Functional and structural age-associated changes in the blood-brain barrier (BBB) may affect the neurovascular unit and contribute to the onset and progression of age-associated neurodegenerative pathologies, including Alzheimer's disease. The current study interrogated the RNA profile of the BBB in an ageing human autopsy brain cohort and an ageing mouse model using combined laser capture microdissection and expression profiling. Only 12 overlapping genes were altered in the same direction in the BBB of both ageing human and mouse cohorts. These included genes with roles in regulating vascular tone, tight junction protein expression and cell adhesion, all processes prone to dysregulation with advancing age. Integrated mRNA and miRNA network and pathway enrichment analysis of the datasets identified 15 overlapping miRNAs that showed altered expression. In addition to targeting genes related to DNA binding and/or autophagy, many of the miRNAs identified play a role in age-relevant processes, including BBB dysfunction and regulating the neuroinflammatory response. Future studies have the potential to develop targeted therapeutic approaches against these candidates to prevent vascular dysfunction in the ageing brain.

Retinal neuronal injury and degeneration is one of the primary manifestations of diabetic retinopathy, a leading cause of vision loss in working age adults. In pathological conditions, including diabetes and some physiological conditions such as aging, protein homeostasis can become disrupted, leading to endoplasmic reticulum (ER) stress. Severe or unmitigated ER stress can lead to cell death, which in retinal neurons results in irreversible loss of visual function. X-box binding protein 1 (XBP1) is a major transcription factor responsible for the adaptive unfolded protein response (UPR) to maintain protein homeostasis in cells undergoing ER stress. The purpose of this study is to determine the role of XBP1-mediated UPR in retinal neuronal survival and function in a mouse model of type 1 diabetes. Using a conditional retina-specific XBP1 knockout mouse line, we demonstrate that depletion of XBP1 in retinal neurons results in early onset retinal function decline, loss of retinal ganglion cells and photoreceptors, disrupted photoreceptor ribbon synapses, and Müller cell activation after induction of diabetes. Our findings suggest an important role of XBP1-mediated adaptive UPR in retinal neuronal survival and function in diabetes.

Peri-implantitis is an inflammatory disease affecting tissues surrounding dental implants. Although it represents a common complication of dental implant treatments, the underlying mechanisms have not yet been fully described. The aim of this study is to identify the role of titanium nanoparticles released form the implants on the chronic inflammation and bone lysis in the surrounding tissue. We analyzed the in vitro effect of titanium (Ti) particle exposure on mesenchymal stem cells (MSCs) and fibroblasts (FU), evaluating cell proliferation by MTT test and the generation of reactive oxygen species (ROS). Subsequently, in vivo analysis of peri-implant Ti particle distribution, histological, and molecular analyses were performed. Ti particles led to a time-dependent decrease in cell viability and increase in ROS production in both MSCs and FU. Tissue analyses revealed presence of oxidative stress, high extracellular and intracellular Ti levels and imbalanced bone turnover. High expression of ZFP467 and the presence of adipose-like tissue suggested dysregulation of the MSC population; alterations in vessel morphology were identified. The results suggest that Ti particles may induce the production of high ROS levels, recruiting abnormal quantity of neutrophils able to produce high level of metalloproteinase. This induces the degradation of collagen fibers. These events may influence MSC commitment, with an imbalance of bone regeneration.

There is ample evidence of the teratogenic effects of prenatal alcohol exposure, with long-term consequences throughout the entire life cycle. Nevertheless, research on risk perception of alcohol consumption among pregnant women is scarce. In order to analyze risk perception of alcohol consumption during pregnancy, a cross-sectional study was conducted with a random sample of 426 pregnant women (in their 20th week of gestation) receiving care at the outpatient clinics of a public university hospital in the southern European city of Seville (Spain). Data were collected through structured face-to-face interviews conducted by trained health professionals using a customized questionnaire. Data analysis included structural equation modeling. Only 48.1% of the sample indicated that the sequelae from alcohol consumption during pregnancy were life-long. The structural equation model showed that a lower risk perception about beer and wine consumption, and a lower educational level, were related to more frequent alcohol consumption. Younger participants showed lower risk perception concerning beer consumption. Higher levels of education were related to a greater risk perception of beer. Healthcare institutions should articulate programs that facilitate health advice regarding alcohol consumption during pregnancy, particularly when providing care for women with low educational levels.

