gebhart/patrepeval huggingface dataset:
Selective Electrical Silencing of Mammalian NeuronsIn Vitroby the Use of Invertebrate Ligand-Gated Chloride Channels (2002)

Selectively reducing the excitability of specific neurons will (1) allow for the creation of animal models of human neurological disorders and (2) provide insight into the global function of specific sets of neurons. We focus on a combined genetic and pharmacological approach to silence neurons electrically. We express invertebrate ivermectin (IVM)-sensitive chloride channels (Caenorhabditis elegans GluCl alpha and beta) with a Sindbis virus and then activate these channels with IVM to produce inhibition via a Cl- conductance. We constructed a three-cistron Sindbis virus that expresses the alpha and beta subunits of a glutamate-gated chloride channel (GluCl) along with the green fluorescent protein (EGFP) marker. Expression of the C. elegans channel does not affect the normal spike activity or GABA/glutamate postsynaptic currents of cultured embryonic day 18 hippocampal neurons. At concentrations as low as 5 nm, IVM activates a Cl- current large enough to silence infected neurons effectively. This conductance reverses in 8 hr. These low concentrations of IVM do not potentiate GABA responses. Comparable results are observed with plasmid transfection of yellow fluorescent protein-tagged (EYFP) GluCl alpha and cyan fluorescent protein-tagged (ECFP) GluCl beta. The present study provides an in vitro model mimicking conditions that can be obtained in transgenic mice and in viral-mediated gene therapy. These experiments demonstrate the feasibility of using invertebrate ligand-activated Cl- channels as an approach to modulate excitability.
Antibody 2G12 Recognizes Di-Mannose Equivalently in Domain- and Nondomain-Exchanged Forms but Only Binds the HIV-1 Glycan Shield if Domain Exchanged (2010)

The broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibody 2G12 targets the high-mannose cluster on the glycan shield of HIV-1. 2G12 has a unique V(H) domain-exchanged structure, with a multivalent binding surface that includes two primary glycan binding sites. The high-mannose cluster is an attractive target for HIV-1 vaccine design, but so far, no carbohydrate immunogen has elicited 2G12-like antibodies. Important questions remain as to how this domain exchange arose in 2G12 and how this unusual event conferred unexpected reactivity against the glycan shield of HIV-1. In order to address these questions, we generated a nondomain-exchanged variant of 2G12 to produce a conventional Y/T-shaped antibody through a single amino acid substitution (2G12 I19R) and showed that, as for the 2G12 wild type (2G12 WT), this antibody is able to recognize the same Manα1,2Man motif on recombinant gp120, Candida albicans, and synthetic glycoconjugates. However, the nondomain-exchanged variant of 2G12 is unable to bind the cluster of mannose moieties on the surface of HIV-1. Crystallographic analysis of 2G12 I19R in complex with Manα1,2Man revealed an adaptable hinge between V(H) and C(H)1 that enables the V(H) and V(L) domains to assemble in such a way that the configuration of the primary binding site and its interaction with disaccharide are remarkably similar in the nondomain-exchanged and domain-exchanged forms. Together with data that suggest that very few substitutions are required for domain exchange, the results suggest potential mechanisms for the evolution of domain-exchanged antibodies and immunization strategies for eliciting such antibodies.
Modern Methods of Bile Acid Analysis by Mass Spectrometry: A View into the Metabolome (2007)

The advent of the “omics” revolution has reawakened an interest in the mass spectrometric analysis of bile acids, particularly in the related fields of lipidomics and metabolomics. This is due to the presence of bile acids in body fluids and their potential to act as biomarkers. Bile acids and bile alcohols are formed from cholesterol in the liver. Bile acids are excreted from the liver into the small intestine via the bile duct conjugated with glycine or taurine at the side-chain carboxyl group. After assisting in the lipolysis and absorption of fats in the intestinal lumen, bile acids are returned to the liver. Bile acids and bile alcohols undergo further metabolism by bacterial and hepatic enzymes during the enterohepatic circulation, including hydrolysis of conjugates, oxidation and reduction, isomerisation, dehydroxylation and hydroxylation. The hydroxyl groups may also be conjugated with sulphuric acid, glucuronic acid, glucose or N-acetylglucosamine in the liver and in extrachepatic organs including intestine and kidney. Thus, the mixture of metabolic products of cholesterol in biological fluids can be very complex. Here we describe modern mass spectrometric methods used to characterise this diverse range of molecules found in biological fluids.
Melanotropic peptides: more than just ‘Barbie drugs’ and ‘sun-tan jabs’? (2010)

