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FKBP ligand homodimers can be used to activate signaling events inside cells and animals that have been engineered to express fusions between appropriate signaling domains and FKBP. However, use of these dimerizers in vivo is potentially limited by ligand binding to endogenous FKBP. We have designed ligands that bind specifically to a mutated FKBP over the wild-type protein by remodeling an FKBP-ligand interface to introduce a specificity binding pocket. A compound bearing an ethyl substituent in place of a carbonyl group exhibited sub-nanomolar affinity and 1,000-fold selectivity for a mutant FKBP with a compensating truncation of a phenylalanine residue. Structural and functional analysis of the new pocket showed that recognition is surprisingly relaxed, with the modified ligand only partially filling the engineered cavity. We incorporated the specificity pocket into a fusion protein containing FKBP and the intracellular domain of the Fas receptor. Cells expressing this modified chimeric protein potently underwent apoptosis in response to AP1903, a homodimer of the modified ligand, both in culture and when implanted into mice. Remodeled dimerizers such as AP1903 are ideal reagents for controlling the activities of cells that have been modified by gene therapy procedures, without interference from endogenous FKBP.

CYSTIC fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane Cl − channel regulated by cyclic AMP-dependent phosphorylation and by intracellular ATP 1–7 . Mutations in CFTR cause cystic fibrosis 8–10 partly through loss of cAMP-regulated Cl − permeability from the plasma membrane of affected epithelia 11,12 . The most common mutation in cystic fibrosis is deletion of phenylalanine at residue 508 (CFTRΔF508) (ref. 10). Studies on the biosynthesis 13,14 and localization 15 of CFTRΔF508 indicate that the mutant protein is not processed correctly and, as a result, is not delivered to the plasma membrane. These conclusions are consistent with earlier functional studies which failed to detect cAMP-stimnlated Cl − channels in cells expressing CFTRΔF508 (refs 16,17). Chloride channel activity was detected, however, when CFTRΔF508 was expressed in Xenopus oocytes 18 , Vero cells 19 and Sf9 insect cells 20 . Because oocytes and Sf9 cells are typically maintained at lower temperatures than mammalian cells, and because processing of nascent proteins can be sensitive to temperature 21 , we tested the effect of temperature on the processing of CFTRΔF508. Here we show that the processing of CFTRΔF508 reverts towards that of wild-type as the incubation temperature is reduced. When the processing defect is corrected, cAMP-regulated Cl − channels appear in the plasma membrane. These results reconcile previous contradictory observations and suggest that the mutant most commonly associated with cystic fibrosis is temperature-sensitive.

Most voice features used in predicting the voice when a person has voted with instability in the vocal fold vibration cause problems in estimating such period; as a result of this challenge, scientists have focused on the development of powerful features independent of pitch estimation. The major goal of this paper is to study and investigate the Acoustic Voice Analysis methods ( AVA ) based on adaptive features. This investigation will lead to the development of a system of detection. The essential parts of this topic is related to database (described later), sampling the sounds (and satisfying) from the German database with many diseases, degenerative neurological disease (such as chronic inflammation of the larynx and vocal fold nodules). Under the supervision of the used algorithm to accomplish the above task, the Mel-Frequency Cepstral Coefficients (MFCCs with different Jitter and Shimmer), as by likely flux model mixture (GMM) are used in the AVA. MATLAB was used to simulate such a study for the extraction of features as well as making the training and testing process. The achieved results showed that with some kind of analysis, it is possible to find different sound patterns of diseases, e.g. excessive twang, where additional spectral components exist due to the increase in air flow in nasal cavities. Another focal point is some mathematical transformations both in the temporal domain or frequency. These changes can improve the capacity of some voice features voice; however, there is a need to multivariate analysis of parameters which measure the various problems in the process of phonation; after that, it is necessary to analyse the importance of finding and sorting those features that provide more information. Finally, automatic classification of pathological voices was made using any of the known techniques for this purpose. Our achieved results prove that a good classification rate needs efficient features to characterize each class, in this work, on one hand the accuracy of system increases with the number of parameters (best accuracy with 39 coefficients including Jitter & Shimmer) which means that the difference between normal and abnormal become noticeable with second derivate of MFCC and energy more than the others.

The use of low molecular weight organic compounds to induce dimerization or oligomerization of engineered proteins has wide-ranging utility in biological research as well as in gene and cell therapies. Chemically induced dimerization can be used to activate intracellular signal transduction pathways or to control the activity of a bipartite transcription factor. Dimerizer systems based on the natural products cyclosporin, FK506, rapamycin, and coumermycin have been described. However, owing to the complexity of these compounds, adjusting their binding or pharmacological properties by chemical modification is difficult. We have investigated several families of readily prepared, totally synthetic, cell-permeable dimerizers composed of ligands for human FKBP12. These molecules have significantly reduced complexity and greater adaptability than natural product dimers. We report here the efficacies of several of these new synthetic compounds in regulating two types of protein dimerization events inside engineered cells--induction of apoptosis through dimerization of engineered Fas proteins and regulation of transcription through dimerization of transcription factor fusion proteins. One dimerizer in particular, AP1510, proved to be exceptionally potent and versatile in all experimental contexts tested.

