6,667 research outputs found
Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives
In cystic fibrosis (CF), the deletion of phenylalanine 508 (F508del) in the CF transmembrane conductance regulator (CFTR) leads to misfolding and premature degradation of the mutant protein. These defects can be targeted with pharmacological agents named potentiators and correctors. During the past years, several efforts have been devoted to develop and approve new effective molecules. However, their clinical use remains limited, as they fail to fully restore F508del-CFTR biological function. Indeed, the search for CFTR correctors with different and additive mechanisms has recently increased. Among them, drugs that modulate the CFTR proteostasis environment are particularly attractive to enhance therapy effectiveness further. This Perspective focuses on reviewing the recent progress in discovering CFTR proteostasis regulators, mainly describing the design, chemical structure, and structure-activity relationships. The opportunities, challenges, and future directions in this emerging and promising field of research are discussed, as well
Size-segregated aerosol chemical composition at a boreal site in southern Finland, during the QUEST project
International audienceSize-segregated aerosol samples were collected during the QUEST field campaign at Hyytiälä, a boreal forest site in Southern Finland, during spring 2003. Aerosol samples were selectively collected during both particle formation events and periods in which no particle formation occurred. A comprehensive characterisation of the aerosol chemical properties (water-soluble inorganic and organic fraction) and an analysis of the relevant meteorological parameters revealed how aerosol chemistry and meteorology combine to determine a favorable "environment" for new particle formation. The results indicated that all events, typically favored during northerly air mass advection, were background aerosols (total mass concentrations range between 1.97 and 4.31 µg m-3), with an increasingly pronounced marine character as the northerly air flow arrived progressively from the west and, in contrast, with a moderate SO2-pollution influence as the air arrived from more easterly directions. Conversely, the non-event aerosol, transported from the south, exhibited the chemical features of European continental sites, with a marked increase in the concentrations of all major anthropogenic aerosol constituents. The higher non-event mass concentration (total mass concentrations range between 6.88 and 16.30 µg m-3) and, thus, a larger surface area, tended to suppress new particle formation, more efficiently depleting potential gaseous precursors for nucleation. The analysis of water-soluble organic compounds showed that clean nucleation episodes were dominated by aliphatic biogenic species, while non-events were characterised by a large abundance of anthropogenic oxygenated species. Interestingly, a significant content of ?-pinene photo-oxidation products was observed in the events aerosol, accounting for, on average, 72% of their WSOC; while only moderate amounts of these species were found in the non-event aerosol. If the organic vapors condensing onto accumulation mode particles are responsible also for the growth of newly formed thermodynamically stable clusters, our finding allows one to postulate that, at the site, ?-pinene photo-oxidation products (and probably also photo-oxidation products from other terpenes) are the most likely species to contribute to the growth of nanometer-sized particles
Biofilm formation on dental implant surface treated by implantoplasty : an in situ study
Peri-implantitis is a biofilm-related disease whose characteristics are peri-implant tissues inflammation and bone resorption. Some clinical trials report beneficial effects after implantoplasty, namely the surgical smoothening of the implant surface, but there is a lack of data about the development of the bacterial biofilm on those smoothened surfaces. The aim of this study is to evaluate how implantoplasty influences biofilm formation. Three implants with moderately rough surfaces (control) and three implants treated with implantoplasty (test) were set on a tray reproducing the supra- and sub-gingival environment. One volunteer wore this tray for five days. Every 24 h, plaque coverage was measured and, at the end of the period of observartion, the implant surfaces were analyzed using scanning electron microscopy and confocal laser scanning microscopy. The proportion of implant surface covered with plaque was 65% (SD = 7.07) of the control implants and 16% (SD = 0) of the test implants. Untreated surfaces showed mature, complex biofilm structures with wide morphological diversity, and treated surfaces did not show the formation of mature biofilm structures. This study supports the efficacy of implantoplasty in reducing plaque adhesion and influencing biofilm formation. These results can be considered a preliminary proof of concept, but they may encourage further studies about the effects of implantoplasty on biofilm formation
In-depth analysis of the Naming Game dynamics: the homogeneous mixing case
Language emergence and evolution has recently gained growing attention
through multi-agent models and mathematical frameworks to study their behavior.
Here we investigate further the Naming Game, a model able to account for the
emergence of a shared vocabulary of form-meaning associations through
social/cultural learning. Due to the simplicity of both the structure of the
agents and their interaction rules, the dynamics of this model can be analyzed
in great detail using numerical simulations and analytical arguments. This
paper first reviews some existing results and then presents a new overall
understanding.Comment: 30 pages, 19 figures (few in reduced definition). In press in IJMP
Inference of population splits and mixtures from genome-wide allele frequency data
Many aspects of the historical relationships between populations in a species
are reflected in genetic data. Inferring these relationships from genetic data,
however, remains a challenging task. In this paper, we present a statistical
model for inferring the patterns of population splits and mixtures in multiple
populations. In this model, the sampled populations in a species are related to
their common ancestor through a graph of ancestral populations. Using
genome-wide allele frequency data and a Gaussian approximation to genetic
drift, we infer the structure of this graph. We applied this method to a set of
55 human populations and a set of 82 dog breeds and wild canids. In both
species, we show that a simple bifurcating tree does not fully describe the
data; in contrast, we infer many migration events. While some of the migration
events that we find have been detected previously, many have not. For example,
in the human data we infer that Cambodians trace approximately 16% of their
ancestry to a population ancestral to other extant East Asian populations. In
the dog data, we infer that both the boxer and basenji trace a considerable
fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to
domestication, and that East Asian toy breeds (the Shih Tzu and the Pekingese)
result from admixture between modern toy breeds and "ancient" Asian breeds.
