gebhart/patrepeval huggingface dataset:
Angiopoietin-2 Is Critical for Cytokine-Induced Vascular Leakage (2013)

Genetic experiments (loss-of-function and gain-of-function) have established the role of Angiopoietin/Tie ligand/receptor tyrosine kinase system as a regulator of vessel maturation and quiescence. Angiopoietin-2 (Ang-2) acts on Tie2-expressing resting endothelial cells as an antagonistic ligand to negatively interfere with the vessel stabilizing effects of constitutive Ang-1/Tie-2 signaling. Ang-2 thereby controls the vascular response to inflammation-inducing as well as angiogenesis-inducing cytokines. This study was aimed at assessing the role of Ang-2 as an autocrine (i.e. endothelial-derived) regulator of rapid vascular responses (within minutes) caused by permeability-inducing agents. Employing two independent in vivo assays to quantitatively assess vascular leakage (tracheal microsphere assay, 1-5 min and Miles assay, 20 min), the immediate vascular response to histamine, bradykinin and VEGF was analyzed in Ang-2-deficient (Ang-2(-/-)) mice. In comparison to the wild type control mice, the Ang2(-/-) mice demonstrated a significantly attenuated response. The Ang-2(-/-) phenotype was rescued by systemic administration (paracrine) of an adenovirus encoding Ang-2. Furthermore, cytokine-induced intracellular calcium influx was impaired in Ang-2(-/-) endothelioma cells, consistent with reduced phospholipase activation in vivo. Additionally, recombinant human Ang-2 (rhAng-2) alone was unable to induce vascular leakage. In summary, we report here in a definite genetic setting that Ang-2 is critical for multiple vascular permeability-inducing cytokines.
Early Neuropathologic Effects of Mild or Moderate Hypoxemia after Controlled Cortical Impact Injury in Rats (1997)

Hypoxemia has detrimental effects after traumatic brain injury (TBI) in both experimental models and humans. The purpose of this study was to determine the effect of mild or moderate hypoxemia on early histologic and motor functional outcome after controlled cortical impact (CCI) in rats. Anesthetized rats underwent CCI and were randomized to receive mild (FiO2 = 13%, n = 6), moderate (FiO2 = 11%, n = 9), or no (FiO2 = 33%, n = 6) hypoxemia for 30 min after trauma. Sham-operated rats without hypoxemia (n = 7) were used as controls. Motor function (beam balance latency) was assessed on days 0-5. Rats were killed 7 days after injury and their brains removed for assessment of survival of hippocampal neurons and contusion volume. Terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end labeling (TUNEL) was performed on brain sections from rats killed at 6, 24, and 72 h after CCI and moderate hypoxemia to assess DNA fragmentation in situ. Mild and moderate hypoxemia augmented motor function deficits after CCI in a dose-dependent manner. Moderate hypoxemia after CCI reduced 7-day survival of CA3 neurons but not CA1 neurons vs. sham (55 [46-86] vs. 99 [95-130], p < 0.05, and 79 [63-86] vs. 101 [81-123], NS, respectively; % uninjured hemisphere, median [range]). The addition of mild or moderate hypoxemia did not increase contusion volume. TUNEL-positive neurons were seen in ipsilateral cortex and dentate gyrus at 6, 24, and 72 h after trauma, and in ipsilateral CA3 hippocampal neurons and thalamus at 24 and 72 h. Moderate hypoxemia augments CA3 neuronal death and early motor functional deficits after CCI. The pattern of DNA fragmentation in selectively vulnerable neurons suggests that apoptosis may play a role in the delayed neuronal death seen after TBI.
α-Amino Acid Phenolic Ester Derivatives:  Novel Water-Soluble General Anesthetic Agents Which Allosterically Modulate GABAA Receptors (2001)

In the search for a novel water-soluble general anesthetic agent the activity of an alpha-amino acid phenolic ester lead, identified from patent literature, was markedly improved. In addition to improving in vivo activity in mice, good in vitro activity at GABA(A) receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo activity was found, supporting a protein-mediated mechanism of action for anesthesia involving allosteric modulation of GABA(A) receptors. alpha-Amino acid phenolic ester 19, as the hydrobromide salt Org 25435, was selected for clinical evaluation since it retained the best overall anesthetic profile coupled with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and recovery from anesthesia at doses of 3 and 4 mg/kg.
Antimicrobial peptides melittin and cecropin inhibit replication of human immunodeficiency virus 1 by suppressing viral gene expression. (1998)

