gebhart/patrepeval huggingface dataset:
Pre-Clinical Considerations in the Assessment of Immunogenicity for Protein Therapeutics (2010)

Protein therapeutics offer distinct advantages over other classes of drugs largely due to the high level of target specificity and generally low toxicity. Problems have, however, been encountered with some protein therapeutics inducing undesirable immune responses in patients. This immunogenicity can produce pleiotropic effects including the development of a high affinity B cell-mediated humoral response that is often directed against the therapeutic. Opinions are divided as to the principal causes of clinical immunogenicity and, as a result, this area has been the subject of much research. One thing that has emerged as a result of this intense activity is the development of pre-clinical models that can provide a level of prediction of the immunogenic potential of novel protein therapeutics before administration in man.
erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships (1995)

Overexpression of the erbB-2 oncogene has been linked to poor prognosis in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2. Functional group modification in the ansa ring was performed stereoselectively and regiospecifically without the need for protection strategies. Essential functional groups that were required for anti-erbB-2 activity were the 7-carbamate and the 2,3-double bond. Modification of the functional groups at the other positions was permitted. Structure-activity relationships are described for 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.
A multifaceted approach to understanding the botnet phenomenon (2006)

The academic community has long acknowledged the existence of malicious botnets, however to date, very little is known about the behavior of these distributed computing platforms. To the best of our knowledge, botnet behavior has never been methodically studied, botnet prevalence on the Internet is mostly a mystery, and the botnet life cycle has yet to be modeled. Uncertainty abounds. In this paper, we attempt to clear the fog surrounding botnets by constructing a multifaceted and distributed measurement infrastructure. Throughout a period of more than three months, we used this infrastructure to track 192 unique IRC botnets of size ranging from a few hundred to several thousand infected end-hosts. Our results show that botnets represent a major contributor to unwanted Internet traffic - 27% of all malicious connection attempts observed from our distributed darknet can be directly attributed to botnet-related spreading activity. Furthermore, we discovered evidence of botnet infections in 11% of the 800,000 DNS domains we examined, indicating a high diversity among botnet victims. Taken as a whole, these results not only highlight the prominence of botnets, but also provide deep insights that may facilitate further research to curtail this phenomenon.
16S rRNA Gene Sequencing in Routine Identification of Anaerobic Bacteria Isolated from Blood Cultures (2010)

A comparison between conventional identification and 16S rRNA gene sequencing of anaerobic bacteria isolated from blood cultures in a routine setting was performed (n = 127). With sequencing, 89% were identified to the species level, versus 52% with conventional identification. The times for identification were 1.5 days and 2.8 days, respectively.
Stable integration of an mdx skeletal muscle cell line into dystrophic (mdx) skeletal muscle: evidence for stem cell status. (1997)

We have previously described a method for the derivation of long term cultures of undifferentiated myoblasts from the skeletal muscle of dystrophic (mdx) mice (J. Smith and P. N. Schofield, Exp. Cell Res., 210: 86-93, 1994). We now show that a clonal mdx-derived skeletal muscle cell line labeled with a retrovirus conferring beta-galactosidase activity and G418 resistance (PD50A) is capable of incorporation into mdx skeletal muscle myofibers for up to 14 months with no incidence of tumor formation. After a lag period of 5 days, injected PD50A cells disperse throughout the injected tibialis anterior muscle and take up satellite cell positions on the perimeter of myofiber bundles. PD50A cells begin to incorporate into fused muscle syncitium as early as 8 weeks after injection and persist for at least 14 months. We have rederived myoblasts expressing beta-galactosidase from PD50A-injected muscles 12 months after injection, demonstrating that a reserve of mononuclear proliferation-competent PD50A cells are present in host muscle up to a year after their original introduction. These data support the contention that myoblasts derived by this culture method are functionally representative of a class of skeletal muscle "stem cells" and thus have potential both as agents for cellular therapy of intransigent diseases such as Duchenne muscular dystrophy as well as being a useful tool for the further investigation of normal muscle development.
Discovering Disease-specific Biomarker Genes for Cancer Diagnosis and Prognosis (2010)

