gebhart/patrepeval huggingface dataset:
Love and authentication (2008)

Passwords are ubiquitous, and users and service providers alike rely on them for their security. However, good passwords may sometimes be hard to remember. For years, security practitioners have battled with the dilemma of how to authenticate people who have forgotten their passwords. Existing approaches suffer from high false positive and false negative rates, where the former is often due to low entropy or public availability of information, whereas the latter often is due to unclear or changing answers, or ambiguous or fault prone entry of the same. Good security questions should be based on long-lived personal preferences and knowledge, and avoid publicly available information. We show that many of the questions used by online matchmaking services are suitable as security questions. We first describe a new user interface approach suitable to such security questions that is offering a reduced risks of incorrect entry. We then detail the findings of experiments aimed at quantifying the security of our proposed method.
NADH Oxidase Activity of Rat Cardiac Sarcoplasmic Reticulum Regulates Calcium-Induced Calcium Release (2003)

NADH and Ca2+ have important regulatory functions in cardiomyocytes related to excitation-contraction coupling and ATP production. To elucidate elements of these functions, we examined the effect of NADH on sarcoplasmic reticulum (SR) Ca2+ release and the mechanisms of this regulation. Physiological concentrations of cytosolic NADH inhibited ryanodine receptor type 2 (RyR2)-mediated Ca2+-induced Ca2+ release (CICR) from SR membranes (IC50=120 micromol/L) and significantly lowered single channel open probability. In permeabilized single ventricular cardiomyocytes, NADH significantly inhibited the amplitude and frequency of spontaneous Ca2+ release. Blockers of electron transport prevented the inhibitory effect of NADH on CICR in isolated membranes and permeabilized cells, as well as on the activity of RyR2 channels reconstituted in lipid bilayer. An endogenous NADH oxidase activity from rat heart copurified with SR enriched with RyR2. A significant contribution by mitochondria was excluded as NADH oxidation by SR exhibited >9-fold higher catalytic activity (8.8 micromol/mg protein per minute) in the absence of exogenous mitochondrial complex I (ubiquinone) or complex III (cytochrome c) electron acceptors, but was inhibited by rotenone and pyridaben (IC50=2 to 3 nmol/L), antimycin A (IC50=13 nmol/L), and diphenyleneiodonium (IC50=28 micromol/L). Cardiac junctional SR treated with [3H](trifluoromethyl)diazirinyl-pyridaben specifically labeled a single 23-kDa PSST-like protein. These data indicate that NADH oxidation is tightly linked to, and essential for, negative regulation of the RyR2 complex and is a likely component of an important physiological negative-feedback mechanism coupling SR Ca2+ fluxes and mitochondrial energy production.
Development and Regulation of Rhodopsin Kinase in Rat Pineal and Retina (1986)

Rhodopsin kinase, once thought to be a retinal enzyme, was recently found at high levels in the pineal gland. In the present study the developmental pattern and the regulation by environmental lighting of this enzyme in both tissues was studied in the rat. Enzyme activity was present in the neonatal pineal gland several days earlier than in the retina, and increased gradually up to 20 days of age and remained at that level thereafter; the retinal enzyme appeared to increase until day 60. Pineal and retinal rhodopsin kinase activities showed a 25% increase in in the middle of the dark and the beginning of the light period, respectively. Exposure to constant light caused a 50% decrease in rhodopsin kinase levels in both tissues. However, only pineal rhodopsin kinase activity declined followed bilateral superior cervical ganglionectomy. This indicates pineal rhodopsin kinase activity is similar to other pineal enzymes in that it is controlled by light acting through the sympathetic nervous system. In contrast, the light-induced decrease in retinal rhodopsin kinase may be due to the direct destructive effect of light on the retina. The finding of neural control of pineal rhodopsin kinase in the pineal gland of adult rats is consistent with a function of the enzyme in the neural regulation of pineal function.
Expression of monocyte chemoattractant protein‐1 and interleukin‐8 receptors on subsets of T cells: correlation with transendothelial chemotactic potential (1996)