Protein supplementation might improve body composition and exercise performance. Supplements containing whey protein (WP) have received the most attention, but other protein sources such as beef protein (BP) are gaining popularity. We conducted a systematic review and meta-analysis of randomized controlled trials that compared the effects of exercise training combined with BP, WP or no protein supplementation (NP), on body composition or exercise performance. Secondary endpoints included intervention effects on total protein intake and hematological parameters. Seven studies (n = 270 participants) were included. No differences were found between BP and WP for total protein intake (standardized mean difference (SMD) = 0.04, p = 0.892), lean body mass (LBM) (SMD = -0.01, p = 0.970) or fat mass (SMD = 0.07, p = 0.760). BP significantly increased total daily protein intake (SMD = 0.68, p < 0.001), LBM (SMD = 0.34, p = 0.049) and lower-limb muscle strength (SMD = 0.40, p = 0.014) compared to NP, but no significant differences were found between both conditions for fat mass (SMD = 0.15, p = 0.256), upper-limb muscle strength (SMD = 0.16, p = 0.536) or total iron intake (SMD = 0.29, p = 0.089). In summary, BP provides similar effects to WP on protein intake and body composition and, compared to NP, might be an effective intervention to increase total daily protein intake, LBM and lower-limb muscle strength.

Chronic musculoskeletal (MSK) pain is one of the most common medical complaints worldwide and musculoskeletal injuries have an enormous social and economical impact. Current pharmacological and surgical treatments aim to relief pain and restore function; however, unsatiscactory outcomes are commonly reported. In order to find an accurate treatment to such pathologies, over the last years, there has been a significantly increasing interest in cellular therapies, such as adipose-derived mesenchymal stem cells (AMSCs). These cells represent a relatively new strategy in regenerative medicine, with many potential applications, especially regarding MSK disorders, and preclinical and clinical studies have demonstrated their efficacy in muscle, tendon, bone and cartilage regeneration. Nevertheless, several worries about their safety and side effects at long-term remain unsolved. This article aims to review the current state of AMSCs therapy in the treatment of several MSK diseases and their clinical applications in veterinary and human medicine.

Obesity is known to cause skeletal muscle wasting. This study investigated the effect and the possible mechanism of fish oil on skeletal muscle wasting in an obese rat model. High-fat (HF) diets were applied to induce the defects of lipid metabolism in male Sprague-Dawley rats with or without substitution of omega-3 fatty acids-enriched fish oil (FO, 5%) for eight weeks. Diets supplemented with 5% FO showed a significant decrease in the final body weight compared to HF diet-fed rats. The decreased soleus muscle weights in HF diet-fed rats could be improved by FO substitution. The decreased myosin heavy chain (a muscle thick filament protein) and increased FOXO3A and Atrogin-1 (muscle atrophy-related proteins) protein expressions in soleus muscles of HF diet-fed rats could also be reversed by FO substitution. FO substitution could also significantly activate adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation, peroxisome-proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α), and PPARγ protein expression and lipoprotein lipase (LPL) mRNA expression in soleus muscles of HF diet-fed rats. These results suggest that substitution of FO exerts a beneficial improvement in the imbalance of lipid and muscle metabolisms in obesity. AMPK/PGC-1α signaling may play an important role in FO-prevented obesity-induced muscle wasting.

