Complex diseases such as neurodegenerative disorders and cancer constitute a growing public health problem due to the rising incidence and lack in effective therapies. Since pharmacotherapy based on ...a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy for the search of new drug candidates. Plant-derived isoquinoline alkaloids comprise a vast source of multimodal agents with unique structural diversity, and variated range of pharmacological activities. This review offers an exhaustive compilation of the pharmacological relevance and multi-target potential of natural isoquinolines, emphasizing their features and promising activity in complex diseases such as Alzheimer, Parkinson, and Cancer. Selected examples were discussed in depth to illustrate the most relevant structural motifs and their possible relationship with the multimodal activity offering a comprehensive baseline in the search and optimization of isoquinoline scaffolds with polypharmacological potential for complex diseases.
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Using two languages on an everyday basis appears to have a positive effect on general-purpose executive control in bilinguals. However, the neural correlates of this effect remain poorly understood. ...To investigate the brain bases of the bilingual advantage in executive control, we tested 21 Spanish monolinguals and 19 Spanish-Catalan early bilinguals in a non-verbal task-switching paradigm. As expected based on previous experiments on non-verbal task switching, we found activation in the right inferior frontal cortex and the anterior cingulate of monolingual participants. While bilingual participants showed a reduced switching cost, they activated the left inferior frontal cortex and the left striatum, a pattern of activation consistent with networks thought to underlie language control. Overall, these results support the hypothesis that bilinguals' early training in switching back and forth between their languages leads to the recruitment of brain regions involved in language control when performing non-linguistic cognitive tasks.
•Conventional and Ultra-High Pressure Homogenization emulsions were studied.•Oxidative stability and interfacial properties of emulsions were analyzed.•Lipid oxidation of emulsions decreased with ...oil-phase volume fraction.•Emulsions (100–200MPa) with 20% of oil exhibited the best oxidative stability.
Ultra-High Pressure Homogenization (100–300MPa) has great potential for technological, microbiological and nutritional aspects of fluid processing. Its effect on the oxidative stability and interfacial properties of oil-in-water emulsions prepared with 4% (w/v) of soy protein isolate and soybean oil (10 and 20%, v/v) were studied and compared to emulsions treated by conventional homogenization (15MPa). Emulsions were characterized by particle size, emulsifying activity index, surface protein concentration at the interface and by transmission electron microscopy. Primary and secondary lipid oxidation products were evaluated in emulsions upon storage. Emulsions with 20% oil treated at 100 and 200MPa exhibited the most oxidative stability due to higher amount of oil and protein surface load at the interface. This manuscript addresses the improvement in oxidative stability in emulsions treated by UHPH when compared to conventional emulsions.
Food insecurity (FI) remains a global public health problem. FI is more prevalent in low-and middle-income countries than high-income countries. FI is related with worse cognitive outcomes including ...cognitive function, cognitive decline, and cognitive impairment. Few studies have sought to identify how patterns of FI relate with cognitive function in old age and the potential mechanisms underlying this association.
Data from the 2015 and 2018 waves of the Mexican Health and Aging Study (n = 9,654, age 50+) were used in this study. Reports of FI in 2015 and 2018 were combined to create four patterns of FI groups: "persistently food secure", "became food secure", "became food insecure", and "persistently food insecure". Linear regression was used to estimate associations between patterns of FI and cognitive task performance. The mediating roles of depressive symptoms, body mass index, and chronic conditions were tested using Karlson, Holm, and Breen methodology.
Approximately half of the sample were persistently food secure, 17% became food secure, 14% became FI, and 15% experienced persistent FI. When adjusting for demographic/socioeconomic confounders, persistent FI related with worse Verbal Learning, Verbal Recall, Visual Scanning, and Verbal Fluency performance compared to the persistently food secure. Becoming FI related with worse Verbal Learning, Visual Scanning, and Verbal Fluency. Mediation analyses provided support for depressive symptoms mediating associations between FI and poorer cognition, where 48% of the association between persistent FI and worse Verbal Recall performance was attributed to higher depressive symptoms. Becoming food secure was not associated with cognitive performance compared to the persistently food secure.
FI may represent an important modifiable risk factor for poorer cognitive outcomes among older adults. Public health efforts should focus on providing stable food access to older adults, especially those living in poverty.
Treatment with tumour necrosis factor inhibitors (TNF-i) plus methotrexate (MTX), but not MTX monotherapy alone, inhibits joint damage progression even at higher levels of disease activity. Such ...disassociation of disease activity and structural damage has not been shown for biological agents other than TNF-i.
To evaluate whether interleukin 6 (IL-6) inhibition with tocilizumab (TCZ) interferes with joint destruction beyond its effects on disease activity.
A random 90% sample of data from the (The Tocilizumab Safety and the Prevention of Structural Joint Damage Study) LITHE trial on active rheumatoid arthritis (RA) despite MTX was used, which compared addition of placebo (n=117) with addition of TCZ (n=414) every 4 weeks. Baseline and 1-year values of clinical and serological variables were correlated with changes to 1 year of the total Genant-modified Sharp score (TGSS) using a Spearman test, and the progression of TGSS, erosion and joint space narrowing (JSN) scores in groups with low and high disease activity were compared for placebo and TCZ (Kruskal-Wallis).
