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Background Research suggests that the positive affect system may be an important yet underexplored treatment target in anxiety and depression. Existing interventions primarily target the negative affect system, yielding modest effects on measures of positive emotions and associated outcomes (e.g., psychological well‐being). The objective of the present pilot study was to evaluate the efficacy of a new transdiagnostic positive activity intervention (PAI) for anxiety and depression. Method Twenty‐nine treatment‐seeking individuals presenting with clinically impairing symptoms of anxiety and/or depression were randomly allocated to a 10‐session protocol comprised of PAIs previously shown in nonclinical samples to improve positive thinking, emotions, and behaviors (e.g., gratitude, acts of kindness, optimism; n = 16) or a waitlist (WL) condition (n = 13). Participants were assessed at pre‐ and posttreatment, as well as 3‐ and 6‐month follow‐up, on measures of positive and negative affect, symptoms, and psychological well‐being. ClinicalTrials.gov Identifier: NCT02330627 Results The PAI group displayed significantly larger improvements in positive affect and psychological well‐being from pre‐ to posttreatment compared to WL. Posttreatment and follow‐up scores in the PAI group were comparable to general population norms. The PAI regimen also resulted in significantly larger reductions in negative affect, as well as anxiety and depression symptoms, compared to WL. Improvements across all outcomes were large in magnitude and maintained over a 6‐month follow‐up period. Conclusions Targeting the positive affect system through a multicomponent PAI regimen may be beneficial for generating improvements in positive emotions and well‐being, as well as reducing negative affect and symptoms, in individuals with clinically impairing anxiety or depression.

Climatic change is pointed as one of the major challenges for global food security. Based on current models of climate change, reduction in precipitations and in turn, increase in the soil salinity will be a sharp constraint for crops productivity worldwide. In this context, root fungi appear as a new strategy to improve plant ecophysiological performance and crop yield under abiotic stress. In this study, we evaluated the impact of the two fungal endophytes Penicillium brevicompactum and P. chrysogenum isolated from Antarctic plants on nutrients and Na + contents, net photosynthesis, water use efficiency, yield and survival in tomato and lettuce, facing salinity stress conditions. Inoculation of plant roots with fungal endophytes resulted in greater fresh and dry biomass production, and an enhanced survival rate under salt conditions. Inoculation of plants with the fungal endophytes was related with a higher up/down-regulation of ion homeostasis by enhanced expression of the NHX1 gene. The two endophytes diminished the effects of salt stress in tomato and lettuce, provoked a higher efficiency in photosynthetic energy production and an improved sequestration of Na + in vacuoles is suggested by the upregulating of the expression of vacuolar NHX1 Na + /H + antiporters. Promoting plant-beneficial interactions with root symbionts appears to be an environmentally friendly strategy to mitigate the impact of climate change variables on crop production.

Osteoblasts are crucial bone-building cells that maintain bone homeostasis, whereas inflammatory stimuli can inhibit osteogenesis and activate inflammatory response. N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes and plays important roles in multiple biological processes. However, whether m6A modification affects osteoblast differentiation and inflammatory response remains unknown. To address this issue, we investigated the expression of the N6-adenosine methyltransferase METTL3 and found that it was upregulated during osteoblast differentiation and downregulated after LPS stimulation. We then knocked down METTL3 and observed decreased levels of osteogenic markers, ALP activity, and mineralized nodules, as well as Smad1/5/9 phosphorylation, in LPS-induced inflammation. METTL3 knockdown promoted the mRNA expression and stability of negative regulators of Smad signaling, Smad7 and Smurf1, the same regulatory pattern identified when the m6A-binding protein YTHDF2 was silenced. Moreover, METTL3 depletion enhanced proinflammatory cytokine expression and increased the phosphorylation of ERK, p38, JNK, and p65 in MAPK and NF-κB signaling pathways. The increase in cytokine expression was inhibited after MAPK signaling inhibitor treatment. All data suggest that METTL3 knockdown inhibits osteoblast differentiation and Smad-dependent signaling by stabilizing Smad7 and Smurf1 mRNA transcripts via YTHDF2 involvement and activates the inflammatory response by regulating MAPK signaling in LPS-induced inflammation.

Triple-negative breast cancers (TNBCs) are characterized by a poor prognosis and lack of targeted treatments, and thus, new therapeutic strategies are urgently needed. Inhibitors against programmed death-1 (PD-1)/PD-1 ligand (PD-L1) have shown significant efficacy in various solid cancers, but their activity against TNBCs remains limited. Here, we report that human TNBCs molecularly stratified for high levels of PD-L1 (PD-L1 High ) showed significantly enriched expression of immune and cancer stemness pathways compared with those with low PD-L1 expression (PD-L1 Low ). In addition, the PD-L1 High cases were significantly associated with a high stemness score (SS High ) signature. TNBC cell lines gated for aldehyde dehydrogenase (ALDH) and CD44 stemness markers exhibited increased levels of PD-L1 versus their ALDH-negative and CD44 Low counterparts, and PD-L1 High cells generated significantly more mammospheres than PD-L1 Low cells. Murine mammary SCA-1-positive tumor cells with PD-L1 High expression generated tumors in vivo with higher efficacy than PD-L1 Low cells. Furthermore, treatment of TNBC cells with selective WNT inhibitors or activators downregulated or upregulated PD-L1 expression, respectively, implying a functional cross-talk between WNT activity and PD-L1 expression. Remarkably, human TNBC samples contained tumor elements co-expressing PD-L1 with ALDH1A1 and/or CD44v6. Additionally, both PD-L1-/SCA1-positive and ALDH1A1-positive tumor elements were found in close contact with CD3-, and PD-1-positive T cells in murine and human tumor samples. Overall, our study suggests that PD-L1-positive tumor elements with a stemness phenotype may participate in the complex dynamics of TNBC-related immune evasion, which might be targeted through WNT signaling inhibition.

