Bioengineered spider silk is a biomaterial that has exquisite mechanical properties, biocompatibility, and biodegradability. Iron oxide nanoparticles can be applied for the detection and analysis of biomolecules, target drug delivery, as MRI contrast agents and as therapeutic agents for hyperthermia-based cancer treatments. In this study, we investigated three bioengineered silks, MS1, MS2 and EMS2, and their potential to form a composite material with magnetic iron oxide nanoparticles (IONPs). The presence of IONPs did not impede the self-assembly properties of MS1, MS2, and EMS2 silks, and spheres formed. The EMS2 spheres had the highest content of IONPs, and the presence of magnetite IONPs in these carriers was confirmed by several methods such as SEM, EDXS, SQUID, MIP-OES and zeta potential measurement. The interaction of EMS2 and IONPs did not modify the superparamagnetic properties of the IONPs, but it influenced the secondary structure of the spheres. The composite particles exhibited a more than two-fold higher loading efficiency for doxorubicin than the plain EMS2 spheres. For both the EMS2 and EMS2/IONP spheres, the drug revealed a pH-dependent release profile with advantageous kinetics for carriers made of the composite material. The composite spheres can be potentially applied for a combined cancer treatment via hyperthermia and drug delivery.

Assessment of genetic diversity and population structure in crops is essential for breeding and germplasm conservation. A collection of 354 bread wheat genotypes, including Mediterranean landraces and modern cultivars representative of the ones most widely grown in the Mediterranean Basin, were characterized with 11196 single nucleotide polymorphism (SNP) markers. Total genetic diversity (HT) and polymorphic information content (PIC) were 0.36 and 0.30 respectively for both landraces and modern cultivars. Linkage disequilibrium for the modern cultivars was higher than for the landraces (0.18 and 0.12, respectively). Analysis of the genetic structure showed a clear geographical pattern for the landraces, which were clustered into three subpopulations (SPs) representing the western, northern and eastern Mediterranean, whereas the modern cultivars were structured according to the breeding programmes that developed them: CIMMYT/ICARDA, France/Italy, and Balkan/eastern European countries. The modern cultivars showed higher genetic differentiation (GST) and lower gene flow (0.1673 and 2.49, respectively) than the landraces (0.1198 and 3.67, respectively), indicating a better distinction between subpopulations. The maximum gene flow was observed between landraces from the northern Mediterranean SPs and the modern cultivars released mainly by French and Italian breeding programmes.

Current diagnostics are inadequate to meet the challenges presented by co-infection with Mycobacterium tuberculosis (Mtb) and HIV, the leading cause of death for HIV-infected individuals. Improved characterization of Mtb/HIV coinfection as a distinct disease state may lead to better identification and treatment of affected individuals.

Different classes of antidepressants, such as tricyclic antidepressants, selective serotonin reuptake inhibitor (SSRI), and serotonin and norepinephrine reuptake inhibitor (SNRI), have been shown to increase GDNF production in astrocytes, which could be a key mechanism of the psychotropic effect of antidepressants. The antidepressant mirtazapine is a noradrenaline and specific serotonergic antidepressant (NaSSA) and does not block reuptake of catecholamines and serotonin. The present study examined the effect of mirtazapine on GDNF expression in rat C6 astroglial cells (C6 cells) and rat primary cultured cortical astrocytes (primary astrocytes). Mirtazapine treatment significantly increased GDNF mRNA expression and GDNF release in both C6 cells and primary astrocytes. In primary astrocytes, mirtazapine also increased the expressions of brain-derived neurotrophic factor mRNA. To mimic mirtazapine's putative mechanism of action, cells were treated with either a α2-adrenoceptor antagonist (yohimbine), 5-HT2 receptor antagonist (ketanserin), 5-HT3 receptor antagonist (ondansetron), or a mixture of these--no effect on GDNF mRNA expression was observed. Mirtazapine treatment increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and the mirtazapine-induced GDNF and BDNF expression were blocked by MAPK/ERK kinase (MEK) inhibitor (U0126). Furthermore, the effect of mirtazapine on ERK phosphorylation and expressions of GDNF and BDNF was antagonized by Gi/o inhibitor (pertussis toxin), lysophosphatidic acid-1 (LPA1) receptor antagonist (AM966), and LPA1/LPA3 receptors antagonist (Ki16425). The current findings demonstrate that the NaSSA mirtazapine, similar to other classes of antidepressants, increases GDNF expression through a Gi/o coupled LPA1 receptor-mediated ERK pathway. The current findings suggest a general mechanism underlying the psychotropic effect antidepressants.