In the tourism industry, environmental management is a critical component for sustaining competitive advantage (Barrett, 1992), starting to recognize environmental improvement as an economic and competitive opportunity, rather than an annoying cost or inevitable threat. Unfortunately, there has been no consistent approach to environmental marketing practices in tourism. Some destinations neglect their environmental obligations, perhaps due to lack of guidelines and examples of best practice, or perhaps because they don’t understand the benefits. Others exploit environmental communication for short-term gains, or fail to tell visitors about their environmental initiatives (Wight, 1994). A field survey was conducted based on qualitative approach, in order to investigate tourism and ecological experts 'opinions about specific environmental issues helping in applying responsible marketing for fragile areas. The purpose of the study is to highlight the complex relationship between tourism marketing and the environment protection responsibility and recommending environmentally responsible actions to Egyptian travel companies selling eco holidays, thus helping in the development of sustainable competitive strategies.

Gene therapy was originally conceived as a medical intervention to replace or correct defective genes in patients with inherited disorders. However, it may have much broader potential as an alternative delivery platform for protein therapeutics, such as cytokines, hormones, antibodies and novel engineered proteins. One key technical barrier to the widespread implementation of this form of therapy is the need for precise control over the level of protein production. A suitable system for pharmacologic control of therapeutic gene expression would permit precise titration of gene product dosage, intermittent or pulsatile treatment, and ready termination of therapy by withdrawal of the activating drug. We set out to design such a system with the following properties: (1) low baseline expression and high induction ratio; (2) positive control by an orally bioavailable small–molecule drug; (3) reduced potential for immune recognition through the exclusive use of human proteins; and (4) modularity to allow the independent optimization of each component using the tools of protein engineering. We report here the properties of this system and demonstrate its use to control circulating levels of human growth hormone in mice implanted with engineered human cells.

The objective of this study was to determine the factors associated with death in patients hospitalized for tetanus. This study collected prospectively over a twelve (12) month period, the epidemiological, clinical and evolutionary data, and proceeded to an analysis of the factors associated with the death of hospitalized patients. We collected 32 patients with tetanus, or 5% of the total number of hospitalized patients. The average age was 36 ± 14 years. The sex ratio was 15 (30/2). The iatrogenic entrance door was found in 5 (15%) patients. Respiratory complications were the most frequent, ie 9 cases (28%). The most commonly used treatment regimen (28 cases, 88%) was the combination of metronidazole, diazepam, and anti-tetanus serum with an average hospital stay of 23 days. A Dakar prognostic score greater than or equal to 3, the presence of complications and a hospital stay of less than or equal to 7 days were the main factors associated with the death. Tetanus remains common in Guinea with a high lethality rate. Improving immunization coverage is imperative.The objective of this study was to determine the factors associated with death in patients hospitalized for tetanus. This study collected prospectively over a twelve (12) month period, the epidemiological, clinical and evolutionary data, and proceeded to an analysis of the factors associated with the death of hospitalized patients. We collected 32 patients with tetanus, or 5% of the total number of hospitalized patients. The average age was 36 ± 14 years. The sex ratio was 15 (30/2). The iatrogenic entrance door was found in 5 (15%) patients. Respiratory complications were the most frequent, ie 9 cases (28%). The most commonly used treatment regimen (28 cases, 88%) was the combination of metronidazole, diazepam, and anti-tetanus serum with an average hospital stay of 23 days. A Dakar prognostic score greater than or equal to 3, the presence of complications and a hospital stay of less than or equal to 7 days were the main factors associated with the death. Tetanus remains common in Guinea with a high lethality rate. Improving immunization coverage is imperative.

An accurate spatial representation of protein-protein interaction networks is needed to achieve a realistic and biologically relevant representation of interactomes. Here, we leveraged the spatial information included in Proximity-Dependent Biotin Identification (BioID) interactomes of SARS-CoV-2 proteins to calculate weighted distances and model the organization of the SARS-CoV-2-human interactome in three dimensions (3D) within a cell-like volume. Cell regions with viral occupancy were highlighted, along with the coordination of viral proteins exploiting the cellular machinery. Profiling physical intra-virus and virus-host contacts enabled us to demonstrate both the accuracy and the predictive value of our 3D map for direct interactions, meaning that proteins in closer proximity tend to interact physically. Several functionally important virus-host complexes were detected, and robust structural models were obtained, opening the way to structure-directed drug discovery screens. This PPI discovery pipeline approach brings us closer to a realistic spatial representation of interactomes, which, when applied to viruses or other pathogens, can provide significant information for infection. Thus, it represents a promising tool for coping with emerging infectious diseases. The modelling of the SARS-CoV-2 spatial organization within a cell-like volume combined with physical virus/host contacts profiling brings a realistic spatial representation of SARS-CoV-2/human interactome.

L’objectif de cette étude est d’analyser les facteurs associés au décès chez les patients hospitalisés pour tétanos. Cette étude a recueilli de façon prospective, sur une période de 12 mois, les données épidémiologiques, cliniques et évolutives, puis procédé à une analyse des facteurs associés au décès des patients hospitalisés. Nous avons colligé 32 patients atteints de tétanos, soit 5 % du total des patients hospitalisés. L’âge moyen était de 36 ± 14 ans. Le sex-ratio était de 15 (30/2). La porte d’entrée iatrogène a été retrouvée chez 5 (15 %) patients. Les complications respiratoires étaient les plus fréquentes, soit 9 cas (28 %). Le schéma de traitement le plus utilisé (28 cas, 88 %) a été l’association de métronidazole, de diazépam et de sérum anti-tétanique avec une durée moyenne d’hospitalisation de 23 jours. Un score pronostique de Dakar supérieur ou égal à 3, la présence de complications et une durée d’hospitalisation inférieure ou égale à 7 jours ont été les principaux facteurs associés au décès. Le tétanos reste fréquent en Guinée avec un taux de létalité élevé. L’amélioration de la couverture vaccinale est impérative