gebhart/patrepeval huggingface dataset:
Expression cloning of a novel zinc finger protein that binds to the c-fos serum response element. (1992)

Induction of c-fos transcription by serum growth factors requires the serum response element (SRE). The SRE is a multifunctional element which responds to several positively and negatively acting signals. To identify cellular proteins that might mediate functions of the SRE, we screened a human cDNA expression library with an SRE probe. We report the isolation and characterization of SRE-ZBP, a previously unidentified SRE-binding protein. SRE-ZBP is a member of the C2H2 zinc finger family of proteins exemplified by TFIIIA and the Drosophila Krüppel protein. The seven tandemly repeated zinc finger motifs in SRE-ZBP are sufficient for high-affinity binding to the SRE. We show that SRE-ZBP is a nuclear protein and identify a candidate cellular protein encoded by the SRE-ZBP gene. Because we cannot detect any DNA-binding activity attributable to the endogenous protein, we propose that SRE-ZBP activity may be subject to posttranslational regulation. Like c-fos mRNA, SRE-ZBP mRNA is serum inducible in HeLa cells, but with slower kinetics. The role of SRE-ZBP in the regulation of c-fos transcription remains unestablished, but this protein binds to a region of the SRE where mutations lead to derepression.
Synthesis of propenamides with anti-malarial activities and 3D-QSAR study. (2003)

The activity of anti-W2 depends mostly on steric interaction and the activity of anti-D6 depends on both steric and electrostatic interaction.
Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells (1995)

Integration of human papillomavirus type 16 (HPV-16) DNA into a host chromosome has been hypothesized to result in altered expression of two viral transforming genes, E6 and E7, in cervical cancers. In order to investigate the role that changes in viral genomic state and gene expression play in cervical carcinogenesis, we have derived clonal populations of human cervical epithelial cells which harbor multiple copies of either extrachromosomal or integrated viral DNA. The clonal populations harboring extrachromosomal HPV-16 DNA stably maintained approximately 1,000 viral copies for at least 15 passages (approximately 100 cell doublings), which contrasted with the unstable HPV-16 replicons in the parental counterpart. In the clonal populations harboring integrated viral DNA, 3 to 60 copies of HPV-16 DNA were found integrated in either of two forms: type 1, in which all the copies of HPV-16 DNA were disrupted in the E2 open reading frame upon integration, and type 2, in which intact viral copies were flanked by disrupted viral copies and cellular sequences. Despite the lower HPV-16 DNA copy number, the clonal populations with integrated viral DNA had levels of E7 protein that were in most cases higher than those found in the clonal populations harboring extrachromosomal viral DNA. Irrespective of viral genomic state, the clonal populations were capable of undergoing terminal differentiation and unable to form colonies in soft agar, which is indicative of the nontumorigenic nature of these cells. Importantly, a cell population with integrated viral DNA was found to outgrow another with extrachromosomal DNA when these cells were cocultured over a period of time. Thus, integration of human papillomaviral DNA correlates with increased viral gene expression and cellular growth advantage. These observations are consistent with the hypothesis that integration provides a selective advantage to cervical epithelial precursors of cervical carcinoma.
A Quantum Dot Conjugated Sugar Ball and Its Cellular Uptake. On the Size Effects of Endocytosis in the Subviral Region (2004)

The lipophilic CdSe quantum dot (QD) coated with trioctylphosphine oxide (TOPOQD) can be extracted from chloroform into water upon interaction with macrocyclic glycocluster amphiphile 1. The QD-conjugated and highly fluorescent sugar ball of a size of 15 nm (TOPOQD1) thus solubilized in water readily invades Hela cells via endocytosis. The endocytic activity of TOPOQD1 (15 nm), in light of those of the micellar homoaggregate of 1 (5 nm) and the virus-like 1-DNA conjugate (50 nm) as references, reveals a dramatic size effect (50 > 15 > 5) in the subviral size region. The optimal size at approximately 50 nm indicates that size complementarity which governs molecular recognition in small host-guest systems also plays key roles in the encapsulation of nanometric guest particles by the endocytic vesicles (</=100 nm) as a macrobiomolecular host. The work thus suggests an utmost importance of size control at the viral size when designing molecular (gene, drug, probe, etc.) delivery machines.
Multifunctional transcription factor YY1: a therapeutic target in human cancer? (2006)

