The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway mediates multiple adaptive T-cell functions, but recent studies have shown that calcineurin/NFAT signaling also ...contributes to innate immunity and regulates the homeostasis of innate cells. Myeloid cells, including granulocytes and dendritic cells, can promote inflammation, regulate adaptive immunity, and are essential mediators of early responses to pathogens. Microbial ligation of pattern-recognition receptors, such as TLR4, CD14, and dectin 1, is now known to induce the activation of calcineurin/NFAT signaling in myeloid cells, a finding that has provided new insights into the molecular pathways that regulate host protection. Inhibitors of calcineurin/NFAT binding, such as cyclosporine A and FK506, are broadly used in organ transplantation and can act as potent immunosuppressive drugs in a variety of different disorders. There is increasing evidence that these agents influence innate responses as well as inhibiting adaptive T-cell functions. This review focuses on the role of calcineurin/NFAT signaling in myeloid cells, which may contribute to the various unexplained effects of immunosuppressive drugs already being used in the clinic.
Objectives
Dietary protein intake is of great significance for the bone health of middle-aged and elderly people. This study is aimed to explore the relationships between dietary protein intake and ...the risk of osteoporosis in middle-aged and older individuals among US population.
Methods
Based on the National Health and Nutrition Examination Survey (NHANES), this study includes a total of 20497 participants during 2005–2008, and identify 4707 middle-aged and older people aged 45 years or above. Demographic data and relevant dietary intake information are acquired through in-home management questionnaires. The logistic regression models are established to identify the odds ratio (OR) and 95% confidence interval (CI) of OP in each quartile category of energy-adjusted dietary protein intake. The receiver operating characteristic (ROC) curve is applied to explore the optimal cut-off value of daily dietary protein intake for predicting risk of OP.
Results
442 participants with OP are identified among 4707 middle-aged and older people, and the dietary protein intake of OP group is significantly lower than that of non-OP group (P<0.001). The logistic regression analysis shows that with the increase of daily dietary protein intake, the prevalence of OP in each quartile category decreases gradually (P<0.001). This trend is not altered in univariate model (P<0.001), as well as the adjustments for the covariates of age and BMI (Model 1, P<0.001), the covariates of sex (Model 2, P=0.036), the covariates of smoking, drinking alcohol, education, ratio of family income to poverty, hypertension and diabetes (Model 3, P<0.001), and the covariates of dietary intake (Model 4, P=0.008). Moreover, we also identify that the daily dietary protein intake of 61.2g is the optimal cut-off value for predicting risk of OP.
Conclusion
In general, among US population, the lower daily dietary protein intake is positively related to the ascending risk of OP in middle-aged and older individuals.
Summary
Background
There has been no large‐scale population‐based study on the relationship between pyogenic liver abscesses (PLA) and subsequent cancer risk.
Aim
To estimate all cancer risk ...following a diagnosis of PLA.
Methods
Based on Taiwan's National Health Insurance Research Database, 1257 patients with PLA without prior cancers in the period 1996–2008 were identified and followed‐up. The standard incidence ratio (SIR) of each cancer was calculated as the number of observed cancer cases arising among the PLA patients divided by the expected case number of cancer cases according to the national cancer rates.
Results
Of the 1257 PLA patients identified, 598 (47.6%) had diabetes mellitus. After a median (±s.d.) follow‐up of 3.33 ± 3.45 years, 186 were diagnosed with cancers, including 56 liver cancer, 22 biliary tract cancer and 40 colorectal cancer patients. Patients with PLA had a higher risk of all cancers (SIR, 3.83; 95% CI, 3.30–4.42), liver cancer (SIR, 7.87; 95% CI, 5.94–10.21), biliary tract cancer (SIR, 34.58; 95% CI, 21.67–52.36) and colorectal cancer (SIR, 5.27; 95% CI, 3.76–7.18). The highest SIRs of all cancers, liver cancer, biliary tract cancer and colorectal cancer occurred within 90 days of follow‐up (360.82; 95% CI, 278.46–459.91, 257.28; 95% CI, 186.17–346.56, 1153.38; 95% CI 694.08–1801.24, and 52.63; 95% CI 25.2–96.8 respectively).
