Aglaia odorata Lour. is a traditional Chinese medicinal plant possessing properties of improving blood circulation, and it is widely used in the treatment of dizziness, traumatic injuries and bruises.

Vertebral fractures are the hallmark of osteoporosis. MicroRNAs (miRNAs) are a prominent class of gene regulators likely to affect bone homeostasis, including bone remodelling and fracture healing by altering gene expression in bone cells.

Chronic cerebral hypoperfusion is an important risk factor for vascular dementia (VaD) and other brain dysfunctions, for which there are currently no effective medications available. In the present study, we investigated the potential therapeutic effects of cornel iridoid glycoside (CIG) on VaD in rats modeled by permanent bilateral common carotid artery ligation (2-vessel occlusion, 2VO). The object recognition test (ORT) and Morris water maze (MWM) test were conducted to evaluate the learning and memory function. Western blot analysis and immunohistochemical staining were used to detect the expression of related proteins. Results showed that intragastric administration of CIG (30, 60, and 120 mg/kg) for 3 months significantly increased the discrimination index in ORT and decreased the escape latency in MWM test, ameliorating the learning and memory deficit in 2VO rats. Further data indicated that CIG increased the expression of neurotrophic factors (NGF and BDNF) and their receptors (TrkA and TrkB), glutamate receptor subunits (NMDAR1 and GluR2) in the cerebral cortex and hippocampus of 2VO rats. In addition, CIG elevated the expression of PI3K subunits p110α and p85, further upregulated the phosphorylation of Akt, GSK3β-ser9 and CREB in the cerebral cortex and hippocampus at 3 months after 2VO surgery. Collectively, CIG treatment improved learning and memory deficit induced by chronic cerebral hypoperfusion via increasing neurotrophic factors thus protecting glutamate receptors and activating PI3K/Akt/GSK3β/CREB signaling pathway in rats. These results suggest that CIG may be beneficial to VaD therapy.

Mesenchymal stem or stromal cells are currently under clinical investigation for multiple diseases. While their mechanism of action is still not fully elucidated, vesicles secreted by MSCs are believed to recapitulate their therapeutic potentials to some extent. Microvesicles (MVs), also called as microparticles or ectosome, are among secreted vesicles that could transfer cytoplasmic cargo, including RNA and proteins, from emitting (source) cells to recipient cells. Given the importance of MVs, we here attempted to establish a method to isolate and characterize MVs secreted from unmodified human bone marrow derived MSCs (referred to as native MSCs, and their microvesicles as Native-MVs) and IFNγ stimulated MSCs (referred to as IFNγ-MSCs, and their microvesicles as IFNγ-MVs). We first describe an ultracentrifugation technique to isolate MVs from the conditioned cell culture media of MSCs. Next, we describe characterization and quality control steps to analyze the protein and RNA content of MVs. Finally, we examined the potential of MVs to exert immunomodulatory effects through induction of regulatory T cells (Tregs). Secretory vesicles from MSCs are promising alternatives for cell therapy with applications in drug delivery, regenerative medicine, and immunotherapy.

This paper reports a laser capture microdissection-tandem mass tag-quantitative proteomics analysis of Al-sensitive cells in root tips. Cherry tomato (Solanum lycopersicum var. cerasiforme 'LA2710') seedlings were treated under 15 μM Al3+ activity for 13 d. Root-tip longitudinal fresh frozen tissue sections of 10 μm thickness were prepared. The Al-sensitive root zone and cells were determined using histochemical analysis of root-tips and micro-sections. A procedure for collecting the Al-sensitive cells using laser capture microdissection-protein extraction-tandem mass tag-proteomics analysis was developed. Proteomics analysis of 18 μg protein/sample with three biological replicates per treatment condition identified 3879 quantifiable proteins each associated with two or more unique peptides. Quantified proteins constituted a broad range of Kyoto Encyclopedia of Genes and Genomes pathways when searched in the annotated tomato genome. Differentially expressed proteins between the Al-treated and non-Al treated control conditions were identified, including 128 Al-up-regulated and 32 Al-down-regulated proteins. Analysis of functional pathways and protein-protein interaction networks showed that the Al-down-regulated proteins are involved in transcription and translation, and the Al-up-regulated proteins are associated with antioxidant and detoxification and protein quality control processes. The proteomics data are available via ProteomeXchange with identifier PXD010459 under project title 'LCM-quantitative proteomics analysis of Al-sensitive tomato root cells'. SIGNIFICANCE: This paper presents an efficient laser capture microdissection-tandem mass tag-quantitative proteomics analysis platform for the analysis of Al sensitive root cells. The analytical procedure has a broad application for proteomics analysis of spatially separated cells from complex tissues. This study has provided a comprehensive proteomics dataset expressed in the epidermal and outer-cortical cells at root-tip transition zone of Al-treated tomato seedlings. The proteomes from the Al-sensitive root cells are valuable resources for understanding and improving Al tolerance in plants.