Software implementing the model described here, called TreeMix, is available at
http://treemix.googlecode.comComment: 28 pages, 6 figures in main text. Attached supplement is 22 pages, 15
figures. This is an updated version of the preprint available at
http://precedings.nature.com/documents/6956/version/
Dirac Neutrino Dark Matter
We investigate the possibility that dark matter is made of heavy Dirac
neutrinos with mass in the range [O(1) GeV- a few TeV] and with suppressed but
non-zero coupling to the Standard Model Z as well as a coupling to an
additional Z' gauge boson. The first part of this paper provides a
model-independent analysis for the relic density and direct detection in terms
of four main parameters: the mass, the couplings to the Z, to the Z' and to the
Higgs. These WIMP candidates arise naturally as Kaluza-Klein states in
extra-dimensional models with extended electroweak gauge group SU(2)_L* SU(2)_R
* U(1). They can be stable because of Kaluza-Klein parity or of other discrete
symmetries related to baryon number for instance, or even, in the low mass and
low coupling limits, just because of a phase-space-suppressed decay width. An
interesting aspect of warped models is that the extra Z' typically couples only
to the third generation, thus avoiding the usual experimental constraints. In
the second part of the paper, we illustrate the situation in details in a
warped GUT model.Comment: 35 pages, 25 figures; v2: JCAP version; presentation and plots
improved, results unchange
Comparative evaluation of solubility, cytotoxicity and photostability studies of resveratrol and oxyresveratrol loaded nanosponges
Resveratrol and oxyresveratrol are natural polyphenolic stilbenes with several important pharmacological activities. However, low solubility and aqueous instability are the major limitations in their drug delivery applications. In the present work, we demonstrated the encapsulation of resveratrol and oxyresveratrol with nanosponge to improve solubility and stability. Several characterization techniques were used to confirm the encapsulation of both drug molecules within the nanosponges. The high encapsulation efficiency of resveratrol (77.73%) and oxyresveratrol (80.33%) was achieved within the nanosponges. Transmission electron microscopy suggested uniform spherical size particles of resveratrol and oxyresveratrol loaded nanosponges. Compared to free drugs, better protection against UV degradation was observed for resveratrol-loaded nanosponge (2-fold) and oxyresveratrol-loaded nanosponge (3-fold). Moreover, a higher solubilization of resveratrol- and oxyresveratrol-loaded nanosponges lead to a better antioxidant activity compared to drug molecules alone. Cytotoxicity studies against DU-145 prostate cancer cell lines further suggested improved activity of both resveratrol and oxyresveratrol-loaded nanosponges without any significant toxicity of blank nanosponges
Number of comorbidities and their impact on perioperative outcome and costs - a single centre cohort study
AIMS OF THE STUDY: Multimorbidity is a growing global health problem, resulting in an increased perioperative risk for surgical patients. Data on both the prevalence of multimorbidity and its impact on perioperative outcome are limited. The American Society of Anesthesiologists (ASA) classification uses only the single most severe systemic disease to define the ASA class and ignores multimorbidity. This study aimed to assess the number and type of all anaesthesia-relevant comorbidities and to analyse their impact on outcome and hospital costs. METHODS: This cohort study is nested in the ClassIntra(R) validation study and includes only patients enrolled at the University Hospital of Basel. Approximately 30 patients per surgical discipline undergoing any type of in-hospital surgery were followed up until hospital discharge to record all intra- and postoperative adverse events. In addition, the type and severity of all perioperatively relevant comorbidities were extracted from the electronic medical record according to a predefined list. The primary endpoint was the number of all anaesthesia-relevant comorbidities by ASA class. Using structural equation models, the direct and indirect effects of comorbidities on costs were estimated after adjustment for the ASA class and further relevant confounders and mediators. RESULTS: Of 320 enrolled patients, 27 were ASA I (8%), 150 ASA II (47%), 116 ASA III (36%) and 27 ASA IV (8%). The median number of comorbidities per patient was 5 (range 0-18), this number significantly increasing with higher ASA class: 1 comorbidity (95% CI 0.0-2.0) in ASA I, 4 comorbidities (3.8-4.2) in ASA II, 9 (8.1-9.9) in ASA III and 12 (10-14) in ASA IV patients. Independent of ASA class, each additional comorbidity increased hospital costs by EUR 1,198 (95% CI 288-2108) with almost identical proportions of direct and indirect effects. The number of anaesthesia-relevant comorbidities also increased postoperative complications and postoperative length of hospital stay. CONCLUSIONS: Multimorbidity in perioperative patients is highly prevalent and has a relevant impact on hospital costs, independent of the ASA class. Incorporating multimorbidity into the ASA classification might be warranted to improve its predictive ability and support adequate reimbursement
Statistical properties of genealogical trees
We analyse the statistical properties of genealogical trees in a neutral
model of a closed population with sexual reproduction and non-overlapping
generations. By reconstructing the genealogy of an individual from the
population evolution, we measure the distribution of ancestors appearing more
than once in a given tree. After a transient time, the probability of
repetition follows, up to a rescaling, a stationary distribution which we
calculate both numerically and analytically. This distribution exhibits a
universal shape with a non-trivial power law which can be understood by an
exact, though simple, renormalization calculation. Some real data on human
genealogy illustrate the problem, which is relevant to the study of the real
degree of diversity in closed interbreeding communities.Comment: Accepted for publication in Phys. Rev. Let
Confocal Laser Scanner Evaluation of Bactericidal Effect of Chitosan Nanodroplets Loaded with Benzalkonium Chloride
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