The aim of this study was to evaluate the structural, physical, and antifungal characteristics of starch edible films added with nanocomposites and Mexican oregano (Lippia berlandieri Schauer) essential oil (EO). Starch edible films were formulated with Mexican oregano EO (0%, 1%, or 2% v/v) and bentonite or halloysite (2%). Physical properties such as L* (luminosity), hue, film thickness, and O2 and CO2 permeability were determined. Structural analysis was carried out via atomic force microscopy (AFM). Antifungal activity against Aspergillus niger, Fusarium spp., and Rhizopus spp. was evaluated. The addition of EO and nanocomposites reduced luminosity, providing color to the edible films. Film thickness increased through the addition of EO concentration. O2 and CO2 permeability was increased by bentonite/EO films, and for halloysite films, CO2 permeability decreased as EO concentration increased. The addition of EO with both nanocomposites shows an evident morphological change in film structure, decreasing pore density and increasing pore size. In general, Mexican oregano EO added to edible starch films has an adequate fungicidal effect. The most sensitive microorganism tested was A. niger. Edible films added with Mexican oregano EO and nanocomposites show better physical and antifungal properties due to an adequate structural change in the biopolymer matrix.

The family Totiviridae currently contains five genera Totivirus, Victorivirus, Leishmavirus, Trichomonasvirus, and Giardiavirus. Members in this family generally have a set of two-open reading frame (ORF) elements in their genome with the 5'-proximal ORF (ORF1) encoding a capsid protein (CP) and the 3'-proximal one (ORF2) for RNA-dependent RNA polymerase (RdRp). How the downstream open reading frames (ORFs) are expressed is genus-specific. All victoriviruses characterized thus far appear to use the stop/restart translation mechanism, allowing for the expression of two separate protein products from bicitronic genome-sized viral mRNA, while the totiviruses use a -1 ribosomal frame-shifting that leads to a fusion product of CP and RdRp. We report the biological and molecular characterization of a novel victorivirus termed Alternaria alternata victorivirus 1 (AalVV1) isolated from Alternaria alternata in Pakistan. The phylogenetic and molecular analyses showed AalVV1 to be distinct from previously reported victoriviruses. AalVV1 appears to have a sequence signature required for the -1 frame-shifting at the ORF1/2 junction region, rather than a stop/restart key mediator. By contrast, SDS-polyacrylamide gel electrophoresis and peptide mass fingerprinting analyses of purified virion preparations suggested the expression of two protein products, not a CP-RdRp fusion product. How these proteins are expressed is discussed in this study. Possible effects of infection by this virus were tested in two fungal species: A. alternata and RNA silencing proficient and deficient strains of Cryphonectria parasitica, a model filamentous fungus. AalVV1 showed symptomless infection in all of these fungal strains, even in the RNA silencing deficient C. parasitica strain.

The objective of this study is to estimate the number of deaths attributable to cardiovascular diseases and diet-related cancers that could be prevented or delayed in the Nordic countries, i.e., Sweden, Denmark, Finland, Norway, and Iceland, if adults adhere to the Nordic Nutrition Recommendations (NNR). A sex- and age-group specific epidemiological macro-simulation model was used to estimate the preventable deaths due to the differences between country specific actual intake and recommended intake of changes in food components. Data included in the model are a baseline scenario (actual dietary intake), a counterfactual scenario (recommended intake), and age-and sex-specific mortality for cardiovascular and diet-related cancer diseases, together with the total population risk of a specific year. Monte Carlo analyses with 5000 iterations were performed to produce the 95% uncertainty intervals. The model predicts that Iceland would benefit the most by adhering to the NNR, followed by Finland. In all the Nordic countries, the highest benefit would be achieved by adhering to the fruits and vegetable intakes, except Denmark, where a lower recommended intake of salt would provide the highest benefit. For men, fruits and vegetables could have saved more lives compared to other dietary components for all the Nordic countries, while for women, dietary fiber was the most prominent factor, except in Iceland. The Nordic Council should consider policies for promoting healthy eating according to the needs of each country.

The global epidemic of type 2 diabetes (T2D) is a challenging health problem. Lifestyle changes, including nutrition therapy, areimportant for the prevention and management of T2D. Seaweeds contain several bioactive substances with potential health properties and may be a low-cost alternative functional food in the prevention of T2D.