The multifunctional transcription factor Yin Yang 1 (YY1) is a complex protein that has been shown to play pivotal roles in development, differentiation, cellular proliferation and apoptosis. It can act as a transcriptional repressor, an activator, or an initiator element binding protein that directs and initiates transcription of numerous cellular and viral genes. Because the expression and function of YY1 are known to be intimately associated with cell-cycle progression, the physiological significance of YY1 activity has recently been applied to models of cancer biology. Several lines of evidence imply that YY1 expression and/or activation is associated with tumourigenesis, in addition to its regulatory roles in normal biological processes. However, controversial results also raised and indicated that further studies are still needed to piece all of the seemingly contradictory data into a complete picture. On the basis of YY1 regulations and functions, novel drugs and specific treatment strategies may be developed with new therapeutic applications for tumour patients in the future.
Efficacy and safety of low‐dose otelixizumab anti‐CD3 monoclonal antibody in preserving C‐peptide secretion in adolescent type 1 diabetes: DEFEND‐2, a randomized, placebo‐controlled, double‐blind, multi‐centre study (2013)

Efficacy and tolerability of otelixizumab was similar to DEFEND-1. The 3.1-mg dose was non-efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required. Clinical Trials Registry No: NCT 00763451.
Interactions among three distinct CesA proteins essential for cellulose synthesis (2003)

In a screen to identify novel cellulose deficient mutants, three lines were shown to be allelic and define a novel complementation group, irregular xylem5 (irx5). IRX5 was cloned and encodes a member of the CesA family of cellulose synthase catalytic subunits (AtCesA4). irx5 plants have an identical phenotype to previously described mutations in two other members of this gene family (IRX1 and IRX3). IRX5, IRX3, and IRX1 are coexpressed in exactly the same cells, and all three proteins interact in detergent solubilized extracts, suggesting that three members of this gene family are required for cellulose synthesis in secondary cell walls. The association of IRX1 and IRX3 was reduced to undetectable levels in the absence of IRX5. Consequently, these data suggest that IRX5, IRX3, and IRX1 are all essential components of the cellulose synthesizing complex and the presence of all three subunits is required for the correct assembly of this complex.
Cytoskeletal organization defects and abortive activation in human oocytes after IVF and ICSI failure (2000)

In this study, we analysed the distribution of beta tubulins to detect spindle and cytoplasmic microtubules, alpha acetylated tubulins for sperm microtubules and chromatin configuration in oocytes showing fertilization failure after conventional IVF or intracytoplasmic sperm injection (ICSI). A total of 450 human oocytes that failed to fertilize were studied 20-40 h after IVF or ICSI. In all, 287 oocytes were stained for immunofluorescence and chromosomal spreads were performed by Tarkowski's air-drying method in 163 IVF or ICSI oocytes that did not develop pronuclei after the extrusion of a second polar body. Immunofluorescence analysis showed that the main reason of fertilization failure after IVF was no sperm penetration (55.5%). The remaining oocytes showed different abnormal patterns, e.g. oocyte activation failure (15.1%) and defects in pronuclei apposition (19.2%). On the other hand, fertilization failure after ICSI was mainly associated to incomplete oocyte activation (39.9%), and to a lesser extent with defects in pronuclei apposition (22.6%) and failure of sperm penetration (13.3%). A further 13.3% of the ICSI oocytes arrested their development at the metaphase of the first mitotic division. The chromosomal spreads allowed the analysis of abortive activations, in which no pronuclei formed but a second polar body was extruded. Immunofluorescence and cytogenetic analysis provided a useful tool to improve infertility diagnosis and prognosis in each particular case.
Characterization of the Vaccinia Virus A35R Protein and Its Role in Virulence (2005)

