gebhart/patrepeval huggingface dataset:
Substrate specificities and structure-activity relationships for the nucleotidylation of antibiotics catalyzed by aminoglycoside nucleotidyltransferase 2"-I (1988)

Aminoglycoside nucleotidyltransferase 2''-I (formerly gentamicin adenylyltransferase) conveys antibiotic resistance to Gram-negative bacteria by transfer of AMP to the 2''-hydroxyl group of 4,6-substituted deoxystreptamine-containing aminoglycosides. The kinetics constants of thirteen aminoglycoside antibiotics and the magnesium chelates of eight nucleotide triphosphates were determined with purified enzyme. Eleven of the antibiotics exhibit substrate inhibition attributed to secondary binding of the aminoglycoside to an enzyme-AMP-aminoglycoside complex. Maximal velocities vary by only 4-fold, versus variation of values of Vmax/Km for the aminoglycosides of nearly 4000-fold, consistent with a Theorell-Chance kinetic mechanism as proposed for this enzyme [Gates, C. A., & Northrop, D. B. (1988) Biochemistry (second of three papers in this issue)] with the added specification that the binding of aminoglycosides is in rapid equilibrium. Under these conditions, Vmax/Km becomes kcat/Kd, where kcat is the net rate constant for catalysis (but not turnover) and Kd is the dissociation constant of aminoglycosides from a complex with enzyme and nucleotide. Values of kcat fall closely together into three distinct sets, with the 3',4'-dideoxygentamicins greater than gentamicins greater than kanamycins. These sets reflect unusual structure-activity correlations which are specific for catalysis but have nothing to do with the maximal velocity of this enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
The Reliability and Repeatability of a Lameness Scoring System for Use as an Indicator of Welfare in Dairy Cattle (2001)

In 16 dairy herds, a lameness scoring system which was reasonably quick and easy to use was evaluated with regard to reliability and repeatability. The ultimate aim was to include it into an on-farm welfare assessment protocol. Locomotion scores in individual cows (n = 206) were significantly correlated with the heel and sole disorder indices obtained at routine claw trimmings (e.g. index for hind limb lesions: r(s) = 0.40, p = 0.0001 ; Spearman Rank Correlation Coefficients). The inclusion of lesions caused by digital dermatitis increased correlation coefficients when hind limbs and all four feet were considered (r(s) = 0.47/0.50). The inter-observer repeatability of locomotion scores in individual cows was high, and the variation between observers was low when calculated as a percentage of animals within each scoring class. Thus the locomotion scoring system proved to be a useful tool for assessing lameness, and as such a valuable part of on-farm welfare assessment in dairy cattle. It is recommended that scoring be performed at least twice during the housing period.
Highly Selective Hydrolytic Kinetic Resolution of Terminal Epoxides Catalyzed by Chiral (salen)CoIIIComplexes. Practical Synthesis of Enantioenriched Terminal Epoxides and 1,2-Diols (2002)

The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H(2)O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.
Constrained filtering with contact detection data for the localization and registration of continuum robots in flexible environments (2012)

This paper presents a novel filtering technique that uses contact detection data and environmental stiffness estimates to register and localize a robot with respect to an a priori 3D surface model. The algorithm leverages geometric constraints within a Kalman filter framework and relies on two distinct update procedures: 1) an equality constrained step for when the robot is forcefully contacting the environment, and 2) an inequality constrained step for when the robot lies in the free-space of the environment. This filtering procedure registers the robot by incrementally eliminating probabilistically infeasible state space regions until a high likelihood solution emerges. In addition to registration and localization, the algorithm can estimate the deformation of the surface model and can detect false positives with respect to contact estimation. This method is experimentally evaluated with an experiment involving a continuum robot interacting with a bench-top flexible structure. The presented algorithm produces an experimental error in registration (with respect to the end-effector position) of 1.1 mm, which is less than 0.8 percent of the robot length.
Optic-Nerve Degeneration in Alzheimer's Disease (1986)

