gebhart/patrepeval huggingface dataset:
568. Comparison of Antigen-Specific Immune Responses Elicited by Recombinant Simian Adenoviral Vectors with Deletions in Either E1, or E1/E3, or E1/E4 Regions (2004)

Replication-defective adenoviral vectors based on human serotype 5 (H5) have emerged as very effective vaccine carriers. However, the neutralizing antibodies to AdH5 vector by previous natural infections will very likely impair its vaccine efficacy. Therefore, our lab developed replication-defective simian adenoviral C7 vectors to circumvent interference by pre-existing immunity to human AdH5. Early regions of AdH5 genome, including E1, E3, and E4, have been suggested to influence persistence of transgene expression and vector toxicity in mice. Therefore, we used Ebola Zaire virus envelope glycoprotein (Ebo GP) as a model antigen to create a panel of C7 vaccine vectors, including C7.000CMVGP with a deletion in E1 region, C7.010CMVGP with deletions in both E1 and E3 regions, and C7.001CMVGP with deletions in both E1 and E4 regions. The transgene expression cassette was incorporated into E1 regions of these vectors. By western blot analysis, C7.000CMVGP and C7.010CMVGP vectors yielded very similar level of GP expression, while C7.001CMVGP vector produced significantly less GP protein in transduced A549 cells. By intracellular cytokine staining with H-2k restricted GP-specific peptide as stimulant, similar frequencies of CD8+ T cells producing IFN-g were observed in B10BR mice vaccinated with C7.000CMVGP or C7.001CMVGP, while slightly higher frequencies of CD8+ T cells producing IFN-g were observed in B10BR mice vaccinated with C7.010CMVGP. Total IgG responses to GP, measured by ELISA, were equivalent in serum from vaccinated mice with either of these vectors. We are currently investigating whether a single administration of either of these vectors can protect mice against lethal challenge of a mouse-adapted strain of Ebola Zaire virus. Ongoing study also indicated that better GP-specific T cell and B cell responses can be achieved by priming with either C7.010CMVGP or C7.001CMVGP and boosting with H5CMVGP than by priming with C7.000CMVGP and boosting with H5CMVGP. Overall, these data suggested that multi-defective simian adenoviral vectors may be better vaccine carriers.
Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina. (2000)

The presence of lutein and zeaxanthin in human ROS membranes raises the possibility that they function as antioxidants in this cell compartment. The finding of a higher concentration of these carotenoids in ROS of the perifoveal retina lends support to their proposed protective role in age-related macular degeneration.
Antiinflammatory activity of N-(2-benzoylphenyl)alanine derivatives (1984)

A series of N-(2-benzoylphenyl)alanine derivatives were synthesized and tested for antiinflammatory activity in the Evans blue-carrageenan induced pleural effusion assay. The target compounds were envisioned to bind to a receptor site on the cyclooxygenase enzyme by a mechanism first proposed by Appleton and Brown. Of the 21 compounds prepared, two were found to be one-tenth as potent as indomethacin in the pleurisy model and one compound was tested and found to be weakly active in the adjuvant arthritis model.
The Mammalian Target of Rapamycin Complex 1 Regulates Leptin Biosynthesis in Adipocytes at the Level of Translation: The Role of the 5′-Untranslated Region in the Expression of Leptin Messenger Ribonucleic Acid (2008)

Leptin production by adipose cells in vivo is increased after feeding and decreased by food deprivation. However, molecular mechanisms that control leptin expression in response to food intake remain unknown. Here, we test the hypothesis that leptin expression in adipose cells is regulated by nutrient- and insulin-sensitive mammalian target of rapamycin complex 1 (mTORC1)-mediated pathway. The activity of mTORC1 in 3T3-L1 adipocytes was up-regulated by stable expression of either constitutively active Rheb or dominant-negative AMP-activated protein kinase. In both cases, expression of endogenous leptin was significantly elevated at the level of translation. To investigate the role of leptin 5'-untranslated region (UTR) in the regulation of protein expression, we created bicistronic reporter constructs with and without the 5'-UTR. We found that the presence of leptin 5'-UTR renders mRNA resistant to regulation by mTORC1. It appears, therefore, that mTORC1 controls translation of leptin mRNA via a novel mechanism that does not require the presence of either the 5'-terminal oligopyrimidine tract or the 5'-UTR.
Reversible expression of flagella in Campylobacter jejuni (1985)

