Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA known to be highly expressed in several tumors. In colorectal cancer (CRC), MALAT1 promotes cell proliferation, metastasis, and invasion in vitro and in vivo. This study aimed to investigate the effect of MALAT1 on the proliferation, migration, and drug sensitivity of CRC cells in vitro and in vivo and the mechanisms involved therein. We observed increased expression of MALAT1 in six CRC cell lines compared to that in normal cells, suggesting its involvement in CRC progression. Downregulation of MALAT1 inhibited cell migration and induced apoptosis in vitro and inhibited tumor growth and metastasis in nude mice. Furthermore, MALAT1 silencing downregulated the expression of ATP-binding cassette transporters (ABC), breast cancer resistance protein (BCRP), and multi-drug resistance proteins including MDR1 and MRP1, resulting in decreased resistance of cancer cells to 5-FU. In addition, the metastasis and invasion of HCT-116 and HCT-116/5-FU cells were regulated via targeting miR-20b-5p. Based on these observations, we infer that inhibition of MALAT1 suppressed CRC progression and metastasis and improved the sensitivity of cancer cells to 5-FU. The present study proposes a new direction to investigate the molecular mechanisms underlying the invasion and metastasis of CRC, whereby the interaction between MALAT1 and miR-20b-5p could be a novel therapeutic target for CRC.

Exposure to airborne particulate matter (PM) has significant effects on human health mainly leading to cardio-respiratory diseases. However very few data are available regarding the impact of PM on the skin, so to better understand the impact of fine particle (PM0.3-2.5) on both inflammatory response and epidermal structure, we exposed a reconstructed human epidermis (RHE) to several doses of PM collected in Cotonou (Benin, West Africa). After 24 h of exposure, inflammatory response, histological observations, and gene expression related to oxidative stress, antioxidant defense and structural damages were determined. No PM-linked changes in tissue morphology or membrane integrity were observable. PM was however cytotoxic in a dose dependent manner. An inflammatory response appeared as shown by the increase in IL-1α and IL-8 cytokine productions. PM also induced oxidative stress, leading to an increase in 4-HNE immunostaining and to the up-regulation of HMOX1, MT1G and MT1E. Finally, PM had a negative impact on fundamental skin functions such as tissue anchorage, cell differentiation, cornification / skin desquamation and apoptosis. Our data show that airborne fine particles have an adverse effect on skin integrity, most probably leading to accelerated ageing.

Muscular fibrosis is caused by excessive accumulation of extracellular matrix (ECM) that replaces functional tissue, and it is a feature of several myopathies and neuropathies. Knowledge of the biology and regulation of pro-fibrotic factors is critical for the development of new therapeutic strategies. Upon unilateral sciatic nerve transection, we observed accumulation of ECM proteins such as collagen and fibronectin in the denervated hindlimb, together with increased levels of the profibrotic factors transforming growth factor type β (TGF-β) and connective tissue growth factor (CTGF/CCN2). In mice hemizygous for CTGF/CCN2 or in mice treated with a blocking antibody against CTGF/CCN2, we observed reduced accumulation of ECM proteins after denervation as compared to control mice, with no changes in fibro/adipogenic progenitors (FAPs), suggesting a direct role of CTGF/CCN2 on denervation-induced fibrosis. During time course experiments, we observed that ECM proteins and CTGF/CCN2 levels are increased early after denervation (2-4 days), while TGF-β signaling shows a delayed kinetics of appearance (1-2 weeks). Furthermore, blockade of TGF-β signaling does not decrease fibronectin or CTGF levels after 4 days of denervation. These results suggest that in our model CTGF/CCN2 is not up-regulated by canonical TGF-β signaling early after denervation and that other factors are likely involved in the early fibrotic response following skeletal muscle denervation.

