gebhart/patrepeval huggingface dataset:
Nonreplicating Persistence ofMycobacteriumTuberculosis (2001)

There is ample clinical evidence, as well as evidence from animal experiments, that Mycobacterium tuberculosis can persist in tissues for months to decades without replicating, yet with the ability to resume growth and activate disease. Our knowledge of both macrophage physiology and the nature of tuberculous lesions in man and animals suggests that hypoxia is a major factor in inducing nonreplicating persistence (NRP) of tubercle bacilli. In vitro models reinforce this conclusion and provide insights into mechanisms that make NRP possible. There is evidence from in vitro models that the strategies employed by the bacilli to permit hypoxic NRP include restriction of biosynthetic activity to conserve energy, induction of alternative energy pathways, and stabilization of essential cell components to lessen the need for repair or replacement.
Cationically-modified nanoparticles for the pulmonary delivery of the telomerase inhibitor 2';-O-Methyl RNA for the treatment of lung cancer (2008)

Lung cancer is one of the main causes of cancer-related death worldwide. One of the reasons behind the extensive tumour growth is telomerase enzyme, which is notably expressed in cancer cells. Recent strategies for cancer therapy include, therefore, telomerase inhibition with antisense RNA. A major challenge is the weak cellular uptake of these nucleotide-based drugs which necessitates the choice of appropriate carrier systems. The aim of this study was hence to evaluate chitosan-modified PLGA nanoparticles (cNP) as carrier for the antisense oligonucleotide 2'-O-Methyl-RNA (OMR) and their efficacy as inhalation therapy. Modification of the process parameters revealed the tuneability of the NP synthesis in terms of size and surface charge. Studying the cellular uptake of fluorescent cNPs with increasing amounts of chitosan showed better uptake in A549 than in Calu-3 cells. Chitosan significantly improved the uptake and binding with OMR; however, higher chitosan content reduced the uptake efficiency. Uptake studies under in vivo mimicking conditions using air-interface cultures showed superior cellular uptake of OMR/cNP nanoplexes compared to free OMR. As a proof of the concept, the ability of OMR to reduce telomerase activity was demonstrated.\n\nIn conclusion, the concept of telomerase inhibition based on nanoscale delivery of antisense oligonucleotides represents a step forward to a new generation of cancer therapeutics.
The adenovirus DNA-binding protein stimulates the rate of transcription directed by adenovirus and adeno-associated virus promoters (1990)

The DNA-binding protein (DBP) encoded by the E2A region of adenovirus type 5 was found to enhance the expression of a reporter gene controlled by several different promoters within transfected cells. The rate of synthesis of correctly initiated transcripts was increased by the DBP. The adeno-associated virus P5 promoter and the adenovirus E1A and E2A early and major late promoters responded to the DBP by increases in expression ranging from 6- to 27-fold, while the adenovirus E4 promoter was slightly inhibited by DBP. The adenovirus major late promoter showed a greater response to DBP than to the E1A transactivator protein, suggesting that the DBP plays a central role in activation of the late promoter.
Total Parenteral Nutrition in Bone Marrow Transplantation (1984)

Bone marrow transplantation (BMT) is associated with severe metabolic stress secondary to anorexia, mucositis, enteritis, and infection. We compared nutritional parameters and clinical outcomes of 22 patients who received prophylactic total parenteral nutrition (TPN) to those of 22 controls, matched for age and diagnosis, who received nutritional support ad libitum. Over the 5-week study period, the TPN group averaged caloric intakes greater than 1.5 X basal energy expediture (BEE) per day and gained 2.5% of body weight; the control group averaged less than 0.9 X BEE and lost 3.7% of body weight. Visceral protein status as reflected by serum albumin was not different. Engraftment of donor marrow cells was 3 days earlier (p less than 0.01) in the TPN group than in the controls, despite there being no significant difference in the number of marrow cells each group received. There was no difference in the two groups' clinical outcomes; mortality, duration of hospital stay, and incidences of sepsis, graft-versus-host disease, and return of malignancy were equivalent. Thus, patients who received prophylactic TPN engrafted sooner than patients who did not; however, overall clinical outcome was unaffected by TPN. Controlled studies of prophylactic TPN are indicated for the BMT patient population.
Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE (1998)