Baseline variables were similar among the groups. Change of TGSS was lower in patients receiving TCZ than placebo (TCZ: 0.29 ± 0.96; placebo: 0.90 ± 1.92; p=0.0007). In patients receiving placebo, the correlation with TGSS change was significant for baseline scores of the simplified disease activity index (SDAI; r=0.18, p=0.047) and swollen joint count 28 (r=0.22, p=0.019), with similar trends for C-reactive protein. Similar correlations were seen for SDAI, clinical disease activity index, disease activity score 28 at 1 year with x-ray change during that year (r=0.26-0.28, p=0.002-0.006). In contrast, none of the baseline or 1-year variables showed significant correlation with x-ray changes in patients receiving TCZ+MTX, suggesting a disassociation of the link between disease activity and damage by TCZ. Finally, for patients in remission or with low disease activity, progression of TGSS, erosion and JSN was similar among treatment groups (TGSS: placebo, 0.4±1.1; TCZ, 0.2 ± 0.7; p=NS), while for patients with moderate or high disease activity placebo-treated patients progression was significantly greater (TGSS: 1.2 ± 2.2 vs 0.4 ± 1.2; p=0.0009).
IL-6 inhibition with TCZ plus MTX retards joint damage progression independently of its impact on disease activity. Similar effects have hitherto been reported only for TNF-i. This indicates that the effects of IL-6 inhibition on progression of joint damage in RA are among the most profound currently attainable.
New sets of CMS underlying-event parameters (“tunes”) are presented for the
pythia
8 event generator. These tunes use the NNPDF3.1 parton distribution functions (PDFs) at leading (LO), ...next-to-leading (NLO), or next-to-next-to-leading (NNLO) orders in perturbative quantum chromodynamics, and the strong coupling evolution at LO or NLO. Measurements of charged-particle multiplicity and transverse momentum densities at various hadron collision energies are fit simultaneously to determine the parameters of the tunes. Comparisons of the predictions of the new tunes are provided for observables sensitive to the event shapes at LEP, global underlying event, soft multiparton interactions, and double-parton scattering contributions. In addition, comparisons are made for observables measured in various specific processes, such as multijet, Drell–Yan, and top quark-antiquark pair production including jet substructure observables. The simulation of the underlying event provided by the new tunes is interfaced to a higher-order matrix-element calculation. For the first time, predictions from
pythia
8 obtained with tunes based on NLO or NNLO PDFs are shown to reliably describe minimum-bias and underlying-event data with a similar level of agreement to predictions from tunes using LO PDF sets.
Background Compositional differences in the bronchial bacterial microbiota have been associated with asthma, but it remains unclear whether the findings are attributable to asthma, to aeroallergen ...sensitization, or to inhaled corticosteroid treatment. Objectives We sought to compare the bronchial bacterial microbiota in adults with steroid-naive atopic asthma, subjects with atopy but no asthma, and nonatopic healthy control subjects and to determine relationships of the bronchial microbiota to phenotypic features of asthma. Methods Bacterial communities in protected bronchial brushings from 42 atopic asthmatic subjects, 21 subjects with atopy but no asthma, and 21 healthy control subjects were profiled by using 16S rRNA gene sequencing. Bacterial composition and community-level functions inferred from sequence profiles were analyzed for between-group differences. Associations with clinical and inflammatory variables were examined, including markers of type 2–related inflammation and change in airway hyperresponsiveness after 6 weeks of fluticasone treatment. Results The bronchial microbiome differed significantly among the 3 groups. Asthmatic subjects were uniquely enriched in members of the Haemophilus , Neisseria , Fusobacterium , and Porphyromonas species and the Sphingomonodaceae family and depleted in members of the Mogibacteriaceae family and Lactobacillales order. Asthma-associated differences in predicted bacterial functions included involvement of amino acid and short-chain fatty acid metabolism pathways. Subjects with type 2–high asthma harbored significantly lower bronchial bacterial burden. Distinct changes in specific microbiota members were seen after fluticasone treatment. Steroid responsiveness was linked to differences in baseline compositional and functional features of the bacterial microbiome. Conclusion Even in subjects with mild steroid-naive asthma, differences in the bronchial microbiome are associated with immunologic and clinical features of the disease. The specific differences identified suggest possible microbiome targets for future approaches to asthma treatment or prevention.
The observation of the standard model (SM) Higgs boson decay to a pair of bottom quarks is presented. The main contribution to this result is from processes in which Higgs bosons are produced in ...association with a W or Z boson (VH), and are searched for in final states including 0, 1, or 2 charged leptons and two identified bottom quark jets. The results from the measurement of these processes in a data sample recorded by the CMS experiment in 2017, comprising 41.3 fb^{-1} of proton-proton collisions at sqrts=13 TeV, are described. When combined with previous VH measurements using data collected at sqrts=7, 8, and 13 TeV, an excess of events is observed at m_{H}=125 GeV with a significance of 4.8 standard deviations, where the expectation for the SM Higgs boson is 4.9. The corresponding measured signal strength is 1.01±0.22. The combination of this result with searches by the CMS experiment for H→bbover ¯ in other production processes yields an observed (expected) significance of 5.6 (5.5) standard deviations and a signal strength of 1.04±0.20.
Several diseases of the airways have a strong component of allergic inflammation in their cause, including allergic rhinitis, asthma, polypoid chronic rhinosinusitis, eosinophilic bronchitis, and ...others. Although the roles played by antigens and pathogens vary, these diseases have in common a pathology that includes marked activation of epithelial cells in the upper airways, the lower airways, or both. Substantial new evidence indicates an important role of epithelial cells as both mediators and regulators of innate immune responses and adaptive immune responses, as well as the transition from innate immunity to adaptive immunity. The purpose of this review is to discuss recent studies that bear on the molecular and cellular mechanisms by which epithelial cells help to shape the responses of dendritic cells, T cells, and B cells and inflammatory cell recruitment in the context of human disease. Evidence will be discussed that suggests that secreted products of epithelial cells and molecules expressed on their cell surfaces can profoundly influence both immunity and inflammation in the airways.
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