The vaccinia virus A35R gene is highly conserved among poxviruses and encodes a previously uncharacterized hydrophobic acidic protein. Western blotting with anti-A35R peptide antibodies indicated that the protein is expressed early in infection and resolved as a single sharp band of approximately 23 kDa, slightly higher than the 20 kDa predicted from its sequence. The protein band appeared to be the same molecular weight on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, whether expressed in an in vitro transcription/translation system without microsomes or expressed in infected cells, suggesting that it was not glycosylated. A mutant virus with the A35R gene deleted (vA35Delta) formed wild-type-sized plaques on all cell lines tested (human, monkey, mouse, and rabbit); thus, A35R is not required for replication and does not appear to be a host range gene. Although the A35R protein is hydrophobic, it is unlikely to be an integral membrane protein, as it partitioned to the aqueous phase during TX-114 partitioning. The protein could not be detected in virus-infected cell supernatants. A35R localized intracellularly to the virus factories, where the first stages of morphogenesis occur. The vA35Delta mutant formed near-normal levels of the various morphogenic stages of infectious virus particles and supported normal acid-induced fusion of virus-infected cells. Despite normal growth and morphogenesis in vitro, the vA35Delta mutant virus was attenuated in intranasal challenge of mice compared to wild-type and A35R rescue virus. Thus, the intracellular A35R protein plays a role in virulence. The A35R has little homology to any protein outside of poxviruses, suggesting a novel virulence mechanism.
Clinical Outcomes After Arthroscopic Psoas Lengthening: The Effect of Femoral Version (2012)

Patients with increased femoral anteversion may be at greater risk for inferior clinical outcomes after arthroscopic lengthening of a symptomatic, snapping psoas tendon. The psoas tendon may be an important passive and dynamic stabilizer of the hip in these patients, and release may result in a greater alteration of kinematics with high-demand activities, particularly terminal extension and external rotation when the tendon is typically at its highest tension. These results may help surgeons identify which patients may be at risk for inferior clinical outcome after psoas lengthening.
Longitudinal In Vivo Imaging to Assess Blood Flow and Oxygenation in Implantable Engineered Tissues (2012)

The functionality of vascular networks within implanted prevascularized tissues is difficult to assess using traditional analysis techniques, such as histology. This is largely due to the inability to visualize hemodynamics in vivo longitudinally. Therefore, we have developed dynamic imaging methods to measure blood flow and hemoglobin oxygen saturation in implanted prevascularized tissues noninvasively and longitudinally. Using laser speckle imaging, multispectral imaging, and intravital microscopy, we demonstrate that fibrin-based tissue implants anastomose with the host (severe combined immunodeficient mice) in as short as 20 h. Anastomosis results in initial perfusion with highly oxygenated blood, and an increase in average hemoglobin oxygenation of 53%. However, shear rates in the preformed vessels were low (20.8±12.8 s(-1)), and flow did not persist in the vast majority of preformed vessels due to thrombus formation. These findings suggest that designing an appropriate vascular network structure in prevascularized tissues to maintain shear rates above the threshold for thrombosis may be necessary to maintain flow following implantation. We conclude that wide-field and microscopic functional imaging can dynamically assess blood flow and oxygenation in vivo in prevascularized tissues, and can be used to rapidly evaluate and improve prevascularization strategies.
Abstract 2733: LJM716: an anti-HER3 antibody that inhibits both HER2 and NRG driven tumor growth by trapping HER3 in the inactive conformation. (2012)