The v-raf murine sarcoma viral homolog B1 (BRAF) inhibitor drug vemurafenib (PLX4032) is used to treat melanoma; however, epidemiological evidence reveals that it could cause cutaneous keratoacanthomas and squamous cell carcinoma in cancer patients with the most prevalent HRASQ61L mutation. In a two-stage skin carcinogenesis mouse model, the skin papillomas induced by 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) (DT) resemble the lesions in BRAF inhibitor-treated patients. In this study, we investigated the bioactivity of Mentha aquatica var. Kenting Water Mint essential oil (KWM-EO) against PDV cells, mouse keratinocytes bearing HRASQ61L mutation, and its effect on inhibiting papilloma formation in a two-stage skin carcinogenesis mouse model with or without PLX4032 co-treatment. Our results revealed that KWM-EO effectively attenuated cell viability, colony formation, and the invasive and migratory abilities of PDV cells. Induction of G2/M cell-cycle arrest and apoptosis in PDV cells was also observed. KWM-EO treatment significantly decreased the formation of cutaneous papilloma further induced by PLX4032 in DT mice (DTP). Immunohistochemistry analyses showed overexpression of keratin14 and COX-2 in DT and DTP skin were profoundly suppressed by KWM-EO treatment. This study demonstrates that KWM-EO has chemopreventive effects against PLX4032-induced cutaneous side-effects in a DMBA/TPA-induced two-stage carcinogenesis model and will be worth further exploration for possible application in melanoma patients.

Extracellular matrix remodeling plays a pivotal role during mesenchyme patterning into different lineages. Tension exerted from cell membrane receptors bound to extracellular matrix ligands is transmitted by the cytoskeleton to the cell nucleus inducing gene expression. Here, we used dendrimer-based arginine-glycine-aspartic acid (RGD) uneven nanopatterns, which allow the control of local surface adhesiveness at the nanoscale, to unveil the adhesive requirements of mesenchymal tenogenic and osteogenic commitments. Cell response was found to depend on the tension resulting from cell-substrate interactions, which affects nuclear morphology and is regulated by focal adhesion size and distribution.

Fracture treatment in osteoporotic patients is still challenging. Osteoporosis emerges when there is an imbalance between bone formation and resorption in favor of resorption by osteoclasts. Thus, new implant materials for osteoporotic fracture treatment should promote bone formation and reduce bone resorption. Nanoparticles can serve as drug delivery systems for growth factors like Brain-Derived Neurotrophic Factor (BDNF), which stimulated osteoblast differentiation. Therefore, polyelectrolyte complex nanoparticles (PEC-NPs) consisting of poly(l-lysine) (PLL) and cellulose sulfate (CS), with or without addition of BDNF, were used to analyze their effect on osteoclasts in vitro. Live cell images showed that osteoclast numbers decreased after application of high PLL/CS PEC-NPs concentrations independent of whether BDNF was added or not. Real-time RT-PCR revealed that relative mRNA expression of cathepsin K and calcitonin receptor significantly declined after incubation of osteoclasts with high concentrations of PLL/CS PEC-NPs. Furthermore, Enzyme-Linked Immunosorbent Assay indicated that tartrate-resistant acidic phosphatase 5b activity was significantly reduced in the presence of high PLL/CS PEC-NPs concentrations. Consistent with these results, the pit formation analysis showed that less hydroxyapatite was resorbed by osteoclasts after incubation with high concentrations of PLL/CS PEC-NPs. BDNF had no influence on osteoclasts. We conclude that highly concentrated PLL/CS PEC-NPs dosages decreased osteoclastogenesis and osteoclasts activity. Moreover, BDNF might be a promising growth factor for osteoporotic fracture treatment since it did not increase osteoclast activity.

