys52, Lys59, Arg136, and Arg140 did not affect the TPO activity significantly in our system. The identified receptor binding regions of TPO are analogous to those of human growth hormone and erythropoietin. Based on the similarity of these three cytokines, we propose that Lys138 of helix D and Pro42 and Glu50 of loop AB may constitute one binding region, whereas Arg10 and Lys14 of helix A may constitute the other binding region to dimerize the receptors.
Preferential Activation of the 8–17 Deoxyribozyme by Ca Ions (2000)

The 8-17 deoxyribozyme is a small RNA-cleaving DNA molecule of potential therapeutic interest. Here, the cleavage rates of 16 variants of the 8-17 deoxyribozyme were measured in the presence of different divalent metal ions. Despite the fact that 8-17 was originally selected in vitro for activity in the presence of Mg(2+) (Santoro, S. W., and Joyce, G. F. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 4262-4266) nearly all the 8-17 variants exhibited substantially higher (up to 20-fold) reaction rates in Ca(2+) as compared with Mg(2+). This preference for calcium ions critically depended on the nucleoside residues at two specific positions of the deoxyribozyme core. The Ca(2+) specificity of 8-17 is strongly reminiscent of the properties of Mg5, an RNA phosphodiester-cleaving deoxyribozyme previously isolated by Faulhammer and Famulok (Faulhammer, D., and Famulok, M. (1996) Angew. Chem. Int. Ed. Engl. 35, 2837-2841). Indeed, analysis of the Mg5 sequence revealed the presence of a complete 8-17 motif, coincident with the conserved region of Mg5. An 8-17 deoxyribozyme modeled after the Mg5 conserved region displayed catalytic features comparable with those reported for the full-length Mg5 deoxyribozyme.
Effect of a Synthetic Factor Xa Inhibitor, YM-60828, on Blood Vessel Patency in Combination with a Thrombolytic Agent and on Blood Loss from the Operation Site in a Rat Model of Arterial Thrombosis (1998)

We examined the adjunctive effect of a novel factor Xa inhibitor, YM-60828, on vessel patency and blood loss from the operation site after successful thrombolysis with a modified tissue-type plasminogen activator (moPA) in an electrically-induced carotid artery thrombosis model in rats. Five minutes after the induction of occlusive thrombus, a test drug (YM-60828, argatroban, heparin or saline) was administered by i.v. bolus injection followed by continuous infusion. Thrombolysis was induced with moPA by i.v. bolus injection at a dose of 650,000 IU/ kg. YM-60828 at 1 mg/kg i.v. followed by 3 mg/kg/h significantly prevented reocclusion, increased the duration of patency, and improved vessel patency after successful thrombolysis without any significant increase in blood loss from the operation site. Argatroban at 1 mg/kg i.v. followed by 3 mg/kg/h and heparin at 300 U/kg i.v. followed by 150 U/kg/h also significantly improved these parameters, but were accompanied by a significant increase in blood loss. These results suggest that the factor Xa inhibitor YM-60828 may be a potent and useful adjunctive agent with a lower risk of bleeding complications than argatroban and heparin in thrombolytic therapy.
Synthetic Studies of Biologically Active Marine Cyclopeptides (1995)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthetic Studies of Biologically Active Marine CyclopeptidesPeter WipfCite this: Chem. Rev. 1995, 95, 6, 2115–2134Publication Date (Print):September 1, 1995Publication History Published online1 May 2002Published inissue 1 September 1995https://pubs.acs.org/doi/10.1021/cr00038a013https://doi.org/10.1021/cr00038a013research-articleACS PublicationsRequest reuse permissionsArticle Views2723Altmetric-Citations527LEARN 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
Diels–Alder Click-Cross-Linked Hydrogels with Increased Reactivity Enable 3D Cell Encapsulation (2018)