The differential expression of chemokine receptors may be an important mechanism for the regulation of T cell migration. To test this, we examined the expression and function of the monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 receptors on various population of T cells. Using a simple and reliable transendothelial chemotaxis assay, both MCP-1 and IL-8 were shown to be chemotactic for subsets of blood T cells, although the relative response varied from donor to donor. To examine receptor expression and correlate it with chemotaxis of T cell subsets, monoclonal antibodies (mAb) to the receptors were produced by immunizing mice either with synthetic peptides (MCP-1 receptor), or with receptor transfectants (IL-8 receptors A and B). A flow cytometric analysis of blood T cells with an anti-MCP-1 receptor mAb revealed low expression on the CD26hi subset and undetectable expression on other T cells. Staining of T cells with anti-Il-8RA and anti-IL-8RB showed much higher levels of expression, but only on a subset of CD3+ cells which were CD8+ and CD56+. That IL-8 and MCP-1 attracted distinct subsets of T cells was best illustrated using the CD26 marker, since IL-8R+ T cells were CD26-, whereas T cells expressing detectable MCP-1R or which responded to MCP-1 in chemotaxis assays were CD26hi. T cells activated in vitro with anti-CD3 up-regulated expression of the MCP-1 receptor, but not the IL-8 receptors, and were attracted to MCP-1 much more efficiently than resting T cells. These results show that there is a clear distinction between the IL-8 and MCP-1-responsive T cell populations and that chemokine receptor expression on T cells may be regulated with respect to linkage as well as cellular activation.
Lung cancer in women (2012)

Recent biological advances in tumor research provide clear evidence that lung cancer in females is different from that in males. These differences appear to have a direct impact on the clinical presentation, histology, and outcomes of lung cancer. Women are more likely to present with lung adenocarcinoma, tend to receive a diagnosis at an earlier age, and are more likely to be diagnosed with localized disease. Women may also be more predisposed to molecular aberrations resulting from the carcinogenic effects of tobacco, but do not appear to be more susceptible than men to developing lung cancer. The gender differences found in female lung cancer make it mandatory that gender stratification is used in clinical trials in order to improve the survival rates of patients with lung cancer.
Theranostic Mesoporous Silica Nanoparticles Biodegrade after Pro-Survival Drug Delivery and Ultrasound/Magnetic Resonance Imaging of Stem Cells (2015)

Increasing cell survival in stem cell therapy is an important challenge for the field of regenerative medicine. Here, we report theranostic mesoporous silica nanoparticles that can increase cell survival through both diagnostic and therapeutic approaches. First, the nanoparticle offers ultrasound and MRI signal to guide implantation into the peri-infarct zone and away from the most necrotic tissue. Second, the nanoparticle serves as a slow release reservoir of insulin-like growth factor (IGF)-a protein shown to increase cell survival. Mesenchymal stem cells labeled with these nanoparticles had detection limits near 9000 cells with no cytotoxicity at the 250 µg/mL concentration required for labeling. We also studied the degradation of the nanoparticles and showed that they clear from cells in approximately 3 weeks. The presence of IGF increased cell survival up to 40% (p<0.05) versus unlabeled cells under in vitro serum-free culture conditions.
Postantibiotic Colonization with Clostridium difficile in Nursing Home Patients (1990)

Clostridium difficile causes pseudomembranous colitis and is responsible for 20% to 25% of cases of postantibiotic diarrhea. In an earlier study, nursing-home patients with C. difficile infection were noted to have a high mortality rate. Because most of these infected patients had been treated with antibiotics, it was not clear whether this high mortality rate was associated with C. difficile infection or simply with antibiotic treatment. A prospective study was carried out to determine the rate of postantibiotic C. difficile colonization and risk factors for infection in patients in a 233-bed long-term care facility, as well as to determine whether C. difficile infection is associated with increased mortality. During a six-month period 150 courses of antibiotics were prescribed for 108 patients. Stool specimens were collected from 36 (33%) patients following the first course of antibiotic treatment, and 12 (33%) were infected with C. difficile. Risk factors for infection included ward location and stool incontinence. Age, body-mass index less than or equal to 18 kg/m2, and diagnoses of dementia and pressure scores tended to be associated with infection, but not significantly. Early mortality rates did not differ, but 12-month mortality for the infected patients was higher (83% vs 50%, P = .05). Therefore, we conclude that postantibiotic C. difficile infection serves as a marker of death in nursing-home patients, one that can be differentiated from the risk of antibiotic treatment alone. This increased death rate may be related in part to clinically unrecognized pseudomembranous colitis or, alternatively, to absorption of C. difficile toxins or even endotoxin from the gut lumen into the systemic circulation.
Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils (2005)