The large amounts of microarray data provide us a great opportunity to identify gene expression profiles (GEPs) in different tissues or disease states. Disease-specific biomarker genes likely share GEPs that are distinct in disease samples as compared with normal samples. The similarity of the GEPs may be evaluated by Pearson Correlation Coefficient (PCC) and the distinctness of GEPs may be assessed by Kolmogorov-Smirnov distance (KSD). In this study, we used the PCC and KSD metrics for GEPs to identify disease-specific (cancer-specific) biomarkers. We first analyzed and compared GEPs using microarray datasets for smoking and lung cancer. We found that the number of genes with highly different GEPs between comparing groups in smoking dataset was much larger than that in lung cancer dataset; this observation was further verified when we compared GEPs in smoking dataset with prostate cancer datasets. Moreover, our Gene Ontology analysis revealed that the top ranked biomarker candidate genes for prostate cancer were highly enriched in molecular function categories such as 'cytoskeletal protein binding' and biological process categories such as 'muscle contraction'. Finally, we used two genes, ACTC1 (encoding an actin subunit) and HPN (encoding hepsin), to demonstrate the feasibility of diagnosing and monitoring prostate cancer using the expression intensity histograms of marker genes. In summary, our results suggested that this approach might prove promising and powerful for diagnosing and monitoring the patients who come to the clinic for screening or evaluation of a disease state including cancer.
Active damping of LC-filters for high power drives using synchronous optimal pulsewidth modulation (2008)

To meet the increasing demand on very low switching frequencies of power semiconductors in order to reduce switching losses, synchronous optimal pulsewidth modulation (SO-PWM) techniques provide an appropriate solution. They result from offline calculations, assuming steady state operation of the drive system. These drives are often used with an LC output filter, which represents a resonant circuit. Therefore, only in steady state operations does the combination of an LC-filter with offline optimized pulse patterns deliver satisfactory behavior of the drive system. Changes in operating conditions cause weakly damped oscillations in the filter, followed by high overcurrents in the motor, which can be described as dynamic modulation errors. In this paper, a novel control method is proposed in order to keep the benefits of SO-PWM in dynamic operations when applied to drives with LC-filters. The method actively damps the LC-filter resonance and compensates the dynamic modulation errors without increasing the switching frequency. The effectiveness and dynamic capability of the introduced control technique are presented by simulation results of a 2.4 kV induction motor drive.
Synthesis of Potential Anticancer Agents. XXVI. The Alkylation of 6-Chloropurine2 (1961)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis of Potential Anticancer Agents. XXVI. The Alkylation of 6-Chloropurine2John A. Montgomery and Carroll Temple Jr.Cite this: J. Am. Chem. Soc. 1961, 83, 3, 630–635Publication Date (Print):February 1, 1961Publication History Published online1 May 2002Published inissue 1 February 1961https://doi.org/10.1021/ja01464a031RIGHTS & PERMISSIONSArticle Views374Altmetric-Citations113LEARN 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 InReddit PDF (738 KB) Get e-Alertsclose Get e-Alerts
Functions of heparan sulfate proteoglycans in cell signaling during development (2004)

Heparan sulfate proteoglycans (HSPGs) are cell-surface and extracellular matrix macromolecules that are composed of a core protein decorated with covalently linked glycosaminoglycan (GAG) chains. In vitro studies have demonstrated the roles of these molecules in many cellular functions, and recent in vivo studies have begun to clarify their essential functions in development. In particular, HSPGs play crucial roles in regulating key developmental signaling pathways, such as the Wnt, Hedgehog, transforming growth factor-beta, and fibroblast growth factor pathways. This review highlights recent findings regarding the functions of HSPGs in these signaling pathways during development.
A unified model for techniques on video-shot transition detection (2005)

A first step required to allow video indexing and retrieval of visual data is to perform a temporal segmentation, that is, to find the location of camera-shot transitions, which can be either abrupt (i.e., cuts) or gradual (e.g., fades, dissolves, wipes). After a critical review of most approaches seeking to solve this problem, we propose a unified detection model (both for abrupt and all types of gradual transitions), as well as an implementation whose results improve upon those of all the inspected reports. The innovation of the approach presented here is centered on mapping the space of inter-frame distances onto a new space of decision better suited to achieving a sequence-independent thresholding. This mapping aims to consider frame ordering information within the thresholding process; it is based on the parametric modeling of the patterns that transitions generate on the distances' output. As opposed to most reviewed works, our results are detailed over a large and representative sample of more than 1500 cuts and 250 gradual transitions, which make up a significant part (200 min) of the MPEG-7 testing material; this ensures a high degree of confidence in the validity of our approach.
IκB Kinases α and β Show a Random Sequential Kinetic Mechanism and Are Inhibited by Staurosporine and Quercetin (1999)