Conclusions
Pyogenic liver abscesses may herald the onset of cancer, especially hepato‐biliary and colon cancer. Further surveys should be conducted for the detection of occult cancers in such patients.
Probiotics can stabilize gut flora, regulate intestinal immunity and protect the host from enteric diseases; however, their roles in oral health have received little attention compared to their roles ...in gut health. Nowadays, the prevalence of sugar‐sweetened foods and abuse of antibiotics contribute towards dysbiosis of oral microbiota and drug resistance development in oral pathogens, resulting in various intractable oral diseases. We screened the antibacterial activities of viable and heat‐killed probiotic strains against the oral pathogens Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans. The probiotic strains Lactobacillus salivarius subsp. salicinius AP‐32, L. rhamnosus CT‐53, L. paracasei ET‐66 and Bifidobacterium animalis subsp. lactis CP‐9 displayed strong antipathogenic activities, whereas heat‐killed AP‐32, CT‐53 and ET‐66 displayed high levels of pathogen inhibition. The antibacterial activities of these probiotics were not associated with their H2O2 production; L. acidophilus TYCA02 produced high levels of H2O2 but merely exhibited moderate antibacterial activities. Oral tablets containing probiotics showed positive inhibitory effects against oral pathogens, particularly those containing viable probiotics. Our results indicate that probiotics prevent the growth of oral pathogens and improve oral health, providing insights into the antipathogenic efficacy of different probiotic species and their potential role in functional foods that improve oral health.
Significance and Impact of the Study
Our study provides insights into the antipathogenic efficacy of different probiotic species and their potential roles in developing functional foods to improve oral health. We showed that the probiotic strains Lactobacillus salivarius subsp. salicinius AP‐32, L. rhamnosus CT‐53, L. paracasei ET‐66 and Bifidobacterium animalis subsp. lactis CP‐9 have great potential for use in the development of functional foods to improve oral health. Since active probiotics may provide strong and long‐term protection, the development of functional food products should favour the use of viable bacteria.
Significance and Impact of the Study: Our study provides insights into the antipathogenic efficacy of different probiotic species and their potential roles in developing functional foods to improve oral health. We showed that the probiotic strains Lactobacillus salivarius subsp. salicinius AP‐32, L. rhamnosus CT‐53, L. paracasei ET‐66 and Bifidobacterium animalis subsp. lactis CP‐9 have great potential for use in the development of functional foods to improve oral health. Since active probiotics may provide strong and long‐term protection, the development of functional food products should favour the use of viable bacteria.
Mitochondria take part in a network of intracellular processes that regulate homeostasis. Defects in mitochondrial function are key pathophysiological changes during AKI. Although Wnt/β-catenin ...signaling mediates mitochondrial dysfunction in chronic kidney fibrosis, little is known of the influence of β-catenin on mitochondrial function in AKI. To decipher this interaction, we generated an inducible mouse model of tubule-specific β-catenin overexpression (TubCat), and a model of tubule-specific β-catenin depletion (TubcatKO), and induced septic AKI in these mice with lipopolysaccharide (LPS) and aseptic AKI with bilateral ischemia-reperfusion. In both AKI models, tubular β-catenin stabilization in TubCat animals significantly reduced BUN/serum creatinine, tubular damage (NGAL-positive tubules), apoptosis (TUNEL-positive cells) and necroptosis (phosphorylation of MLKL and RIP3) through activating AKT phosphorylation and p53 suppression; enhanced mitochondrial biogenesis (increased PGC-1α and NRF1) and restored mitochondrial mass (increased TIM23) to re-establish mitochondrial homeostasis (increased fusion markers OPA1, MFN2, and decreased fission protein DRP1) through the FOXO3/PGC-1α signaling cascade. Conversely, kidney function loss and histological damage, tubular cell death, and mitochondrial dysfunction were all aggravated in TubCatKO mice. Mechanistically, β-catenin transfection maintained mitochondrial mass and activated PGC-1α via FOXO3 in LPS-exposed HK-2 cells. Collectively, these findings provide evidence that tubular β-catenin mitigates cell death and restores mitochondrial homeostasis in AKI through the common mechanisms associated with activation of AKT/p53 and FOXO3/PGC-1α signaling pathways.