The amygdala plays a critical role in emotional-affective aspects of behaviors and pain modulation. The central nucleus of amygdala (CeA) serves major output functions, and neuroplasticity in the CeA is linked to pain-related behaviors in different models. Activation of Gi/o-coupled group II metabotropic glutamate receptors (mGluRs), which consist of mGluR2 and mGluR3, can decrease neurotransmitter release and regulate synaptic plasticity. Group II mGluRs have emerged as targets for neuropsychiatric disorders and can inhibit pain-related processing and behaviors. Surprisingly, site and mechanism of antinociceptive actions of systemically applied group II mGluR agonists are not clear. Our previous work showed that group II mGluR activation in the amygdala inhibits pain-related CeA activity, but behavioral and spinal consequences remain to be determined. Here we studied the contribution of group II mGluRs in the amygdala to the antinociceptive effects of a systemically applied group II mGluR agonist (LY379268) on behavior and spinal dorsal horn neuronal activity, using the kaolin/carrageenan-induced knee joint arthritis pain model. Audible and ultrasonic vocalizations (emotional responses) and mechanical reflex thresholds were measured in adult rats with and without arthritis (5-6 h postinduction). Extracellular single-unit recordings were made from spinal dorsal horn wide dynamic range neurons of anesthetized (isoflurane) rats with and without arthritis (5-6 h postinduction). Systemic (intraperitoneal) application of a group II mGluR agonist (LY379268) decreased behaviors and activity of spinal neurons in the arthritis pain model but not under normal conditions. Stereotaxic administration of LY379268 into the CeA mimicked the effects of systemic application. Conversely, stereotaxic administration of a group II mGluR antagonist (LY341495) into the CeA reversed the effects of systemic application of LY379268 on behaviors and dorsal horn neuronal activity in arthritic rats. The data show for the first time that the amygdala is the critical site of action for the antinociceptive behavioral and spinal neuronal effects of systemically applied group II mGluR agonists.

Non-alcoholic steatohepatitis (NASH) is a progressive inflammatory and fibrotic disease. However, the progression mechanism of NASH is not well understood. Bile acids are endogenous molecules that regulate cholesterol homeostasis, lipid solubilization in the intestinal lumen, and metabolic signaling via several receptors. In this study, we investigated the relationship between bile acid composition and NASH-associated fibrosis using a mouse model fed choline-deficient, L-amino-acid-defined, high-fat diet with 0.1% methionine (CDAHFD). C57BL/6 J mice fed CDAHFD developed NASH and fibrosis within few weeks. With the progress of NASH-associated liver fibrosis, altered bile acid composition was observed in the liver, bile, and peripheral plasma. Decreased mRNA levels of bile acid metabolizing enzymes such as Cyp7a1 and Baat were observed in contrast to increased Sult2a1 level in the liver. Increased mRNA levels of Ostβ and Abcc4 and decreased in mRNA levels of Bsep, Abcc2, Ntcp, and Oatp1b2, suggesting that bile acids efflux from hepatocytes into the peripheral plasma rather than into bile. In conclusion, the changes in bile acid metabolizing enzymes and transporters expression, resulting in increasing the total bile acid concentration in the plasma, signify a protection mechanism by the hepatocyte to reduce hepatotoxicity during disease progression to NASH but may promote liver fibrosis.

To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Parkinson's disease (PD) is often managed with L-3,4-dihydroxyphenylalanine (L-DOPA), which is still the gold standard to relieve the clinical motor symptoms of PD. However, chronic use of L-DOPA leads to significant motor complications, especially L-DOPA-induced dyskinesia (LID), which limit the therapeutic benefit. Few options are available for the pharmacological management of LID partly due to the inadequacy of our mechanistic understanding of the syndrome. We focused on the role of the histamine (HA) H2 receptor (H2R) in the striatum, which others have shown to be involved in the development of LID. We generated LID in a hemiparkinsonian mouse model and tested the signaling effects of ranitidine, an H2R antagonist. We used histidine decarboxylase deficient mice (Hdc-Ko) which lacks HA to study the role of G-protein-coupled receptor kinases (GRKs) in HA deficiency. Loss of HA in Hdc-Ko mice did not result in the downregulation of GRKs, especially GRK3 and GRK6, which were previously found to be reduced in hemiparkinsonian animal models. Ranitidine, when given along with L-DOPA, normalized the expression of GRK3 in the dopamine-depleted striatum thereby inhibiting LID in mice. The extracellular signal regulated kinase and ΔFosB signaling pathways were attenuated in the lesioned striatum when ranitidine was combined with L-DOPA than L-DOPA alone. These results demonstrate that ranitidine inhibits LID by normalizing the levels of GRK3, extracellular signal regulated kinase activation, and FosB accumulation in the dopamine-depleted striatum via HA H2R antagonism.