Alzheimer's disease is a dementing disorder of unknown cause in which there is degeneration of neuronal subpopulations in the central nervous system. In postmortem studies, we found widespread axonal degeneration in the optic nerves of 8 of 10 patients with Alzheimer's disease. The retinas of four of the patients were also examined histologically, and three had a reduction in the number of ganglion cells and in the thickness of the nerve-fiber layer. There was no retinal neurofibrillary degeneration or amyloid angiopathy, which are typically seen in the brains of patients with Alzheimer's disease. The changes we observed in the patients with Alzheimer's disease were clearly distinguishable from the findings in 10 age-matched controls and represent a sensory-system degeneration that occurs in Alzheimer's disease. Study of the retina in patients with this disease may be helpful diagnostically, and isolation of the affected ganglion cells may facilitate molecular analysis of the disorder.
[Reduction of FHIT gene expression in primary lung cancer]. (2002)

Reduction of FHIT gene expression might be associated with the oncogenesis and progression of human lung cancer; Smoking may be one of the important reasons of reduction of FHIT gene expression in lung cancer patients.
Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics (2005)

Neurodegenerative diseases are major contributors to disability and disease, with Alzheimer's and Parkinson's diseases the most prevalent. This major reference reviews the rapidly advancing knowledge of pathogenesis and treatment of neurodegenerative diseases in the context of a comprehensive survey of each disease and its clinical features. The editors and contributors are among the leading experts in the field internationally. Covering basic science, diagnostic tools and therapeutic approaches, the book focuses on all aspects of neurodegenerative disease, including the normal aging process. The dementias, prion diseases, Parkinson's disease and atypical parkinsonisms, neurodegenerative ataxias, motor neuron diseases, degenerative diseases with chorea, iron and copper disorders, and mitochondrial diseases, are all methodically presented and discussed, with extensive illustrations. In each case the underlying genetics, neuropathological and clinical issues are fully reviewed, making this the most complete as well as the most authoritative reference available to clinicians and neuroscientists
A Dynamic in vitro BBB Model for the Study of Immune Cell Trafficking into the Central Nervous System (2010)

Although there is significant evidence correlating overreacting or perhaps misguided immune cells and the blood-brain barrier (BBB) with the pathogenesis of neuroinflammatory diseases, the mechanisms by which they enter the brain are largely unknown. For this purpose, we revised our humanized dynamic in vitro BBB model (DIV-BBBr) to incorporate modified hollow fibers that now feature transmural microholes (2 to 4 μm Ø) allowing for the transendothelial trafficking of immune cells. As with the original model, this new DIV-BBBr reproduces most of the physiological characteristics of the BBB in vivo. Measurements of transendothelial electrical resistance (TEER), sucrose permeability, and BBB integrity during reversible osmotic disruption with mannitol (1.6 mol/L) showed that the microholes do not hamper the formation of a tight functional barrier. The in vivo rank permeability order of sucrose, phenytoin, and diazepam was successfully reproduced in vitro. Flow cessation followed by reperfusion (Fc/Rp) in the presence of circulating monocytes caused a biphasic BBB opening paralleled by a significant increase of proinflammatory cytokines and activated matrix metalloproteinases. We also observed abluminal extravasation of monocytes but only when the BBB was breached. In conclusion, the DIV-BBBr represents the most realistic in vitro system to study the immune cell trafficking across the BBB.
CMOS Single-Chip Electronic Compass With Microcontroller (2007)

We present a CMOS single-chip electronic compass sensor including the complete digital signal processing for accurate heading calculation. The device's analog part consists of Hall- based three-axis magnetic field transducer with integrated magnetic concentrator that operates as a passive magnetic amplifier. The analog amplification chain features a gain of up to 20 000. A true-12-bit extended counting ADC converts the amplified magnetic field signals into the digital domain, where a 16-bit microcontroller calculates the heading information and outputs it via an SPI interface. The compass sensor is realized in 0.35 mum low-voltage CMOS technology plus a simple batch processing step for deposition of a metal layer. The compact die size of 2.3 mm times 2.8 mm allows for packaging into a standard 4 mm times 5 mm times 1 mm surface-mount plastic package. The heading resolution is better than 0.5deg, and the accuracy better than plusmn2deg.
Respiratory Syncytial Virus Vaccines (1998)

Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness (LRI) in infants and children worldwide and causes significant LRI in the elderly and in immunocompromised patients. The goal of RSV vaccination is to prevent serious RSV-associated LRI. There are several obstacles to the development of successful RSV vaccines, including the need to immunize very young infants, who may respond inadequately to vaccination; the existence of two antigenically distinct RSV groups, A and B; and the history of disease enhancement following administration of a formalin-inactivated vaccine. It is likely that more than one type of vaccine will be needed to prevent RSV LRI in the various populations at risk. Although vector delivery systems, synthetic peptide, and immune-stimulating complex vaccines have been evaluated in animal models, only the purified F protein (PFP) subunit vaccines and live attenuated vaccines have been evaluated in recent clinical trials. PFP-2 appears to be a promising vaccine for the elderly and for RSV-seropositive children with underlying pulmonary disease, whereas live cold-passaged (cp), temperature-sensitive (ts) RSV vaccines (denoted cpts vaccines) would most probably be useful in young infants. The availability of cDNA technology should allow further refinement of existing live attenuated cpts candidate vaccines to produce engineered vaccines that are satisfactorily attenuated, immunogenic, and phenotypically stable.
Semi-preparative scale purification of enterococcal bacteriocin enterocin EJ97, and evaluation of substrates for its production (2007)

The influence of substrate composition on the production of enterocin EJ97 and the conditions for semi-preparative bacteriocin recovery have been studied. Final bacteriocin concentrations of 12.5 or 15.6 mg/l were obtained in the commercial media brain heart infusion broth (BHI) and tryptic soya broth, respectively. The bacteriocin was also produced in the complex medium CM (8.75 mg/l), in which the vitamin supplement was essential for production. Some combinations of meat peptone and yeast extract plus either soy peptone or BHI also supported bacteriocin production, at concentrations of 6.25-7.5 mg/l. In cow milk (whole, half-skimmed, and skimmed), the final bacteriocin concentrations obtained ranged from 7.5 to 11.25 mg/l. Highest bacteriocin activity was obtained by using pasteurised milk whey as growth substrate (up to 25 mg/l), suggesting that this bacteriocin can be obtained on a large scale by using this cheap food-grade industrial by-product. Highest bacteriocin titres were always obtained after 8 h of incubation at 37 degrees C. Semi-preparative concentration and purification of enterocin EJ97 produced in a complex medium was achieved by bulk cation exchange chromatography without previous cell separation, followed by reversed-phase chromatography. This two-step procedure allowed preparation of milligram quantities of purified bacteriocin, which is an improvement compared to purification procedures established for most other bacteriocins (35). The availability of purified enterocin EJ97 will facilitate other studies such as the elucidation of its molecular structure and its interaction with target bacteria.
MicroRNA Regulation of Oncolytic Herpes Simplex Virus-1 for Selective Killing of Prostate Cancer Cells (2009)

Our study is the first to show that inclusion of specific miRNA target sequences into the 3'-UTR of an essential HSV-1 gene is a viable strategy for restricting viral replication and oncolysis to cancer cells while sparing normal tissues.
Internet of Things and M2m Communications (2024)