Engineered hydrogels have been extensively used to direct cell function in 3D cell culture models, which are more representative of the native cellular microenvironment than conventional 2D cell culture. Previously, hyaluronan-furan and bis-maleimide polyethylene glycol hydrogels were synthesized via Diels-Alder chemistry at acidic pH, which did not allow encapsulation of viable cells. In order to enable gelation at physiological pH, the reaction kinetics were accelerated by replacing the hyaluronan-furan with the more electron-rich hyaluronan-methylfuran. These new click-cross-linked hydrogels gel faster and at physiological pH, enabling encapsulation of viable cells, as demonstrated with 3D culture of 5 different cancer cell lines. The methylfuran accelerates Diels-Alder cycloaddition yet also increases the retro Diels-Alder reaction. Using computational analysis, we gain insight into the mechanism of the increased Diels-Alder reactivity and uncover that transition state geometry and an unexpected hydrogen-bonding interaction are important contributors to the observed rate enhancement. This cross-linking strategy serves as a platform for bioconjugation and hydrogel synthesis for use in 3D cell culture and tissue engineering.
Role of striatal l‐DOPA in the production of dyskinesia in 6‐hydroxydopamine lesioned rats (2006)

We explored possible differences in the peripheral and central pharmacokinetics of L-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with L-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatal L-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of L-DOPA, plasma L-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels of L-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal L-DOPA levels. Intrastriatal infusion of L-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response to L-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation of L-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of L-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.
Differential expression of the 67 kDa laminin receptor in cancer. (1993)

During tumor invasion and metastasis, cancer cells interact with host tissues. Penetration of the extracellular matrix by cancer cells is mediated in part by interaction of cell surface receptors with laminin, the major glycoprotein component of the basement membrane. A variety of cell surface laminin binding proteins have been identified, including members of both the integrin and non-integrin families. The 67 kDa laminin receptor is a non-integrin protein with a high affinity for laminin. Immunohistochemical, immunoblot, RNA blot and in situ hybridization studies have demonstrated that levels of 67 kDa laminin receptor protein and/or mRNA are increased in a variety of human adenocarcinomas. In contrast, cancers of squamous cell origin may not demonstrate the same pattern of laminin receptor expression.
Identification of mRNAs Regulated by Interferon-γ in Cultured Rat Astrocytes by PCR Differential Display (1995)

We have used RNA differential display to identify specific mRNA species that are regulated by interferon-gamma (IFN gamma) treatment of enriched astrocyte cultures. Following a 24-hour treatment with IFN, mRNA was subjected to differential display using 15 different random primers. 105 upregulated and 5 downregulated cDNAs were selected for further sequencing and identification. Northern blot analysis confirmed the upregulation of 13 genes identical or highly similar to: intercrine adrenomedullin, H-rev 107, CAP-like protein, ATP synthase epsilon-subunit, complement C3, S-100 beta, Ca2+ ATPase, mg11, IFN-upregulated 56-kD protein mRNA, laminin receptor-like protein, protein tyrosine phosphatase, and zic. These data suggest that exposure to IFN gamma results in a complex change in the pattern of astrocyte gene expression.
A Frequency Domain Approach To Intra Mode Selection In H.264/Avc (2005)

Publication in the conference proceedings of EUSIPCO, Antalya, Turkey, 2005
Resistance to HER2-directed antibodies and tyrosine kinase inhibitors (2011)

The antibody trastuzumab and the tyrosine kinase inhibitor lapatinib are approved by the FDA for the treatment of HER2-overexpressing breast cancer. These anti-HER2 drugs are changing the natural history of HER2-overexpressing breast cancer. However, therapeutic resistance to trastuzumab or lapatinib, as either single-agents or in combination with chemotherapy in the metastatic setting, typically occurs within months of starting therapy. Several mechanisms of trastuzumab-resistance have been reported that include signaling from other HER receptors, signaling from receptor tyrosine kinases (RTKs) outside of the HER (ErbB) family, increased phosphatidylinositol 3-kinase signaling, and the presence of truncated forms of HER2. Mechanisms of resistance to lapatinib also point to increased phosphatidylinositol 3-kinase signaling as well as derepression/activation of compensatory survival pathways. In this review, we discuss how these models and mechanisms enhance our understanding of the clinical resistance to HER2-directed therapies.
Theoretical and experimental analysis on InAlGaAs/AlGaAs active region of 850-nm vertical-cavity surface-emitting lasers (2006)

