Summary Objective Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is ...currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal. Methods The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007 and 2009 at the behest of the Osteoarthritis Research Society International Federal Drug Administration initiative (OARSI FDA initiative). Results This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers. Conclusions Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within 1–2 years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical effect. As in vitro biomarkers are increasingly investigated in the context of specific drug treatments, advances in the field can be expected that will lead to rapid expansion of the list of available biomarkers with increasing understanding of the molecular processes that they represent.
Particle accelerators are used in a wide variety of fields, ranging from medicine and biology to high-energy physics. The accelerating fields in conventional accelerators are limited to a few tens of ...MeV m-1, owing to material breakdown at the walls of the structure. Thus, the production of energetic particle beams currently requires large-scale accelerators and expensive infrastructures. Laser-plasma accelerators have been proposed as a next generation of compact accelerators because of the huge electric fields they can sustain (>100 GeV m-1). However, it has been difficult to use them efficiently for applications because they have produced poor-quality particle beams with large energy spreads, owing to a randomization of electrons in phase space. Here we demonstrate that this randomization can be suppressed and that the quality of the electron beams can be dramatically enhanced. Within a length of 3 mm, the laser drives a plasma bubble that traps and accelerates plasma electrons. The resulting electron beam is extremely collimated and quasi-monoenergetic, with a high charge of 0.5 nC at 170 MeV.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plasmas are an attractive medium for the next generation of particle accelerators because they can support electric fields greater than several hundred gigavolts per meter. These accelerating fields ...are generated by relativistic plasma waves-space-charge oscillations-that can be excited when a high-intensity laser propagates through a plasma. Large currents of background electrons can then be trapped and subsequently accelerated by these relativistic waves. In the forced laser wake field regime, where the laser pulse length is of the order of the plasma wavelength, we show that a gain in maximum electron energy of up to 200 megaelectronvolts can be achieved, along with an improvement in the quality of the ultrashort electron beam.
Approximate Bayesian computation allows for statistical analysis using models with intractable likelihoods. In this paper we consider the asymptotic behaviour of the posterior distribution obtained ...by this method. We give general results on the rate at which the posterior distribution concentrates on sets containing the true parameter, the limiting shape of the posterior distribution, and the asymptotic distribution of the posterior mean. These results hold under given rates for the tolerance used within the method, mild regularity conditions on the summary statistics, and a condition linked to identification of the true parameters. Implications for practitioners are discussed.
Multicomponent quantum chemistry methods such as the nuclear-electronic orbital (NEO) method allow the consistent quantum mechanical treatment of electrons and nuclei. The development of ...computationally practical, accurate, and robust multicomponent wave function methods is challenging because of the importance of orbital relaxation effects. Herein the variational orbital-optimized coupled cluster with doubles (NEO-OOCCD) method and the orbital-optimized second-order Møller–Plesset perturbation theory (NEO-OOMP2) method with scaled-opposite-spin (SOS) versions are developed and applied to molecular systems in which a proton and all electrons are treated quantum mechanically. The results highlight the importance of orbital relaxation in multicomponent wave function methods. The NEO-SOS′-OOMP2 method, which scales the electron–proton correlation energy as well as the opposite-spin and same-spin components of the electronic correlation energy, is found to achieve nearly the same level of accuracy as the NEO-OOCCD method for proton densities, proton affinities, and optimized geometries. An advantage of the NEO-SOS′-OOMP2 method is that it can be implemented with N 4 scaling, where N is a measure of the system size. This method will enable future multicomponent wave function calculations of structures, energies, reaction paths, and dynamics for substantially larger chemical systems.
Abstract Osteoarthritis (OA) is considered as a chronic disease with a long “silent” period. The diagnosis is generally based on clinical symptoms and radiographic changes. However X-ray has a poor ...sensitivity and a relatively large precision error that does not allow an early detection of OA or the monitoring of joint damage progression. The limitations of the tools that are currently available for OA assessment have been the impetus to identify specific biological markers that reflect quantitative and dynamic variations in joint remodeling. Research has focused on the structural components of cartilage matrix, especially type II collagen degradation markers. In spite of a significant increase of some markers in individuals with early stage of OA, the large overlap with control subjects indicates that the current biomarkers used alone have limited diagnostic potential. However, the combination of specific markers seems to improve the prediction of disease progression at the individual level. Several types of treatment have been investigated but the lack of medications with definitively demonstrated chondroprotective activity has limited the assessment of the potential role of biomarkers for monitoring patients' responses to the treatment of OA. In this review, we will use the BIPED classification that appeared in 2006 for OA markers to describe the potential usage of a given marker 5. This article is part of a Special Issue entitled "Osteoarthritis".