Campylobacter jejuni 81116 and A3249 undergo a bidirectional transition between flagellated (Fla+) and aflagellated (Fla-) phenotypes. When measured in culture medium, the Fla+----Fla- transition occurred at a rate of 3.1 X 10(-3) to 5.9 X 10(-3) per cell per generation, and the Fla- to Fla+ transition occurred at a rate of 4.0 X 10(-7) to 8.0 X 10(-7) per cell per generation. However, passage through a rabbit intestine markedly favored the Fla+ phenotype.
Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle (2005)

Glycogen synthase kinase-3 (GSK3) has been implicated in the multifactorial etiology of skeletal muscle insulin resistance in animal models and in human type 2 diabetic subjects. However, the potential molecular mechanisms involved are not yet fully understood. Therefore, we determined if selective GSK3 inhibition in vitro leads to an improvement in insulin action on glucose transport activity in isolated skeletal muscle of insulin-resistant, prediabetic obese Zucker rats and if these effects of GSK3 inhibition are associated with enhanced insulin signaling. Type I soleus and type IIb epitrochlearis muscles from female obese Zucker rats were incubated in the absence or presence of a selective, small organic GSK3 inhibitor (1 microM CT118637, Ki < 10 nM for GSK3alpha and GSK3beta). Maximal insulin stimulation (5 mU/ml) of glucose transport activity, glycogen synthase activity, and selected insulin-signaling factors [tyrosine phosphorylation of insulin receptor (IR) and IRS-1, IRS-1 associated with p85 subunit of phosphatidylinositol 3-kinase, and serine phosphorylation of Akt and GSK3] were assessed. GSK3 inhibition enhanced (P <0.05) basal glycogen synthase activity and insulin-stimulated glucose transport in obese epitrochlearis (81 and 24%) and soleus (108 and 20%) muscles. GSK3 inhibition did not modify insulin-stimulated tyrosine phosphorylation of IR beta-subunit in either muscle type. However, in obese soleus, GSK3 inhibition enhanced (all P < 0.05) insulin-stimulated IRS-1 tyrosine phosphorylation (45%), IRS-1-associated p85 (72%), Akt1/2 serine phosphorylation (30%), and GSK3beta serine phosphorylation (39%). Substantially smaller GSK3 inhibitor-mediated enhancements of insulin action on these insulin signaling factors were observed in obese epitrochlearis. These results indicate that selective GSK3 inhibition enhances insulin action in insulin-resistant skeletal muscle of the prediabetic obese Zucker rat, at least in part by relieving the deleterious effects of GSK3 action on post-IR insulin signaling. These effects of GSK3 inhibition on insulin action are greater in type I muscle than in type IIb muscle from these insulin-resistant animals.
Dexmedetomidine inhibits inflammation in microglia cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades (2018)

NOD-like receptor 3 (NLRP3) plays critical roles in the initiation of inflammasome-mediated inflammation in microglia, thus becomes an important therapeutic target of Alzheimer's disease (AD). Dexmedetomidine (Dex), a new type of clinical anesthetic agent, shows anti-inflammatory properties and inhibits postoperative cognitive dysfunction in AD patients. The present study was aimed to investigate effect of Dex on NLRP3 activity in activated microglia and reveal the underlying mechanisms. The human microglia clone 3 (HMC3) cells were exposed to 100 ng/ml LPS and 5 mM ATP, in the presence and absence of doses of Dex. Data from ELISA and Western blot assays showed that Dex abrogated the promoting effects of LPS/ATP on the release of pro-inflammatory cytokines including IL-1β and IL-18 in the cell medium and the expression of NLRP3 and its downstream target caspase-1 in HMC3 cells. Furthermore, the present study found that exposure of HMC3 cells to LPS/ATP increased nuclear protein levels of transcription factor c-Fos, but treatment with Dex reversed the increase in c-Fos, as indicated by Western blot and immunofluorescence measures. Luciferase reported assay revealed that c-Fos can bind to the promoter region of <i>NLRP3</i> gene and positively regulate the expression. These results suggest that Dex inhibiting c-Fos nuclear protein levels promoted by LPS/ATP blocks the up-regulation of NLRP3. This suggestion is supported by co-immunoprecipitation and PCR studies, in which Dex decreased the amount of c-Fos that binds to NLRP3 under the stimulation of LPS/ATP. The present study revealed that Dex inhibits inflammation in microglia cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades, which adds new understanding of the anti-inflammatory mechanism of Dex.
Design of liposomes to improve delivery of macrophage-augmenting agents to alveolar macrophages. (1980)