While ultraviolet radiation (UVR) is a major cause of skin ageing and carcinogenesis, public pursuit of a novel tanning strategy circumventing the need for UVR is increasingly reported in the media and scientific press. This involves the subcutaneous self-administration of unregulated products labelled as melanotan I and/or II, synthetic analogues of α-melanocyte stimulating hormone (α-MSH), as obtained via the internet, tanning salons and gyms. The Medicines and Healthcare products Regulatory Authority has recently raised awareness of the public health risk of transmission of blood-borne viruses from the needle sharing that may occur, and of the potential impurity of these products. Dermatologists should also be aware that these agents can complicate the clinical presentation of patients with pigmented lesions; their use may be suspected in unexpectedly tanned individuals with rapidly pigmenting naevi. Meanwhile, the regulated α-MSH analogue afamelanotide (Clinuvel Pharmaceuticals Ltd, Melbourne, Australia) is showing promise for its photoprotective potential, and is undergoing phase II and III clinical trials in people with photosensitivity disorders and those prone to nonmelanoma skin cancer. The photoprotective and other biological effects of α-MSH analogues await full determination.
A reference map of a human pituitary adenoma proteome (2003)

In order to compare the proteomes from different cell types of pituitary adenomas for our long-term goal to clarify the molecular mechanisms that participate in the formation of pituitary adenoma, and to detect any tumor-related marker for an "early-stage" diagnosis, the two-dimensional gel electrophoresis (2-DE) reference map of a pituitary adenoma tissue proteome is described here. A vertical, two-dimensional (2-D) polyacrylamide gel electrophoresis system and PDQuest image analysis software have been used to provide a high level of between-gel reproducibility and to accurately array each protein expressed in a pituitary adenoma tissue. Mass spectrometry (matrix-assisted laser desorption/ionization-time of flight MALDI-TOF and liquid chromatography-electrospray ionization-quadrupole-ion trap LC-ESI-Q-IT) and protein databases were used to characterize each protein in the 2-D gel. The results demonstrate that a good reproducibility of the 2-D gel pattern was attained. The position deviation of matched spots among four 2-D gels was 1.95 +/- 0.45 mm in the isoelectric focusing direction, and 1.70 +/- 0.53 mm in the sodium dodecyl sulfate-polyacrylamide gel electrophoresis direction. A total of ca. 1000 protein spots were separated by 2-DE, and 135 protein spots that represent 111 proteins were characterized with mass spectrometry (96 spots for MALDI-TOF, 39 spots for LC-ESI-Q-IT). The characterized proteins include pituitary hormones, cellular signals, enzymes, cellular-defense proteins, cell-structure proteins, transport proteins, etc. Those proteins were located in the cytoplasmic, cellular membrane, mitochondrial, endoplasmic reticulum, nuclear, ribonucleosome, extracellular fractions, or were secreted in plasma, etc. Those identified proteins contribute to a functional profile of the pituitary adenoma proteome. These data will be used to expand the proteome database of the human pituitary, which can be accessed in the website http://www.utmem.edu /proteomics.
Recombinant anti-EGFR immunotoxin 425(scFv)-ETA' demonstrates anti-tumor activity against disseminated human pancreatic cancer in nude mice (2005)

Pancreatic carcinoma is the fifth leading cause of cancer-related deaths in North America and Europe. Major reasons for the high mortality rate include the inability to detect pancreatic cancer at an early stage, extensive local invasion, and early formation of lymphatic and hematogenous metastases. Consequently, novel and effective therapies need to be developed urgently in order to improve the outcome of patients. Since overexpression of the epidermal growth factor receptor (EGFR) in pancreatic tumors correlates with advanced clinical staging, increased tumor size and reduced patient survival, this receptor represents an appropriate target for immunotherapy. We recently generated the recombinant immunotoxin 425(scFv)-ETA' by genetically fusing the anti-EGFR single chain variable fragment 425(scFv) to a truncated version of Pseudomonas aeroginosa exotoxin A (ETA'). The 425(scFv)-ETA' fusion protein was functionally expressed in the periplasmic space of Escherichia coli and was purified using a combination of metal-ion affinity and anion exchange chromatography. The protein showed specific binding to and toxicity against the EGFR-positive, metastatic pancreatic carcinoma cell line L3.6pl, but not to control cell systems. We report the anti-tumor activity of this recombinant immunotoxin in a disseminated human pancreatic cancer nude mouse model. After intravenous (i.v.) injection of L3.6pl cells into immunodeficient nude mice, both single (20 microg on day 1 after challenge) and repeated (10 microg on days 1, 2, 3 and 4 after tumor cell injection) i.v. administration of 425(scFv)-ETA' resulted in a significant reduction in the average number of lung metastases from 56.25 per animal in the control groups to 0.875 per animal (single injection) and 0.286 per animal (repeated injection), respectively, in the experimental groups. In summary, this is the first report showing an in vivo anti-tumor effect caused by the recombinant immunotoxin 425(scFv)-ETA' against disseminated growing metastatic human pancreatic carcinoma cells. Our data suggest that EGFR-specific antibody toxins could be suitable for further clinical investigation in the development of therapies for pancreatic carcinoma.
Quantitative analysis of one-dimensional gel electrophoresis profiles (1990)

