gebhart/patrepeval huggingface dataset:
Use of monoclonal antibodies in local passive immunization to prevent colonization of human teeth by Streptococcus mutans (1987)

Local passive immunization with monoclonal antibodies (MAbs) raised against streptococcal antigen (SA) I/II protects monkeys against colonization of teeth by Streptococcus mutans and the subsequent development of dental caries. In this study we extended the preclinical experiments to human subjects. In the first study of eight healthy subjects, four had anti-SA I/II MAb (immunoglobulin G2a [IgG2a]) and four had saline applied to their teeth on three occasions. A streptomycin-resistant S. mutans strain (Guy K2 strain, serotype c) was then implanted onto the teeth, and the organism was cultured sequentially from dental plaque and saliva up to 100 days after the first treatment with MAb. Decreased colonization by S. mutans was found in the dental plaque collected from smooth surfaces and fissures and in saliva of subjects whose teeth were treated with the MAb, as compared with the saline-treated control subjects. The experiment was then repeated on seven new subjects, and the effect of anti-SA I/II MAb was compared with that of an unrelated MAb to Campylobacter jejuni. The results again showed a consistently lower level of colonization of teeth in the anti-SA I/II MAb-treated subjects as compared with those sham immunized with the unrelated MAb. There was little difference in serum IgG, IgM, or IgA, gingival fluid IgG, or salivary IgA anti-SA I/II antibodies between the immunized and sham-immunized subjects, before and after the investigation. No side effects were observed, and the gingival and plaque indices remained unchanged. A sensitive radioimmunoassay failed to detect changes in anti-MAb (IgG2a) antibodies in any of the three fluids examined. We suggest that local passive immunization by means of MAb might be an alternative approach in the prevention of colonization of teeth by S. mutans and the development of dental caries.
Cloned pre‐implantation mouse embryos show correct timing but altered levels of gene expression (2004)

Abstract Mammalian embryos obtained by somatic nuclear transfer (NT) struggle to survive throughout development, encountering a number of hurdles leading to wrong functional reprogramming of the donor genome. However, despite these obstacles, some of these embryos continue their development, as if the required transcriptional functions are somehow satisfied. The amount of information gathered on the kinetics and quantitative profile of gene expression in NT pre‐implantation embryos is still scarce and limited to a handful of genes described in two species, bovine and mouse. Using a single‐cell sensitive semi‐quantitative RT‐PCR, we have compared the onset and profile of abundance of Hprt , Tsx , Bex1 , Bax , Cpt2 , and Oct4 genes, in in vitro fertilised and NT‐derived mouse 1‐cell, 2‐cell, 4‐cell embryos, morulae, and blastocysts. The genes analysed were activated in NT embryos at approximately the correct time compared to control embryos, indicating that the reprogramming phenomenon is developmentally regulated and that the somatic genome is quickly rearranged towards an embryonic‐type of expression during the early stages of segmentation. Despite the right timing of genes onset, the high degree of variability in the number of transcripts found in NT embryos at the latest stages of pre‐implantation development, suggests that genome reprogramming is incomplete and inaccurate. Mol. Reprod. Dev. 70: 146–154, 2005. © 2005 Wiley‐Liss, Inc.
Mechanisms of Focal Adhesion Kinase Regulation (2005)

Focal adhesion kinase (FAK) is a tyrosine kinase whose phosphorylation state and activity is tightly linked to cell adhesion to the extracellular matrix through integrin receptors. FAK's regulation by adhesion places it in a key position to be able to influence cellular events that are either dependent on cell adhesion like cell proliferation and survival, or that require modulation of cell adhesion like cell migration. FAK's involvement in cellular pathways that regulate cell growth and cell movement suggests that it may contribute to the development of cancer or other diseases. FAK's possible involvement in these pathways makes it a potential drug target. In this review we will focus on the developing view how FAK's activity and phosphorylation are regulated within the cell. Specifically, we will address the contribution of integrins and growth factor dependent pathways to FAK's activation. The role of the tyrosine kinase Src in FAK's regulation will be discussed. The contribution of various negative regulators of FAK's phosphorylation on its regulation including phosphatases and proteases will be discussed. Lastly, the emerging role of FAK's amino terminal FERM like domain in FAK's regulation will be explored. FAK's function within a cell are tightly linked to its phosphorylation state, thus understanding its normal regulation in the cell will provide important insight into drug development by highlighting novel regulatory mechanisms within FAK that potentially may be exploited.
Rapid Quantification of the Latent Reservoir for HIV-1 Using a Viral Outgrowth Assay (2013)