Transcriptome wide changes in human skeletal muscle after acute (anabolic) and chronic resistance exercise (RE) induced hypertrophy have been extensively determined in the literature. We have also recently undertaken DNA methylome analysis (850,000 + CpG sites) in human skeletal muscle after acute and chronic RE, detraining and retraining, where we identified an association between DNA methylation and epigenetic memory of exercise induced skeletal muscle hypertrophy. However, it is currently unknown as to whether all the genes identified in the transcriptome studies to date are also epigenetically regulated at the DNA level after acute, chronic or repeated RE exposure. We therefore aimed to undertake large scale bioinformatical analysis by pooling the publicly available transcriptome data after acute (110 samples) and chronic RE (181 samples) and comparing these large data sets with our genome-wide DNA methylation analysis in human skeletal muscle after acute and chronic RE, detraining and retraining. Indeed, after acute RE we identified 866 up- and 936 down-regulated genes at the expression level, with 270 (out of the 866 up-regulated) identified as being hypomethylated, and 216 (out of 936 downregulated) as hypermethylated. After chronic RE we identified 2,018 up- and 430 down-regulated genes with 592 (out of 2,018 upregulated) identified as being hypomethylated and 98 (out of 430 genes downregulated) as hypermethylated. After KEGG pathway analysis, genes associated with ‘cancer’ pathways were significantly enriched in both bioinformatic analysis of the pooled transcriptome and methylome datasets after both acute and chronic RE. This resulted in 23 (out of 69) and 28 (out of 49) upregulated and hypomethylated and 12 (out of 37) and 2 (out of 4) downregulated and hypermethylated ‘cancer’ genes following acute and chronic RE respectively. Within skeletal muscle tissue, these ‘cancer’ genes predominant functions were associated with matrix/actin structure and remodelling, mechano-transduction (e.g. PTK2/Focal Adhesion Kinase and Phospholipase D- following chronic RE), TGF-beta signalling and protein synthesis (e.g. GSK3B after acute RE). Interestingly, 51 genes were also identified to be up/downregulated in both the acute and chronic RE pooled transcriptome analysis as well as significantly hypo/hypermethylated after acute RE, chronic RE, detraining and retraining. Five genes; FLNB, MYH9, SRGAP1, SRGN, ZMIZ1 demonstrated increased gene expression in the acute and chronic RE transcriptome and also demonstrated hypomethylation in these conditions. Importantly, these 5 genes demonstrated retained hypomethylation even during detraining (following training induced hypertrophy) when exercise was ceased and lean mass returned to baseline (pre-training) levels, identifying them as genes associated with epigenetic memory in skeletal muscle. Importantly, for the first time across the transcriptome and epigenome combined, this study identifies novel differentially methylated genes associated with human skeletal muscle anabolism, hypertrophy and epigenetic memory.

BackgroundIt is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1).MethodsWe investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition.Results[18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion.ConclusionsHuman TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

Purpose We tested the hypothesis that both post-exercise and passive cold water immersion (CWI) increases PGC-1α and VEGF mRNA expression in human skeletal muscle. Method Study 1 Nine males completed an intermittent running protocol (8 × 3-min bouts at 90 % V ˙ O 2 max , interspersed with 3-min active recovery (1.5-min at 25 % and 1.5-min at 50 % V ˙ O 2 max ) before undergoing CWI (10 min at 8 °C) or seated rest (CONT) in a counterbalanced, randomised manner. Study 2 Ten males underwent an identical CWI protocol under passive conditions. Results Study 1 PGC-1α mRNA increased in CONT (~3.4-fold; P  < 0.001) and CWI (~5.9-fold; P  < 0.001) at 3 h post-exercise with a greater increase observed in CWI ( P  < 0.001). VEGFtotal mRNA increased after CWI only (~2.4-fold) compared with CONT (~1.1-fold) at 3 h post-exercise ( P  < 0.01). Study 2 Following CWI, PGC-1α mRNA expression was significantly increased ~1.3-fold ( P  = 0.001) and 1.4-fold ( P  = 0.0004) at 3 and 6 h, respectively. Similarly, VEGF165 mRNA was significantly increased in CWI ~1.9-fold ( P  = 0.03) and 2.2-fold ( P  = 0.009) at 3 and 6 h post-immersion. Conclusions Data confirm post-exercise CWI augments the acute exercise-induced expression of PGC-1α mRNA in human skeletal muscle compared to exercise per se. Additionally CWI per se mediates the activation of PGC-1α and VEGF mRNA expression in human skeletal muscle. Cold water may therefore enhance the adaptive response to acute exercise.

