gebhart/patrepeval huggingface dataset:
Toxicology of choroid plexus: Special reference to metal-induced neurotoxicities (2000)

The chemical stability in the brain underlies normal human thinking, learning, and behavior. Compelling evidence demonstrates a definite capacity of the choroid plexus in sequestering toxic heavy metal and metalloid ions. As the integrity of blood-brain and blood-CSF barriers, both structurally and functionally, is essential to brain chemical stability, the role of the choroid plexus in metal-induced neurotoxicities has become an important, yet under-investigated research area in neurotoxicology. Metals acting on the choroid plexus can be categorized into three major groups. A general choroid plexus toxicant can directly damage the choroid plexus structure such as mercury and cadmium. A selective choroid plexus toxicant may impair specific plexus regulatory pathways that are critical to brain development and function, rather than induce massive pathological alteration. The typical examples in this category include lead-induced alteration in transthyretin production and secretion as well as manganese interaction with iron in the choroid plexus. Furthermore, a sequestered choroid plexus toxicant, such as iron, silver, or gold, may be sequestered by the choroid plexus as an essential CNS defense mechanism. Our current knowledge on the toxicological aspect of choroid plexus research is still incomplete. Thus, the future research needs have been suggested to focus on the role of choroid plexus in early CNS development as affected by metal sequestration in this tissue, to explore how metal accumulation alters the capacity of the choroid plexus in regulation of certain essential elements involved in the etiology of neurodegenerative diseases, and to better understand the blood-CSF barrier as a defense mechanism in overall CNS function.
Impact of Culture on Knowledge Management: A Meta-Analysis and Framework (2012)

Culture, both national and organizational, can have profound impacts on knowledge management. Yet the literature on exactly how culture impacts knowledge management is complex with no clear generalizable results. A meta-analysis was conducted on 52 articles from ten IS journals for the years 2000–2010 combining both quantitative and qualitative studies in a unique methodological approach. Key findings include a marked shift away from normative language towards more interpretive and critical discourse emphasizing the power issues inherent in the cultural context of knowledge management. Trust and openness are key organizational cultural dimensions that impact knowledge management processes, but these traits are achieved through effective business leadership, rather than a particular technological artifact. The most striking generalizable finding from the cross-case analysis is that organizational culture can overcome or mitigate differences in national culture. An overall framework is provided to illustrate the findings and to serve as an important guidepost for future research.
Elimination-addition mechanisms of acyl group transfer: the hydrolysis and synthesis of carbamates (1977)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTElimination-addition mechanisms of acyl group transfer: the hydrolysis and synthesis of carbamatesHuda Al-Rawi and Andrew WilliamsCite this: J. Am. Chem. Soc. 1977, 99, 8, 2671–2678Publication Date (Print):April 1, 1977Publication History Published online1 May 2002Published inissue 1 April 1977https://pubs.acs.org/doi/10.1021/ja00450a045https://doi.org/10.1021/ja00450a045research-articleACS PublicationsRequest reuse permissionsArticle Views525Altmetric-Citations21LEARN 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
THE ROLE OF THE TCR DURING THE LHC ERA (2000)

The era of the Large Hadron Collider (LHC) requires a thorough preparation of the work environment of CERN's Technical Control Room (TCR) to ensure the quality of services as demanded by the clients. Therefore the relationship between the TCR, its clients and its suppliers has to be identified and formal contracts should be established that fix a general agreement on the responsibilities and services of each of the involved parties. Also the internal organization of the TCR, operation procedures, information channels, the training of the operators and various parts of the control system have to be evolved. This paper describes the modifications which have to be implemented to adapt the existing TCR services to the LHC requirements. Moreover, some new services are proposed which could be provided to the TCR clients.
A facile route to 1,3,5,7-tetraaminoadamantane. Synthesis of 1,3,5,7-tetranitroadamantane (1980)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA facile route to 1,3,5,7-tetraaminoadamantane. Synthesis of 1,3,5,7-tetranitroadamantaneGilbert P. Sollott and Everett E. GilbertCite this: J. Org. Chem. 1980, 45, 26, 5405–5408Publication Date (Print):December 1, 1980Publication History Published online1 May 2002Published inissue 1 December 1980https://pubs.acs.org/doi/10.1021/jo01314a051https://doi.org/10.1021/jo01314a051research-articleACS PublicationsRequest reuse permissionsArticle Views1249Altmetric-Citations60LEARN 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
The Role of Amino Acid Sequence in the Self-Association of Therapeutic Monoclonal Antibodies: Insights from Coarse-Grained Modeling (2013)

