gebhart/patrepeval huggingface dataset:
Antisense-based therapy for the treatment of spinal muscular atrophy (2012)

One of the greatest thrills a biomedical researcher may experience is seeing the product of many years of dedicated effort finally make its way to the patient. As a team, we have worked for the past eight years to discover a drug that could treat a devastating childhood neuromuscular disease, spinal muscular atrophy (SMA). Here, we describe the journey that has led to a promising drug based on the biology underlying the disease.
Identification of an outer membrane protein required for the transport of lipopolysaccharide to the bacterial cell surface (2004)

Lipopolysaccharide (LPS), also known as endotoxin due to its severe pathophysiological effects in infected subjects, is an essential component of the outer membrane (OM) of most Gram-negative bacteria. LPS is synthesized in the bacterial inner membrane, a process that is now well understood. In contrast, the mechanism of its transport to the outer leaflet of the OM has remained enigmatic. We demonstrate here that the OM protein, known as increased membrane permeability (Imp) or organic solvent tolerance protein, is involved in this process. An Imp-deficient mutant of Neisseria meningitidis was viable and produced severely reduced amounts of LPS. The limited amount of LPS that was still produced was not accessible to LPS-modifying enzymes expressed in the OM or added to the extracellular medium. We conclude therefore that Imp mediates the transport of LPS to the cell surface. The role of Imp in LPS biogenesis and its high conservation among Gram-negative bacteria make it an excellent target for the development of novel antibacterial compounds.
Kinetics of Thermal Death of Bacteria (1971)

Experimental observations on thermal injury and death of bacteria in the stationary phase can be explained by assuming that death results from inactivation of (X(L)) of N critical sites. It is assumed: (i) that inactivation of individual sites occurs at random and follows first-order kinetics, (ii) that the critical sites are identical and of equal heat resistance, and (iii) the bacterial population is homogeneous in heat resistance. A method is described for calculating k (the rate constant for inactivation of individual sites), N (sites per cell), and X(L) (the number which must be inactivated to cause death under the experimental conditions used) from experimental data. Theoretical curves calculated by using this model are identical with experimental curves, providing support for the assumptions used. Calculated values of N and X(L) were 130 and 21.7 for Pseudomonas viscosa and 175 and 2.7 for Salmonella anatum. There is considerable uncertainty in the absolute values of N, but they are probably > 100. It is predicted that X(L) will vary depending on the recovery medium used after heating. This theory is consistent with all experimental observations on thermal injury and death of bacteria.
Bioorganic Approaches Towards HIV Vaccine Design (2003)

The worldwide epidemic of HIV/AIDS urges the development of an effective vaccine. With the identification of HIV as the cause of AIDS about two decades ago, it was once expected that a preventive vaccine would follow closely behind. But the early promise of HIV envelope gp120 as a preventive vaccine was not fulfilled. Broadly neutralizing antibodies and HIV-specific cytotoxic T lymphocytes (CTL) are two immune effectors that an effective HIV vaccine may have to elicit. Experiments in animal models have proved that sufficient levels of neutralizing antibodies can clean up the virus and protect the animals from viral challenge. Therefore, the induction of a broadly neutralizing antibody response remains a principal goal in HIV vaccine development. To achieve persistent infection, HIV has evolved elegant strategies to evade host immune surveillance. These include envelope oligomerization, rapid mutation, heavy glycosylation, and conformational changes. Each level of the HIV's defenses provides an additional dimension of complexity that has to be taken into account in order to come up with a vaccine conferring strong and long lasting immunity. Important progresses have been made in recent years in understanding the structure of HIV envelopes and the molecular mechanism of HIV evasion to the immune system. This in turn has greatly facilitated a rational design of immunogens capable of eliciting broadly neutralizing antibodies against HIV. The present review provides an overview of the major scientific obstacles we are facing in the development of an effective HIV vaccine, and discusses recent progresses in the field with a focus on current approaches toward a neutralizing antibody-based HIV vaccine. The bioorganic aspects of the approaches are emphasized.
Dip‐Pen‐Nanolithographic Patterning of Metallic, Semiconductor, and Metal Oxide Nanostructures on Surfaces (2009)