Antimicrobial peptides are effectors of innate immunity, providing their hosts with rapid non-specific defence against parasitic invaders. In this report, the effects are assessed of two well-characterized antimicrobial amphipathic peptides (melittin and cecropin) on human immunodeficiency virus 1 (HIV-1) replication and gene expression in acutely infected cells at subtoxic concentrations. Production of infectious, cell-free virus was inhibited in a dose-dependent manner, with ID50 values in the range 0.9-1.5 microM for melittin and 2-3 microM for cecropin. Analysis of the effect of melittin on cell-associated virus production revealed decreased levels of Gag antigen and HIV-1 mRNAs. Transient transfection assays with HIV long terminal repeat (LTR)-driven reporter gene plasmids indicated that melittin has a direct suppressive effect on activity of the HIV LTR. HIV LTR activity was also reduced in human cells stably transfected with retroviral expression plasmids for the melittin or cecropin gene. It is concluded that antimicrobial peptides such as melittin and cecropin are capable of inhibiting cell-associated production of HIV-1 by suppressing HIV-1 gene expression.
Site-Specific Modification of Pre-mRNA: the 2′-Hydroxyl Groups at the Splice Sites (1992)

A simple and efficient method for synthesizing long, site-specifically modified RNA molecules was developed whereby segments of RNA were joined with the use of bacteriophage T4 DNA ligase. A single hydrogen or O-methyl group was substituted for the 2'-hydroxyl group at either splice site of a nuclear pre-messenger RNA substrate. Splicing of the modified pre-messenger RNA's in vitro revealed that, although a 2'-hydroxyl is not absolutely required at either splice site, the 2'-hydroxyl at the 3' splice site is important for the second step of splicing. These results are compared to previous studies of analogous 2'-hydroxyl groups in the self-splicing Tetrahymena group I intron.
Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment (2006)

The chimeric anti-CD30 IgG1, cAC10, conjugated to eight equivalents of monomethyl auristatin E (MMAE) was previously shown to have potent antitumor activity against CD30-expressing tumors xenografts in mice. Moreover, the therapeutic index was increased by lowering the stoichiometry from 8 drugs/antibody down to 2 or 4. Limitations of such 'partially-loaded' conjugates are low yield (10-30%) as they are purified from mixtures with variable stoichiometry (0-8 drugs/antibody), and heterogeneity as the 2 or 4 drugs are distributed over eight possible cysteine conjugation sites. Here, the solvent-accessible cysteines that form the interchain disulfide bonds in cAC10 were replaced with serine, to reduce the eight potential conjugation sites down to 4 or 2. These Cys-->Ser antibody variants were conjugated to MMAE in near quantitative yield (89-96%) with defined stoichiometries (2 or 4 drugs/antibody) and sites of drug attachment. The engineered antibody-drug conjugates have comparable antigen-binding affinities and in vitro cytotoxic activities with corresponding purified parental antibody-drug conjugates. Additionally, the engineered and parental antibody-drug conjugates have similar in vivo properties including antitumor activity, pharmacokinetics and maximum tolerated dose. Our strategy for generating antibody-drug conjugates with defined sites and stoichiometries of drug loading is potentially broadly applicable to other antibodies as it involves engineering of constant domains.
Complete correction of hemophilia B phenotype by FIX-Padua skeletal muscle gene therapy in an inhibitor-prone dog model (2018)

Key Points Skeletal muscle–directed expression of FIX-Padua resulted in complete correction of HB phenotype in an inhibitor-prone dog model. Long-term immune tolerance to FIX is sustained over years upon multiple challenges with recombinant FIX protein in 2 HB models.
Protection from experimental allergic encephalomyelitis by application of a bacterial superantigen (1992)