Coarse-grained computational models of therapeutic monoclonal antibodies and their mutants can be used to understand the effect of domain-level charge-charge electrostatics on the self-association phenomena at high protein concentrations. The coarse-grained models are constructed for two antibodies at different coarse-grained resolutions by using six different concentrations. It is observed that a particular monoclonal antibody (hereafter referred to as MAb1) forms three-dimensional heterogeneous structures with dense regions or clusters compared to a different monoclonal antibody (hereafter referred to as MAb2) that forms homogeneous structures without clusters. The potential of mean force (PMF) and radial distribution functions (RDF) plots for the mutants (hereafter referred to as M1, M5, M7, and M10) show trends consistent with previously reported experimental observation of viscosities. The mutant referred to as M6 shows strongly attractive interactions that are consistent with previously reported negative second virial coefficients (B(22)) obtained from light-scattering experiments (Yadav et al. Pharm. Res. 2011, 28, 1750-1764; Yadav et al. Mol. Pharmaceutics. 2012, 9, 791-802). Clustering data on MAb1 reveal a small number of large clusters that are hypothesized to be the reason for the high experimental viscosity. This is in contrast with M6 (that differs from MAb1 in only a few amino acids), where cluster analysis reveals the formation of a large number of smaller clusters that is hypothesized to be the reason for the observed lower viscosity. The coarse-grained representations are effective in picking up differences based on local charge distributions of domains to make predictions on the self-association characteristics of these protein solutions.
Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease (2017)

Hedgehog signaling plays a key role in tissue fibrosis, the pathological hallmark of chronic graft-versus-host disease (cGVHD). We conducted a phase 1 trial of sonidegib, a selective antagonist of the hedgehog coreceptor Smoothened, for the treatment of steroid-refractory cGVHD. After a 3+3 study design, sonidegib was administered for up to 12 cycles of 28 days each, using 3 doses: 200 mg/day (dose level 1), 400 mg/day (dose level 2), and 600 mg/day (dose level 3). Seventeen patients were enrolled. The median number of cycles completed was 6 (range, 0-12). There was only 1 dose-limiting toxicity (cohort 2, grade 3 creatine phosphokinase increase) observed. Immunohistochemical evaluation of skin biopsies revealed decreased protein expression of hedgehog signaling pathway molecules with sonidegib therapy. Clinically, 8 patients (47%) had a partial response in skin or sclerodermatous disease, 6 patients had no response, and 3 were not evaluable. Clinical responses were assessed by treating physicians and not by National Institutes of Health criteria. Overall, patients reported worsening of quality of life, which was more severe in clinical nonresponders. Accrual was terminated early as a result of the cumulative toxicity burden not attributed to sonidegib and patient decisions to stop taking sonidegib. We believe hedgehog signaling inhibition warrants further investigation in patients with cGVHD because of the association with clinical responses and immunohistochemical changes. This trial was registered at www.clinicaltrials.gov as #NCT02086513.
Association of the CYP17 gene and CYP19 gene polymorphisms with risk of endometriosis in Japanese women (2002)

The results suggest that the 3 bp I/D polymorphism of the CYP19 gene may be weakly associated with the susceptibility of endometriosis in a Japanese population.
Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. (2001)

Multiple definitions have been used to characterize the outcome of treatments for depression. Beyond the simple criterion of a statistically significant improvement in depression rating scale scores, researchers have had to use more clinically relevant categorical outcomes: response (without remission), remission, nonresponse, partial response, relapse, recurrence, recovery, and, more recently, depressive breakthrough. This article reviews the definitions of these terms and their relevance for the study of treatment-resistant depression.
Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. (1996)

Gene rearrangements activating the RET proto-oncogene are frequently associated with human thyroid carcinomas belonging to the papillary subtype. These arrangements cause the fusion of the tyrosine-kinase domain of RET to the 5'-terminal region of different genes creating the RET/PTC chimeric oncogenes. Here we report the generation of transgenic mice lines expressing the RET/PTC1 oncogene under the control of the thyroid-specific rat thyroglobulin promoter. RET/PTC1-transgenic mice developed thyroid tumors displaying the histological aspect of papillary carcinomas. These tumors were slowly progressive and did not cause premature death of the animals. Two additional mice developed areas of thyroid hyperplasia. Immunohistochemical and reverse-transcriptase polymerase chain reaction analyses confirmed the thyroid-specific expression of the transgene. Given the frequency of activating rearrangements of RET in human papillary thyroid carcinomas we conclude that this animal system could be a good model for studying the neoplastic progression of thyroid carcinomas.
Dual-targeting siRNAs (2010)