Dip-pen nanolithography (DPN) is a powerful method to pattern nanostructures on surfaces by the controlled delivery of an "ink" coating the tip of an atomic force microscope upon scanning and contacting with surfaces. The growing interest in the use of nanoparticles as structural and functional elements for the fabrication of nanodevices suggests that the DPN-stimulated patterning of nanoparticles on surfaces might be a useful technique to assemble hierarchical architectures of nanoparticles that could pave methodologies for functional nanocircuits or nanodevices. This Review presents different methodologies for the nanolithographic patterning of metallic, semiconductor, and metal oxide nanostructures on surfaces. The mechanisms involved in the formation of the nanostructures are discussed and the effects that control the dimensions of the resulting patterns are reviewed. The possible applications of the nanostructures are also addressed.
Real-Time Identification of Bacteria and Candida Species in Positive Blood Culture Broths by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (2010)

Delays in the identification of microorganisms are a barrier to the establishment of adequate empirical antibiotic therapy of bacteremia. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) allows the identification of microorganisms directly from colonies within minutes. In this study, we have adapted and tested this technology for use with blood culture broths, thus allowing identification in less than 30 min once the blood culture is detected as positive. Our method is based on the selective recovery of bacteria by adding a detergent that solubilizes blood cells but not microbial membranes. Microorganisms are then extracted by centrifugation and analyzed by MALDI-TOF-MS. This strategy was first tested by inoculating various bacterial and fungal species into negative blood culture bottles. We then tested positive patient blood or fluid samples grown in blood culture bottles, and the results obtained by MALDI-TOF-MS were compared with those obtained using conventional strategies. Three hundred twelve spiked bottles and 434 positive cultures from patients were analyzed. Among monomicrobial fluids, MALDI-TOF-MS allowed a reliable identification at the species, group, and genus/family level in 91%, 5%, and 2% of cases, respectively, in 20 min. In only 2% of these samples, MALDI-TOF MS did not yield any result. When blood cultures were multibacterial, identification was improved by using specific databases based on the Gram staining results. MALDI-TOF-MS is currently the fastest technique to accurately identify microorganisms grown in positive blood culture broths.
Transgenic mice with pancellular enhanced green fluorescent protein expression in primitive hematopoietic cells and all blood cell progeny (2005)

Transgenic mice homogeneously expressing enhanced green fluorescence protein (EGFP) in primitive hematopoietic cells and all blood cell progeny, including erythrocytes and platelets, have not been reported. Given previous data indicating H2Kb promoter activity in murine hematopoietic stem cells (HSCs), bone marrow (BM), and lymphocytes, an H2Kb enhancer/promoter EGFP construct was used to generate transgenic mice. These mice demonstrated pancellular EGFP expression in both primitive BM Sca-1+Lin-Kit+ cells and side population (SP) cells. Additionally, all peripheral blood leukocytes subsets, erythrocytes, and platelets uniformly expressed EGFP strongly. Competitive BM transplantation assays established that transgenic H2Kb-EGFP HSCs had activity equivalent to wildtype HSCs in their ability to reconstitute hematopoiesis in lethally irradiated mice. In addition, immunohistochemistry revealed EGFP transgene expression in all tissues examined. This transgenic strain should be a useful reagent for both murine hematopoiesis studies and functional studies of specific cell types from particular tissues.
Design, Synthesis, and Structure−Activity Relationships of Novel Non-Imidazole Histamine H3 Receptor Antagonists (2000)