Certain bacterial and viral T cell stimulating proteins ('superantigens') are known to be very potent activators of T cells with certain V beta receptors. When applied in vivo these molecules induce anergy in those T cells responding to them. In this study we have investigated the influence of staphylococcal enterotoxins (SE) on myelin basic protein (MBP)-specific T cells in Lewis rats. As MBP-specific T cells in rats belong exclusively to the V beta 8.2+ CD4+ subset, the induction of experimental allergic encephalomyelitis (EAE) allows for an estimation of the functional state of the respective V beta-bearing T cells after enterotoxin-induced activation. In vitro, various MBP-specific T cell lines showed a strong selective proliferative response to staphylococcal enterotoxin E (SEE) but not to other SE. The in vitro activation by SEE induced encephalitogenic potential in these cells. After application of SEE to Lewis rats the susceptibility to induction of EAE was completely abrogated. Such SEE-treated and MBP-challenged rats did not exhibit any signs of disease and their T cells did not respond to MBP in proliferation tests. This abrogation of EAE was only found with a superantigen capable of interacting specifically with V beta 8.2+ T cells. Superantigen-mediated induction of unresponsiveness may have relevance for the analysis of pathogenetic mechanisms and for therapeutic considerations in certain T cell-mediated autoimmune diseases.
Nairovirus RNA Sequences Expressed by a Semliki Forest Virus Replicon Induce RNA Interference in Tick Cells (2005)

We report the successful infection of the cell line ISE6 derived from Ixodes scapularis tick embryos by the tick-borne Hazara virus (HAZV), a nairovirus in the family Bunyaviridae. Using a recombinant Semliki Forest alphavirus replicon that replicates in these cells, we were able to inhibit replication of HAZV, and we showed that this blockage is mediated by the replication of the Semliki Forest alphavirus replicon; the vector containing the HAZV nucleoprotein gene in sense or antisense orientation efficiently inhibited HAZV replication. Moreover, expression of a distantly related nucleoprotein gene from Crimean-Congo hemorrhagic fever nairovirus failed to induce HAZV silencing, indicating that the inhibition is sequence specific. The resistance of these cells to replicate HAZV correlated with the detection of specific RNase activity and 21- to 24-nucleotide-long small interfering RNAs. Altogether, these results strongly suggest that pathogen-derived resistance can be established in the tick cells via a mechanism of RNA interference.
Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. (1998)

Previous studies have implicated the novel peptide antibiotic human beta-defensin 1 (hBD-1) in the pathogenesis of cystic fibrosis. We describe in this report the isolation and characterization of the second member of this defensin family, human beta-defensin 2 (hBD-2). A cDNA for hBD-2 was identified by homology to hBD-1. hBD-2 is expressed diffusely throughout epithelia of many organs, including the lung, where it is found in the surface epithelia and serous cells of the submucosal glands. A specific antibody made of recombinant peptide detected hBD-2 in airway surface fluid of human lung. The fully processed peptide has broad antibacterial activity against many organisms, which is salt sensitive and synergistic with lysozyme and lactoferrin. These data suggest the existence of a family of beta-defensin molecules on mucosal surfaces that in the aggregate contributes to normal host defense.
Localized and efficient curli nucleation requires the chaperone-like amyloid assembly protein CsgF (2009)

Elucidation of the early events in amyloidogenesis is key to understanding the pathology of, and developing therapies for, amyloid diseases. Critical informants about these early events are amyloid assembly proteins that facilitate the transition from monomer to amyloid fiber. Curli are a functional amyloid whose in vivo polymerization requires a dedicated nucleator protein, CsgB, and an assembly protein, CsgF. Here we demonstrate that without CsgF, curli subunits are released from the cell into the media and are inefficiently polymerized, resulting in fewer and mislocalized curli fibers. CsgF is secreted to the cell surface, where it mediates the cell-association and protease-resistance of the CsgB nucleator, suggesting that CsgF is required for specific localization and/or chaperoning of CsgB for full nucleator activity. CsgF is thus critical to achieve localized and efficient nucleation of fiber subunits into functional, cell-associated amyloid.
Blind channel and carrier frequency offset estimation using periodic modulation precoders (2000)

Previous results have shown that blind channel estimators, which are resilient to the location of channel zeros, color of additive stationary noise, and channel order overestimation errors, can be developed for communication systems equipped with transmitter-induced cyclostationarity precoders. The present paper extends these blind estimation approaches to the more general problem of estimating the unknown intersymbol interference (ISI) and carrier frequency offset/Doppler effects using such precoders. An all-digital open-loop carrier frequency offset estimator is developed, and its asymptotic (large sample) performance is analyzed and compared to the Cramer-Rao bound (CRB). A subspace-based channel identification approach is proposed for estimating, in closed-form, the unknown channel, regardless of the channel spectral nulls. It is shown that compensating for the carrier frequency offset introduces no penalty in the asymptotic performance of the subspace channel estimator. Simulations are presented to corroborate the performance of the proposed algorithms.
Antitumour Effects of 4-Pyridoxate Diammine Hydroxy Platinum, a Novel Cisplatin Derivative, Against Malignant Gliomas In-vitro and In-vivo: A Comparison with Cisplatin (1997)

Antitumour effects of a newly synthesized cisplatin derivative, 4-pyridoxate diammine hydroxy platinum (PyPt), against brain tumours in-vitro and in-vivo were evaluated and compared with cisplatin.