Abstract HER3 (ErbB3) is a member of the ErbB family of receptor tyrosine kinases (RTK). Inappropriate HER2/ HER3 dimerization as a result of HER2 or neuregulin (NRG) over-expression in cancer results in HER3 mediated activation of PI3K signaling. Consequently, HER3 is a mediator of oncogenic transformation. Although, ligand blocking HER3 antibodies inhibit growth of neuregulin driven xenograft models they are ineffective in models of HER2 amplified cancer as HER2 mediated activation of HER3 occurs in a ligand- independent manner. LJM716 is a high affinity HER3- targeted antibody selected from a Human Combinatorial Antibody Library (HuCAL) specifically for its ability to neutralize multiple modes of HER3 activation. LJM716 is a potent inhibitor of HER3/ AKT phosphorylation and proliferation in a range of HER2 amplified and NRG expressing cell lines in vitro. LJM716 induced tumor regression in Fadu (NRG expressing, HNSCC) tumor xenografts and significant tumor growth inhibition (&amp;gt;80%) in a variety of xenograft models including BT474 (HER2 amplified breast). Furthermore, the combination of LJM716 with trastuzumab, cetuximab or PI3K- targeted agents was synergistic in a panel of in vitro cell lines while the in vivo combination of LJM716 with trastuzumab or erlotinib was efficacious in BT474 and L3.3 (pancreatic) tumor xenografts respectively. To further understand the mechanism by which LJM716 inhibits multiple modes of HER3 activation we solved the crystal structure of LJM716 bound to the HER3 extra-cellular domain. This data revealed that LJM716 binds to a novel conformational epitope contained within domains 2 and 4 and appears to trap HER3 in the inactive conformation. Interestingly, LJM716 does not block NRG binding to HER3 nor does it affect the binding affinity of the HER3/ NRG interaction. LJM716 therefore possesses a novel mechanism of action; it prevents the structural rearrangements required for HER3 activation induced by either HER2 or NRG. Thus LJM716 is the first HER3 antibody to display efficacy in both HER2 and ligand driven xenograft models. Based on preclinical data, combining LJM716 with either trastuzumab, cetuximab or PI3K- targeted agents may lead to greater and more sustained clinical efficacy in ErbB driven cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2733. doi:1538-7445.AM2012-2733
Risk of Incident Age-related Eye Diseases in People with an Affected Sibling : The Beaver Dam Eye Study (2001)

The purpose of this investigation was to determine whether age-related cataract and maculopathy in older siblings predicts development of the same in younger siblings. A population-based study of age-related eye diseases was conducted in 1988--1990 in Beaver Dam, Wisconsin, and a follow-up examination was performed 5 years later. Diagnoses of age-related eye diseases were assigned on the basis of gradings of study photographs. There were 1,088 people from 488 sibships with at least two siblings who could contribute information for these analyses. The authors computed odds ratios and 95% confidence intervals for developing the specific lesion and identifying it 5 years later if an older sibling had it at baseline. The odds ratios were 1.65 (95% confidence interval (CI): 0.91, 2.99) for nuclear cataract, 1.62 (95% CI: 0.92, 2.85) for cortical cataract, 1.95 (95% CI: 0.48, 7.95) for posterior subcapsular cataract, 1.82 (95% CI: 0.91, 3.66) for soft drusen, 8.18 (95% CI: 3.34, 20.08) for retinal pigment epithelium depigmentation, 3.59 (95% CI: 1.71, 7.57) for increased retinal pigment, and 10.32 (95% CI: 0.83, 128.58) for exudative age-related maculopathy. These findings suggest that strong family determinants of lesions of age-related maculopathy are likely, less so for age-related cataract, which confer risk of the same lesion in a younger sibling.
Cell-permeable small molecule probes for site-specific labeling of proteinsElectronic supplementary information (ESI) available: experimental details and characterization of compounds. See http://www.rsc.org/suppdata/cc/b3/b309196a/ (2003)

We have successfully synthesized a number of small molecule probes designed for site-specific labeling of N-terminal cysteine-containing proteins expressed in live cells. Their utility for site-specific, covalent modifications of proteins was successfully demonstrated with purified proteins in vitro, and with live bacterial cells in vivo.
Blinded Test in Isolated Female Rabbit Heart Reliably Identifies Action Potential Duration Prolongation and Proarrhythmic Drugs: Importance of Triangulation, Reverse Use Dependence, and Instability (2003)