Activation of transcription factor NF-kappaB is regulated by phosphorylation and subsequent degradation of its inhibitory subunit IkappaB. The signal-induced phosphorylation of IkappaB involves two IkappaB kinases, IKKalpha and IKKbeta. In the present study, we investigated the kinetic mechanisms of IKKalpha and IKKbeta by substrate and product inhibition. For both IKKalpha and IKKbeta, the product ADP was a competitive inhibitor versus ATP and a non-competitive inhibitor versus IkappaBalpha. An alternative peptide substrate, IkappaBalpha-(21-41), was a competitive inhibitor versus IkappaBalpha and a non-competitive inhibitor versus ATP for both kinases. These results rigorously eliminate the possibility of an ordered sequential mechanism and demonstrate that both kinases have a random sequential bi bi mechanism. Two natural compounds, quercetin and staurosporine, had previously been shown to inhibit the NF-kappaB pathway, but the molecular target(s) of these compounds in the event had not been established. Here we demonstrate that quercetin and staurosporine potently inhibit both IKKalpha and IKKbeta. Daidzein, a quercetin analogue that does not inhibit NF-kappaB activation, showed no significant inhibition of either enzyme. This suggests that the inhibitory properties of quercetin and staurosporine in the NF-kappaB pathway are mediated in part by their inhibition of IKKalpha and IKKbeta. Mechanism studies reveal that staurosporine is a competitive inhibitor versus ATP, whereas quercetin serves as a mixed type inhibitor versus ATP. The strong inhibition of IKKbeta by staurosporine (K(i) = 172 nM) and ADP (K(i) = 136 nM) provides a rationale and structural framework for designing potent ATP-site inhibitors of IKKbeta, which is an attractive drug target for inflammatory diseases.
In vitro selection of RNAs that undergo autolytic cleavage with lead(2+) (1992)

An in vitro selection method has been developed to obtain RNA molecules that specifically undergo autolytic cleavage reactions by Pb2+ ion. The method utilizes a circular RNA intermediate which is regenerated following the cleavage reaction to allow amplification and multiple cycles of selection. Pb2+ is known to catalyze a specific cleavage reaction between U17 and G18 of yeast tRNA(Phe). Starting from pools of RNA molecules which have a random distribution of sequences at nine or ten selected positions in the sequence of yeast tRNA(Phe), we have isolated many RNA molecules that undergo rapid and specific self-cleavage with Pb2+ at a variety of different sites. Terminal truncation experiments suggest that most of these self-cleaving RNA molecules do not fold like tRNA. However, two of the variants are cleaved rapidly with Pb2+ at U17 even though they lack the highly conserved nucleotides G18 and G19. Both specific mutations and terminal truncation experiments suggest that the D and T loops of these two variants interact in a manner similar to that of tRNA(Phe) despite the absence of the G18U55 and G19C56 tertiary interactions. A model for an alternate tertiary interaction involving a U17U55 pair is presented. This model may be relevant to the structure of about 100 mitochondrial tRNAs that also lack G18 and G19. The selection method presented here can be directly applied to isolate catalytic RNAs that undergo cleavage in the presence of other metal ions, modified nucleotides, or sequence-specific nucleases.
Synthesis and Structure−Activity Relationships of Dimeric Peptide Antagonists of the Human Immunoglobulin G−Human Neonatal Fc Receptor (IgG−FcRn) Interaction (2010)

The neonatal Fc receptor, FcRn, regulates the half-life of IgG in vivo and may be a target in the treatment of autoimmune disease. Monomeric peptide antagonists of the human IgG-human FcRn interaction were dimerized using three different synthetic methodologies: thiol/alkyl halide coupling of unprotected peptides, reductive alkylation of unprotected peptides, and on-resin amide bond formation with protected peptides. It was found that dimerization of monomeric peptides increased the in vitro activity of the peptide monomers more than 200-fold. Human IgG catabolism experiments in human FcRn transgenic mice were used to assess the in vivo activity of peptide dimers that possessed different linkers, cyclizations, and affinities for FcRn. Overall, it was found that the linker joining two monomeric peptides had only a minor effect on the in vitro potency but that in vitro potency was predictive of in vivo activity.
Plasma gelsolin is a marker and therapeutic agent in animal sepsis* (2007)

We propose that circulation of particulate actin is a marker for sepsis-induced cell injury, that plasma gelsolin has a crucial protective role in sepsis, and that gelsolin replacement represents a potential therapy for this common lethal condition.
Notch Activation Induces Endothelial Cell Cycle Arrest and Participates in Contact Inhibition: Role of p21 Cip1 Repression (2004)