Novel, potent, and selective non-imidazole histamine H(3) receptor antagonists have been prepared based on the low-affinity ligand dimaprit (pK(I) 7.32 +/- 0.12, pK(B) 5.93 +/- 0.17). Detailed structure-activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine (pK(I) 8.38 +/- 0.21, pK(B) 8.39 +/- 0.13), 30, and N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine (pK(I) 8.78 +/- 0.12, pK(B) 8.38 +/- 0.10), 31, exhibit high affinity for the histamine H(3) receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H(1) and H(2), receptor subtypes and a 100-fold selectivity in the sigma(1) binding assay. Compounds 30and 31 are the most potent, selective non-imidazole histamine H(3) receptor antagonists reported in the literature to date.
Reversible inactivation of guanylate cyclase by mixed disulfide formation. (1981)

Highly purified preparations of guanylate cyclase from rat lung were inactivated by several disulfide compounds in a time- and dose-dependent manner. Cystamine and cystine were the most potent disulfides tested, but other compounds which contained the cysteamine moiety (NH2CH2CH2S-), including pantethine and oxidized coenzyme A, were also able to partially inactivate the enzyme. In addition to the decrease in basal activity (measured with either Mg2+-GTP or Mn2+-GTP), disulfide-inhibited enzyme was activated to a lesser extent by nitric oxide. Treatment with dithiothreitol or other reducing agents restored basal activity and increased the level of cGMP production following nitric oxide activation. Control enzyme samples exhibited a single GTP Km of 25 microM or 150 microM with Mn2+ or Mg2+, respectively. However, cystamine-treated enzyme showed these same Km values as well as an additional GTP Km of 2 to 3 microM using either metal ion as cofactor. When [35S]cystine was incubated with purified enzyme, radioactivity was incorporated into the trichloroacetic acid-precipitable protein, and the counts were released following dithiothreitol treatment. In addition, [35S]cystine-labeled enzyme co-migrated with native guanylate cyclase on nondenaturing polyacrylamide gels. These data indicate that mixed disulfides can be formed between guanylate cyclase and certain naturally occurring compounds, and that disulfide formation leads to a reversible loss of enzyme activity.
Intra-articular Hyaluronic Acid in Treatment of Knee Osteoarthritis (2003)

Intra-articular hyaluronic acid has a small effect when compared with an intra-articular placebo. The presence of publication bias suggests even this effect may be overestimated. Compared with lower-molecular-weight hyaluronic acid, the highest-molecular-weight hyaluronic acid may be more efficacious in treating knee OA, but heterogeneity of these studies limits definitive conclusions.
Diagnostic work‐up and management of patients with isolated methylmalonic acidurias in European metabolic centres (2008)

The long-term outcome of patients with methylmalonic aciduria (MMA) is still uncertain due to a high frequency of complications such as chronic renal failure and metabolic stroke. The understanding of this disease is hampered by a huge variation in the management of these patients. The major aim of this study was to evaluate the current practice in different European metabolic centres. A standardized questionnaire was sent to 20 metabolic centres asking for standard procedures for confirmation of diagnosis, testing cobalamin responsiveness, dietary treatment, pharmacotherapy, and biochemical and clinical monitoring. Sixteen of 20 metabolic centres (80%) returned questionnaires on 183 patients: 89 of the patients were classified as mut(0), 36 as mut(-), 13 as cblA, 7 as cblB, and 38 as cblA/B. (1) Confirmation of diagnosis: All centres investigate enzyme activity by propionate fixation in fibroblasts; six centres also perform mutation analysis. (2) Cobalamin response: Ten centres follow standardized protocols showing large variations. A reliable exclusion of nonspecific effects has not yet been achieved by these protocols. (3) Long-term treatment: In cobalamin-responsive patients, most centres use hydroxocobalamin (1-14 mg/week i.m. or 5-20 mg/week orally), while two centres use cyanocobalamin. All cobalamin-nonresponsive patients and most cobalamin-responsive patients are supplemented with L: -carnitine (50-100 mg/kg per day). Fourteen centres use intestinal decontamination by antibiotic therapy. Most centres follow D-A-CH (n = 6) or Dewey (n = 4) recommendations for protein requirements. Fourteen centres regularly use precursor-free amino acid supplements. Standardized monitoring protocols are available in seven centres, again showing high variability.
The use of long-term human leukocyte cell cultures as models for the study of antileukemic agents. (1969)