Factors affecting the localization of liposomes injected i.v. in the lung have been studied to identify the optimal type of liposome for delivery of macrophage-activating agents to the lung to augment the tumoricidal activity of alveolar macrophages (AM). Comparison of pulmonary retention of liposomes of differing size, surface charge, and composition following i.v. injection into inbred mice revealed that large multilamellar (MLV) and reversed-phase-evaporation (REV) liposomes are arrested in the lung more efficiently than are small unilamellar liposomes of identical lipid composition. MLV and REV containing negatively charged amphiphiles arrest in the lung more efficiently than do neutral MLV's or REV's or MULV's and REV's containing positively charged amphiphiles. Comparison of the ability of liposomes containing a variety of negatively charged amphiphiles to localize in the lung established that optimal localization was achieved using MLV and REV prepared from phosphatidylserine (PS) and phosphatidylcholine (PC) (3:7 mol ratio) or PS:PC:lysolecithin (4.95:4.95:0.1 mol ratio). The proportion of these liposomes retained in the lung after i.v. injection was constant over a wide dose range (0.02 to 20 mumol phospholipid per mouse), but hemodilution due to i.v. inoculation of liposomes in volumes exceeding 0.2 ml reduced retention in the lung. Uptake of liposomes by AM was demonstrated by showing that i.v. injection of PS:PC MLV liposomes containing fluorescein-labeled bovine serum albumin resulted in localization of fluorescence within AM recovered by pulmonary lavage. Similarly, AM recovered after i.v. injection of PS:PC MLV liposomes containing lymphokine preparations rich in macrophage-activating factor (MAF) activity exhibited tumoricidal activity. In contrast, macrophages recovered from control animals given injections of unencapsulated MAF or liposomes containing lymphocyte supernatants without MAF activity were devoid of cytotoxic activity. Neutral (PC) MLV liposomes containing MAF, which show only very limited retention in the lung, were ineffective in activating AM in situ. We conclude that negatively charged MLV liposomes (PS:PC, 3:7 mol ratio) localize efficiently in the lung and that macrophage-activating agents encapsulated within such liposomes can successfully activate lung macrophages in situ.
Oncolytic vaccinia virus for the treatment of cancer (2011)

Vaccinia virus has great potential in cancer gene therapy, especially when used as an oncolytic virus. In particular, JX-594 has shown promising preclinical and clinical data, and a multi-continental randomized Phase III trial in hepatocellular carcinoma is expected to start soon.
A HER2-specific Modified Fc Fragment (Fcab) Induces Antitumor Effects Through Degradation of HER2 and Apoptosis (2015)

FS102 is a HER2-specific Fcab (Fc fragment with antigen binding), which binds HER2 with high affinity and recognizes an epitope that does not overlap with those of trastuzumab or pertuzumab. In tumor cells that express high levels of HER2, FS102 caused profound HER2 internalization and degradation leading to tumor cell apoptosis. The antitumor effect of FS102 in patient-derived xenografts (PDXs) correlated strongly with the HER2 amplification status of the tumors. Superior activity of FS102 over trastuzumab or the combination of trastuzumab and pertuzumab was observed in vitro and in vivo when the gene copy number of HER2 was equal to or exceeded 10 per cell based on quantitative polymerase chain reaction (qPCR). Thus, FS102 induced complete and sustained tumor regression in a significant proportion of HER2-high PDX tumor models. We hypothesize that the unique structure and/or epitope of FS102 enables the Fcab to internalize and degrade cell surface HER2 more efficiently than standard of care antibodies. In turn, increased depletion of HER2 commits the cells to apoptosis as a result of oncogene shock. FS102 has the potential of a biomarker-driven therapeutic that derives superior antitumor effects from a unique mechanism-of-action in tumor cells which are oncogenically addicted to the HER2 pathway due to overexpression.
Interleukin‐8 and de novo mammalian angiogenesis (1996)

In the rat mesenteric-window angiogenesis assay (MWAA), the test tissue is natively vascularized, lacks significant physiological angiogenesis and its homeostasis is unperturbed by surgical intervention. Using the rat MWAA, it is shown here that interleukin-8 (IL-8), administered at approximately physiological doses, is able to induce de novo angiogenesis. Human recombinant IL-8 was administered intraperitoneally at two daily doses of 25 pM, 250 pM and 2.5 nM for 5 consecutive days (days 0-4). Using microscopic, computer-aided techniques including image analysis, the de novo angiogenic response was quantified in groups of animals on days 7, 14 and 21 in terms of the relative vascularized area (VA), a measure of the microvascular spatial extension, and the microvascular length (MVL), a measure of microvascular density or length. The total microvascular length (TMVL) was computed from VA x MVL. A statistically significant angiogenic effect was found in terms of MVL on day 7 and in terms of VA and TMVL on day 14 following the treatment with 2.5 nM, whereas MVL was significantly increased in statistical terms on day 14 following the treatment with IL-8 at the low dose of 25 pM. Notably, IL-8 at the intermediate dose of 250 pM did not induce a statistically significant angiogenic effect in terms of VA, MVL or TMVL on any observation occasion, thereby suggesting that the dose-related angiogenic effect of IL-8 may be nonlinear. This appears to be the first paper showing that IL-8 is able to induce de novo angiogenesis in normally vascularized mammalian tissue.
Direct interaction with large-scale display systems using infrared laser tracking devices (2003)