The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier and regulates the movement of nutrients, water, and ions between the choroidal blood supply and the retina. The transport properties of the RPE maintain retinal adhesion and regulate the pH and osmolarity in the space surrounding the photoreceptor cell outer segments. In this report we identify two monocarboxylate transporters, MCT1 and MCT3, expressed in rat RPE. On the basis of Northern and Western blot analyses, MCT1 is expressed in both the neural retina and the RPE, whereas the expression of MCT3 is restricted to the RPE. Using indirect immunolocalization we show that the two transporters are polarized to distinct membrane domains. MCT1 antibody labels the apical surface and the apical processes of the RPE. A polyclonal antibody produced against the carboxy terminus of rat MCT3 labels only the basolateral membrane of the RPE. The demonstration of MCT1 on the apical membrane and MCT3 on the basal membrane identifies specific proteins involved in the discriminate and critical regulation of water and lactate transport from the retina to the choroid.
Spinal shrinkage in females: circadian variation and the effects of circuit weight-training (1987)

Compressive loading of the spine leads to spinal shrinkage and a loss of stature. The aim of this study was to measure the circadian variation in the stature of females and to examine differential effects of spinal loading with the time of day. Ten females aged 20–30 years were studied in nine measurements on a 24-hour period. Between rising and retiring to bed, the mean peak-to-trough variation was 15·4 mm (0·92% of stature). Subjects underwent two sequences of 20 min circuit-training with weights, followed by 20 min reclining in Fowler's position and 20 min standing erect, these being first thing in the morning after 7 hours of sleep and before retiring at midnight. Mean loss of height from circuit-training was 5·4 mm in the morning and 4·3 mm in the evening (P < 0·001): mean height regained in Fowler's position was 4·5 mm and 3·4 mm respectively (P<0·05). There were significant height losses in the subsequent standing posture but no time of day effect. Height losses with exercise were related to the isometric strength of the back muscles and to the perceived exertion. Results support the hypothesis that height losses from a given spinal load will be of smaller amplitude when body height is in the trough of circadian variation.
Extracorporeal Enzyme Reactors for Depletion of Phenylalanine in Phenylketonuria (1987)

Multitubular enzyme reactors with immobilized enzymes were developed to achieve depletion of circulating substrate by extracorporeal means. To act as prototypes, reactors were prepared with immobilized L-phenylalanine ammonia-lyase, an enzyme that metabolizes phenylalanine to trans-cinnamic acid and ammonia without the need for a coenzyme. We report the first application of phenylalanine ammonia-lyase reactors in an extracorporeal circulation system in a patient with phenylketonuria. A phenylalanine level of 1.82 mmol/L (for the last 6 years) decreased to 1.24 mmol/L after 5.5. hours of treatment, without the enzyme entering the circulation. Total phenylalanine depletion from blood and tissue stores was estimated at 1800 mg. The hemodialysis-like procedure proved to be without side effects, specific for phenylalanine, and suitable in the management of pregnant women with phenylketonuria and late-onset hyperphenylalaninemia. The extracorporeal use of enzyme reactors for temporary enzyme replacement represents a new, safe, and effective therapeutic modality.
TGF‐β and Wound Healing (2007)

Wound healing comprises an ordered sequence of events including cell migration and proliferation, synthesis of extracellular matrix, angiogenesis and remodelling. TGF-beta regulates many of these processes. Animal models are used to study healing of simple linear incision wounds and deeper dermal wounds under normal and impaired conditions. TGF-beta increases the rate of healing and the breaking strength of the repaired tissue. It also enhances angiogenesis and consequent blood flow to dermal wounds, partly by stimulating the local release of other growth factors. TGF-beta reverses the adverse affects of glucocorticoids on wound healing and thus may be useful in the treatment of chronic ulcers or wounds in patients whose normal responses have been impaired by therapy with steroids, radiation or other drugs.
Crystal and Molecular Structure of a Collagen-Like Peptide at 1.9 Å Resolution (1994)