In-vitro chemosensitivity of rat (9L and C6) and human (T98G and A172) malignant glioma cell lines was measured using the MTT assay method. The concentration required for 50% growth inhibition (IC50) for PyPt was significantly higher than cisplatin for 9L, C6 and T98G, but significantly lower for A172. This indicates that PyPt is more effective than cisplatin against the human A172 glioma cell line. For in-vivo experiments, rat brain was inoculated with 9L glioma, and PyPt (2.0 mg kg−1) and cisplatin (1.4 mg kg−1) were administered as selective intracarotid infusions. A significant improvement in survival time compared with control animals was found.



Although in-vitro antitumour activity of PyPt was significantly lower than cisplatin in the 9L cell line, in-vivo activity was almost equal to that of cisplatin. Platinum concentration in the brain tumour, 30 min after administration of PyPt, was 2.4-times significantly higher than with cisplatin. This suggests that drug delivery efficiency to the 9L glioma is greater for PyPt than cisplatin. PyPt is an effective cisplatin derivative for the treatment of brain tumours.
The Nimrod Routing Architecture (1996)

We present a scalable internetwork routing architecture, called Nimrod. The Nimrod architecture is designed to accommodate a dynamic internetwork of arbitrary size with heterogeneous service requirements and restrictions and to admit incremental deployment throughout an internetwork. The key to Nimrod's scalability is its ability to represent and manipulate routing-related information at multiple levels of abstraction.
<title>Lightweight rovers for Mars science exploration and sample return</title> (1997)

We report on the development of new mobile robots for Mars exploration missions. These 'lightweight survivable rover (LSR)' systems are of potential interest to both space and terrestrial applications, and are distinguished from more conventional designs by their use of new composite materials, collapsible running gear, integrated thermal-structural chassis, and other mechanical features enabling improved mobility and environmental robustness at reduced mass, volume, and power. Our first demonstrated such rover architecture, LSR-1, introduces running gear based on 2D composite struts and 3D machined composite joints, a novel collapsible hybrid composite-aluminum wheel design, a unit-body structural- thermal chassis with improved internal temperature isolation and stabilization, and a spot-pushbroom laser/CCD sensor enabling accurate, fast hazard detection and terrain mapping. LSR-1 is an approximately .7 $MIL 1.0 meter(Lambda) 2(W X L) footprint six-wheel (20 cm dia.) rocker-bogie geometry vehicle of approximately 30 cm ground clearance, weighing only 7 kilograms with an onboard .3 kilogram multi-spectral imager and spectroscopic photometer. By comparison, NASA/JPL's recently flown Mars Pathfinder rover Sojourner is an 11+ kilogram flight experiment (carrying a 1 kg APXS instrument) having approximately .45 X .6 meter(Lambda) 2(WXL) footprint and 15 cm ground clearance, and about half the warm electronics enclosure (WEE) volume with twice the diurnal temperature swing (-40 to +40 degrees Celsius) of LSR- 1 in nominal Mars environments. We are also developing a new, smaller 5 kilogram class LSR-type vehicle for Mars sample return -- the travel to, localization of, pick-up, and transport back to an Earth return ascent vehicle of a sample cache collected by earlier science missions. This sample retrieval rover R&D prototype has a completely collapsible mobility system enabling rover stowage to approximately 25% operational volume, as well an actively articulated axle, allowing changeable pose of the wheel strut geometry for improved transverse and manipulation characteristics.
Incorporation of Monodisperse Oligoethyleneglycol Amino Acids into Anticonvulsant Analogues of Galanin and Neuropeptide Y Provides Peripherally Acting Analgesics (2012)