Although previous studies demonstrate that appropriate Notch signaling is required during angiogenesis and in vascular homeostasis, the mechanisms by which Notch regulates vascular function remain to be elucidated. Here, we show that activation of the Notch pathway by the ligand Jagged1 reduces the proliferation of endothelial cells. Notch activation inhibits proliferation of endothelial cells in a cell-autonomous manner by inhibiting phosphorylation of the retinoblastoma protein (Rb). During cell cycle entry, p21Cip1 is upregulated in endothelial cells. Activated Notch inhibits mitogen-induced upregulation of p21Cip1 and delays cyclin D-cdk4-mediated Rb phosphorylation. Notch-dependent repression of p21Cip1 prevents nuclear localization of cyclin D and cdk4. The necessity of p21Cip1 for nuclear translocation of cyclin D-cdk4 and S-phase entry in endothelial cells was demonstrated by targeted downregulation of p21Cip1 by using RNA interference. We further demonstrate that when endothelial cells reach confluence, Notch is activated and p21Cip1 is downregulated. Inhibition of the Notch pathway at confluence prevents p21Cip1 downregulation and induces Rb phosphorylation. We suggest that Notch activation contributes to contact inhibition of endothelial cells, in part through repression of p21Cip1 expression.
The Future Prospects of Microbial Cellulose in Biomedical Applications (2006)

Microbial cellulose has proven to be a remarkably versatile biomaterial and can be used in wide variety of applied scientific endeavors, such as paper products, electronics, acoustics, and biomedical devices. In fact, biomedical devices recently have gained a significant amount of attention because of an increased interest in tissue-engineered products for both wound care and the regeneration of damaged or diseased organs. Due to its unique nanostructure and properties, microbial cellulose is a natural candidate for numerous medical and tissue-engineered applications. For example, a microbial cellulose membrane has been successfully used as a wound-healing device for severely damaged skin and as a small-diameter blood vessel replacement. The nonwoven ribbons of microbial cellulose microfibrils closely resemble the structure of native extracellular matrices, suggesting that it could function as a scaffold for the production of many tissue-engineered constructs. In addition, microbial cellulose membranes, having a unique nanostructure, could have many other uses in wound healing and regenerative medicine, such as guided tissue regeneration (GTR), periodontal treatments, or as a replacement for dura mater (a membrane that surrounds brain tissue). In effect, microbial cellulose could function as a scaffold material for the regeneration of a wide variety of tissues, showing that it could eventually become an excellent platform technology for medicine. If microbial cellulose can be successfully mass produced, it will eventually become a vital biomaterial and will be used in the creation of a wide variety of medical devices and consumer products.
Autonomic resource provisioning in cloud systems with availability goals (2013)

The elasticity afforded by cloud computing allows consumers to dynamically request and relinquish computing and storage resources and pay for them on a pay-per-use basis. Cloud computing providers rely on virtualization techniques to manage the dynamic nature of their infrastructure allowing consumers to dynamically allocate and deallocate virtual machines of different capacities. Cloud providers need to optimally decide the best allocation of virtual machines to physical machines as the demand varies dynamically. When making such decisions, cloud providers can migrate VMs already allocated and/or use external cloud providers. This paper considers the problem in which the cloud provider wants to maximize its revenue, subject to capacity, availability SLA, and VM migration constraints. The paper presents a heuristic solution, called Near Optimal (NOPT), to this NP-hard problem and discusses the results of its experimental evaluation in comparison with a best fit (BF) allocation strategy. The results show that NOPT provides a 45% improvement in average revenue when compared with BF for the parameters used in the experiment. Moreover, the NOPT algorithm maintained the availability close to one for all classes of users while BF exhibited a lower availability and even failed to meet the availability SLA at times.
Transport properties of epitaxial YBa2Cu3Ox films at step edges (1991)

To study the current-carrying capability of interconnections between conducting planes in a YBa2Cu3Ox-insulator multilayer system, the transport properties of laser-deposited YBa2Cu3Ox striplines at different step edges in 〈100〉 SrTiO3 substrates were investigated. Step edges with various heights between 100 and 800 nm and slope angles a=2.5°, 10°, 25°, 40°, and 65° were fabricated by Ar+ ion milling. The previous ion milling of one part of the substrate does not affect the crystal growth and the transport properties of the superconductor, which has been checked by electrical and x-ray measurements. Two ways for a high transport current between conducting planes were realized. At flat angles up to 30°, a critical current density of ≳106 A/cm2 at 77 K can be achieved for a step stripline with film thickness d0 smaller than the step height h. If the film thickness d0 is larger than the step height, high superconducting current densities can also be achieved for a≳65°.
An Aptamer–Doxorubicin Physical Conjugate as a Novel Targeted Drug‐Delivery Platform (2006)

Trojan aptamer: A novel strategy for targeted drug delivery to cancer cells was developed through the formation of a physical conjugate (see scheme) between doxorubicin (Dox) and the A10 RNA aptamer that binds to the prostate-specific membrane antigen (PSMA). The aptamer–Dox conjugate could efficiently bind to PSMA-expressing cells, thereby resulting in its uptake and the intracellular release of Dox.