No abstract available

The eyestalks of crustaceans play an essential role in controlling a variety of physiological functions by converting light into hormonal signals. To obtain a more complete description of eyestalk biology in the commercially important Chinese mitten crab (Eriocheir sinensis), we conducted comparative transcriptome analysis of eyestalks during the day and at night using high-throughput sequencing on an Illumina HiSeq 4000 platform. We obtained 47,092 unigenes-including 4771 differentially expressed genes (DEGs)-from eyestalks during the day and at night. We found that 4269 DEGs were upregulated during the day and 502 DEGs were upregulated at night. We identified five DEGs that may contribute to molting, including molt-inhibiting hormone, cuticle, catalase, aquaporin, and ubiquitin-conjugating enzyme; hence, similar to other crustaceans, Eriocheir sinensis may molt at night. We further identified eight DEGs related to behavior regulation, including three glutamate dehydrogenase genes that were upregulated during the day. Thus, changes in the eyestalks may partially compensate for daily changes in illumination in the Chinese mitten crab's normal environment. Our present study is the first genome-wide transcriptome analysis of the eyestalks of Eriocheir sinensis during the day and at night. Our findings provide a valuable insight into the molecular basis of circadian cycle regulation in crustaceans.

Arabinosyl tranferases (embA, embB, embC) are the key enzymes responsible for biogenesis of arabinan domain of arabinogalactan (AG) and lipoarabinomannan (LAM), two major heteropolysaccharide constituents of the peculiar mycobacterial cell envelope. EmbC is predominantly responsible for LAM synthesis and has been commonly associated with Ethambutol resistance. We have screened the FDA library against EmbC to reposition a drug better than Ethambutol with higher binding affinity to Embc. High throughput virtual screening followed by extra precision docking using Glide gave two best leads i.e. Terlipressin and Amikacin with docking score of -11.39 kcal/mol and -10.71 kcal/mol, respectively. Binding mechanics of the selected drugs was elucidated through long range molecular dynamics simulations (100 ns) using binding free energy rescoring, essential dynamics and free energy minima based approaches, thus revealing the most stable binding modes of Terlipressin with EmbC. Our study establishes the EmbC binding potential of the repurposed drugs Terlipressin and Amikacin.

With the ongoing climate change, African rainforests are expected to experience severe drought events in the future. In Africa, the tropical genus Erythrophleum (Fabaceae) includes two forest sister timber tree species displaying contrasting geographical distributions. Erythrophleum ivorense is adapted to wet evergreen Guineo-Congolian forests, whereas E. suaveolens occurs in a wider range of climates, being found in moist dense forests but also in gallery forests under a relatively drier climate. This geographical distribution pattern suggests that the two species might cope differently to drought at the genomic level. Yet, the genetic basis of tolerance response to drought stress in both species is still uncharacterized. To bridge this gap, we performed an RNA-seq approach on seedlings from each species to monitor their transcriptional responses at different levels of drought stress (0, 2 and 6 weeks after stopping watering seedlings). Monitoring of wilting symptoms revealed that E. suaveolens displayed an earlier phenotypic response to drought stress than E. ivorense. At the transcriptomic level, results revealed 2020 (1204 down-regulated/816 up-regulated) and 1495 differentially expressed genes (DEGs) in response to drought stress from a total of 67,432 and 66,605 contigs assembled in E. ivorense and E. suaveolens, respectively. After identifying 30,374 orthologs between species, we found that only 7 of them were DEGs shared between species, while 587 and 458 were differentially expressed only in E. ivorense or E. suaveolens, respectively. GO and KEGG enrichment analysis revealed that the two species differ in terms of significantly regulated pathways as well as the number and expression profile of DEGs (Up/Down) associated with each pathway in the two stress stages. Our results suggested that the two studied species react differently to drought. E. suaveolens seems displaying a prompt response to drought at its early stage strengthened by the down-regulation of many DEGs encoding for signaling and metabolism-related pathways. A considerable up-regulation of these pathways was also found in E. ivorense at the late stage of drought, suggesting this species may be a late responder. Overall, our data may serve as basis for further understanding the genetic control of drought tolerance in tropical trees and favor the selection of crucial genes for genetically enhancing drought resistance.

