Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far.
To define further genetic risk loci for ...sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci.
Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms.
Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3.
Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.
The production of J/ψ pairs in proton–proton collisions at a centre-of-mass energy of 7 TeV has been observed using an integrated luminosity of 37.5 pb−1 collected with the LHCb detector. The ...production cross-section for pairs with both J/ψ in the rapidity range 2<yJ/ψ<4.5 and transverse momentum pTJ/ψ<10 GeV/c isσJ/ψJ/ψ=5.1±1.0±1.1 nb, where the first uncertainty is statistical and the second systematic.
The production of J/ψ mesons in proton–proton collisions at √s = 7 TeV is studied with the LHCb detector at the LHC. The differential cross-section for prompt J/ψ production is measured as a function ...of the J/ψ transverse
momentum pT and rapidity y in the fiducial region pT ∈ 0; 14 GeV/c and y ∈ 2.0; 4.5. The differential cross-section and fraction of J/ψ from b-hadron decays are also measured in the same pT and y ranges. The analysis is based on a data sample corresponding to an integrated luminosity of 5.2 pb−1. The measured cross-sections integrated over the fiducial region are 10.52 ± 0.04 ± 1.40+1.64 −2.20 µb for prompt J/ψ production and 1.14 ± 0.01 ± 0.16 µb for J/ψ from b-hadron decays, where the first uncertainty is statistical and the second systematic. The prompt J/ψ production cross-section is obtained assuming no J/ψ polarisation and the third error indicates the acceptance uncertainty due to this assumption.
Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical ...practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment.
A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis.
The consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term ‘complete biochemical response’ defined as ‘normalization of serum transaminases and IgG below the upper limit of normal’ be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as ‘<50% decrease of serum transaminases within 4 weeks after initiation of treatment’. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for ‘any adverse event possibly related to treatment leading to potential drug discontinuation’.
These definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints.
Consensus among international experts on response criteria and endpoints in autoimmune hepatitis is lacking. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable the comparison of results between clinical trials. Therefore, the International Autoimmune Hepatitis Group (IAIHG) herein presents a statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting.
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•Consensus among experts on response criteria in autoimmune hepatitis is lacking.•A consensus on endpoints is required to set a standard for reporting study results.•Herein, the IAIHG presents a statement on 5 agreed response criteria and endpoints.
At the microscale, cantilever vibrations depend not only on the microstructure's properties and geometry but also on the properties of the surrounding medium. In fact, when a microcantilever vibrates ...in a fluid, the fluid offers resistance to the motion of the beam. The study of the influence of the hydrodynamic force on the microcantilever's vibrational spectrum can be used to either (1) optimize the use of microcantilevers for chemical detection in liquid media or (2) extract the mechanical properties of the fluid. The classical method for application (1) in gas is to operate the microcantilever in the dynamic transverse bending mode for chemical detection. However, the performance of microcantilevers excited in this standard out-of-plane dynamic mode drastically decreases in viscous liquid media. When immersed in liquids, in order to limit the decrease of both the resonant frequency and the quality factor, and improve sensitivity in sensing applications, alternative vibration modes that primarily shear the fluid (rather than involving motion normal to the fluid/beam interface) have been studied and tested: these include in-plane vibration modes (lateral bending mode and elongation mode). For application (2), the classical method to measure the rheological properties of fluids is to use a rheometer. However, such systems require sampling (no in situ measurements) and a relatively large sample volume (a few milliliters). Moreover, the frequency range is limited to low frequencies (less than 200Hz). To overcome the limitations of this classical method, an alternative method based on the use of silicon microcantilevers is presented. The method, which is based on the use of analytical equations for the hydrodynamic force, permits the measurement of the complex shear modulus of viscoelastic fluids over a wide frequency range.
Abstract
Purpose
Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and ...chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM).
Methods
Subjects with new-onset DM (<3 years’ duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index.
Results
The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments.
Conclusions
Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases (NCT03460769).
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•A formulation of lipid-core nanocapsules was efficiently applied to stabilize the lycopene-rich extract from red guava.•NanoLEG particles significantly reduced the viability of human ...breast cancer cells.•NanoLEG did not affect the membrane integrity of sheep blood erythrocytes.