Four clinically active antileukemic drugs were applied to six long-term human leukocyte cultures, derived from patients with acute and chronic myelogenous leukemia, lymphosarcoma, and Burkitt's lymphoma, to a cell line isolated from the peripheral blood of a normal individual and to a line prepared from ascitic lymphocytes of L1210 mouse leukemia. Dose-response and cell exposure time-response curves were obtained in vitro for each of the cytotoxic test agents. These studies provide new insight into the C × T relationships of the four test drugs and indicate that the long-term human leukocyte culture model may be useful in the evaluation of some of the factors determining the effectiveness of a drug as a chemotherapeutic agent.
Towards Dynamic Composition of Hybrid Communication Services (2000)

Due to the deregulation of the telecom network and the Internet, users will have access to an increasing number of heterogeneous communication services and will need to adapt their services or learn new services in order to interact with other users and systems. We propose a dynamic composition method that enables services to be constructed dynamically or “on-the-fly” from existing functional elements (service roles). Roles and actors that play roles are key concepts in our approach. A service role is defined as the part an object takes in a service. Service execution requires that roles are assigned to actors in a coordinated way. Our approach enables the systematic and structured specification of services, and provides mechanisms for service composition and an execution environment.
Persistent oxidative stress in chromosomally unstable cells. (2003)

Past work using the human-hamster hybrid line GM10115 has demonstrated that exposure to a variety of DNA damaging agents can lead to the persistent destabilization of chromosomes. To gain insight into the potential biochemical mechanisms involved in perpetuating the unstable phenotype, groups of clones characterized as stable or unstable were analyzed for indications of oxidative stress. All of the clones were derived from single progenitor cells surviving exposure to ionizing radiation or chemicals. Compared with their stable counterparts, unstable clones possessed elevated levels of reactive oxygen species (ROS) as measured by their enhanced ability to oxidize fluorogenic dyes. Fluorescence automated cell sorting analysis indicated that unstable clones had significantly higher mean fluorescence signals of approximately 2-fold and approximately 1.25-fold, respectively, as derived from the dyes 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and dihydrorhodamine 123, respectively. To determine whether mitochondria might constitute a potential source of ROS, stable and unstable clones of cells were analyzed for mitochondrial content using nonyl acridine orange and function using rhodamine 123. Fluorescence automated cell sorting data indicated that compared with stable clones, unstable clones possessed an elevated number (15% increase in mean nonyl acridine orange fluorescence) of dysfunctional mitochondria (27% decrease in mean rhodamine 123 fluorescence). Interestingly, the consequences of elevated ROS did not translate to an increase in oxidative base damage in nuclear DNA. Analysis of nine different base damage adducts by gas chromatography/mass spectrometry did not reveal significant differences between stable and unstable clones. The data suggest that the perpetuation of many of the abnormal phenotypes associated with genomic instability may be linked to a state of chronic oxidative stress derived in part from dysfunctional mitochondria.
Protein Kinase A Regulates Caspase-9 Activation by Apaf-1 Downstream of Cytochrome c (2005)

The cyclic AMP signal transduction pathway modulates apoptosis in diverse cell types, although the mechanism is poorly understood. A critical component of the intrinsic apoptotic pathway is caspase-9, which is activated by Apaf-1 in the apoptosome, a large complex assembled in response to release of cytochrome c from mitochondria. Caspase-9 cleaves and activates effector caspases, predominantly caspase-3, resulting in the demise of the cell. Here we identified a distinct mechanism by which cyclic AMP regulates this apoptotic pathway through activation of protein kinase A. We show that protein kinase A inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in Xenopus egg extracts and in a human cell-free system. Protein kinase A directly phosphorylates human caspase-9 at serines 99, 183, and 195. However, mutational analysis demonstrated that phosphorylation at these sites is not required for the inhibitory effect of protein kinase A on caspase-9 activation. Importantly, protein kinase A inhibits cytochrome c-dependent recruitment of procaspase-9 to Apaf-1 but not activation of caspase-9 by a constitutively activated form of Apaf-1. These data indicate that extracellular signals that elevate cyclic AMP and activate protein kinase A may suppress apoptosis by inhibiting apoptosome formation downstream of cytochrome c release from mitochondria.
The control of major accidents and hazards directive - implications for electrical and control engineers (1999)