The structure of a protein triple helix has been determined at 1.9 angstrom resolution by x-ray crystallographic studies of a collagen-like peptide containing a single substitution of the consensus sequence. This peptide adopts a triple-helical structure that confirms the basic features determined from fiber diffraction studies on collagen: supercoiling of polyproline II helices and interchain hydrogen bonding that follows the model II of Rich and Crick. In addition, the structure provides new information concerning the nature of this protein fold. Each triple helix is surrounded by a cylinder of hydration, with an extensive hydrogen bonding network between water molecules and peptide acceptor groups. Hydroxyproline residues have a critical role in this water network. The interaxial spacing of triple helices in the crystal is similar to that in collagen fibrils, and the water networks linking adjacent triple helices in the crystal structure are likely to be present in connective tissues. The breaking of the repeating (X-Y-Gly)n pattern by a Gly-->Ala substitution results in a subtle alteration of the conformation, with a local untwisting of the triple helix. At the substitution site, direct interchain hydrogen bonds are replaced with interstitial water bridges between the peptide groups. Similar conformational changes may occur in Gly-->X mutated collagens responsible for the diseases osteogenesis imperfecta, chondrodysplasias, and Ehlers-Danlos syndrome IV.
The viability of distributed antennas for massive MIMO systems (2013)

Massive multiple-input multiple-output (MIMO) is a breakthrough communication technique for providing high spectral efficiency. The idea is to deploy a very large number of antennas at each base station and to use multiuser MIMO transmission to serve a smaller number of users. In this paper, the viability of using distributed antennas for massive MIMO on the uplink is investigated for a particular spatial correlation channel model. Both maximal ratio combining (MRC) and minimum mean squared error (MMSE) beamforming are found to provide higher performance in several distributed settings. An algorithm for remote radio head selection is proposed that allows MRC to approach the performance achieved by the MMSE beamforming solution yet retaining its lower complexity.
Molecular characterization of the clumping factor (fibrinogen receptor) of Staphylococcus aureus (1994)

Four mutants of Staphylococcus aureus strain Newman that were defective in the fibrinogen receptor (clumping factor) were isolated by transposon Tn917 mutagenesis. Southern hybridization analysis of the mutants identified transposon-host DNA junction fragments, one of which was cloned and used to generate a probe to identify and clone the wild-type clumping factor locus (clfA). The mutants failed to form clumps in soluble fibrinogen and adhered poorly to polymethylmethacrylate (PMMA) coverslips coated with fibrinogen. A single copy of the clfA gene, when introduced into the chromosome of the mutant strains, fully complemented the clumping deficiency of these strains and restored the ability of these mutants to adhere to fibrinogen-coated PMMA. In addition, the cloned clfA gene on a shuttle plasmid allowed the weakly clumping strain 8325-4 to form clumps with the same avidity as the wild-type strain Newman and also significantly enhanced the adherence of 8325-4 strains. Thus the formation of clumps in soluble fibrinogen correlated with adherence of bacteria to solid-phase fibrinogen. The clfA gene encodes a fibrinogen-binding protein with an apparent molecular mass of c. 130 kDa. The amino acid sequence of the protein was deduced from the DNA sequence; it was predicted that a 896 residue protein (molecular mass 92 kDa) would be expressed. The putative ClfA protein has features that suggest that it is associated with the cell surface. Furthermore it contains a novel 308 residue region comprising dipeptide repeats predominantly of Asp and Ser ending 28 residues upstream from the LPXTG motif common to wall-associated proteins. Significant homology was found between the ClfA protein and the fibronectin-binding proteins of S. aureus, particularly in the N- and C-termini.
Electrostatically Assembled Polyelectrolyte/Dendrimer Multilayer Films as Ultrathin Nanoreservoirs (2002)

