Due to the rapid increase of new information on the multiple roles of Toll-like receptors (TLRs), this paper reviews several main properties of TLRs and their ligands and signaling pathways. The ...investigation of pathogen infections in knockout mice suggests that specific TLRs play a key role in the activation of immune responses. Although the investigation of TLR biology is just beginning, a number of important findings are emerging. This review focuses on the following seven aspects of this emerging field: (a) a history of TLR and ligand studies; (b) the molecular basis of recognition by TLRs: TLR structures, pathogen-associated molecular pattern binding sites, TLR locations and functional responses; (c) cell types in TLR expression; (d) an overview of TLRs and their ligands: expression and ligands of cell-surface TLRs and of intracellular TLRs; (e) TLR-signaling pathways; (f) discussion: TLRs control of innate and adaptive systems; the trafficking of intracellular TLRs to endolysosomes; investigation of TLRs in regulating microRNA; investigation of crystal structure of TLRs with ligand binding; incidence of infectious diseases associated with single nucleotide polymorphisms (SNPs) in TLR genes; risk of cancer related to SNPs in TLR genes; TLR-ligand mediated anti-cancer effects; and TLR-ligand induced chronic inflammation and tumorigenesis; and (g) conclusions.
No prior twin study has explored the heritability of clinically diagnosed attention deficit hyperactivity disorder (ADHD). Such studies are needed to resolve conflicting results regarding the ...importance of genetic effects for ADHD in adults. We aimed to estimate the relative contribution of genetic and environmental influences for clinically diagnosed ADHD across the lifespan with a specific focus on ADHD in adults.
Information on zygosity and sex was obtained from 59514 twins born between 1959 and 2001 included in the nationwide population-based Swedish Twin Registry. Clinical data for ADHD diagnoses (i.e. stimulant or non-stimulant medication for ADHD) were obtained from the Swedish Prescribed Drug Register (PDR) and from the National Patient Register (i.e. ICD-10 diagnosis of ADHD). Twin methods were applied to clinical data of ADHD diagnoses using structural equation modeling with monozygotic (MZ) and dizygotic (DZ) twins.
The best-fitting model revealed a high heritability of ADHD 0.88, 95% confidence interval (CI) 0.83-0.92 for the entire sample. However, shared environmental effects were non-significant and of minimal importance. The heritability of ADHD in adults was also substantial (0.72, 95% CI 0.56-0.84).
This study shows that the heritability of clinically diagnosed ADHD is high across the lifespan. Our finding of high heritability for clinically diagnosed ADHD in adults indicates that the previous reports of low heritability are best explained by rater effects, and that gene-identification studies of ADHD in adults need to consider pervasiveness (e.g. multiple raters) and developmentally (e.g. childhood-onset criteria) informative data.
ABSTRACT
We use the X-ray luminosity relation of radio-loud quasars (RLQs) to measure these luminosity distances as well as estimate cosmological parameters. We adopt four parametric models of X-ray ...luminosity to test luminosity correlation for RLQs and radio-intermediate quasars (RIQs) and give these cosmological distances. By Bayesian information criterion (BIC), the data suggest that the luminosity relation ${L_X} \propto L_{\rm UV}^{{\gamma _{\rm uv}}}L_{\rm Radio}^{\gamma _{\rm radio}^{\prime }}$ for RLQs has a better goodness of fit, relative to other models, which can be interpreted as this relation being preferred for RLQs. Meanwhile, we compare the results from flat-spectrum radio-loud quasars (FSRLQs) and steep-spectrum radio-loud quasars (SSRLQs), which indicate that their luminosity correlations are not exactly the same. We also consider dividing the RLQ sample into various redshift bins, which can be used to check if the X-ray luminosity relation depends on the redshift. Finally, we apply a combination of RLQs and SN Ia Pantheon to verify the nature of dark energy concerning whether or not its density deviates from the constant, and give the statistical results.
Because malignant cells have altered, usually accelerated, energy consumption, targeting metabolic signaling represents a prevailing strategy for tumor therapy. Phosphoinositide-dependent kinase 1 ...(PDK1) is a proximal signaling molecule of phosphatidylinositol 3-kinase, which is required for metabolic activation. It is still lacking definitive evidence whether inactivation of PDK1 can overwhelm tumorigenesis in vivo. Herein we revealed that mammary-specific ablation of PDK1 could delay tumor initiation, progression and metastasis in a spontaneous mouse tumor model. We also demonstrated that inducible deletion of PDK1 could noticeably shrink the growing breast tumors. However, a small portion of PDK1-deficient tumorigenic cells eventually established tumor lesions, albeit at a relatively later phase, most likely owing to compensatory upregulation of extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Consequently, simultaneous inhibition of PDK1 and Erk1/2 impeded the survival of breast cancer cells. Thus we identify PDK1 as a potential therapeutic target for breast cancer, particularly in combination with an Erk1/2 inhibitor.
Highlights • CP−/− mice and mice that received FAC had high levels of brain iron. • Brain iron accumulation exacerbated TH-positive neurons apoptosis in MPTP-treated mice. • DFO reduced the neuronal ...damage in MPTP-treated CP−/− mice. • Increased oxidative stress was involved in cell apoptosis exacerbated by the increased brain iron.