Invasion and metastasis are the distinct biologic characteristics of cancer, resulting in an exceptionally low 5-year survival rate in pancreatic ductal adenocarcinoma (PDAC). Understanding in detail ...the mechanisms underlying PDAC metastasis is critical for prevention and effective interventions. Long non-coding RNAs (lncRNAs) have been documented as having a critical role in cancer development and progression.
We examined the expression levels of lncRNA ENST00000480739 and osteosarcoma amplified-9 (OS-9) mRNA in a cohort of 35 PDAC patients. Cell proliferation, invasion and migration were examined with and without ENST00000480739 overexpression in PDAC cells.
We determined that the ENST00000480739 expression level was remarkably decreased in tumorous tissues compared with their corresponding non-tumorous tissues. The expression of ENST00000480739 was negatively associated with tumour node metastasis stage and lymph node metastasis. In addition, ENST0000048073 was an independent prognostic factor of survival time in PDAC patients following surgery. Besides, enforced expression of ENST00000480739 suppressed PDAC cells' invasion in vitro. Overexpression of ENST00000480739 significantly increased both mRNA and protein levels of OS-9, and the luciferase assays confirmed that ENST00000480739 positively regulates OS-9 by activating the transcription level of the OS-9 promoter. We further found that ENST00000480739 may target hypoxia-inducible factor-1α (HIF-1α) expression by upregulating OS-9.
These findings suggest that the frequently downregulated ENST00000480739 in PDAC contributes to tumour metastasis and progression by regulating HIF-1α. Long non-coding RNA ENST00000480739 may provide not only a therapeutic potential to suppress metastasis but it may also be a novel biomarker for risk prognostication and personal therapy screening of PDAC patients.
The remarkable fossil record of whales and dolphins (Cetacea) has made them an exemplar of macroevolution. Although their overall adaptive transition from terrestrial to fully aquatic organisms is ...well known, this is not true for the radiation of modern whales. Here, we explore the diversification of extant cetaceans by constructing a robust molecular phylogeny that includes 87 of 89 extant species. The phylogeny and divergence times are derived from nuclear and mitochondrial markers, calibrated with fossils. We find that the toothed whales are monophyletic, suggesting that echolocation evolved only once early in that lineage some 36–34 Ma. The rorqual family (Balaenopteridae) is restored with the exclusion of the gray whale, suggesting that gulp feeding evolved 18–16 Ma. Delphinida, comprising all living dolphins and porpoises other than the Ganges/Indus dolphins, originated about 26 Ma; it contains the taxonomically rich delphinids, which began diversifying less than 11 Ma. We tested 2 hypothesized drivers of the extant cetacean radiation by assessing the tempo of lineage accumulation through time. We find no support for a rapid burst of speciation early in the history of extant whales, contrasting with expectations of an adaptive radiation model. However, we do find support for increased diversification rates during periods of pronounced physical restructuring of the oceans. The results imply that paleogeographic and paleoceanographic changes, such as closure of major seaways, have influenced the dynamics of radiation in extant cetaceans.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is much interest in the tissue of origin of circulating DNA in plasma. Data generated using DNA methylation markers have suggested that hematopoietic cells of white cell lineages are important ...contributors to the circulating DNA pool. However, it is not known whether cells of the erythroid lineage would also release DNA into the plasma.
Using high-resolution methylation profiles of erythroblasts and other tissue types, 3 genomic loci were found to be hypomethylated in erythroblasts but hypermethylated in other cell types. We developed digital PCR assays for measuring erythroid DNA using the differentially methylated region for each locus.
Based on the methylation marker in the ferrochelatase gene, erythroid DNA represented a median of 30.1% of the plasma DNA of healthy subjects. In subjects with anemia of different etiologies, quantitative analysis of circulating erythroid DNA could reflect the erythropoietic activity in the bone marrow. For patients with reduced erythropoietic activity, as exemplified by aplastic anemia, the percentage of circulating erythroid DNA was decreased. For patients with increased but ineffective erythropoiesis, as exemplified by β-thalassemia major, the percentage was increased. In addition, the plasma concentration of erythroid DNA was found to correlate with treatment response in aplastic anemia and iron deficiency anemia. Plasma DNA analysis using digital PCR assays targeting the other 2 differentially methylated regions showed similar findings.