HIV-1 persists in infected individuals in a stable pool of resting CD4(+) T cells as a latent but replication-competent provirus. This latent reservoir is the major barrier to the eradication of HIV-1. Clinical trials are currently underway investigating the effects of latency-disrupting compounds on the persistence of the latent reservoir in infected individuals. To accurately assess the effects of such compounds, accurate assays to measure the frequency of latently infected cells are essential. The development of a simpler assay for the latent reservoir has been identified as a major AIDS research priority. We report here the development and validation of a rapid viral outgrowth assay that quantifies the frequency of cells that can release replication-competent virus following cellular activation. This new assay utilizes bead and column-based purification of resting CD4(+) T cells from the peripheral blood of HIV-1 infected patients rather than cell sorting to obtain comparable resting CD4(+) T cell purity. This new assay also utilizes the MOLT-4/CCR5 cell line for viral expansion, producing statistically comparable measurements of the frequency of latent HIV-1 infection. Finally, this new assay employs a novel quantitative RT-PCR specific for polyadenylated HIV-1 RNA for virus detection, which we demonstrate is a more sensitive and cost-effective method to detect HIV-1 replication than expensive commercial ELISA detection methods. The reductions in both labor and cost make this assay suitable for quantifying the frequency of latently infected cells in clinical trials of HIV-1 eradication strategies.
Stating and manipulating periodicity in the polytope model : Applications to program analysis and optimization (2004)

Myocardial oxygen consumption is regulated by interrelated mechanical and inotropic conditions; there is a parallel increase in the aerobic metabolism and inotropic state during beta-adrenergic stimulation under fixed mechanical conditions. In contrast, there is some evidence that beta-blockade may reduce oxygen consumption through effects independent of its influence on mechanical conditions and contractile state, and that prolonged beta-blockade may sensitize the myocardium to beta-adrenergic stimulation. To clarify these two points, the present study examined the relationship of myocardial energetics to mechanics and inotropism during acute beta-blockade and after the withdrawal of long-term beta-blockade, whereupon the basis for any effect observed was sought by characterizing the number, affinity, and affinity states of the beta-receptors as well as the coupling of activated beta-receptors to cyclic AMP generation. Studies of right ventricular papillary muscles from control and chronically beta-blocked cats demonstrated contractile and energetic properties as well as dose-response behavior and inotropic specificity suggestive of an increase in myocardial sensitivity to beta-adrenoceptor stimulation in the latter group. Assays of cardiac beta-adrenoceptors from further groups of control and pretreated cats, both in cardiac tissue and in isolated cardiac muscle cells, failed to define a difference between the two groups either in terms of receptor number and affinity or in terms of the proportion of receptors in the high-affinity state. However, coupling of the activated beta-adrenoceptors to cyclic AMP generation was enhanced in cardiac muscle cells from chronically beta-blocked cats. These data demonstrate that beta-adrenoceptor blockade (a) produces parallel effects on inotropic state and oxygen consumption without an independent effect on either and (b) increases myocardial sensitivity to beta-adrenergic stimulation after beta-blockade withdrawal, not by "up-regulation" of the cardiac beta-adrenoceptors, but instead by more effective coupling of these receptors when activated to cyclic AMP generation.
Spread of SARS-CoV-2 in the Icelandic Population (2020)