Delivery of neuropeptides into the central and/or peripheral nervous systems supports development of novel neurotherapeutics for the treatment of pain, epilepsy and other neurological diseases. Our previous work showed that the combination of lipidization and cationization applied to anticonvulsant neuropeptides galanin (GAL) and neuropeptide Y (NPY) improved their penetration across the blood-brain barrier yielding potent antiepileptic lead compounds, such as Gal-B2 (NAX 5055) or NPY-B2. To dissect peripheral and central actions of anticonvulsant neuropeptides, we rationally designed, synthesized and characterized GAL and NPY analogues containing monodisperse (discrete) oligoethyleneglycol-lysine (dPEG-Lys). The dPEGylated analogues Gal-B2-dPEG(24), Gal-R2-dPEG(24) and NPY-dPEG(24) displayed analgesic activities following systemic administration, while avoiding penetration into the brain. Gal-B2-dPEG(24) was synthesized by a stepwise deprotection of orthogonal 4-methoxytrityl and allyloxycarbonyl groups, and subsequent on-resin conjugations of dPEG(24) and palmitic acids, respectively. All the dPEGylated analogues exhibited substantially decreased hydrophobicity (expressed as logD values), increased in vitro serum stabilities and pronounced analgesia in the formalin and carrageenan inflammatory pain assays following systemic administration, while lacking apparent antiseizure activities. These results suggest that discrete PEGylation of neuropeptides offers an attractive strategy for developing neurotherapeutics with restricted penetration into the central nervous system.
Multistep Synthesis Using Modular Flow Reactors: Bestmann–Ohira Reagent for the Formation of Alkynes and Triazoles (2009)

Multistep in flow: The Seyferth-Gilbert reagent 1 has been applied in a flow system to rapidly synthesize terminal alkynes. The system has been further applied to synthesize triazole 3 from alcohol 2 in a three-step oxidation/homologation/copper(I)-catalyzed azide-alkyne cycloaddition sequence without isolation of intermediates (see scheme).
PROTECTION AGAINST ALLOGRAFT REJECTION WITH INTERCELLULAR ADHESION MOLECULE-1 ANTISENSE OLIGODEOXYNUCLEOTIDES1 (1998)

Rat ICAM-1 IP-9125 oligo inhibits ICAM-1 protein expression in vitro and in vivo as well as blocks allograft rejection when used for pretreatment of donors, graft perfusion, or postoperative treatment of recipients.
High Power Gallium Nitride Devices for Microwave and RF Control Applications (2000)

Abstract : Gallium Nitride devices were studied for use in microwave and RF control applications, primarily as electronic switch elements. For the test devices studied, broadband switch cutoff frequencies in excess of 130 GHz were seen, with cutoff frequencies as high as 400 GHz possible with the next generation devices. Second order distortion intercept points of greater than 50 dBm should be achievable with current gallium nitride technologies.
Nutrient Availability Regulates SIRT1 Through a Forkhead-Dependent Pathway (2004)

Nutrient availability regulates life-span in a wide range of organisms. We demonstrate that in mammalian cells, acute nutrient withdrawal simultaneously augments expression of the SIRT1 deacetylase and activates the Forkhead transcription factor Foxo3a. Knockdown of Foxo3a expression inhibited the starvation-induced increase in SIRT1 expression. Stimulation of SIRT1 transcription by Foxo3a was mediated through two p53 binding sites present in the SIRT1 promoter, and a nutrient-sensitive physical interaction was observed between Foxo3a and p53. SIRT1 expression was not induced in starved p53-deficient mice. Thus, in mammalian cells, p53, Foxo3a, and SIRT1, three proteins separately implicated in aging, constitute a nutrient-sensing pathway.
Role of Chitinase 3–like-1 and Semaphorin 7a in Pulmonary Melanoma Metastasis (2014)

The prototypic chitinase-like protein Chi3l1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown. To address this gap in knowledge, we investigated the production of Chi3l1 in melanoma lung metastases. We found that Chi3l1 was induced during pulmonary melanoma metastasis and that this induction was regulated by the semaphorin Sema7a, interacting in stimulatory or inhibitory ways with its β1 integrin or Plexin C1 receptors, respectively. In mouse strains with genetic deletions of Chi3l1 or Sema7a, there was a significant reduction in pulmonary metastasis. Notably, antiserum raised against Chi3l1 or Sema7a phenocopied the reduction produced by genetic deletions. Melanoma lung metastasis was also decreased in the absence of IL13Rα2, a recently identified receptor for Chi3l1, consistent with a key role for Chi3l1 in melanoma spread. We confirmed roles for Sema7a and Chi3l1 in pulmonary metastasis of EMT6 breast cancer cells. Taken together, our studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.