Existing large scale display systems generally adopt an indirect approach to user interaction. This is due to the use of standard desktop-oriented devices, such as a mouse on a desk, to control the large wall-sized display. By using an infrared laser pointer and an infrared tracking device, a more direct interaction with the large display can be achieved, thereby reducing the cognitive load of the user and improving their mobility. The challenge in designing such systems is to allow users to interact with objects on the display naturally and easily. Our system addresses this with hotspots, regions surrounding objects of interest, and gestures, movements made with the laser pointer which triggers an action, similar to those found in modern web browsers (e.g. Mozilla and Opera). Finally, these concepts are demonstrated by an add-in module for Microsoft PowerPoint using the NaturalPoint^TM Smart-Nav^TM tracking device.
Multi-robot cooperation through incremental plan-merging (2002)

This paper presents an approach we have recently developed for multi-robot cooperation. It is based on a paradigm where robots incrementally merge their plans into a set of already coordinated plans. This is done through exchange of information about their current state and their future actions. This leads to a generic framework which can be applied to a variety of tasks and applications. The paradigm, called plan-merging paradigm, is presented and illustrated through its application to planning, execution and control of a large fleet of a autonomous mobile robots for load transport tasks in a structured environment.
Cell Cycle-Related Changes in Repopulating Capacity of Human Mobilized Peripheral Blood CD34+ Cells in Non-Obese Diabetic/Severe Combined Immune-Deficient Mice (1998)

Most primitive hematopoietic progenitor cells reside in vivo within the G0/G1 phase of the cell cycle. By simultaneous DNA/RNA staining it is possible to distinguish G0 and G1 states and to isolate cells in defined phases of the cell cycle. We report here the use of cell cycle fractionation to separate human mobilized peripheral blood (MPB) CD34(+) cells capable of repopulating the bone marrow (BM) of non-obese diabetic/severe combined immune-deficient (NOD/SCID) mice. In freshly isolated MPB, repopulating cells were predominant within the G0 phase, because transplantation of CD34(+) cells residing in G0 (G0CD34(+)) resulted on average in a 16.6- +/- 3.2-fold higher BM chimerism than infusion of equal numbers of CD34(+) cells isolated in G1. We then investigated the effect of ex vivo cell cycle progression, in the absence of cell division, on engraftment capacity. Freshly isolated G0CD34(+) cells were activated by interleukin-3 (IL-3), stem cell factor (SCF), and flt3-ligand (FL) for a 36-hour incubation period during which a fraction of cells progressed from G0 into G1 but did not complete a cell cycle. The repopulating capacity of stimulated cells was markedly diminished compared with that of unmanipulated G0CD34(+) cells. Cells that remained in G0 during the 36-hour incubation period and those that traversed into G1 were sorted and assayed separately in NOD/SCID recipients. The repopulating ability of cells remaining in G0 was insignificantly reduced compared with that of unstimulated G0CD34(+) cells. On the contrary, CD34(+) cells traversing from G0 into G1 were largely depleted of repopulating capacity. Similar results were obtained when G0CD34(+) cells were activated by the combination of thrombopoietin-SCF-FL. These studies provide direct evidence of the quiescent nature of cells capable of repopulating the BM of NOD/SCID mice. Furthermore, these data also demonstrate that G0-G1 progression in vitro is associated with a decrease in engraftment capacity.
The crystal structure of α-bungarotoxin at 2.5 Å resolution: relation to solution structure and binding to acetylcholine receptor (1986)