In a population-based study in Iceland, children under 10 years of age and females had a lower incidence of SARS-CoV-2 infection than adolescents or adults and males. The proportion of infected persons identified through population screening did not change substantially during the screening period, which was consistent with a beneficial effect of containment efforts. (Funded by deCODE Genetics-Amgen.).
Persistence of azidothymidine-resistant human immunodeficiency virus type 1 RNA genotypes in posttreatment sera (1992)

The rate of reversion from azidothymidine (zidovudine; AZT) resistance was studied by direct sequencing of human immunodeficiency virus type 1 (HIV-1) virion RNA in sera from four patients who discontinued long-term treatment. Before cessation of treatment, all four patients harbored HIV-1 with multiple mutations reported to confer AZT resistance. In three patients, slow reversions of these mutations starting after 9, 9, and 18 months were detected. The slow reversions indicate that AZT-resistant HIV-1 variants are likely to have an unaltered replicative capacity and pathogenic potential. Furthermore, there were discrepancies between the in vivo RNA sequences and the sequences of virus isolates, indicating that the isolation procedure may select for nonrepresentative virus variants.
Neuropeptide S Ameliorates Cognitive Impairment of APP/PS1 Transgenic Mice by Promoting Synaptic Plasticity and Reducing Aβ Deposition (2019)

Alzheimer's disease (AD) is a devastating disease in the elderly with no known effective treatment. It is characterized by progressive deterioration of memory and cognition. Many new potential targets are being investigated to develop effective therapeutic strategies for AD. Neuropeptide S (NPS) is an endogenous peptide in the central nervous system, which has been shown to play a beneficial role in learning and memory. However, whether NPS can ameliorate cognitive deficits in AD remains unclear. In this study, we examined the effects of NPS treatment on the cognitive behaviors and pathological hallmarks in 8-month-old APPswe/PS1dE9 (APP/PS1) AD mice. We found that the APP/PS1 mice exhibited lower levels of NPS receptors (NPSRs) in the hippocampal area, and NPS administration increased c-Fos expression in the hippocampus and cortex, which suggests the NPS/NPSR system may contribute to the pathogenesis of AD. After an intracerebroventricular injection of NPS (1 nmol) for 2 weeks, we found NPS treatment ameliorated spatial memory deficits and promoted dendrite ramification and spine generation in hippocampal CA1 neurons, which was accompanied by the upregulation of postsynaptic density protein 95 (PSD95) and synapsin1. We also demonstrated that the injection of NPS decreased Aβ plaque deposits by decreasing the γ-secretase activity and the phosphorylation of APP at Thr668. Furthermore, application of NPS reversed the deficits in hippocampal late-phase long-term potentiation (LTP). These findings suggest NPS attenuated cognitive deficits by reducing pathological features in APP/PS1 mice, and NPS might be a potential therapeutic agent for AD.
Review of the biodistribution and toxicity of the insect repellentN,N‐diethyl‐m‐toluamide (DEET) (1986)

A review of the biodistribution and toxicity of the insect repellent N,N-diethyl-m-toluamide (DEET) is presented. Workers using repellent containing this compound may be exposed to greater than 442 g in 6 mo. In human studies, variable penetration into the skin of from 9 to 56% of a topically applied dose and absorption into the circulatory system of approximately 17% have been reported. Excretion of DEET by humans was initially rapid but not as complete as in animal models. Only about one-half of the absorbed DEET was excreted by humans over 5 d. Depot storage of DEET in the skin was also documented. Skin irritant effects, including scarring bullous dermatitis in humans, were reported. One animal study that reported embryotoxicity could not be confirmed by other investigators. The limited testing for mutagenicity and carcinogenicity provided negative results. Neurotoxic effects were observed in workers exposed to 4 g or more per week. Six young girls developed encephalopathies after exposure to unspecified amounts of DEET ranging from small to massive doses. Three of these girls later died. The cause of their death has not been resolved. Because of the lack of information, further research into the absorption, carcinogenicity, and neurotoxic effects is needed.
Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition (2016)