In this paper, we experimentally investigate the influence of the flow rate on the trajectory of ovoid and filamentous bacterial cells of
E. coli
in a low aspect ratio pinch flow fractionation ...device. To that aim, we vary the Reynolds number over two orders of magnitude, while monitoring the dynamics of the cells across our device. At low flow rates, filamentous cells adopt several rotational motions in the pinched segment, which are induced both by the shear rate and by their close interactions with the nearest wall. As a result, the geometrical centre of the filamentous cells deviates towards the centre of the channel, which increases their effective sorting diameter depending on the length of their major axis as well as on the rotational mode they adopt in the pinch. As the flow rate increases, particles are forced to align vertically in the pinch, in the direction of the main shear gradient, which reduces the amplitude of the lateral deviation generated by their rotation. The trajectory of the particles in the expansion is directly determined by their position at the pinch outlet. As a consequence, the position of the filamentous cells at the outlet of the device strongly depends on the flow rate as well as on the length of their major axis. Based on these observations we optimized the flow conditions to successfully extract an ultra high purity sample of filamentous cells from a solution containing mainly ovoid cells.
We achieve high-performance separation of ovoid and filamentous cells of
E. coli
by optimizing the flow conditions in a PFF device.
This study evaluated the effects of treatment with meloxicam (a non-steroidal anti-inflammatory drug), parity, and blood progesterone concentration on the dynamics of the uterine microbiota of 16 ...clinically healthy postpartum dairy cows. Seven primiparous and 9 multiparous postpartum Holstein cows either received meloxicam (0.5 mg/kg SC, n = 7 cows) once daily for 4 days (10 to 13 days in milk (DIM)) or were untreated (n = 9 cows). Endometrial cytology samples were collected by cytobrush at 10, 21, and 35 DIM, from which the microbiota analysis was conducted using 16S rRNA gene sequence analysis. A radioimmunoassay was used to measure progesterone concentration in blood serum samples at 35 DIM and cows were classified as ˃ 1 ng/mL (n = 10) or ≤ 1 ng/mL (n = 6). Alpha diversity for bacterial genera (Chao1, Shannon-Weiner, and Camargo's evenness indices) were not affected by DIM, meloxicam treatment, parity, or progesterone category. For beta diversity (genera level), principal coordinate analysis (Bray-Curtis) showed differences in microbiota between parity groups. At the phylum level, the relative abundance of Actinobacteria was greater in primiparous than multiparous cows. At the genus level, there was lesser relative abundance of Bifidobacterium, Lactobacillus, Neisseriaceae, Paracoccus, Staphylococcus, and Streptococcus and greater relative abundance of Bacillus and Fusobacterium in primiparous than multiparous cows. Bray-Curtis dissimilarity did not differ by DIM at sampling, meloxicam treatment, or progesterone category at 35 DIM. In conclusion, uterine bacterial composition was not different at 10, 21, or 35 DIM, and meloxicam treatment or progesterone category did not affect the uterine microbiota in clinically healthy postpartum dairy cows. Primiparous cows presented a different composition of uterine bacteria than multiparous cows. The differences in microbiota associated with parity might be attributable to changes that occur consequent to the first calving, but this hypothesis should be investigated further.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose:
Periostin (POSTN) is a secreted γ-carboxyglutamic acid-containing protein expressed mainly in the periosteum in adult individuals. POSNT deficient mice develop periodontis and osteoporosis ...with decreased bone strength. The relationship between serum POSTN and bone metabolism and fracture risk in postmenopausal women is unknown.
Subjects and Methods:
Serum POSTN was measured in 607 postmenopausal women (mean age 66.6 ± 8.4 y) from the Os des Femmes de Lyon cohort at the ninth annual follow-up visit (baseline visit of the current analysis). Nonvertebral and clinical vertebral incident fragility fractures were reported annually during 7 years. Areal bone mineral density (BMD; measured by dual energy X-ray absorptiometry) of the hip and bone markers (intact N-terminal propeptide of type I collagen, osteocalcin, and serum type I collagen C-telopeptide) were also measured.
Results:
At baseline, serum POSTN did not correlate with age, bone markers, and BMD. After a median of 7 years of follow-up, 75 women sustained an incident clinical vertebral or nonvertebral fragility fracture. The proportion of women who had an incident fracture was significantly higher in women with levels of POSTN in the highest quartile than that of women in the three other quartiles (19.5% vs 10.1%, P = .018) after adjustment for age and prevalent fracture. The highest quartile of POSTN was associated with an increased risk of incident fracture with a relative risk (95% confidence interval) of 1.88 (1.1–3.2) after adjustment for age, prevalent fracture, and hip BMD T-score. Patients with both low hip BMD (T-score < −2.5) and high levels of POSTN (fourth quartile) had a relative risk of fracture of 7.1 (95% confidence interval 2.4–21.8) after adjustment for age.
Conclusion:
High serum POSTN levels are independently associated with increased fracture risk in postmenopausal women. These data suggest that serum POSTN could be useful to improve fracture risk assessment.
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