Background and purpose: Smoking cessation trials with three high‐affinity partial agonists of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical ...efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human α4β2 nAChRs.
Experimental approach: Rat plasma and brain pharmacokinetics were characterized and used to predict human steady‐state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human α4β2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn‐over.
Key results: A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate α4β2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at α4β2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs.
Conclusions and implications: The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other α4β2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy.
Aim
Human papillomavirus (HPV) infection has been reported in colorectal cancer in many studies. We conducted a meta‐analysis to assess the association between HPV infection and colorectal ...cancer/adenomas in the Chinese population.
Method
Relevant studies up to January 2018 were searched in PubMed, EMBASE, China National Knowledge Infrastructure and the Wanfang database. We used a random effects model to determine the prevalence of HPV and odds ratios (ORs) with 95% confidence intervals (CIs). The I2 statistic and P‐value from the Cochrane Q‐test were used to describe the heterogeneity.
Results
Ten case–control studies involving 766 colorectal cancer patients and 470 controls were included in the meta‐analysis. Among the colorectal cancer patients, the pooled prevalence was 0.45 (95% CI 0.36–0.53). The pooled estimate for OR was 10.78 (95% CI 4.22, 27.53). Among the 193 patients with colorectal adenoma, the pooled prevalence and OR were 0.31 (95% CI 0.24–0.37) and 2.03 (95% CI 0.79, 5.26), respectively. The prevalence of HPV 16 and HPV 18 among HPV‐positive cancers ranged from 57.9% to 100% and 0% to 39.7%, respectively.
Conclusion
The results indicated that HPV infection, especially HPV 16 and HPV 18, is associated with colorectal cancer in the Chinese population.
In this study, we examined the effects of the following eight experimental diets, which varied in fructo oligosaccharides (FOS), mannan oligosaccharides (MOS) and Bacillus clausii concentrations, on ...the Japanese flounder: control diet (no FOS, MOS and B. clausii), diet F (5 g kg−1 FOS), diet M (5 g kg−1 MOS), diet FM (2.5 g kg−1 FOS + 2.5 g kg−1 MOS), diet B (107 cells g−1B. clausii), diet FB (5 g kg−1 FOS + 107 cells g−1B. clausii), diet MB (5 g kg−1 MOS + 107 cells g−1B. clausii) and diet FMB (2.5 g kg−1 FOS + 2.5 g kg−1 MOS + 107 cells g−1B. clausii). Japanese flounder, initially weighing an average of 21 g, were distributed into 24 net cages at a stocking density of 20 fish per cage. Each diet was hand‐fed to three groups of fish twice daily for 56 days. The weight gain rate (WGR) in fish fed diets B, MB and FMB were significantly higher than in fish fed the control diet, where the fish fed diet FMB had the highest WGR. Fish fed any of the diets, except diets F and B, exhibited better feed conversion ratio than those fed the control diet. Diets MB and FMB significantly elevated intestinal protease activity compared with the control diet, but only the diet FMB promoted amylase activity. Feeding diets FB and FMB increased body protein deposition; additionally, feeding diets B, MB and FMB significantly reduced body lipid deposition. Lysozyme (LSZ) activity was significantly higher in fish fed diets B, FB, MB and FMB than in fish fed the control diet. All diets, except diet M, decreased triglyceride (TG) levels compared to the control diet. Low‐density lipoprotein cholesterol levels in fish fed diets F, FB and FMB were significantly lower than in fish fed the control diet. Without exception, no diets affected feeding rate, condition factor, body moisture, ash contents, phagocytic activity of leucocytes or cholesterol or high‐density lipoprotein cholesterol levels. Our results suggest that diets supplemented with FOS, MOS and B. clausii improved growth performance and health benefits of the Japanese flounder more than other diets or the control diet.
SN 2016coi/ASASSN-16fp Prentice, S. J.; Ashall, C.; Mazzali, P. A. ...
Monthly notices of the Royal Astronomical Society,
08/2018, Letnik:
478, Številka:
3
Journal Article
Recenzirano
The optical observations of Ic-4 supernova (SN) 2016coi/ASASSN-16fp, from similar to 2 to similar to 450 d after explosion, are presented along with analysis of its physical properties. The SN shows ...the broad lines associated with SNe Ic-3/4 but with a key difference. The early spectra display a strong absorption feature at similar to 5400 angstrom which is not seen in other SNe Ic-3/4 at this epoch. This feature has been attributed to He I in the literature. Spectral modelling of the SN in the early photospheric phase suggests the presence of residual He in a C/O dominated shell. However, the behaviour of the He I lines is unusual when compared with He-rich SNe, showing relatively low velocities and weakening rather than strengthening over time. The SN is found to rise to peak similar to 16 d after core-collapse reaching a bolometric luminosity of L-p similar to 3 x 10(42) erg s(-1). Spectral models, including the nebular epoch, show that the SN ejected 2.5-4M(circle dot) of material, with similar to 1.5M(circle dot) below 5000 km s(-1), and with a kinetic energy of (4.5-7) x 10(51) erg. The explosion synthesized similar to 0.14M(circle dot) of Ni-56. There are significant uncertainties in E(B - V)(host) and the distance, however, which will affect L-p and M-Ni. SN 2016coi exploded in a host similar to the Large Magellanic Cloud (LMC) and away from star-forming regions. The properties of the SN and the host-galaxy suggest that the progenitor had M-ZAMS of 23-28M(circle dot) and was stripped almost entirely down to its C/O core at explosion.