<b>Purpose:</b> Cyclin E1 (<i>CCNE1</i>) amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target <i>CCNE1</i>-amplified cancers and potential strategies to overcome resistance to targeted agents.<b>Experimental Design:</b> To examine dependency on <i>CDK2</i> in <i>CCNE1</i>-amplified HGSC, we utilized siRNA and conditional shRNA gene suppression, and chemical inhibition using dinaciclib, a small-molecule CDK2 inhibitor. High-throughput compound screening was used to identify selective synergistic drug combinations, as well as combinations that may overcome drug resistance. An observed relationship between <i>CCNE1</i> and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells.<b>Results:</b> We validate <i>CDK2</i> as a therapeutic target by demonstrating selective sensitivity to gene suppression. However, we found that dinaciclib did not trigger amplicon-dependent sensitivity in a panel of HGSC cell lines. A high-throughput compound screen identified synergistic combinations in <i>CCNE1</i>-amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated coamplification of <i>CCNE1</i> and <i>AKT2</i> Overexpression of Cyclin E1 and AKT isoforms, in addition to mutant <i>TP53</i>, imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC.<b>Conclusions:</b> These findings suggest a specific dependency of <i>CCNE1</i>-amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients with <i>CCNE1</i>-amplified HGSC. <i>Clin Cancer Res; 23(7); 1862-74. ©2016 AACR</i>.
Herstatin, an Autoinhibitor of the Human Epidermal Growth Factor Receptor 2 Tyrosine Kinase, Modulates Epidermal Growth Factor Signaling Pathways Resulting in Growth Arrest (2002)

Herstatin is an autoinhibitor of the ErbB family consisting of subdomains I and II of the human epidermal growth factor receptor 2 (ErbB-2) extracellular domain and a novel C-terminal domain encoded by an intron. Herstatin binds to human epidermal growth factor receptor 2 and to the epidermal growth factor receptor (EGFR), blocking receptor oligomerization and tyrosine phosphorylation. In this study, we characterized several early steps in EGFR activation and investigated downstream signaling events induced by epidermal growth factor (EGF) and by transforming growth factor alpha (TGF-alpha) in NIH3T3 cell lines expressing EGFR with and without herstatin. Herstatin expression decreased EGF-induced EGFR tyrosine phosphorylation and delayed receptor down-regulation despite receptor occupancy by ligand with normal binding affinity. Akt stimulation by EGF and TGF-alpha, but not by fibroblast growth factor 2, was almost completely blocked in the presence of herstatin. Surprisingly, EGF and TGF-alpha induced full activation of MAPK in duration and intensity and stimulated association of the EGFR with Shc and Grb2. Although MAPK was fully stimulated, herstatin expression prevented TGF-alpha-induced DNA synthesis and EGF-induced proliferation. The herstatin-mediated uncoupling of MAPK from Akt activation was also observed in Chinese hamster ovary cells co-transfected with EGFR and herstatin. These findings show that herstatin expression alters EGF and TGF-alpha signaling profiles, culminating in inhibition of proliferation.
Review of Ranibizumab Trials for Neovascular Age-Related Macular Degeneration (2011)

Ranibizumab, a recombinant, humanized, monoclonal antibody antigen-binding fragment that neutralizes all VEGF-A isoforms, is the first US FDA-approved therapy for neovascular age-related macular degeneration (AMD) to result in improvement in visual acuity. The benefit of intravitreal ranibizumab applies to all angiographic subtypes of neovascular AMD and across all lesion sizes. The two original phase III studies (ANCHOR and MARINA) demonstrated sustained visual acuity (VA) gains over a two-year monthly dosing schedule. Following these trials, several studies looked at ways to decrease the treatment burden while maintaining similar visual gains. These trials included PIER, PrONTO, EXCITE, SUSTAIN, HORIZON, and CATT. Visual acuity data shows that monthly dosing of ranibizumab produces superior vision outcomes compared to a less-frequent, fixed-dosing schedule. Intravitreal ranibizumab is well tolerated and shown to have a very low rate of adverse ocular or systemic side-effects.
Mutated epitopes of hepatitis B surface antigen fused to the core antigen of the virus induce antibodies that react with the native surface antigen (1997)