p300 is an important histone acetyltransferase in epigenetics, and its overexpression is closely related to various diseases such as cancers. C646 is one of the most representative p300 inhibitors and used in various studies of p300. However, its intrinsic drawbacks such as containing potentially toxic groups prevent it from further development. In order to find potent p300 inhibitors with good drug-like properties, C646 was chosen as the lead compound and a series of new p300 inhibitors were designed based on the principle of bioisosterism and reasonable scaffold hopping, and the structure-activity relationship was systematically explored. Ten of them were found to show comparable inhibitory activity as C646. The most potent compound, 1r (IC50 = 0.16 μM), showed better p300 inhibitory activity than C646 with improved drug-like properties. Western blotting experiment confirmed that 1r could reduce the level of H3K27 acetylation more significantly than C646. Further cellular assay indicated that it could inhibit the proliferation of human breast ductal carcinoma cell T47D and human breast cancer cell MCF7 with the IC50 values of 5.08 μM and 22.54 μM, respectively. Docking study of 1r with p300 protein showed the possible reasons for its higher inhibition activity. Thus, compound 1r might be with potential for development as a novel epigenetic agent targeting p300.

The human brain has been uniquely equipped with the remarkable ability to acquire more than one language, as in bilingual individuals. Previous neuroimaging studies have indicated that learning a second language (L2) induced neuroplasticity at the macrostructural level. In this study, using the quantitative MRI (qMRI) combined with functional MRI (fMRI) techniques, we quantified the microstructural properties and tested whether second language learning modulates the microstructure in the bilingual brain. We found significant microstructural variations related to age of acquisition of second language in the left inferior frontal region and the left fusiform gyrus that are crucial for resolving lexical competition of bilinguals' two languages. Early second language acquisition contributes to enhance cortical development at the microstructural level.

High-fructose diets are associated with not only fat accumulation in liver but also blood adipokine levels. Some studies have shown the involvement of humoral factors in the regulation of adipokines. However, the role of the vagus nerve in expression of adipokines is not fully understood. We attempted to investigate the involvement of the hepatic branch of the vagus nerve (HBVN) in the regulation of plasma adipokine levels in rats fed a high-fructose (HFr) diet. Rats underwent hepatic vagotomy (Vx) or sham operation; thereafter, they were fed a control diet (CT) or HFr diet for 6 weeks. At the sixth week, the oral glucose tolerance test (OGTT) was performed. In the sham-operated group, plasma leptin and adiponectin levels were significantly lower in the HFr group than those in the control group. In contrast, in the Vx group, there was no difference in the respective adipokine levels of the two dietary groups. In OGTT, plasma leptin levels were significantly correlated to the area under the curve (AUC) of plasma insulin levels and insulin levels at some points. Further, the ratio of plasma leptin levels to plasma adiponectin levels was correlated with the AUC of plasma insulin levels. However, the plasma adiponectin level itself did not correlate with plasma insulin levels and insulin AUC. Thus, we showed that HBVN played a key role in down-regulating plasma leptin and adiponectin levels in HFr-fed rats.

Local administration of naked self-replicating mRNA (sr-mRNA) in the skin or muscle using electroporation is effective but hampered by low repeatability. In this manuscript, we demonstrated that intradermal electroporation of sr-mRNA in combination with a protein-based RNase inhibitor increased the expression efficiency, success rate, and repeatability of the data. The RNase inhibitor should be added just before administration because storage of the inhibitor together with the sr-mRNA at -80°C resulted in a partial loss of the beneficial effect. Furthermore, the location of intradermal electroporation also had a major effect on the expression of the sr-mRNA, with the highest and longest expression observed at the tail base of the mice. In contrast with previous work, we did not observe a beneficial effect of calcium ions on the efficacy of naked sr-mRNA after intradermal injection. Finally, another important finding was that the traditional representation of in vivo bioluminescence data as means in logarithmic graphs can mask highly variable data. A more truthful representation can be obtained by showing the individual data points or by displaying median values in combination with interquartile ranges. In conclusion, intradermal sr-mRNA electroporation can be improved by adding an RNase inhibitor and injecting at the tail base.

PCOS women are characterized by insulin resistance and have higher tendency to the development of hepatic steatosis. Fetuin-B has been introduced as a hepatokine/adipokine, which is increased in hepatic steatosis and may be connected with glucose metabolism disturbances. The aim of the study was to evaluate the relationships between serum fetuin-B concentration and indices of insulin resistance, insulin secretion and markers of liver steatosis in PCOS women in comparison to the control group.