In this study, the gain-carrier characteristics of In/sub 0.02/Ga/sub 0.98/As and InAlGaAs quantum wells (QWs) of variant In and Al compositions with an emission wavelength of 838 nm are theoretically investigated. More compressive strain, caused by higher In and Al compositions in InAlGaAs QW, is found to provide higher material gain, lower transparency carrier concentration, and transparency radiative current density over the temperature range of 25-95/spl deg/C. To improve the output characteristics and high-temperature performance of 850-nm vertical-cavity surface-emitting laser (VCSEL), In/sub 0.15/Al/sub 0.08/Ga/sub 0.77/As/Al/sub 0.3/Ga/sub 0.7/As is utilized as the active region, and a high-bandgap 10-nm-thick Al/sub 0.75/Ga/sub 0.25/As electronic blocking layer is employed for the first time. The threshold current and slope efficiency of the VCSEL with Al/sub 0.75/Ga/sub 0.25/As at 25/spl deg/C are 1.33 mA and 0.53 W/A, respectively. When this VCSEL is operated at an elevated temperature of 95/spl deg/C, the increase in threshold current is less than 21% and the decrease in slope efficiency is approximately 24.5%. A modulation bandwidth of 9.2 GHz biased at 4 mA is demonstrated.
Zero forcing and minimum mean-square-error equalization for multiuser detection in code-division multiple-access channels (1996)

In code-division multiple-access (CDMA) systems transmitting over time-varying multipath channels, both intersymbol interference (ISI) and multiple-access interference (MAI) arise. The conventional suboptimum receiver consisting of a bank of matched filters is often inefficient because interference is treated as noise. The optimum multiuser detector is too complex to be implemented at present. Four suboptimum detection techniques based on zero forcing (ZF) and minimum mean-square-error (MMSE) equalization with and without decision feedback (DF) are presented and compared. They combat both ISI and MAI. The computational complexity of all four equalizers is essentially the same. All four equalizers are independent of the size of the data symbol alphabet. It is shown that the performance of the MMSE equalizers is better than that of the corresponding ZF equalizers. Furthermore, the performance of the equalizers with DF is better than that of the corresponding equalizers without DF. The impairing effect of error propagation on the equalizers with DF is reduced by channel sorting.
The REC2 Gene Encodes the Homologous Pairing Protein of Ustilago maydis (1994)

Amino acid sequence analysis has established that the homologous pairing protein of Ustilago maydis, known previously in the literature as rec1, is encoded by REC2, a gene essential for recombinational repair and meiosis with regional homology to Escherichia coli RecA. The 70-kDa rec1 protein is most likely a proteolytic degradation product of REC2, which has a predicted mass of 84 kDa but which runs anomalously during sodium dodecyl sulfate-gel electrophoresis with an apparent mass of 110 kDa. To facilitate purification of the protein product, the REC2 gene was overexpressed from a vector that fused a hexahistidine leader sequence onto the amino terminus, enabling isolation of the REC2 protein on an immobilized metal affinity column. The purified protein exhibits ATP-dependent DNA renaturation and DNA-dependent ATPase activities, which were reactions characteristic of the protein as purified from cell extracts of U. maydis. Homologous pairing activity was established in an assay that measures recognition via non-Watson-Crick bonds between identical DNA strands. A size threshold of about 50 bp was found to govern pairing between linear duplex molecules and homologous single-stranded circles. Joint molecule formation with duplex DNA well under the size threshold was efficiently catalyzed when one strand of the duplex was composed of RNA. Linear duplex molecules with hairpin caps also formed joint molecules when as few as three RNA residues were present.
Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis (2008)

Elevated BALF endostatin levels correlated with a number of elevated cytokines, MMP3 and lung function in IPF. Endostatin is a novel inhibitor of DLEC wound repair, inducing apoptosis and reducing cell viability in a FasL and caspase dependent manner. Endostatin may play a role in aberrant epithelial repair in IPF.
Extending the Mannose 6-Phosphate Glycoproteome by High Resolution/Accuracy Mass Spectrometry Analysis of Control and Acid Phosphatase 5-Deficient Mice (2013)

In mammals, most newly synthesized lumenal lysosomal proteins are delivered to the lysosome by the mannose 6-phosphate (Man6P) targeting pathway. Man6P -containing proteins can be affinity-purified and characterized using proteomic approaches, and such studies have led to the discovery of new lysosomal proteins and associated human disease genes. One limitation to this approach is that in most cell types the Man6P modification is rapidly removed by acid phosphatase 5 (ACP5) after proteins are targeted to the lysosome, and thus, some lysosomal proteins may escape detection. In this study, we have extended the analysis of the lysosomal proteome using high resolution/accuracy mass spectrometry to identify and quantify proteins in a combined analysis of control and ACP5-deficient mice. To identify Man6P glycoproteins with limited tissue distribution, we analyzed multiple tissues and used statistical approaches to identify proteins that are purified with high specificity. In addition to 68 known Man6P glycoproteins, 165 other murine proteins were identified that may contain Man6P and may thus represent novel lysosomal residents. For four of these lysosomal candidates, (lactoperoxidase, phospholipase D family member 3, ribonuclease 6, and serum amyloid P component), we demonstrate lysosomal residence based on the colocalization of fluorescent fusion proteins with a lysosomal marker.
Expression of lipoprotein-associated phospholipase A2 in carotid artery plaques predicts long-term cardiac outcome (2009)