A general method for the one-dimensional quantitative analysis of band profiles from an autoradiographed or stained gel is described. Curved lanes may be tracked, noise across the width of the band reduced by local averaging of densities within a selected window, and background-corrected density profiles produced. Sections of each profile can be subjected to a choice of three methods of peak-area determination, depending on the type of gel and the requirements of the analysis being carried out. In the first method, simple integration is used to measure the area under the profile between any two positions. The second method integrates a Gaussian distribution fitted to a single peak. Where bands overlap, the third method resolves peaks into their component areas, taking into account the observed increase in the width of the band in the direction of electrophoretic migration. This is incorporated into a least-squares profile-fitting method, which is shown to be both accurate and efficient.
Potential and Prospects of Continuous Polyhydroxyalkanoate (PHA) Production (2015)

Together with other so-called "bio-plastics", Polyhydroxyalkanoates (PHAs) are expected to soon replace established polymers on the plastic market. As a prerequisite, optimized process design is needed to make PHAs attractive in terms of costs and quality. Nowadays, large-scale PHA production relies on discontinuous fed-batch cultivation in huge bioreactors. Such processes presuppose numerous shortcomings such as nonproductive time for reactor revamping, irregular product quality, limited possibility for supply of certain carbon substrates, and, most of all, insufficient productivity. Therefore, single- and multistage continuous PHA biosynthesis is increasingly investigated for production of different types of microbial PHAs; this goes for rather crystalline, thermoplastic PHA homopolyesters as well as for highly flexible PHA copolyesters, and even blocky-structured PHAs consisting of alternating soft and hard segments. Apart from enhanced productivity and constant product quality, chemostat processes can be used to elucidate kinetics of cell growth and PHA formation under constant process conditions. Furthermore, continuous enrichment processes constitute a tool to isolate novel powerful PHA-producing microbial strains adapted to special environmental conditions. The article discusses challenges, potential and case studies for continuous PHA production, and shows up new strategies to further enhance such processes economically by developing unsterile open continuous processes combined with the application of inexpensive carbon feedstocks.
Characterization of amyloidogenic immunoglobulin light chains directly from serum by on‐line immunoafﬁnity isolation (2004)

Primary systemic amyloidosis (AL) is characterized by the overproduction of immunoglobulin light chain proteins by a monoclonal, terminally differentiated B-lymphocyte or plasma cell clone. The free immunoglobulin light chains are deposited in an abnormal conformation as amyloid in a variety of organs in the body. The mechanism of amyloid formation is not well understood, but appears to be associated with some form of cleavage of the immunoglobulin light chain with subsequent aggregate formation. In an attempt to characterize the structure of amyloid-forming light chain proteins we developed an on-line immunoaffinity purification and subsequent characterization of free kappa and free lambda immunoglobulin light chains by electrospray ionization mass spectrometry. The methodology is totally automated and requires 20 micro L of serum. Mass spectral analysis of Bence Jones proteins under non-denaturing conditions was also utilized to examine the tertiary and quaternary structure of light chain proteins and clearly shows covalent dimer formation of lambda type light chain. This type of on-line assay may prove helpful in elucidating distinguishing features capable of discriminating AL from benign monoclonal gammopathies of undetermined significance as well as diagnosing AL.
C5a peptidase alters clearance and trafficking of group A streptococci by infected mice (1996)

Group A streptococcal C5a peptidase (SCPA) specifically cleaves the human serum chemotaxin C5a at the polymorphonuclear leukocyte (PMNL) binding site. This study tested the proposal that SCPA contributes to virulence by retarding the influx of inflammatory cells and clearance of streptococci during the first few hours after infection. To investigate the specific contribution of SCPA to the virulence of group A streptococci, scpA insertion and deletion mutants were created by directed plasmid insertion into scpA and gene replacement. The precise locations of insertion and deletion mutations were confirmed by PCR and DNA sequence analysis. The impact of mutation on virulence was investigated with a mouse air sac model of inflammation. Experiments evaluated clearance of streptococci from the air sac within 4 h after infection. SCPA- streptococci were cleared more efficiently than wild-type bacteria. Localization of streptococci in lymph nodes and spleens of infected mice revealed a significant difference between mutant and wild-type streptococci. PMNLs and other granulocytes that infiltrated the air sac were quantitated by single-color flow cytometry. The total cellular infiltrate was greater and PMNLs dominated the granulocytic infiltrates of air sacs inoculated with SCPA- mutant bacteria. The data obtained are consistent with the possibility that SCPA- streptococci are initially cleared from the site of infection primarily by PMNLs. Moreover, mutant and wild-type streptococci followed different paths of dissemination. SCPA- bacteria were transported to lymph nodes, whereas wild-type streptococci avoided transport to the lymph nodes and rapidly spread to the spleen.
Regression of Coronary Atherosclerosis During Treatment of Familial Hypercholesterolemia With Combined Drug Regimens (1990)