The Internet of Things is the emerging technology which interconnects smart objects using wireless communications. After having been extensively studied in academic labs, the Internet of Things is now widely applied in the industrial world (e.g. domestic automation, smart metering, smart cities). Internet of Things and M2M Communications presents the key concepts used in the Internet of Things. In particular, Machine to Machine (M2M) communications have to be energy efficient so that all the smart objects may operate for years on a single battery. Besides, whilst constructing an efficient global digital world combining personal/private and external/general data, security and privacy issues have also to be covered adequately. Contents: Part I. Energy Constrained IoT Effect of Data Aggregation in M2M Networks OR-AHad: An Opportunistic Routing Algorithm for Energy Harvesting WSN An Off-line Tool for Accurately Estimating the Lifetime of a Wireless Mote Part II. Transmission Scheduling Delay-Constrained Scheduling in Wireless Sensor Networks Distributed Scheduling for Cooperative Tracking in Hierarchical Wireless Sensor Networks Time Synchronization on Cognitive Radio Ad Hoc Networks: A Bio-Inspired Approach Part III. Security & Tests Secure Access Control and Authority Delegation Based on Capability and Context Awareness for Federated IoT Jamming and Physical Layer Security for Cooperative Wireless Communication Performance Modeling and Simulation of Machine-to-Machine (M2M) Systems
Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY‐142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines (2009)

Mutations in KRAS or BRAF frequently manifest in constitutive activation of the MEK1/2-ERK1/2 signalling pathway. The MEK1/2-selective inhibitor, AZD6244 (ARRY-142886), blocks ERK1/2 activation and is currently undergoing clinical evaluation. Tumour cells can vary markedly in their response to MAPK or ERK kinase (MEK) inhibitors, and the presence of a BRAF mutation is thought to predict sensitivity, with the RAS mutations being associated with intrinsic resistance. We analysed cell proliferation in a panel of 19 colorectal cancer cell lines and found no simple correlation between BRAF or KRAS mutation and sensitivity to AZD6244, though cells that harbour neither mutation tended to be resistant. Cells that were sensitive arrested in G(1) and/or underwent apoptosis and the presence of BRAF or KRAS mutation was not sufficient to predict either fate. Cell lines that were resistant to AZD6244 exhibited low or no ERK1/2 activation or exhibited coincident activation of ERK1/2 and protein kinase B (PKB), the latter indicative of activation of the PI3K pathway. In cell lines with coincident ERK1/2 and PKB activation, sensitivity to AZD6244 could be re-imposed by any of the 3 distinct PI3K/mTOR inhibitors. We conclude that AZD6244 is effective in colorectal cancer cell lines with BRAF or KRAS mutations. Sensitivity to MEK1/2 inhibition correlates with a biochemical signature; those cells with high ERK1/2 activity (whether mutant for BRAF or KRAS) evolve a dependency upon that pathway and tend to be sensitive to AZD6244 but this can be offset by high PI3K-dependent signalling. This may have implications for the use of MEK inhibitors in combination with PI3K inhibitors.
Development of IL-5 Receptor Antagonists (2002)

A wealth of both clinical and pre-clinical data has strongly implicated the eosinophil in the pathogenesis of asthma, highlighting this cell type as a potential target for novel anti-inflammatory approaches to asthma therapy. The Th2 lymphocyte derived cytokine Interleukin-5 (IL-5) has emerged as the key regulator of eosinophil production, thus identifying IL-5 as the principal molecular target for therapeutic intervention. This review highlights both the pharmaceutical approaches, and the major challenges, to the identification of small molecule and protein antagonists of the IL-5 receptor. Using examples of known inhibitors we discuss their current status and highlight the major development hurdles in progressing these molecules into the market place.
Diseases: New Concepts of Pathogenesis and Their Therapeutic Implications (2006)

Neurodegenerative diseases as diverse as Alzheimer's, Parkinson's, and Creutzfeldt-Jakob disease share a common pathogenetic mech- anism involving aggregation and deposition of misfolded proteins, which leads to progressive central nervous system disease. Although the type of aggregated protein and the regional and cellular distribu- tion of deposition vary from disease to disease, these disorders may all be linked by similar pathways of protein aggregation with fibril formation and amyloid deposition. This perspective on pathogene- sis suggests that a wide variety of neurodegenerative diseases can be grouped mechanistically as brain amyloidoses, an outlook that yields novel insights into potential therapeutic approaches that may be ap- plicable across the broad spectrum of neurodegenerative disease.
Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease (1992)