The aims of this study were to produce poly-ɛ-caprolactone lipid-core nanocapsules containing lycopene-rich extract from red guava (LEG), to characterize those nanoparticles and to evaluate their cytotoxic effects on human breast cancer cells. Lipid-core nanocapsules containing the extract (nanoLEG) were produced by the method of interfacial deposition of the preformed polymer. The nanoparticles were characterized by Dynamic Light Scattering (DLS), Polydispersity Index, Zeta Potential, pH, Encapsulation Efficiency, Nanoparticle Tracking Analysis (NTA), Atomic Force Microscopy (AFM) and Transmission Electron Microscopy (TEM). Cell viability was evaluated by the MTT dye reduction method in the human breast cancer MCF-7 cell line and inhibition of ROS and NF-κB was assayed in living human microglial cell line (HMC3) by time-lapse images microscopy. A hemolytic activity assay was carried out with sheep blood. Data showed that nanoparticles average size was around 200 nm, nanoparticles concentration/mL was around 0.1 µM, negative zeta potential, pH < 5.0 and spherical shape, with low variation during a long storage period (7 months) at 5 °C, indicating stability of the system and protection against lycopene degradation. The percentage of encapsulation varied from 95% to 98%. The nanoLEG particles significantly reduced the viability of the MCF-7 cells after 24 h (61.47%) and 72 h (55.96%) of exposure, even at the lowest concentration tested (6.25–200 μg/ml) and improved on the cytotoxicity of free LEG to MCF-7. NanoLEG inhibited LPS-induced NF-kB activation and ROS production in microglial cells. The particles did not affect the membrane integrity of sheep blood erythrocytes at the concentrations tested (6.25–200 μg/mL). Thus, the formulation of lipid-core nanocapsules with a polysorbate 80-coated poly-ɛ-caprolactone wall was efficiently applied to stabilize the lycopene-rich extract from red guava, generating a product with satisfactory physico-chemical and biological properties for application as health-promoting nanotechnology-based nutraceutical, emphasizing its potential to be used as a cancer treatment.
In contrast to the western honey bee,
, other honey bee species have been largely neglected despite their importance and diversity. The genetic basis of the evolutionary diversification of honey bees ...remains largely unknown. Here, we provide a genome-wide comparison of three honey bee species each representing one of the three subgenera of honey bees, namely the dwarf (
), giant (
) and cavity-nesting (
) honey bees with bumblebees as outgroup. Our analyses resolve the phylogeny of honey bees with the dwarf honey bees diverging first. We find that evolution of increased eusocial complexity in
proceeds via increases in the complexity of gene regulation, which is in agreement with previous studies. However, this process seems to be related to pathways other than transcriptional control. Positive selection patterns across
reveal a trade-off between maintaining genome stability and generating genetic diversity, with a rapidly evolving piRNA pathway leading to genomes depleted of transposable elements, and a rapidly evolving DNA repair pathway associated with high recombination rates in all
species. Diversification within
is accompanied by positive selection in several genes whose putative functions present candidate mechanisms for lineage-specific adaptations, such as migration, immunity, and nesting behavior.
Evidence for the decay X(3872)→ψ(2S)γ Ajaltouni, Z.; An, L.; Andreotti, M. ...
Nuclear physics. B,
09/2014, Letnik:
886, Številka:
C
Journal Article
Recenzirano
Odprti dostop
Evidence for the decay mode X(3872)→ψ(2S)γ in B+→X(3872)K+ decays is found with a significance of 4.4 standard deviations. The analysis is based on a data sample of proton–proton collisions, ...corresponding to an integrated luminosity of 3 fb−1, collected with the LHCb detector, at centre-of-mass energies of 7 and 8 TeV. The ratio of the branching fraction of the X(3872)→ψ(2S)γ decay to that of the X(3872)→J/ψγ decay is measured to beB(X(3872)→ψ(2S)γ)B(X(3872)→J/ψγ)=2.46±0.64±0.29, where the first uncertainty is statistical and the second is systematic. The measured value does not support a pure DD¯⁎ molecular interpretation of the X(3872) state.
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