Because the surface-to-volume ratio of quasi-two-dimensional materials is extremely high, understanding their surface characteristics is crucial for practically controlling their intrinsic properties ...and fabricating p-type and n-type layered semiconductors. Van der Waals crystals are expected to have an inert surface because of the absence of dangling bonds. However, here we show that the surface of high-quality synthesized molybdenum disulfide (MoS2) is a major n-doping source. The surface electron concentration of MoS2 is nearly four orders of magnitude higher than that of its inner bulk. Substantial thickness-dependent conductivity in MoS2 nanoflakes was observed. The transfer length method suggested the current transport in MoS2 following a two-dimensional behavior rather than the conventional three-dimensional mode. Scanning tunneling microscopy and angle-resolved photoemission spectroscopy measurements confirmed the presence of surface electron accumulation in this layered material. Notably, the in situ-cleaved surface exhibited a nearly intrinsic state without electron accumulation.
Parasitic helminths release molecular effectors into their hosts and these effectors can directly damage host tissue and modulate host immunity. Excreted/secreted proteins (ESPs) are one category of ...parasite molecular effectors that are critical to their success within the host. However, most studies of nematode ESPs rely on in vitro stimulation or culture conditions to collect the ESPs, operating under the assumption that in vitro conditions mimic actual in vivo infection. This assumption is rarely if ever validated. Entomopathogenic nematodes (EPNs) are lethal parasites of insects that produce and release toxins into their insect hosts and are a powerful model parasite system. We compared transcriptional profiles of individual Steinernema feltiae nematodes at different time points of activation under in vitro and in vivo conditions and found that some but not all time points during in vitro parasite activation have similar transcriptional profiles with nematodes from in vivo infections. These findings highlight the importance of experimental validation of ESP collection conditions. Additionally, we found that a suite of genes in the neuropeptide pathway were downregulated as nematodes activated and infection progressed in vivo, suggesting that these genes are involved in host-seeking behavior and are less important during active infection. We then characterized the ESPs of activated S. feltiae infective juveniles (IJs) using mass spectrometry and identified 266 proteins that are released by these nematodes. In comparing these ESPs with those previously identified in activated S. carpocapsae IJs, we identified a core set of 52 proteins that are conserved and present in the ESPs of activated IJs of both species. These core venom proteins include both tissue-damaging and immune-modulating proteins, suggesting that the ESPs of these parasites include both a core set of effectors as well as a specialized set, more adapted to the particular hosts they infect.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Two experiments were conducted to investigate the immune‐enhancing effect of dietary supplement with Astragalus polysaccharides (APS) on the Pacific white shrimp, Litopenaeus vannamei. In experiment ...1, the optimal APS dose was determined based on the immune responses of shrimps fed APS diet for 30 days. In experiment 2, the effect of APS supplementation on immune response of shrimp suffering white spot syndrome virus (WSSV) challenge was determined. Results showed that the total haemocyte count and phagocytic activity in shrimps fed APS diets significantly (p < .05) increased in comparison with those fed the basal diet. Dietary supplement with APS markedly (p < .05) increased the activity of phenoloxidase (PO), total superoxide dismutase (SOD), lysozyme (LZM), acid phosphatase and alkaline phosphatase in shrimp hemolymph, but decreased the maleic dialdehyde (MDA) content. Significantly higher (p < .05) activity on PO, SOD and LZM and lower (p < .05) MDA content have also been found in shrimps suffering WSSV challenge. Therefore, APS could be used as a safe and effective feed additive in shrimp aquaculture, and the optimal dose of APS for the Pacific white shrimp was suggested to be 0.2 g/kg based on our results.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Jaw deviation is frequently seen in Class III patients. The aim of the study was to investigate asymmetric features of skeletal, dental and soft tissues in three types of jaw asymmetry based on our ...previously reported classification system. The cone-beam computed tomography (CBCT) images of 70 Class III patients were analysed. Group 1 patients showed large shift of menton and synchronous but smaller ramus deviation. The maxillomandibular complex had roll and yaw rotations to the menton-deviation side. Maxillary and dental asymmetry was obvious in transverse and vertical dimensions. Cant of occlusal plane and lip line was apparent. Group 2 patients also exhibited menton and ramus deviation to the same side but the discrepancy in ramus width was larger than menton shift. Asymmetry in Group 2 resulted from a bodily side shift of the maxillomandibular complex without obvious rotation. Group 3 patients had menton and ramus deviated in opposite directions which seemed secondary to a yaw rotation. Double-jaw surgery is generally required for Groups 1 and 3 while Group 2 patients may be successfully treated by mandibular surgery only provided that arch width discrepancy can be managed by orthodontic measures.
Current influenza vaccines provide limited protection against circulating influenza A viruses. A universal influenza vaccine will eliminate the intrinsic limitations of the seasonal flu vaccines. ...Here we report methodology to generate double-layered protein nanoparticles as a universal influenza vaccine. Layered nanoparticles are fabricated by desolvating tetrameric M2e into protein nanoparticle cores and coating these cores by crosslinking headless HAs. Representative headless HAs of two HA phylogenetic groups are constructed and purified. Vaccinations with the resulting protein nanoparticles in mice induces robust long-lasting immunity, fully protecting the mice against challenges by divergent influenza A viruses of the same group or both groups. The results demonstrate the importance of incorporating both structure-stabilized HA stalk domains and M2e into a universal influenza vaccine to improve its protective potency and breadth. These potent disassemblable protein nanoparticles indicate a wide application in protein drug delivery and controlled release.
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