In a multicenter pilot study, 19 patients with severe acute graft- versus-host disease (aGVHD) refractory to conventional therapy and serotherapy with a monoclonal anti-interleukin-2 receptor antibody were treated by in vivo infusion of a monoclonal anti-tumor necrosis factor alpha (TNF alpha) antibody (B-C7). Ten patients were grafted from a genotypically identical sibling, five from an HLA-mismatched family member, and four from an HLA-matched unrelated donor. Before B-C7 treatment, 15 patients had grade IV and four had grade III GVHD. In all cases, patients received cyclosporine/methotrexate as aGVHD prophylaxis. Patients were administered increasing doses of antibody (from 0.1 to 0.4 mg/kg). The antibody was infused in bolus daily for 4 days and then every other day twice (6 doses). No side effects were observed during treatment regardless of the dose level used. Changes in peripheral blood cell counts occurred in 8 of the 19 patients and appeared to be unrelated to B-C7. No truly complete response was observed; eight patients achieved a very good partial response (42.6%) and six a partial response (31.5%). The treatment was ineffective in five patients (26.4%). When present, the response occurred early (less than 3 days). In the 14 responding patients, gut lesions responded best (100%), followed by skin (85%) and liver (35.7%) lesions. In 9 of 11 evaluable patients (81%), GVHD recurred when treatment was discontinued in a median delay of 3 days (range, 2 to 120 days). All except one died from aGVHD. Two patients did not experience GVHD recurrence and are still alive 13 and 18 months post-bone marrow transplantation. This pilot study shows that a monoclonal anti-TNF alpha antibody may be of benefit to some patients with severe refractory aGVHD, but is ineffective to prevent GVHD recurrence in the majority of cases.
Transcriptional Control of Receptor Activator of Nuclear Factor-κB Ligand by the Protein Kinase A Activator Forskolin and the Transmembrane Glycoprotein 130-Activating Cytokine, Oncostatin M, Is Exerted through Multiple Distal Enhancers (2006)

Receptor activator of nuclear factor-B ligand (RankL) is a potent osteoclastogenic cytokine the expression of which is regulated at the transcriptional level by 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ], protein kinase A (PKA) activators such as PTH and transmembrane glycoprotein 130 (gp130)activating cytokines such as oncostatin M. We recently identified five highly conserved chromatin domains located significant distances upstream of the RankL transcriptional start site that contribute to the ability of 1,25-(OH) 2 D 3 and its receptor to enhance RankL gene output. We therefore screened these five common regulatory regions for their potential ability to mediate the actions of PKA-and gp130-activators using a directed chromatin immunoprecipitation approach employing antibodies to the PKA target cAMP response element-binding protein (CREB) and the gp130 target signal transducer and activator of transcription 3. CREB was identified at each of the upstream regulatory regions; signal transducer and activator of
Rationale for Bcl‐XL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies (2000)

The three-dimensional structure of the anti-apoptotic protein Bcl-xL complexed to a 25-residue peptide from the death promoting region of Bad was determined using NMR spectroscopy. Although the overall structure is similar to Bcl-xL bound to a 16-residue peptide from the Bak protein (Sattler et al., 1997), the Bad peptide forms additional interactions with Bcl-xL. However, based upon site-directed mutagenesis experiments, these additional contacts do not account for the increased affinity of the Bad 25-mer for Bcl-xL compared to the Bad 16-mer. Rather, the increased helix propensity of the Bad 25-mer is primarily responsible for its greater affinity for Bcl-xL. Based on this observation, a pair of 16-residue peptides were designed and synthesized that were predicted to have a high helix propensity while maintaining the interactions important for complexation with Bcl-xL. Both peptides showed an increase in helix propensity compared to the wild-type and exhibited an enhanced affinity for Bcl-xL.