Drug-induced proarrhythmia is a rare but potentially lethal adverse drug reaction. To test whether the SCREENIT system (an automated computerized test apparatus), using an isolated perfused heart obtained from female rabbits, could correctly identify agents that lengthen the action potential duration (APD) and drugs known to induce proarrhythmia, 14 drugs (penicillin G, haloperidol, adriamycin, indapamide, verapamil, aspirin, lidocaine, clomipramine, propranolol, erythromycin, quinidine, terfenadine, amiodarone, and thioridazine) were coded and submitted for a blinded test. Of these drugs, eight are reported to induce QT prolongation in the clinic (adriamycin, clomipramine, quinidine, amiodarone, and thioridazine), while three do not lengthen and three shorten the QT. To test for reproducibility, four drugs were given in duplicate (haloperidol, aspirin, erythromycin, and terfenadine). The drug effects on monophasic APD, conduction, instability (index of variability of APD), triangulation (index of duration of fast repolarization), and reverse use dependence were measured at five drug concentrations (0.05, 0.15, 0.5, 1.5, and 5 mg/l). All 14 blinded drugs, in the concentrations used, were correctly identified as to their effects on APD and conduction. The drugs eliciting drug-induced proarrhythmia in patients were also identified as promoting instability, triangulation, and reverse use dependence in the rabbit heart. Importantly, none of the safe agents was labeled as proarrhythmic, and the results were very consistent between duplications. In conclusion, SCREENIT correctly identifies prolongation of APD, accurately separates safe agents form proarrhythmic drugs, and has highly reproducible results. Thus, the isolated perfused rabbit heart can be a valuable tool in a preclinical proarrhythmia test battery in drug development.
A Facile Synthesis of Sulfides Using S-Aryl-isothiuronium Intermediates (1986)

Abstract A variety of sulfides were conveniently prepared by a treatment of aryl iodides with thiourea in the presence of a nickel(0) catalyst, then with CaO, and finally with a variety of electrophiles such as alkyl, acyl, silyl, aryl, or alkenyl halides.
ChemInform Abstract: NEW HETEROCYCLIC SYSTEMS. IV. DERIVATIVES OF (1)BENZOTHIEPINE (1977)

Abstract Das bereits bekannte Benzothiepin (I), dessen Synthese verbessert werden konnte, wird in das Thiophen (III) übergeführt, das bei Oxidation mit Peressigsäure in das Monosulfon (exklusive Oxidation am Thiepin‐S‐Atom) übergeht.
Development of a nanoparticulate formulation of retinoic acid that suppresses Th17 cells and upregulates regulatory T cells (2010)

Retinoic acid (RA) is a small molecule capable of shunting developing T cells away from the Th17 lineage and towards the Treg phenotype, making it a potentially useful therapeutic for autoimmune and inflammatory diseases. However, therapy can be complicated by systemic toxicity and unpredictable bioavailability, making a targeted drug delivery vehicle for local therapy desirable. A promising approach is the use of nanoparticles, which have been demonstrated to increase potency and decrease toxicity of therapies in a variety of disease models including Th17 mediated diseases. Nanoparticles can also be targeted to specific cell types via surface modification, further increasing the potential specificity of this approach. We therefore constructed a nanoparticulate drug delivery platform from poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating and releasing RA. Here we report the fabrication, characterization, and in vitro bioactivity of this platform. We demonstrate that RA containing PLGA nanoparticles suppress IL-17 production and ROR-γ(t) expression in T cells polarized towards the Th17 phenotype in vitro with similar potency to that of free drug. Furthermore, we show that these particles enhance TGF-β dependent Foxp3 expression and IL-10 production of T cells in vitro with similar potency to free RA. Finally, we demonstrate that T cells polarized towards the Th17 phenotype in the presence of free and nanoparticulate RA have similarly suppressed ability to induce IL-6 production by fibroblasts. Our findings demonstrate the feasibility of RA delivery via biodegradable nanoparticles and represent an exciting technology for the treatment of autoimmune and inflammatory diseases.
Request and conquer: exposing cross-origin resource size (2016)

Numerous initiatives are encouraging website owners to enable and enforce TLS encryption for the communication between the server and their users. Although this encryption, when configured properly, completely prevents adversaries from disclosing the content of the traffic, certain features are not concealed, most notably the size of messages. As modern-day web applications tend to provide users with a view that is tailored to the information they entrust these web services with, it is clear that knowing the size of specific resources, an adversary can easily uncover personal and sensitive information. In this paper, we explore various techniques that can be employed to reveal the size of resources. As a result of this in-depth analysis, we discover several design flaws in the storage mechanisms of browsers, which allows an adversary to expose the exact size of any resource in mere seconds. Furthermore, we report on a novel size-exposing technique against Wi-Fi networks. We evaluate the severity of our attacks, and show their worrying consequences in multiple real-world attack scenarios. Furthermore, we propose an improved design for browser storage, and explore other viable solutions that can thwart size-exposing attacks.