It is well established that preexposure of human neutrophils to proinflammatory cytokines markedly augments the production of reactive oxygen species (ROS) to subsequent stimuli. This priming event is thought to be critical for localizing ROS to the vicinity of the inflammation, maximizing their role in the resolution of the inflammation, and minimizing the damage to surrounding tissue. We have used a new generation of isoform-selective phosphoinositide 3-kinase (PI3K) inhibitors to show that ROS production under these circumstances is regulated by temporal control of class I PI3K activity. Stimulation of tumor necrosis factor-alpha (TNF-alpha)-primed human neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP) results in biphasic activation of PI3K; the first phase is largely dependent on PI3Kgamma, and the second phase is largely dependent on PI3Kdelta. The second phase of PI3K activation requires the first phase; it is this second phase that is augmented by TNF-alpha priming and that regulates parallel activation of ROS production. Surprisingly, although TNF-alpha-primed mouse bone marrow-derived neutrophils exhibit superficially similar patterns of PI3K activation and ROS production in response to fMLP, these responses are substantially lower and largely dependent on PI3Kgamma alone. These results start to define which PI3K isoforms are responsible for modulating neutrophil responsiveness to infection and inflammation.
Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. (1994)

The principal taxol biotransformation reaction of humans and of human hepatic in vitro preparations is 6 alpha-hydroxylation of the taxane ring, but a separate, minor hydroxylation pathway (metabolite B formation) also exists. Taxol metabolism was studied using membrane fractions from Hep G2 cells infected with recombinant vaccinia viruses that contain complementary DNAs encoding several human cytochrome P450 enzymes. Only P450 2C8 formed detectable 6 alpha-hydroxytaxol. Metabolite B formation was catalyzed by complementary DNA-expressed 3A3 and 3A4, but not by 3A5. Each P450 3A preparation catalyzed felodipine oxidation. The apparent Km and Vmax values for taxol 6 alpha-hydroxylation were 5.4 +/- 1.0 microM and 30 +/- 1.5 nmol/min/nmol P450, respectively, for complementary DNA-expressed P450 2C8; the values were 4.0 +/- 1.0 microM and 0.87 +/- 0.06 nmol/min/mg protein, respectively, for human hepatic microsomes. The inhibition of 6 alpha-hydroxytaxol formation by quercetin was competitive with an apparent Ki of 1.3 or 1.1 microM with 2C8 or hepatic microsomes, respectively; retinoic acid was inhibitory, showing an apparent Ki of 27 microM with hepatic microsomes; inhibition by tolbutamide was complex, weak, and unlikely to be clinically relevant. The correlation between hepatic 2C8 protein content and 6 alpha-hydroxytaxol formation was high (r2 = 0.82), while the correlation with 2C9 content was low (r2 = 0.38). These data show that human biotransformation routes of taxol result from catalysis by specific enzymes of two P450 families and that taxol 6 alpha-hydroxylation is a useful indicator of P450 2C8 activity in human hepatic microsomes.
Nanoassembly routes stimulate conflicting antibody quantity and quality for transmission-blocking malaria vaccines (2017)