Despite advances in coverage and quality of prevention of mother-to-child transmission (PMTCT) programs, infant protection from postnatal HIV infection remains an issue in high HIV-burdened countries. We designed a quality improvement (QI) intervention-the Partnership for HIV-Free Survival (PHFS)-to improve infant survival. PHFS convened leaders in 6 sub-Saharan African nations to discover together the best strategies for implementing and scaling up existing PMTCT protocols to ensure optimal health of mother-baby pairs and HIV-free infant survival. We used 3 core technical components-rapid adaptive design, collaborative learning, and scale-up/sustainability designs-to test strategies for accelerating effective PMTCT programming in complex, resource-poor settings. Learning generated included the need for increased ownership and codesign of improvement initiatives with Ministries of Health, better integration of initiatives into existing programs, and the need to sustain QI capability throughout the system. PHFS can serve as a design prototype for future global networks aiming to accelerate improvement, learning, and results.

As a newly discovered cytokine, interleukin 9 was initially considered a T-lymphocyte growth factor. Interleukin 9 affects target cells by binding to a member of the γc-family of receptors and is involved in inflammation, autoimmune diseases, and other ailments. In recent years, mounting evidence reveals that interleukin 9 exerts antitumor effects, which has attracted considerable attention. Many previous studies were performed in vivo by establishing a mouse model of melanoma. Here, interleukin 9 protein and messenger RNA expression levels were both low in colon carcinoma tissue specimens, as assessed by immunohistochemistry and quantitative real-time polymerase chain reaction. In addition, interleukin 9 expression in these samples was correlated with TNM staging, Dukes staging, lymph node metastasis, and good prognosis, but not with gender, age, tumor size, tumor differentiation, and hepatic metastasis. In vivo, by establishing a mouse subcutaneous allograft model, we found that interleukin 9 overexpression inhibited tumor growth and resulted in longer survival time. Then, antitumor immune responses were increased by interleukin 9 as demonstrated by flow cytometry. Furthermore, interleukin 9 was shown to exert antitumor effects by regulating T-cell function and killing tumor cells in the tumor microenvironment. Overall, this study revealed that interleukin 9 exerts robust antitumor effects in colon cancer and transforms the tumor microenvironment in vivo.

In this meta-analysis, we investigated the association of methylenetetrahydrofolate reductase, vitamin D receptor, and interleukin-16 gene polymorphisms with the risk of renal cell carcinoma. We searched the PubMed and Cochrane Library databases up to July 1, 2017, and included 12 eligible case-control studies in our analysis. The vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype were all associated with the risk of renal cell carcinoma in Asian populations. However, methylenetetrahydrofolate reductase (rs1801133 and rs1801131), vitamin D receptor (TaqI and Fok1), and interleukin-16 (rs4778889 and rs11556218) gene polymorphisms were not associated with the risk of renal cell carcinoma. Our study indicates that the vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype are associated with renal cell carcinoma risk.

This study aimed at (1) comparing the accuracies of genomic prediction for parasite resistance in sheep based on whole-genome sequence (WGS) data to those based on 50k and high-density (HD) single nucleotide polymorphism (SNP) panels; (2) investigating whether the use of variants within quantitative trait loci (QTL) regions that were selected from regional heritability mapping (RHM) in an independent dataset improved the accuracy more than variants selected from genome-wide association studies (GWAS); and (3) comparing the prediction accuracies between variants selected from WGS data to variants selected from the HD SNP panel.

Flavescence dorée is the most serious grapevine yellows disease in Europe. It is caused by phytoplasmas which are transmitted from grapevine to grapevine by the leafhopper Scaphoideus titanus. Differences in susceptibility among grapevine varieties suggest the existence of specific genetic features associated with resistance to the phytoplasma and/or possibly with its vector. In this work, RNA-Seq was used to compare early transcriptional changes occurring during the three-trophic interaction between the phytoplasma, its vector and the grapevine, represented by two different cultivars, one very susceptible to the disease and the other scarcely susceptible.

Breeding programs benefit from information about marker-trait associations for many traits, whether the goal is to place those traits under active selection or to maintain them through background selection. Association studies are also important for identifying accessions bearing potentially useful alleles by characterizing marker-trait associations and allelic states across germplasm collections. This study reports the results of a genome-wide association study and evaluation of epistatic interactions for four agronomic and seed-related traits in soybean.