The Control of Major Accidents and Hazards Directive is the replacement of an existing regulation which came out of the EEC (Seveso Directive) and is known as CIMAH in the UK, the scope of the newer directive is wider and will require to be adopted within industries which have no track record of managing such legislation. The author describes a case study which is a safety report within the existing CZMAH regulations which will be updated to meet the new requirements. The case study is that for an agrochemical active ingredient plant, the utility in question is the power system. In the event of a power system failure the operation of some critical drives will cease which will prevent the circulation of cooling water to the chemical reactors which at certain stages of the process can be exothermic, the failure could lead to over pressurisation of the reactor leading to the release of toxic chemicals into the environment. Options to counter the probability of failure are many and varied from fully installed spare pumps through to emergency shut down systems to take the process through to a safe state. The chosen system was a closed loop cooling water system with a cooling tower and three pumps; of the three pumps one would be operational, one standby and one available for maintenance.
Electric tweezers: Experimental study of positive dielectrophoresis-based positioning and orientation of a nanorod (2007)

The manipulation of individual micrometer sized objects has been the focus of significant research efforts over the last few years. A previously proposed method for the arbitrary manipulation of nanoparticles is experimentally demonstrated. This method employs dielectrophoretic forces for the planar control of the motion and orientation of such nanoparticles between a set of microfabricated electrodes. Each electrode is approximated as a set of sources, namely, an unknown point charge and induced dipole. Imposing constraints on the electric field at the location of the particle and requiring self-consistency uniquely determine the sources. They can then be subsequently used to determine the set of electrode voltages that creates an electric field that will produce the prescribed orientation and force on the particle. The drag coefficients of a nanorod are experimentally determined by sequentially applying a constant force both parallel and perpendicular to its axis and observing a resulting motion. With the drag coefficients in hand, the velocity rather than force can be prescribed, and the rod is directed to move accurately at oblique angles to its orientation. The rod is in a constant state of unstable equilibrium and requires negative feedback to maintain a fixed position. The automation of such feedback is demonstrated, allowing a controlled travel of the nanostructures over complex paths.
The Immune Epitope Database and Analysis Resource: From Vision to Blueprint (2005)

A planned repository of immune epitope data with associated analysis tools should be a boon to vaccine development
The development and application of wireless capsule endoscopy (2004)

The introduction of the Video Capsule Endoscope (VCE) by Given Imaging Ltd. (Yoqneam, Israel) in 2001, and its subsequent approval by the FDA as a first line tool in the detection of abnormalities of the small bowel, is indicative of the rapid acceptance of capsule endoscopy by the practicing gastroenterological community. An extensive clinical trials program consistently revealed a high diagnostic yield of the VCE when compared to other diagnostic modalities of the small intestine. The capsule endoscope contains a miniature color video camera, illumination sources, lens, transmitter/controller, antenna, and a power source. It is small enough to easily swallow (11 x 26 mm), and it is propelled through the gastrointestinal (GI) tract by peristalsis. Its development was enabled by a series of technological breakthroughs that occurred at the close of the 20th century. The VCE is one of the most exciting examples of the recent trend for minimally invasive autonomous medical tools in diagnostic, monitoring, and therapeutic applications. Expanding applications of the VCE to additional parts of the GI tract, adding physiological sensors, and--in the more remote future--addition of therapeutic capabilities will likely occur as this new branch of endoscopy develops.