Plant Reactome (https://plantreactome.gramene.org) is an open-source, comparative plant pathway knowledgebase of the Gramene project. It uses Oryza sativa (rice) as a reference species for manual curation of pathways and extends pathway knowledge to another 82 plant species via gene-orthology projection using the Reactome data model and framework. It currently hosts 298 reference pathways, including metabolic and transport pathways, transcriptional networks, hormone signaling pathways, and plant developmental processes. In addition to browsing plant pathways, users can upload and analyze their omics data, such as the gene-expression data, and overlay curated or experimental gene-gene interaction data to extend pathway knowledge. The curation team actively engages researchers and students on gene and pathway curation by offering workshops and online tutorials. The Plant Reactome supports, implements and collaborates with the wider community to make data and tools related to genes, genomes, and pathways Findable, Accessible, Interoperable and Re-usable (FAIR).

The volume of biological, chemical and functional data deposited in the public domain is growing rapidly, thanks to next generation sequencing and highly-automated screening technologies. These datasets represent invaluable resources for drug discovery, particularly for less studied neglected disease pathogens. To leverage these datasets, smart and intensive data integration is required to guide computational inferences across diverse organisms. The TDR Targets chemogenomics resource integrates genomic data from human pathogens and model organisms along with information on bioactive compounds and their annotated activities. This report highlights the latest updates on the available data and functionality in TDR Targets 6. Based on chemogenomic network models providing links between inhibitors and targets, the database now incorporates network-driven target prioritizations, and novel visualizations of network subgraphs displaying chemical- and target-similarity neighborhoods along with associated target-compound bioactivity links. Available data can be browsed and queried through a new user interface, that allow users to perform prioritizations of protein targets and chemical inhibitors. As such, TDR Targets now facilitates the investigation of drug repurposing against pathogen targets, which can potentially help in identifying candidate targets for bioactive compounds with previously unknown targets. TDR Targets is available at https://tdrtargets.org.

In type 1 and type 2 diabetes mellitus, increased cardiac fibrosis, stiffness and associated diastolic dysfunction may be the earliest pathological phenomena in diabetic cardiomyopathy. Endothelial-mesenchymal transition (EndMT) in endothelia cells (ECs) is a critical cellular phenomenon that increases cardiac fibroblasts (CFs) and cardiac fibrosis in diabetic hearts. The purpose of this paper is to explore the molecular mechanism of miR-21 regulating EndMT and cardiac perivascular fibrosis in diabetic cardiomyopathy. In vivo, hyperglycaemia up-regulated the mRNA level of miR-21, aggravated cardiac dysfunction and collagen deposition. The condition was recovered by inhibition of miR-21 following with improving cardiac function and decreasing collagen deposition. miR-21 inhibition decreased cardiac perivascular fibrosis by suppressing EndMT and up-regulating SMAD7 whereas activating p-SMAD2 and p-SMAD3. In vitro, high glucose (HG) up-regulated miR-21 and induced EndMT in ECs, which was decreased by inhibition of miR-21. A highly conserved binding site of NF-κB located in miR-21 5'-UTR was identified. In ECs, SMAD7 is directly regulated by miR-21. In conclusion, the pathway of NF-κB/miR-21/SMAD7 regulated the process of EndMT in T1DM, in diabetic cardiomyopathy, which may be regarded as a potential clinical therapeutic target for cardiac perivascular fibrosis.

Although management guidelines exist for several genes associated with a 2-fold to 5-fold increase in the relative risk for certain cancers, the value of testing for them remains controversial.

Azodicarbonamide is a dough-enhancer used in the process of breadmaking in countries like Nigeria. While there have been suggestions that it is a sensitizer of the respiratory system, there is a dearth of information on its effects on the central nervous system.