We report the preparation of loadable ultrathin, multilayered polyelectrolyte/dendrimer films by the sequential electrostatic deposition of negatively charged poly(styrenesulfonate) (PSS) and a positively charged fourth generation poly(amidoamine) dendrimer (4G PAMAM). Multilayers were first constructed on planar supports to examine their layer-by-layer growth. Quartz crystal microbalance (QCM) measurements showed regular growth for each layer deposited, while UV−vis spectrophotometry revealed an adsorption−desorption trend to film formation, with partial PSS removal upon deposition of 4G PAMAM. PSS/4G PAMAM films were subsequently constructed on spherical latex colloids. Fluorescence spectroscopy showed that the films, when exposed to dye-containing solutions, acted as nanoreservoirs, sequestering the charged molecules from solution due to the presence of the oppositely charged dendrimer. Release of the entrapped dye molecules was subsequently achieved by concentration-dependent diffusion in isotonic saline solutions, illustrating the potential of the dendrimer-based films as systems for the uptake and release of various compounds.
Evaluation of practical chromatographic procedures for identification of clinical isolates of mycobacteria (1991)

After experimental conditions were established, 366 strains of mycobacteria belonging to 23 different species were studied for fatty acids, secondary alcohols, and mycolic acid cleavage products by capillary gas-liquid chromatography. Additionally, the mycolic acid pattern was studied by thin-layer chromatography. Capillary gas-liquid chromatography allowed direct identification of the following Mycobacterium spp.: M. kansasii, M. marinum, M. szulgai, M. xenopi, M. malmoense, and M. gordonae. The patterns of mycolic acid methyl esters recorded for the test strains of M. chelonae and M. agri may be of value in the identification of these species. Moreover, the combined use of the two chromatographic techniques provided precise identification of the M. tuberculosis complex, M. simiae, M. fallax, M. triviale, and M. chelonae-like organisms. A minimal set of biochemical tests is usually required to obtain identification to the species level when chromatographic procedures alone are not sufficient. Under the reported experimental conditions, thin-layer chromatography and capillary gas-liquid chromatography are rapid and very useful techniques for the identification of mycobacteria.
Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease (2014)

The heart is a highly specialized organ with essential function for the organism throughout life. The significance of DNA methylation in shaping the phenotype of the heart remains only partially known. Here we generate and analyse DNA methylomes from highly purified cardiomyocytes of neonatal, adult healthy and adult failing hearts. We identify large genomic regions that are differentially methylated during cardiomyocyte development and maturation. Demethylation of cardiomyocyte gene bodies correlates strongly with increased gene expression. Silencing of demethylated genes is characterized by the polycomb mark H3K27me3 or by DNA methylation. De novo methylation by DNA methyltransferases 3A/B causes repression of fetal cardiac genes, including essential components of the cardiac sarcomere. Failing cardiomyocytes partially resemble neonatal methylation patterns. This study establishes DNA methylation as a highly dynamic process during postnatal growth of cardiomyocytes and their adaptation to pathological stress in a process tightly linked to gene regulation and activity.
Role of the substrate strain in the sheet resistance stability of NiSi deposited on Si(100) (1999)

In order to study the influence of strain on the formation and stability of NiSi, Ni has been deposited on strained and relaxed Si(100) n-type substrates. Strained Si substrates have been produced by depositing a pseudomorphic silicon film onto a 3000 Å thick relaxed Si0.8Ge0.2 film. Raman spectroscopy has established that the silicon film is strained. The presence of a characteristic cross-hatch pattern has been identified by atomic force microscopy. Measurements show that the sheet resistance (Rs) of the silicide formed on strained silicon remains stable up to 700 °C while the Rs of the silicide formed on bulk silicon (100) shows a significant increase at 600 °C . X-ray photoelectron spectroscopy shows that the NiSi–NiSi2 phase transition occurs at a higher temperature and is, therefore, not responsible for the Rs instability. Scanning electron microscopy measurements indicate that islanding occurs in the temperature region of the resistivity increase. Photoelectron emission microscopy has been employed to observe the surface morphology during annealing, and islanding is not observed until a higher annealing temperature for the NiSi on strained Si. The increase in Rs is apparently correlated to the islanding of NiSi which appears at lower temperature on the bulk silicon substrate than on the strained silicon substrate. The stability of the NiSi film on the strained Si substrate is related to the strain induced by thermal expansion and the increased lattice constant of the strained Si.
Excipients for Semisolid Formulations (2006)