We conducted a randomized, controlled trial in 72 patients with heterozygous familial hypercholesterolemia to test whether reducing plasma low-density lipoprotein levels by diet and combined drug regimens can induce regression of coronary lesions. Four hundred fifty-seven lesions were measured before and after a 26-month interval by computer-based quantitative angiography. The primary outcome variable was within-patient mean change in percent area stenosis. Mean low-density lipoprotein cholesterol levels decreased from 7.32 +/- 1.5 to 4.45 +/- 1.6 mmol/L. The mean change in percent area stenosis among controls was +0.80, indicating progression, while the mean change for the treatment group was -1.53, indicating regression (P = .039 by two-tailed t test for the difference between groups). Regression among women, analyzed separately, was also significant. The change in percent area stenosis was correlated with low-density lipoprotein levels on trial. We conclude that reduction of low-density lipoprotein cholesterol levels can induce regression of atherosclerotic lesions of the coronary arteries in patients with familial hypercholesterolemia. The anticipation of benefit from treatment applies to women and men alike.
Neurally Adjusted Ventilatory Assist: A Ventilation Tool or a Ventilation Toy? (2011)

Mechanical ventilation has, since its introduction into clinical practice, undergone a major evolution from controlled ventilation to various modes of assisted ventilation. Neurally adjusted ventilatory assist (NAVA) is the newest development. The implementation of NAVA requires the introduction of a catheter to measure the electrical activity of the diaphragm (EA(di)). NAVA relies, opposite to conventional assisted ventilation modes, on the EA(di) to trigger the ventilator breath and to adjust the ventilatory assist to the neural drive. The amplitude of the ventilator assist is determined by the instantaneous EA(di) and the NAVA level set by the clinician. The NAVA level amplifies the EA(di) signal and determines instantaneous ventilator assist on a breath-to-breath basis. Experimental and clinical data suggest superior patient-ventilator synchrony with NAVA. Patient-ventilator asynchrony is present in 25% of mechanically ventilated patients in the intensive care unit and may contribute to patient discomfort, sleep fragmentation, higher use of sedation, development of delirium, ventilator-induced lung injury, prolonged mechanical ventilation, and ultimately mortality. With NAVA, the reliance on the EA(di) signal, together with an intact ventilatory drive and intact breathing reflexes, allows integration of the ventilator in the neuro-ventilatory coupling on a higher level than conventional ventilation modes. The simple monitoring of the EA(di) signal alone may provide the clinician with important information to guide ventilator management, especially during the weaning process. Although, until now, little evidence proves the superiority of NAVA on clinically relevant end points, it seems evident that patient populations (eg, COPD and small children) with major patient-ventilator asynchrony may benefit from this new ventilatory tool.
Space/wavelength-routed ATM access architecture based on cascaded programmable arrayed-waveguide gratings (1998)

Summary form only given. Wavelength routing in access networks is becoming attractive due to increased security, decreasing wavelength division multiplexing (WDM) component costs, and wider available bandwidths. In this paper, we propose a novel access architecture that addresses 1000 optical network units (ONUs) using just 100 wavelengths. The architecture incorporates cascaded coarse and fine programmable arrayed-waveguide gratings (AWGs) in the exchange, and passive non-temperature-controlled coarse AWGs at the remote nodes (RNs). Both types of coarse AWGs are designed to have near-rectangular passbands of 4-nm 3 dB width, equal to the free spectral range (FSR) of the fine AWG. This allows the same basic coarse AWG design to be replicated at the RNs or within the exchange, thus reducing costs. Each AWG has 10 output ports. The cyclic properties of AWGs have been utilized to make simple space-switching devices, controlled by applying a single voltage. The functionality afforded by the trapezoidal active region within the AWG also allows the device to be temperature stabilized by adjusting the voltage with closed-loop control.
A phase 2 multicentre study of siltuximab, an anti‐interleukin‐6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma (2013)

Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥ 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including ≥ grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity.
Internal Porosity of Corn Extrudate Air Cell Wall (1987)

Transmission electron microscopy was used to observe structures within the air cell wall of a corn-based extrudate. Modified fixation and embedding techniques were employed to obtain optimum thin sections. Photomicrographs from these sections showed minute air cells measuring approximately 5 um or less. The size of air cells might impose a limiting factor on the infusion of particulate materials throughout the extrudate matrix.