Recent studies revealed that macrophages are polarized towards the M2 phenotype in an ovalbumin (OVA)-induced asthmatic model. Alveolar macrophages (AMs) are immune barriers in alveoli to various pathogens in the respiratory tract; AMs suppress Th2 cell proliferation, inhibit interleukin (IL)-4, IL-5, and IL-13 secretion, and protect against airway hyperresponsiveness in allergic asthma. However, the polarization status and effects of different types of AMs in the pathogenesis of asthma are not known. ATP/P2X7r, expressed mainly on macrophages and dendritic cells, is associated with acute and chronic asthmatic airway inflammation and Th2 immune responses in mice and humans and functions by activating the NLRP3 inflammasome complex and inducing proinflammatory cytokine release (IL-1β and IL-18). Therefore, we evaluated the association between the ATP/P2X7r axis and different types of AMs in the pathology of allergic asthma. A murine AM-depleted asthma model was established by administration of clodronate-encapsulated liposomes, and M1-or M2-AMs were adoptively transferred to confirm the effects of different AMs in allergic asthma. Brilliant Blue G and BzATP were administered to OVA/HDM-induced mice in vivo. Lipopolysaccharide + OVA, ATP, Brilliant Blue G, and BzATP were used to stimulate AMs isolated from control and asthmatic mice. We found that selective depletion of AMs aggravated lung inflammation in asthmatic mice. Further, M2-type AMs may play a key role in mediating asthmatic inflammatory responses via the adoptive transfer of M2-type AMs to AM-depleted asthmatic mice, and the phenotype of AMs differentiated to M2 type in asthma. P2X7r expression in M2-type AMs was higher than that in M1-type AMs. Activating P2X7r induced polarization of M2-type AMs and inhibited polarization of M1-type AMs, while blockage of P2X7r had the opposite effect. The ATP/P2X7r axis may participate in the pathogenesis of asthma by mediating the M2-type AM polarization.

During keratinocyte stratification and wound healing, keratinocytes undergo a switch between differentiation and motility. However, limited knowledge exists on the mechanisms of the switch. We have previously demonstrated that the expression of CD9 was changed in different wound stages and involved in the regulation of keratinocyte migration. In this study, we showed that CD9 expression was increased in both human and mouse keratinocytes undergoing differentiation. CD9 overexpression in keratinocytes stimulated terminal differentiation and reduced cell motility. CD9 silencing inhibited calcium-induced keratinocyte differentiation and increased cell motility. Furthermore, CD9 overexpression recruited E-cadherin to the plasma membrane and subsequently activated PI3K/Akt signaling, while CD9 knockdown inhibited the recruitment of E-cadherin to the plasma membrane and PI3K/Akt activation. Importantly, silencing E-cadherin expression or inhibiting PI3K/Akt signaling reversed CD9 overexpression-induced differentiation and -reduced motility. These results demonstrate that CD9 acts as an important node that regulates keratinocyte differentiation and motility. The recruitment of E-cadherin to the plasma membrane and activation of the PI3K/Akt signaling pathway mediated by CD9 play an important role in these processes.

Non-suicidal self-injury (NSSI) is a serious clinical problem that is common in adolescents. Novel, biologically-informed approaches for treating NSSI in adolescents are needed to prevent negative outcomes such as chronic NSSI and future suicide attempts. N-acetylcysteine (NAC) has been used successfully to address other conditions that involve repetitive maladaptive behaviors and may have utility in addressing NSSI. This study explored neural circuit changes following an open-label, 8-week trial of NAC in female adolescents with NSSI. We measured whole-brain resting-state functional connectivity (RSFC) of the amygdala and the nucleus accumbens before and after treatment using resting-state functional neuroimaging. Usable neuroimaging data from both pre- and post-treatment were available for 18 participants. Reduction in NSSI frequency was associated with a decrease in left amygdala RSFC with right supplementary motor area (SMA), but with an increase in right amygdala RSFC with right inferior frontal cortex. For nucleus accumbens, a reduction in NSSI frequency was associated with a decrease in connectivity between right nucleus accumbens and left superior medial frontal cortex. We also report change in similar circuits accompanying clinical improvement in depression and global psychopathology measures. These preliminary findings suggest amygdala and nucleus accumbens-based circuits as potential treatment targets, and set the stage for future research designed to confirm these neural targets using randomized, placebo-controlled designs to confirm clinical efficacy and mechanisms of effect.

Previous studies in the Central African Republic (CAR) have reported the presence of hepatitis B virus (HBV) recombinant genotype E/D and a suspicion of immune escape mutants (IEMs), without further investigation into their impact on prevention and diagnosis. Consequently, this study investigated HBV mutations among hepatitis B surface antigen (HBsAg)-positive patients attending Institut Pasteur de Bangui in the CAR.

Predictive coding theories of perception highlight the importance of constantly updated internal models of the world to predict future sensory inputs. Importantly, such theories suggest that prediction-error signalling should be specific to the violation of predictions concerning distinct attributes of the same stimulus. To interrogate this as yet untested prediction, we focused on two different aspects of face perception (identity and orientation) and investigated whether cortical regions which process particular stimulus attributes also signal prediction violations with respect to those same stimulus attributes. We employed a paradigm using sequential trajectories of images to create perceptual expectations about face orientation and identity, and then parametrically violated each attribute. Using MEG data, we identified double dissociations of expectancy violations in the dorsal and ventral visual streams, such that the right fusiform gyrus showed greater prediction-error signals to identity violations than to orientation violations, whereas the left angular gyrus showed the converse pattern of results. Our results suggest that perceptual prediction-error signalling is directly linked to regions associated with the processing of different stimulus properties.