For considerate use of limited freshwater resources in arid regions, it is very important to recycle the evapotranspiration water in greenhouse production for sustainable agriculture. In addition, in ...a typical greenhouse, ideal conditions for plants are set at low temperature, which is provided by evaporative cooling systems and ventilation, and this leads to more water waste. In this study, a water harvesting system was devised in the ventilation air path and our simulation for hot months showed that in a large-scale greenhouse, daily 9.5 tons of water is directed out of the greenhouse and 3.3 tons of them can be returned to the system by this device. A case study in a semi-arid area (Isfahan, Iran) showed that this system can provide 50% of water demand in summer. Such a system may provide feasible solutions for low growth yields in water-stressed regions and agriculture-dependent economies.
•An AWH system was proposed to recover water from humid air in the greenhouse.•Harvested water is saved for irrigation or cooling system applications.•The system's potential to be used in summer has been tested.•A mathematical model has been applied to estimate the greenhouse water recovery.•Even in arid regions, this system can provide 50% of water demand of a greenhouse.
Solar flares and coronal mass ejections are the most powerful explosions in the Sun. They are major sources of potentially destructive space weather conditions. However, the possible causes of their ...initiation remain controversial. Using high-resolution data observed by the New Solar Telescope of Big Bear Solar Observaotry, supplemented by Solar Dynamics Observatory observations, we present unusual observations of a small-scale emerging flux rope near a large sunspot, whose eruption produced an M-class flare and a coronal mass ejection. The presence of the small-scale flux rope was indicated by static nonlinear force-free field extrapolation as well as data-driven magnetohydrodynamics modeling of the dynamic evolution of the coronal three-dimensional magnetic field. During the emergence of the flux rope, rotation of satellite sunspots at the footpoints of the flux rope was observed. Meanwhile, the Lorentz force, magnetic energy, vertical current, and transverse fields were increasing during this phase. The free energy from the magnetic flux emergence and twisting magnetic fields is sufficient to power the M-class flare. These observations present, for the first time, the complete process, from the emergence of the small-scale flux rope, to the production of solar eruptions.
Summary
Background
Patients with leprosy have a very low risk of Alzheimer disease (AD) and β‐amyloid (Aβ) deposition is significantly lower in the brain tissue of elderly patients with leprosy ...compared with age‐matched controls. Apolipoprotein E (ApoE) plays a critical role in lipid metabolic pathways and in the brain, facilitating the proteolytic clearance of Aβ. We hypothesized that APOE confers risk of leprosy as lipid metabolism is involved in Mycobacterium leprae infection.
Objectives
To investigate the potential genetic associations between APOE and leprosy in two independent Chinese case–control cohorts from the Yuxi and Wenshan prefectures, Yunnan Province of Southwest China.
Methods
Five APOE single‐nucleotide polymorphisms (SNPs) were analysed in 1110 individuals (527 patients and 583 controls) from the Yuxi prefecture using a SNaPshot assay. Genetic variations in the entire APOE exons were screened in 1788 individuals (798 patients and 990 controls) from the Wenshan prefecture using next‐generation sequencing technology.
Results
The AD‐associated SNPs rs405509 and rs439401 increased the risk of leprosy per se and multibacillary leprosy (P < 0·005), but the APOE‐ε4 allele did not. The SNPs rs405509 and rs439401 were cis expression quantitative trait loci (eQTL) for APOE expression in human skin. Differential APOE mRNA expression was observed in skin lesions of patients with type I reaction leprosy and those with multibacillary leprosy. APOE and related lipid genes are involved in an interaction network with leprosy susceptibility genes.
Conclusions
The APOE gene is associated with leprosy, most likely by regulating lipid‐metabolism‐related genes.
What's already known about this topic?
Host genetic factors could influence susceptibility to leprosy, which is a chronic infectious and neurological disease.
Previous studies have reported a significantly lower level of β‐amyloid (Aβ) deposition in the brain tissues of elderly people with leprosy compared with age‐matched controls.
Apolipoprotein E (ApoE) facilitates proteolytic clearance and homeostasis of Aβ peptides in the brain.
What does this study add?
Common variants of APOE were associated with multibacillary leprosy in Han Chinese.