Lipoprotein-associated phospholipase A(2) expression in carotid artery plaques is a predictor of long-term cardiac outcome. The current study supports the concept of atherosclerosis as a systemic disease with multi-focal complications and personalized medicine.
[Percutaneous penetration ability of dexamethasone-amlodipine besylate compound gel and its effect on survival of ischemic random skin flap]. (2010)

In 0.3%DXM/0.5%AB compound gel, DXM and AB might penetrate into skin tissue, which could significantly increase the survival area of ischemic skin flap.
Development of Farnesyl Transferase Inhibitors: A Review (2005)

Farnesyl transferase inhibitors are a new class of biologically active anticancer drugs. The exact mechanism of action of this class of agents is, however, currently unknown. The drugs inhibit farnesylation of a wide range of target proteins, including Ras. It is thought that these agents block Ras activation through inhibition of the enzyme farnesyl transferase, ultimately resulting in cell growth arrest. In preclinical models, the farnesyl transferase inhibitors showed great potency against tumor cells; yet in clinical studies, their activity was far less than anticipated. Reasons for this disappointing clinical outcome might be found in the drug-development process. In this paper, we outline an algorithm that is potentially useful for the development of biologically active anticancer drugs. The development of farnesyl transferase inhibitors, from discovery to clinical trials, is reviewed on the basis of this algorithm. We found that two important steps of this algorithm were underestimated. First, understanding of the molecular biology of the defective pathway has mainly been focused on H-Ras activation, whereas activation of K-Ras or other farnesylated proteins is probably more important in tumorigenesis. Inhibition of farnesylation is possibly not sufficient, because geranylgeranylation might activate K-Ras and suppress the effect of farnesyl transferase inhibitors. Furthermore, a well-defined proof of concept in preclinical and clinical studies has not been achieved. Integrating the proposed algorithm in future studies of newly developed biologically active anti-cancer drugs might increase the rate of success of these compounds in patients.
A Management System for Network-Shareable Locally Installed Software: Merging RPM and the Depot Scheme Under Solaris (2001)

Efficient management of locally installed software is a recurring central theme of system administration. We report here on an experimental merger of two previously independent systems: Redhat's RPM Package Manager ( RPM ), an open-source database-driven system developed by a major Linux vendor to manage software on a single host; and, an enhanced version of depot , a well-established set of conventions used to manage software that is installed on a server and shared over a network with multiple (possibly heterogeneous) clients. The combination remedies shortcomings in both systems, but to be fully effective, extensions to RPM are required, particularly to its database system. The results of this study point the way toward a second-generation network-distributed version of RPM .
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies (2009)

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical negative regulator of immune responses. Uniquely among known inhibitory receptors, its genetic ablation results in a fulminating and fatal lymphoproliferative disorder. This central regulatory role led to the development of antibodies designed to block CTLA-4 activity in vivo, aiming to enhance immune responses against cancer. Despite their preclinical efficacy and promising clinical activity against late stage metastatic melanoma, the critical cellular targets for their activity remains unclear. In particular, debate has focused on whether the effector T cell (T(eff)) or regulatory T cell (T reg cell) compartment is the primary target of antibody-mediated blockade. We developed a mouse expressing human instead of mouse CTLA-4, allowing us to evaluate the independent contributions of CTLA-4 blockade of each T cell compartment during cancer immunotherapy in an in vivo model of mouse melanoma. The data show that although blockade on effector cells significantly improves tumor protection, unicompartmental blockade on regulatory cells completely fails to enhance antitumor responses. However, concomitant blockade of both compartments leads to a synergistic effect and maximal antitumor activity. We conclude that the combination of direct enhancement of T(eff) cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti-CTLA-4 antibodies during cancer immunotherapy.