The role of nitric oxide (NO) in cancer progression has largely been studied in the context of tumor NOS2 expression. However, pro- versus anti-tumor signaling is also affected by tumor cell-macrophage interactions. While these cell-cell interactions are partly regulated by NO, the functional effects of NO flux on proinflammatory (M1) macrophages are unknown. Using a triple negative murine breast cancer model, we explored the potential role of macrophage Nos2 on 4T1 tumor progression. The effects of NO on macrophage phenotype were examined in bone marrow derived macrophages from wild type and Nos2-/- mice following in vitro stimulation with cytokine/LPS combinations to produce low, medium, and high NO flux. Remarkably, Nos2 induction was spatially distinct, where Nos2high cells expressed low cyclooxygenase-2 (Cox2) and vice versa. Importantly, in vitro M1 polarization with IFNγ+LPS induced high NO flux that was restricted to cells harboring depolarized mitochondria. This flux altered the magnitude and spatial extent of hypoxic gradients. Metabolic and single cell analyses demonstrated that single cell Nos2 induction limited the generation of hypoxic gradients in vitro, and Nos2-dependent and independent features may collaborate to regulate M1 functionality. It was found that Cox2 expression was important for Nos2high cells to maintain NO tolerance. Furthermore, Nos2 and Cox2 expression in 4T1 mouse tumors was spatially orthogonal forming distinct cellular neighborhoods. In summary, the location and type of Nos2high cells, NO flux, and the inflammatory status of other cells, such as Cox2high cells in the tumor niche contribute to Nos2 inflammatory mechanisms that promote disease progression of 4T1 tumors.

Galectin-3 (Gal-3) is a multifunctional glycan-binding protein that participates in many pathophysiological events and has been described as a biomarker and potential therapeutic target for severe disorders, such as cancer. Several probes for Gal-3 or its ligands have been developed, however both the pathophysiological mechanisms and potential biomedical applications of Gal-3 remain not fully assessed. Molecular imaging using bioluminescent probes provides great sensitivity for in vivo and in vitro analysis for both cellular and whole multicellular organism tracking and target detection. Here, we engineered a chimeric molecule consisting of Renilla luciferase fused with mouse Gal-3 (RLuc-mGal-3). RLuc-mGal-3 preparation was highly homogenous, soluble, active, and has molecular mass of 65,870.95 Da. This molecule was able to bind to MKN45 cell surface, property which was inhibited by the reduction of Gal-3 ligands on the cell surface by the overexpression of ST6GalNAc-I. In order to obtain an efficient and stable delivery system, RLuc-mGal-3 was adsorbed to poly-lactic acid nanoparticles, which increased binding to MKN45 cells in vitro. Furthermore, bioluminescence imaging showed that RLuc-mGal-3 was able to indicate the presence of implanted tumor in mice, event drastically inhibited by the presence of lactose. This novel bioluminescent chimeric molecule offers a safe and highly sensitive alternative to fluorescent and radiolabeled probes with potential application in biomedical research for a better understanding of the distribution and fate of Gal-3 and its ligands in vitro and in vivo.

Homologous recombination (HR) is a highly conserved pathway that can facilitate the repair of DNA double-strand breaks (DSB). Several Deubiquitinases (DUB) have been implicated as key players in DNA damage repair (DDR) through HR. Here, we report USP22, a DUB that is highly overexpressed in multiple cancer types, is necessary for HR through a direct interaction with PALB2 through its C-terminal WD40 domain. This interaction stimulates USP22 catalytic activity in vitro. Furthermore, we show USP22 is necessary for BRCA2, PALB2, and Rad51 recruitment to DSBs and this is, in part, through USP22 stabilizing BRCA2 and PALB2 levels. Taken together, our results describe a role for USP22 in DNA repair. IMPLICATIONS: This research provides new and exciting mechanistic insights into how USP22 overexpression promotes chemoresistance in lung cancer. We believe this study, and others, will help aid in developing targeted drugs toward USP22 and known binding partners for lung cancer treatment.

No abstract available

Urbanization represents a profound shift in human behaviour, and has considerable cultural and health-associated consequences1,2. Here, we investigate chemical and microbial characteristics of houses and their human occupants across an urbanization gradient in the Amazon rainforest, from a remote Peruvian Amerindian village to the Brazilian city of Manaus. Urbanization was found to be associated with reduced microbial outdoor exposure, increased contact with housing materials, antimicrobials and cleaning products, and increased exposure to chemical diversity. The degree of urbanization correlated with changes in the composition of house bacterial and microeukaryotic communities, increased house and skin fungal diversity, and an increase in the relative abundance of human skin-associated fungi and bacteria in houses. Overall, our results indicate that urbanization has large-scale effects on chemical and microbial exposures and on the human microbiota.