Fusion of peptide epitopes to the core antigen (HBcAg) of hepatitis B virus (HBV) enhances their immunogenicity, both quantitatively and qualitatively. In a number of vaccine-induced mutants of HBV, glycine145 of the surface antigen S polypeptide (HBsAg) has been replaced by arginine, resulting in loss of cross-reactivity with antibodies to normal (wild-type) HBsAg. HBcAg fusion proteins carrying the immunodominant epitope of HBsAg, in which glycine145 was replaced by arginine, glutamic acid, or lysine, were produced in Escherichia coli and formed particles that displayed HBc antigenicity and immunogenicity similar to that of HBcAg itself. The fusion proteins also elicited T-cell proliferative responsiveness to HBcAg and HBsAg. Fusions carrying either wild-type or mutated epitopes of HBsAG showed HBs antigenicity in immunoblot analysis and antigen-capture immunoradiometric assay, but both mutant and wild-type derivatives induced antibodies that cross-reacted with wild-type HBsAG. The results emphasise the potential for HBcAg fusion proteins in vaccines by broadening the antibody response in a way that could confer protection against both wild-type and variant form of HBV.
Data collecting and processing for substation integration enhancement (2004)

The issue of substation integration is recognized as a very important one ever since the process of technological development brought a multitude of new computer-based devices and functions into substation operation. During the relatively short time period after the first microprocessors were invented, a myriad of computer-based devices found their application in power engineering. Those devices had a variety of input and output data formats, which hampered exchange of data among different devices.&#13;\nRecent initiatives for standardization of substation data formats and communication protocols have progressed to facilitate production of devices with standardized data formats and data exchange capabilities. Central substation computers now have an opportunity to collect and process data from such computer-based devices.&#13;\nAn advanced data collecting and processing solution is developed and implemented as Integrated Substation Software in an effort to enhance substation integration. This report describes a solution that comprises data generation using a substation model, data collecting from modeled apparatus and instruments and finally application of data processing and consistency checking algorithms for creating outputs. The process of data collecting and processing is automated and repeated in equidistant time intervals. Results of processing and related reports are concisely displayed on the user interface screen and exported through data files.&#13;\nThe Substation Integration Software was tested through the set of scenarios where each scenario is used to test one of the processing and consistency checking algorithms. The results show that measurements are improved and applicable for usage by other substation and system-wide applications.
Phase Transition of a Disordered Nuage Protein Generates Environmentally Responsive Membraneless Organelles (2015)

Cells chemically isolate molecules in compartments to both facilitate and regulate their interactions. In addition to membrane-encapsulated compartments, cells can form proteinaceous and membraneless organelles, including nucleoli, Cajal and PML bodies, and stress granules. The principles that determine when and why these structures form have remained elusive. Here, we demonstrate that the disordered tails of Ddx4, a primary constituent of nuage or germ granules, form phase-separated organelles both in live cells and in vitro. These bodies are stabilized by patterned electrostatic interactions that are highly sensitive to temperature, ionic strength, arginine methylation, and splicing. Sequence determinants are used to identify proteins found in both membraneless organelles and cell adhesion. Moreover, the bodies provide an alternative solvent environment that can concentrate single-stranded DNA but largely exclude double-stranded DNA. We propose that phase separation of disordered proteins containing weakly interacting blocks is a general mechanism for forming regulated, membraneless organelles.
Ultrafast Graphene Oxide Humidity Sensors (2013)

Sensors allow an electronic device to become a gateway between the digital and physical worlds, and sensor materials with unprecedented performance can create new applications and new avenues for user interaction. Graphene oxide can be exploited in humidity and temperature sensors with a number of convenient features such as flexibility, transparency and suitability for large-scale manufacturing. Here we show that the two-dimensional nature of graphene oxide and its superpermeability to water combine to enable humidity sensors with unprecedented response speed (∼30 ms response and recovery times). This opens the door to various applications, such as touchless user interfaces, which we demonstrate with a 'whistling' recognition analysis.