We have developed an algorithm for the prediction of dual-targeting short interfering RNAs (siRNAs) in which both strands are deliberately designed to separately target different mRNA transcripts with complete complementarity. An advantage of this approach versus the use of two separate duplexes is that only two strands, as opposed to four, are competing for entry into the RNA-induced silencing complex. We chose to design our dual-targeting siRNAs as Dicer substrate 25/27mer siRNAs, since design features resembling pre-microRNAs (miRNAs) can be introduced for Dicer processing. Seven different dual-targeting siRNAs targeting genes that are potential targets in cancer therapy have been developed including Bcl2, Stat3, CCND1, BIRC5, and MYC. The dual-targeting siRNAs have been characterized for dual target knockdown in three different cell lines (HEK293, HCT116, and PC3), where they were as effective as their corresponding single-targeting siRNAs in target knockdown. The algorithm developed in this study should prove to be useful for predicting dual-targeting siRNAs in a variety of different targets and is available from http://demo1.interagon.com/DualTargeting/.
Transient appearance of "no-reflow" phenomenon in Mongolian gerbils. (1980)

We investigated the existence of the "no-reflow" phenomenon in focal cerebral ischemia. Regional cerebral blood flow was studied in Mongolian gerbils perfused with a carbon-black particle suspension after cerebral ischemia prior to decapitation and compared with 14C-antipyrine autoradiographic images. The correlation between the occurrence of the "no-reflow" phenomenon and systemic arterial blood pressure change was also examined. We found that the phenomenon was transient in character and that its manifestation was related to the transient fall in arterial blood pressure observed immediately after clip release and with stagnation of venous blood flow. The phenomenon disappeared in animals in which the arterial blood pressure was artificially increased after clip release.
Toward a Biochemical Understanding of Human Intervertebral Disc Degeneration and Herniation (1997)

Cells of the intervertebral discs are biologically responsive and increase their production of matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2 when stimulated by interleukin-1 beta. The effect is more dramatic in normal, nondegenerated discs where spontaneous synthesis of these mediators is low. Nevertheless, cells of the herniated degenerated discs where spontaneous production was high were still capable of further increasing their synthesis of several of these biochemical agents in response to interleukin-1 beta. Endogenously produced nitric oxide appears to have a strong inhibitory effect on the production of interleukin-6, which suggests that autocrine mechanisms play an important role in the regulation of disc cell metabolism.
Mustard Prodrugs for Activation by Escherichia coli Nitroreductase in Gene-Directed Enzyme Prodrug Therapy (1997)

Twenty nitrogen mustard analogues derived from 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954, 1) were evaluated as candidate prodrugs for gene-directed enzyme prodrug therapy (GDEPT) in Chinese hamster V79 cell lines engineered to express Escherichia coli nitroreductase (NR). Structural variations within the series included the use of N-dihydroxypropyl and (N-dimethylamino)ethyl carboxamide side chains, the use of chloro, bromo, mesyl, and iodo leaving groups on the mustards, and regioisomeric changes. The compounds were assayed for cytotoxicity (IC50) with the NR-expressing and controls of non-NR-expressing cell lines. The proportion of NR-expressing cells required in a mixture for nonexpressing cells to experience 50% of their cytotoxicity (termed the TE50) was used to assess the compounds' ability to induce a bystander effect. This study suggests that 5-[N,N-bis(2-bromoethyl)amino]-2,4-dinitrobenzamide (8), 5-[N,N-bis(2-iodoethyl)amino]-2,4-dinitrobenzamide (9), 2-[N,N-bis(2-bromoethyl)-amino]-3,5-dinitrobenzamide (13), and 2-[N,N-bis(2-iodoethyl)amino]-3,5-dinitrobenzamide (14) showed considerable improvements over 1, exhibiting greater potency, higher IC50 ratios, and lower TE50s, and are thus superior prodrugs to 1 for GDEPT.
Identification of Novel Ligands for the Gabapentin Binding Site on the α2δ Subunit of a Calcium Channel and Their Evaluation as Anticonvulsant Agents (1998)

As part of a program to investigate the structure-activity relationships of Gabapentin (Neurontin), a number of alkylated analogues were synthesized and evaluated in vitro for binding to the Gabapentin binding site located on the alpha2delta subunit of a calcium channel. A number of other bridged and heterocyclic analogues are also reported along with their in vitro data. Two compounds showing higher affinity than Gabapentin were selected for evaluation in an animal model of epilepsy. One of these compounds, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexyl)acetic acid hydrochloride (19), was shown to be effective in this model with a profile similar to that of Gabapentin itself.
In-peptide synthesis of di-oxazolidinone and dehydroamino acid–oxazolidinone motifs as β-turn inducers (2013)