Semisolids constitute a signiﬁcant portion of pharmaceutical dosage forms. They serve as carriers for drugs that are topically delivered by way of skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear lining (1). The primary advantage of topical delivery is the direct accessibility of the drug to affected tissues, with minimal, systemic side effects. In some cases, for systemic delivery, topical application enables delivery of therapeutic agents, avoiding ﬁrst-pass gastrointestinal tract and hepatic metabolism and allowing maintenance of constant drug levels in the bloodstream. However, it is also generally recognized that the bioavailability of topically applied drugs is very low. The vehicle plays a key role in the appearance, feel, and successful application of a topical drug (2). Excipients, in large part, determine the physical properties of the vehicle as well as its ability to modify the stratum corneum or the mucosa to deliver the drug effectively. For example, it is possible to enhance the bioavailability by employment of an innocuous chemical means to reversibly improve the solubility of the drug in the barrier, e.g., stratum corneum, and facilitate diffusion of the drug through the barrier (3). Excipients, such as fatty acids, alcohols, amines, and amides, are absorbed into the barrier where they alter the overall solvent potential of the barrier. At the same time, the enhancers may disrupt the ordered lipid structure within the barrier, thereby lowering its viscosity. These physicochemical changes will facilitate drug partition from a topically applied formulation into the barrier as well as diffusion of drug molecules through the barrier. Thus, the understanding of excipients and proper selection is critical to successful formulation of semisolid dosage forms to meet the therapeutic needs.
A dumbbell-shaped, double-hairpin structure of DNA: a thermodynamic investigation (1987)

We report the first calorimetric and spectroscopic investigation on a member of a new class of nucleic acid secondary structures in which both ends of a duplex core are closed by single-stranded loops. Such structures can be formed intramolecularly from appropriately designed base sequences. We have synthesized the 24-mer sequence shown, and we present calorimetric, spectroscopic, and electrophoretic (formula; see text) evidence that it adopts a dumbbell-shaped, double-hairpin structure. Our data allow us to reach the following conclusions: (1) The phosphodiester gap in the center of the core duplex of the dumbbell does not reduce the transition enthalpy relative to that measured for the corresponding octameric duplex d(GGAATTCC)2. (2) Incorporation of a 5'-phosphate group into the gap decreases the thermal stability of the dumbbell relative to its unphosphorylated sequence. On the basis of the salt dependence of this effect, we propose that the phosphorylation--induced decrease in thermal stability is electrostatic in origin. From the changes in the transition enthalpy and entropy, we suggest that the phosphorylation-induced decrease in thermal stability of the double hairpin arises from electrostatically induced based unstacking at the nick. (3) The thymine residues in the loop behave both electrostatically and enthalpically like denatured single strands. Published nuclear magnetic resonance studies reveal partial stacking of thymine residues in the loops of linear hairpin structures. If this feature persists in the double-hairpin structure, then the spatial overlap of thymine residues in the loops does not necessarily produce a favorable enthalpic contribution. (4) When both ends of the nicked octameric core duplex are constrained by loops of only four thymine residues, the dumbbell structure may adopt conformations in which the 5' and 3' ends at the nick are twisted relative to the helical axis and therefore are not in phase. Such conformations would account for the observed resistance of the double-hairpin structure to ligation, since the 3'OH and 5'P would no longer be collinear.
Comparison of three indirect immunoassay formats on a common paper-based microfluidic device architecture (2016)

The ability to detect antibodies that are generated during an immune response is integral to the diagnosis and monitoring of infections.
Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 Inhibitors (2011)

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.