The total number of scholarly publications grows day by day, making it necessary to explore and use simple yet effective ways to expose their metadata. Schema.org supports adding structured metadata to web pages via markup, making it easier for data providers but also for search engines to provide the right search results. Bioschemas is based on the standards of schema.org, providing new types, properties and guidelines for metadata, i.e., providing metadata profiles tailored to the Life Sciences domain. Here we present our proposed contribution to Bioschemas (from the project "Biotea"), which supports metadata contributions for scholarly publications via profiles and web components. Biotea comprises a semantic model to represent publications together with annotated elements recognized from the scientific text; our Biotea model has been mapped to schema.org following Bioschemas standards.

Automatically detecting mentions of pharmaceutical drugs and chemical substances is key for the subsequent extraction of relations of chemicals with other biomedical entities such as genes, proteins, diseases, adverse reactions or symptoms. The identification of drug mentions is also a prior step for complex event types such as drug dosage recognition, duration of medical treatments or drug repurposing. Formally, this task is known as named entity recognition (NER), meaning automatically identifying mentions of predefined entities of interest in running text. In the domain of medical texts, for chemical entity recognition (CER), techniques based on hand-crafted rules and graph-based models can provide adequate performance. In the recent years, the field of natural language processing has mainly pivoted to deep learning and state-of-the-art results for most tasks involving natural language are usually obtained with artificial neural networks. Competitive resources for drug name recognition in English medical texts are already available and heavily used, while for other languages such as Spanish these tools, although clearly needed were missing. In this work, we adapt an existing neural NER system, NeuroNER, to the particular domain of Spanish clinical case texts, and extend the neural network to be able to take into account additional features apart from the plain text. NeuroNER can be considered a competitive baseline system for Spanish drug and CER promoted by the Spanish national plan for the advancement of language technologies (Plan TL). PharmacoNER Tagger can be accessed at https://github.com/PlanTL-SANIDAD/PharmacoNER.

Gene set enrichment analysis (GSEA) is a popular tool to identify underlying biological processes in clinical samples using their gene expression phenotypes. GSEA measures the enrichment of annotated gene sets that represent biological processes for differentially expressed genes (DEGs) in clinical samples. GSEA may be suboptimal for functional gene sets; however, because DEGs from the expression dataset may not be functional genes per se but dysregulated genes perturbed by bona fide functional genes. To overcome this shortcoming, we developed network-based GSEA (NGSEA), which measures the enrichment score of functional gene sets using the expression difference of not only individual genes but also their neighbors in the functional network. We found that NGSEA outperformed GSEA in identifying pathway gene sets for matched gene expression phenotypes. We also observed that NGSEA substantially improved the ability to retrieve known anti-cancer drugs from patient-derived gene expression data using drug-target gene sets compared with another method, Connectivity Map. We also repurposed FDA-approved drugs using NGSEA and experimentally validated budesonide as a chemical with anti-cancer effects for colorectal cancer. We, therefore, expect that NGSEA will facilitate both pathway interpretation of gene expression phenotypes and anti-cancer drug repositioning. NGSEA is freely available at www.inetbio.org/ngsea.

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the biosynthesis of 17β-estradiol. Novel estrone-based compounds bearing various 15β-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17β-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17β-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers.

10H-1,9-diazaphenothiazine was obtained in the sulphurisation reaction of diphenylamine with elemental sulphur and transformed into new 10-substituted derivatives, containing alkyl and dialkylaminoalkyl groups at the thiazine nitrogen atom. The 1,9-diazaphenothiazine ring system was identified with advanced 1H and 13C NMR techniques (COSY, NOESY, HSQC and HMBC) and confirmed by X-ray diffraction analysis of the methyl derivative. The compounds exhibited significant anticancer activities against the human glioblastoma SNB-19, melanoma C-32 and breast cancer MDA-MB-231 cell lines. The most active 1,9-diazaphenothiazines were the derivatives with the propynyl and N, N-diethylaminoethyl groups being more potent than cisplatin. For those two compounds, the expression of H3, TP53, CDKN1A, BCL-2 and BAX genes was detected by the RT-QPCR method. The proteome profiling study showed the most probable compound action on SNB-19 cells through the intrinsic mitochondrial pathway of apoptosis. The 1,9-diazaphenotiazine system seems to be more potent than known isomeric ones (1,6-diaza-, 1,8-diaza-, 2,7-diaza- and 3,6-diazaphenothiazine).

To systematically review studies quantifying the association between primary chronic headaches and persistent low back pain (LBP).