Physical exercise has a neuroprotective effect and is an important treatment after ischemic stroke. Promoting neurogenesis and myelin repair in the penumbra is an important method for the treatment of ischemic stroke. However, the role and potential mechanism of exercise in neurogenesis and myelin repair still needs to be clarified. The goal of the present study was to ascertain the possible effect of treadmill training on the neuroprotective signaling pathway in juvenile rats after ischemic stroke. The model of middle cerebral artery occlusion (MCAO) in juvenile rats was established and then the rats were randomly divided into 9 groups. XAV939 (an inhibitor of the Wnt/β-catenin pathway) was used to confirm the effects of the Wnt/β-catenin signaling pathway on exercise-mediated neurogenesis and myelin repair. Neurological deficits were detected by modified neurological severity score, the injury of brain tissue and the morphology of neurons was detected by hematoxylin-eosin staining and Nissl staining, and the infarct volume was detected by 2,3,5-triphenyl tetrazolium chloride staining. The changes in myelin were observed by Luxol fast blue staining. The neuron ultrastructure was observed by transmission electron microscopy. Immunofluorescence and western blots analyzed the molecular mechanisms. The results showed that treadmill exercise improved neurogenesis, enhanced myelin repair, promoted neurological function recovery and reduced infarct volume. These were the results of the upregulation of Wnt3a and nucleus β-catenin, brain-derived neurotrophic factor (BDNF) and myelin basic protein (MBP). In addition, XAV939 inhibited treadmill exercise-induced neurogenesis and myelin repair, which was consistent with the downregulation of Wnt3a, nucleus β-catenin, BDNF and MBP expression, and the deterioration of neurological function. In summary, treadmill exercise promotes neurogenesis and myelin repair by upregulating the Wnt/β-catenin signaling pathway, to improve the neurological deficit caused by focal cerebral ischemia/reperfusion.

Grapevine (Vitis vinifera L.) is a species well known for its adaptation to radiation. However, photomorphogenic factors related to UV-B responses have not been molecularly characterized. We cloned and studied the role of UV-B RECEPTOR (UVR1), ELONGATED HYPOCOTYL 5 (HY5), and HY5 HOMOLOGUE (HYH) from V. vinifera. We performed gene functional characterizations, generated co-expression networks, and tested them in different environmental conditions. These genes complemented the Arabidopsis uvr8 and hy5 mutants in morphological and secondary metabolic responses to radiation. We combined microarray and RNA sequencing (RNA-seq) data with promoter inspections to identify HY5 and HYH putative target genes and their DNA binding preferences. Despite sharing a large set of common co-expressed genes, we found different hierarchies for HY5 and HYH depending on the organ and stress condition, reflecting both co-operative and partially redundant roles. New candidate UV-B gene markers were supported by the presence of HY5-binding sites. These included a set of flavonol-related genes that were up-regulated in a HY5 transient expression assay. We irradiated in vitro plantlets and fruits from old potted vines with high and low UV-B exposures and followed the accumulation of flavonols and changes in gene expression in comparison with nonirradiated conditions. UVR1, HY5, and HYH expression varied with organ, developmental stage, and type of radiation. Surprisingly, UVR1 expression was modulated by shading and temperature in berries, but not by UV-B radiation. We propose that the UV-B response machinery favours berry flavonol accumulation through the activation of HY5 and HYH at different developmental stages at both high and low UV-B exposures.

The biological functions of the Eph/ephrin system have been intensively investigated and well documented so far since its discovery in 1987. Although the Eph/ephrin system has been implicated in pathological settings such as Alzheimer's disease and cancer, the molecular mechanism of the Eph/ephrin system in those diseases is not well understood. Especially in cancer, recent studies have demonstrated that most of Eph and ephrin are up‐ or down‐regulated in various types of cancer, and have been implicated in tumor progression, tumor malignancy, and prognosis. However, they lack consistency and are in controversy. The localization patterns of EphA1 and EphA2 in mouse lungs are very similar, and both knockout mice showed similar phenotypes in the lungs. Ephrin‐A1 that is a membrane‐anchored ligand for EphAs was co‐localized with EphA1 and EphA2 in lung vascular endothelial cells. We recently uncovered the molecular mechanism of ephrin‐A1‐induced lung metastasis by understanding the physiological function of ephrin‐A1 in lungs. This review focuses on the function of EphA1, EphA2, and ephrin‐A1 in tumors and an establishment of pre‐metastatic microenvironment in the lungs. ADAM12‐cleaved ephrin‐A1 induces receptor endocytosis and RhoA activation leading to cell retraction. Cleaved ephrin‐A1 competes for pre‐existing Eph/ephrin interactions. Ephrin‐A1‐stimulated vascular endothelial cells are shrunk, and thereby enhances lung vascular permeability.