The risk single‐nucleotide polymorphisms rs405509 and rs439401 were cis expression quantitative trait loci for APOE expression in human skin.
ApoE may interact with proteins that are coded as leprosy‐risk genes.
What is the translational message?
Our findings suggested that APOE is associated with leprosy, and this might be mediated by the altered expression of APOE and its potential role in lipid metabolic pathways during Mycobacterium leprae infection.
Future studies that explore the potential function of APOE during leprosy onset may offer a novel therapeutic target in leprosy.
Linked Article: Morgado de Abreu et al. Br J Dermatol 2018; 178:833–834
Plain language summary available online
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Summary
Background
Treatments for autoimmune blistering diseases have significant risk of medical complications and quality of life impacts during treatment, and it is difficult to differentiate ...these impacts from disease burden or the effects of treatment.
Objectives
To develop a quality of life instrument specific to the effects of treatments used in patients with autoimmune bullous disease (AIBD).
Methods
A comprehensive item generation process was used to build a 45‐item pilot Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire, distributed to 70 patients with AIBD. Experts in bullous disease refined the pilot ABQOL, selecting only those questions pertaining to the treatment effects. This pilot Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) questionnaire was administered to 70 patients, before factor analysis was performed to yield the final questionnaire of 17 questions. Validity and reliability were evaluated across a range of indices.
Results
Face and content validity were established through a comprehensive patient interview process, expert review and summaries of treatments used. The questionnaire was found to have appropriate correlation with the Dermatology Life Quality Index (r = 0·64) and the level of treatments used (P < 0·01), and was found to be responsive to overall variations in treatment burden. The TABQOL was also found to be a reliable instrument as evaluated by internal consistency (Cronbach α = 0·892) and test–retest reliability (r = 0·99).
Conclusions
We have shown that the TABQOL questionnaire is a valid and reliable instrument that may to be used to measure treatment burden in AIBD and serve as an end point in clinical trials.
What's already known about this topic?
Treatments for autoimmune bullous disease (AIBD) have a significant risk of medical complications and quality of life impacts during treatment.
It is difficult to differentiate quality of life impacts from disease burden or the effects of treatment.
What does this study add?
The Treatment of Autoimmune Bullous Disease Quality of Life questionnaire allows quantitative measurement of treatment‐based quality of life impacts in AIBDs.
Longitudinal measurements allow consideration of optimal balance between disease control and treatment burden.
Objective: To clarify the effects of isoflavone intake on bone resorption and bone formation. Methods: We identified randomized controlled trials related to urinary deoxypyridinoline (Dpyr, a bone ...resorption marker) and serum bone-specific alkaline phosphatase (BAP, a bone formation marker) listed on MEDLINE (January 1966-April 2006), the Cochrane Controlled Trials Register, EMBASE (1985-January 2006), Science Citation Index and PUBMED (updated till April 2006). Results: Nine studies with a total of 432 subjects were selected for meta-analysis. The urinary Dpyr concentration in subjects who consumed isoflavones decreased significantly by -2.08 nmol/mmol (95% confidence interval (CI): -3.82 to -0.34 nmol/mmol) in comparison with that in subjects who did not consume isoflavones. Isoflavone intake vs placebo intake significantly increased serum BAP by 1.48 microgram/l (95% CI: 0.22-2.75 microgram/l). Decreases in the urinary Dpyr concentration with isoflavone intake of <90 mg/day and with treatment lasting less than 12 weeks were -2.34 nmol/mmol (95% CI: -4.46 to -0.22 nmol/mmol) and -2.03 nmol/mmol (95% CI: -3.20 to -0.85 nmol/mmol), respectively. Conclusions: Isoflavone intervention significantly inhibits bone resorption and stimulates bone formation. These favorable effects occur even if <90 mg/day of isoflavones are consumed or the intervention lasts less than 12 weeks.
This study presents a novel approach for the fabrication of commercially pure titanium (CP–Ti) components. The approach conferred superb strength to CP-Ti without sacrificing its ductility. A yield ...strength of 807 MPa combined with 19.15% elongation was realized through selective laser melting (SLM) by using a high-power laser and incorporating solute atoms from the Ar−N2 reactive atmosphere. Mechanical properties and microstructures of the as-printed CP-Ti were systematically investigated. Transmission electron microscopy, electron backscatter diffraction, and atom probe tomography were employed to reveal the mechanism underlying the in-situ reaction between CP-Ti and the reactive atmosphere. Results suggested that nitrogen generally dissolved in the α′-Ti matrix as interstitial solute atoms. The beneficial N content has a critical limit of ~0.43 wt%. The ductility of CP-Ti will decrease drastically if its N content exceeds this limit. A constitutive model was developed for describing the tensile deformation behavior of the in-situ strengthened CP-Ti over various solute contents and grain sizes. This work demonstrates a promising methodology for the fabrication of high-performance metallic components and extends the fundamental understanding of SLM process under the reactive atmosphere.
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