Vaccine development efforts have recently focused on enabling strong immune responses to poorly immunogenic antigens, via display on multimerisation scaffolds or virus like particles (VLPs). Typically such studies demonstrate improved antibody titer comparing monomeric and nano-arrayed antigen. There are many such studies and scaffold technologies, but minimal side-by-side evaluation of platforms for both the amount and efficacy of antibodies induced. Here we present direct comparison of three leading platforms displaying the promising malaria transmission-blocking vaccine (TBV) target Pfs25. These platforms encompass the three important routes to antigen-scaffold linkage: genetic fusion, chemical cross-linking and plug-and-display SpyTag/SpyCatcher conjugation. We demonstrate that chemically-conjugated Qβ VLPs elicited the highest quantity of antibodies, while SpyCatcher-AP205-VLPs elicited the highest quality anti-Pfs25 antibodies for transmission blocking upon mosquito feeding. These quantative and qualitative features will guide future nanoassembly optimisation, as well as the development of the new generation of malaria vaccines targeting transmission.
Mass-encoded synthetic biomarkers for multiplexed urinary monitoring of disease (2011)

Biomarkers are becoming increasingly important in the clinical management of complex diseases, yet our ability to discover new biomarkers remains limited by our dependence on endogenous molecules. Here we describe the development of exogenously administered 'synthetic biomarkers' composed of mass-encoded peptides conjugated to nanoparticles that leverage intrinsic features of human disease and physiology for noninvasive urinary monitoring. These protease-sensitive agents perform three functions in vivo: they target sites of disease, sample dysregulated protease activities and emit mass-encoded reporters into host urine for multiplexed detection by mass spectrometry. Using mouse models of liver fibrosis and cancer, we show that these agents can noninvasively monitor liver fibrosis and resolution without the need for invasive core biopsies and substantially improve early detection of cancer compared with current clinically used blood biomarkers. This approach of engineering synthetic biomarkers for multiplexed urinary monitoring should be broadly amenable to additional pathophysiological processes and point-of-care diagnostics.
TiO2 nanocomposites with high refractive index and transparency (2011)

Transparent polymer nanocomposites with high refractive index were prepared by grafting polymer chains onto anatase TiO2 nanoparticlesvia a combination of phosphate ligand engineering and alkyne-azide “click” chemistry. Highly crystalline TiO2 nanoparticles with 5 nm diameter were synthesized by a solvothermal method and used as high refractive index filler. The synthesized phosphate-azide ligand anchors strongly onto the TiO2 nanoparticle surface and the azide end group allows for attachment of poly(glycidyl methacrylate) (PGMA) polymer chains through an alkyne-azide “click” reaction. The refractive index of the composite material increased linearly from 1.5 up to 1.8 by increasing the loading of TiO2 particles to 30 vol % (60 wt %). UV-vis spectra show that the nanocomposites exhibited a transparency around 90% throughout the visible light range. It was also found that the PGMA-grafted TiO2 nanoparticles can be well dispersed into a commercial epoxy resin, forming transparent high refractive index TiO2-epxoy nanocomposites.
Live Attenuated Influenza Viruses Containing NS1 Truncations as Vaccine Candidates against H5N1 Highly Pathogenic Avian Influenza (2008)

Due to the high mortality associated with recent, widely circulating strains of H5N1 influenza virus in poultry, the recurring introduction of H5N1 viruses from birds to humans, and the difficulties in H5N1 eradication by elimination of affected flocks, an effective vaccine against HPAI (highly pathogenic avian influenza) is highly desirable. Using reverse genetics, a set of experimental live attenuated vaccine strains based on recombinant H5N1 influenza virus A/Viet Nam/1203/04 was generated. Each virus was attenuated through expression of a hemagglutinin protein in which the polybasic cleavage site had been removed. Viruses were generated which possessed a full-length NS1 or a C-terminally truncated NS1 protein of 73, 99, or 126 amino acids. Viruses with each NS genotype were combined with a PB2 polymerase gene which carried either a lysine or a glutamic acid at position 627. We predicted that glutamic acid at position 627 of PB2 would attenuate the virus in mammalian hosts, thus increasing the safety of the vaccine. All recombinant viruses grew to high titers in 10-day-old embryonated chicken eggs but were attenuated in mammalian cell culture. Induction of high levels of beta interferon by all viruses possessing truncations in the NS1 protein was demonstrated by interferon bioassay. The viruses were each found to be highly attenuated in a mouse model. Vaccination with a single dose of any virus conferred complete protection from death upon challenge with a mouse lethal virus expressing H5N1 hemagglutinin and neuraminidase proteins. In a chicken model, vaccination with a single dose of a selected virus encoding the NS1 1-99 protein completely protected chickens from lethal challenge with homologous HPAI virus A/Viet Nam/1203/04 (H5N1) and provided a high level of protection from a heterologous virus, A/egret/Egypt/01/06 (H5N1). Thus, recombinant influenza A/Viet Nam/1203/04 viruses attenuated through the introduction of mutations in the hemagglutinin, NS1, and PB2 coding regions display characteristics desirable for live attenuated vaccines and hold potential as vaccine candidates in poultry as well as in mammalian hosts.
Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153) (2016)

Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.
Multi-Center Pre-clinical Consortia to Enhance Translation of Therapies and Biomarkers for Traumatic Brain Injury: Operation Brain Trauma Therapy and Beyond (2018)

Current approaches have failed to yield success in the translation of neuroprotective therapies from the pre-clinical to the clinical arena for traumatic brain injury (TBI). Numerous explanations have been put forth in both the pre-clinical and clinical arenas. Operation Brain Trauma Therapy (OBTT), a pre-clinical therapy and biomarker screening consortium has, to date, evaluated 10 therapies and assessed three serum biomarkers in nearly 1,500 animals across three rat models and a micro pig model of TBI. OBTT provides a unique platform to exploit heterogeneity of TBI and execute the research needed to identify effective injury specific therapies toward precision medicine. It also represents one of the first multi-center pre-clinical consortia for TBI, and through its work has yielded insight into the challenges and opportunities of this approach. In this review, important concepts related to consortium infrastructure, modeling, therapy selection, dosing and target engagement, outcomes, analytical approaches, reproducibility, and standardization will be discussed, with a focus on strategies to embellish and improve the chances for future success. We also address issues spanning the continuum of care. Linking the findings of optimized pre-clinical consortia to novel clinical trial designs has great potential to help address the barriers in translation and produce successes in both therapy and biomarker development across the field of TBI and beyond.
Gene delivery by cationic lipids: in and out of an endosome (2007)

Cationic lipids are exploited as vectors ('lipoplexes') for delivering nucleic acids, including genes, into cells for both therapeutic and cell biological purposes. However, to meet therapeutic requirements, their efficacy needs major improvement, and better defining the mechanism of entry in relation to eventual transfection efficiency could be part of such a strategy. Endocytosis is the major pathway of entry, but the relative contribution of distinct endocytic pathways, including clathrin- and caveolae-mediated endocytosis and/or macropinocytosis is as yet poorly defined. Escape of DNA/RNA from endosomal compartments is thought to represent a major obstacle. Evidence is accumulating that non-lamellar phase changes of the lipoplexes, facilitated by intracellular lipids, which allow DNA to dissociate from the vector and destabilize endosomal membranes, are instrumental in plasmid translocation into the cytosol, a prerequisite for nuclear delivery. To further clarify molecular mechanisms and to appreciate and overcome intracellular hurdles in lipoplex-mediated gene delivery, quantification of distinct steps in overall transfection and proper model systems are required.
A novel tumor necrosis factor‐α mutant with significantly enhanced cytotoxicity and receptor binding affinity (1998)

A novel tumor necrosis factor-alpha mutant (mutant M3), in which Ser and Tyr at positions 52 and 56 were substituted by Ile and Phe, respectively, along with deletion of 7 N-terminal amino acids, was prepared and its biological activities were investigated. The mutant exhibited a 14- to 24-fold increase in the cytotoxicity relative to the wild-type TNF on various cancer cell lines. The binding affinity of the mutant to TNF-R55 and TNF-R75 receptors was over 10-fold higher than that of the wild-type. TNF-alpha and the mutant show similar CD spectra in the far-UV region, indicating that the overall structure was not influenced by the mutations. The production of highly potent TNF-alpha mutant utilizing increase of hydrophobicity in the region 52-56 may provide a structural basis for a design of optimized TNF-alpha as a therapeutic purpose.