We report collection of 2.5 A resolution X-ray diffraction data from newly grown crystals of the rare 'small unit cell' form of the long snake neurotoxin, alpha-bungarotoxin. The previous model of the molecule has been rebuilt, and refined using least-square methods to a crystallographic residual of 0.24 at 2.5 A resolution. alpha-Bungarotoxin's crystal structure is compared with the crystal structures of two other snake neurotoxins (cobratoxin and erabutoxin), and with its solution structure inferred from spectroscopic studies. Significant differences include less beta-sheet in bungarotoxin's crystal structure than in solution, or in the crystal structures of other neurotoxins, and an unusual orientation in the crystal of the invariant tryptophan. The functional, binding surface of bungarotoxin is described; it consists primarily of hydrophobic and hydrogen-bonding groups and only a few charged side-chains. The structure is compared with experimental binding parameters for neurotoxins.
Human immunodeficiency virus type 1 pol gene mutations in an AIDS patient treated with multiple antiretroviral drugs (1993)

Multiple mutations were found in the human immunodeficiency virus pol gene following treatment of an AIDS patient with antiretroviral drugs. After approximately 2.5 years of monthly alternating therapy with 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), most of the pol sequences amplified from the patient's peripheral blood mononuclear cell DNA contained known AZT resistance mutations at codons 41, 67, and 215 and a putative ddC resistance mutation at codon 69 as well as other novel mutations. These mutations persisted for 6 months after the patient was switched to 2',3'-dideoxyinosine monotherapy. Mutations known to be associated with 2',3'-dideoxyinosine resistance did not occur during this time. Antiviral susceptibility testing of point mutants, introduced into the genetic background of laboratory strain NL4-3, showed that the codon 41 mutation antagonized ddC resistance when present with the codon 69 mutation. However, this antagonism was not found with a chimeric mutant containing the patient's pol gene sequence from codons 25 to 218, implying that other mutations compensated for the antagonism. Thus, alternating therapy with AZT and ddC resulted in the selection of viruses resistant to both drugs.
Structural Features that Give Rise to the Unusual Stability of RNA Hairpins Containing GNRA Loops (1991)

The most frequently occurring RNA hairpins in 16S and 23S ribosomal RNA contain a tetranucleotide loop that has a GNRA consensus sequence. The solution structures of the GCAA and GAAA hairpins have been determined by nuclear magnetic resonance spectroscopy. Both loops contain an unusual G-A base pair between the first and last residue in the loop, a hydrogen bond between a G base and a phosphate, extensive base stacking, and a hydrogen bond between a sugar 2'-end OH and a base. These interactions explain the high stability of these hairpins and the sequence requirements for the variant and invariant nucleotides in the GNRA tetranucleotide loop family.
The relationship of eosinophil granule proteins to ions in the sputum of patients with cystic fibrosis (2000)

Increased sputum levels of eosinophil granule proteins have been reported despite normal eosinophil numbers in peripheral blood and in the lung in cystic fibrosis (CF). Mechanisms of eosinophil priming and activation are still unclear in CF. In the present study we investigated whether ion concentrations in the sputa of CF patients are related to eosinophil activity. We assessed concentrations of eosinophil cationic protein (ECP), eosinophil protein X (EPX), major basic protein (MBP) and ions (Na+, Cl-, Ca2+, Mg2+) in sputum samples of 29 children with CF as well as in 10 controls with bronchial asthma. Patients with CF demonstrated significantly higher levels of ECP, Na+, Cl- and Ca2+ levels than asthmatics (P < 0.04, P < 0.0001, P < 0.0001, P < 0.02). No differences were seen between concentrations of EPX and Mg2+ in the two groups. In CF, eosinophil granule proteins correlated significantly with Ca2+ and Mg2+ concentrations (ECP, P < 0.0001, r = 0.65, P < 0.0001, r = 0.66; MBP, P < 0.03, r = 0.41, P < 0.03, r = 0.42), furthermore inversely with Cl- concentrations (ECP, P < 0. 0003, r = - 0.63; EPX, P < 0.02, r = - 0.45; MBP, P < 0.03, r = - 0. 41) but not with Na+ levels. ECP, Na+ and Cl- were also correlated with lung function variables (FVC, P < 0.04, r = - 0.38, P < 0.02, r = 0.44, P < 0.03, r = 0.41; FEV1, P < 0.007, r = - 0.49, P < 0.006, r = 0.5, P < 0.008, r = 0.48; MEF50, P < 0.003, r = - 0.54, NS, P < 0.03, r = 0.42; MEF25, P < 0.039, r = - 0.4, P < 0.005, r = 0.51, P < 0.05, r = 0.37). Our results demonstrated a significant relationship of eosinophil degranulation and ions in CF, indicating that ion composition in CF sputa may be at least partly be responsible for high levels of eosinophil products despite low eosinophil numbers.