Erythroid DNA is a hitherto unrecognized major component of the circulating DNA pool and is a noninvasive biomarker for differential diagnosis and monitoring of anemia.
Cloud condensation nuclei (CCN) concentrations were measured at Egbert, a rural site in Ontario, Canada during the spring of 2007. The CCN concentrations were compared to values predicted from the ...aerosol chemical composition and size distribution using κ-Köhler theory, with the specific goal of this work being to determine the hygroscopic parameter (κ) of the oxygenated organic component of the aerosol, assuming that oxygenation drives the hygroscopicity for the entire organic fraction of the aerosol. The hygroscopicity of the oxygenated fraction of the organic component, as determined by an Aerodyne aerosol mass spectrometer (AMS), was characterised by two methods. First, positive matrix factorization (PMF) was used to separate oxygenated and unoxygenated organic aerosol factors. By assuming that the unoxygenated factor is completely non-hygroscopic and by varying κ of the oxygenated factor so that the predicted and measured CCN concentrations are internally consistent and in good agreement, κ of the oxygenated organic factor was found to be 0.22±0.04 for the suite of measurements made during this five-week campaign. In a second, equivalent approach, we continue to assume that the unoxygenated component of the aerosol, with a mole ratio of atomic oxygen to atomic carbon (O/C) ≈ 0, is completely non-hygroscopic, and we postulate a simple linear relationship between κorg and O/C. Under these assumptions, the κ of the entire organic component for bulk aerosols measured by the AMS can be parameterised as κorg=(0.29±0.05)·(O/C), for the range of O/C observed in this study (0.3 to 0.6). These results are averaged over our five-week study at one location using only the AMS for composition analysis. Empirically, our measurements are consistent with κorg generally increasing with increasing particle oxygenation, but high uncertainties preclude us from testing this hypothesis. Lastly, we examine select periods of different aerosol composition, corresponding to different air mass histories, to determine the generality of the campaign-wide findings described above.
Summary
In a cohort of 393 Chinese women, by using high-resolution peripheral quantitative computed tomography (HR-pQCT), we found that significant cortical bone loss occurred after midlife. ...Prominent increase in cortical porosity began at the fifth decade but reached a plateau before the sixth decade. Trabecular bone loss was already evident in young adulthood and continued throughout life.
Introduction
This study aimed to investigate age-related differences in volumetric bone mineral density (vBMD), microarchitecture, and estimated bone strength at peripheral skeleton in Chinese female population.
Methods
In a cross-sectional cohort of 393 Chinese women aged 20–90 years, we obtained vBMD, microarchtecture, and micro-finite element-derived bone strength at distal radius and tibia using HR-pQCT.
Results
The largest predictive age-related difference was found for cortical porosity (Ct.Po) which showed over four-fold and two-fold differences at distal radius and tibia, respectively, over the adulthood. At both sites, cortical bone area, vBMD, and thickness showed significant quadratic association with age with significant decrease beginning after midlife. Change of Ct.Po became more prominent between age of 50 and 57 (0.26 %/year at distal radius, 0.54 %/year at distal tibia, both
p
≤ 0.001) but thereafter, reached a plateau (0.015 and 0.028 %/year, both
p
> 0.05). In contrast, trabecular vBMD and microarchitecture showed linear association with age with significant deterioration observed throughout adulthood. Estimated age of peak was around age of 20 for trabecular vBMD and microarchitecture and Ct.Po and age of 40 for cortical vBMD and microarchitecture. Estimated stiffness and failure load peaked at mid-30s at the distal radius and at age 20 at distal tibia.
Conclusions
Age-related differences in vBMD and microarchitecture in Chinese women differed by bone compartments. Significant cortical bone loss occurred after midlife. Prominent increase in Ct.Po began at the fifth decade but appeared to be arrested before the sixth decade. Loss of trabecular bone was already evident in young adulthood and continued throughout life.
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