Small and easy-to-do mimetics of β-turns are of great interest to interfere with protein-protein recognition events mediated by β-turn recognition motifs. We propose a straightforward procedure for constraining the conformation of tetrapeptides lacking a pre-formed scaffold. According to the stereochemistry array, N-Ts tetrapeptides including Thr or PhSer (phenylserine) at the positions 2 or 3 gave rise in a single step to the sequences Oxd(2)-Oxd(3) or ΔAbu(2)-Oxd(3) (Oxd, oxazolidin-2-one; ΔAbu, 2,3-dehydro-2-aminobutyric). These pseudo-Pro residues displayed highly constrained ϕ, ψ, and χ dihedral angles, and induced clear β-turns or inverse turns of type I or II, as determined by extensive spectroscopic and computational analyses.
High resolution imaging of in vivo cardiac dynamics using color Doppler optical coherence tomography (1997)

Color Doppler optical coherence tomography (CDOCT) is a noninvasive technique for simultaneous high spatial resolution (~20 aem) imaging and high velocity resolution (~500 aem/s) imaging flowmetry in living tissues. In this paper, we demonstrate a reconstruction method which overcomes fundamental limitations on Doppler flow mapping associated with both high- and low-speed imaging. This algorithm is successful in retaining the high velocity resolution of CDOCT while eliminating motion artifact caused by slow image acquisition in samples which exhibit repetitive motion. We demonstrate reconstruction of blood flow throughout a beating Xenopus laevis heart and surrounding vasculature using gated CDOCT reconstruction.
Disruption of the cysteine-75 and zinc ion coordination is not sufficient to activate the precursor of human matrix metalloproteinase 3 (stromelysin 1) (1993)

Matrix metalloproteinases (MMPs) are activated in vitro from their precursors (proMMPs) by multiple means such as treatment with proteinases, mercurial compounds, chaotropic agents, sodium dodecyl sulfate, HOCl, and heat. The latency of proMMPs is stabilized by intramolecular interaction of the single cysteine residue in the conserved sequence PRCG(V/N)PD of the propeptide and the zinc atom at the active site. The activation of proMMP-1 (interstitial procollagenase) by multiple treatments has been explained by the "cysteine switch" model, in which the disruption of the Cys-Zn interaction is considered to be critical for activation [Springman, E. B., Angleton, E. L., Birkedal-Hansen, H., & VanWart, H. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 364-368]. To further test this hypothesis we dissociated the Cys-Zn interaction by specifically modifying Cys-75 of proMMP-3 (prostromelysin 1) with iodoacetamide, (4-aminophenyl)mercuric acetate (APMA), or 5,5'-dithiobis(2-nitrobenzoate) and examined the expression of enzymic activity. The enzymic assays of the modified proMMP-3s against protein and synthetic substrates did not reveal any significant activity. The modified 57-kDa proMMP-3s were stable and did not show spontaneous activation. Activation of the modified proMMP-3s required further treatment with APMA or a proteinase and was accompanied by conversion of the proMMP-3 to a 45-kDa species. Circular dichroism studies of proMMP-3 treated with HgCl2 demonstrated time-dependent conformational changes in proMMP-3 prior to the expression of proteolytic activity and processing of the zymogen to lower molecular weight species. These results indicate that the disruption of the Cys-Zn coordination alone is not sufficient to activate proMMP-3.(ABSTRACT TRUNCATED AT 250 WORDS)
Efficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse (2004)

Abstract To generate temporally controlled targeted somatic mutations selectively and efficiently in hepatocytes, we established SA +/CreERT2 mice in which the tamoxifen‐dependent Cre‐ER T2 recombinase coding sequence preceded by an internal ribosomal entry site was inserted in the 3′ untranslated region of the serum albumin (SA) gene. Whereas the wildtype SA allele was strongly expressed in the liver and at lower levels in some extrahepatic tissues, SA‐Cre‐ER T2 fusion transcripts were only detected in the liver. The Cre‐ER T2 protein was expressed in most if not all hepatocytes, and tamoxifen (Tam) treatments of adult mice at various ages efficiently induced Cre‐mediated recombination of LoxP flanked (floxed) alleles in these cells, but none in other cell types or tissues. Thus, SA +/CreERT2 mice should be of great value to analyze gene function in the liver and to establish animal models of human diseases. genesis 39:167–172, 2004. © 2004 Wiley‐Liss, Inc.