The term executive functions (EF) describes a set of higher cognitive abilities/skills needed for goal-oriented and flexible behavior. In contrast to a multitude of functional neuroimaging studies of EF performance, only limited and partially inconclusive data is available for the structural-neuroanatomical underpinnings of EFs, particularly in healthy adults.

Resting-state functional MRI (R-fMRI) studies have demonstrated widespread alterations in brain function in patients with major depressive disorder (MDD). However, a clear and consistent conclusion regarding a repeatable pattern of MDD-relevant alterations is still limited due to the scarcity of large-sample, multisite datasets. Here, we address this issue by including a large R-fMRI dataset with 1434 participants (709 patients with MDD and 725 healthy controls) from five centers in China. Individual functional activity maps that represent very local to long-range connections are computed using the amplitude of low-frequency fluctuations, regional homogeneity and distance-related functional connectivity strength. The reproducibility analyses involve different statistical strategies, global signal regression, across-center consistency, clinical variables, and sample size. We observed significant hypoactivity in the orbitofrontal, sensorimotor, and visual cortices and hyperactivity in the frontoparietal cortices in MDD patients compared to the controls. These alterations are not affected by different statistical analysis strategies, global signal regression and medication status and are generally reproducible across centers. However, these between-group differences are partially influenced by the episode status and the age of disease onset in patients, and the brain-clinical variable relationship exhibits poor cross-center reproducibility. Bootstrap analyses reveal that at least 400 subjects in each group are required to replicate significant alterations (an extent threshold of P < .05 and a height threshold of P < .001) at 50% reproducibility. Together, these results highlight reproducible patterns of functional alterations in MDD and relevant influencing factors, which provides crucial guidance for future neuroimaging studies of this disorder.

Ultrasonic vocalizations (USV) of mice are produced in and emitted by the larynx. However, which anatomical elements of the mouse larynx are involved and to which aspects of USV they contribute is not clear. Frequency and amplitude parameters of mice, deficient in the clock gene Period1 (mPer1-/- mice) are distinguishably different compared to C3H wildtype (WT) controls. Because structural differences in the larynx may be a reason for the different USV observed, we analyzed laryngeal anatomy of mPer1-/- mice and WT control animals using micro-computed-tomography and stereology.

Erythropoietin (EPO) is a secreted hormone that stimulates the production of red blood cells, and the level of EPO is increased under hypoxia. The expression of EPO is regulated not only by the hypoxia-inducible factor (HIF) but also partly through epigenetic modifications, including histone acetylation and methylation. In this study, we report that histone H3K9 demethylase JMJD1 A is regulated by HIF-2α in HepG2 cells under hypoxia. Knockdown or over-expression of JMJD1 A can decrease or increase EPO expression, respectively. JMJD1 A can interact with HIF-2α to form a co-activator complex, which binds to the hypoxia response elements of EPO and increases EPO expression by catalyzing demethylation of H3K9me2, a transcription suppression marker. The results demonstrate that JMJD1 A is a co-activator of EPO expression.

Similar to elderly humans, aged outbred Long-Evans rats exhibit individual differences in memory abilities, including a subset of aged rats that maintain memory function on par with young adults. Such individuals provide a basis for investigating mechanisms of resilience to age-related decline. The present study examined hippocampal gene expression in young adults and aged rats with preserved memory function under behavioral task conditions well established for assessing information processing central to the formation of episodic memory. Although behavioral measures and hippocampal gene induction associated with neural activity and synaptic plasticity were similar across age groups, a marker for inhibitory interneuron function in the hippocampal formation was distinctively increased only in aged rats but not in young adults. Because heightened hippocampal neural activity is associated with age-related memory impairment across species, including rats, monkeys, and humans, this finding may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging.

Mixed Cr(III)-Fe(III) (oxy)hydroxides are important Cr-bearing phases in natural, unpolluted soil. Fires frequently affect large areas of land around the world, causing the temporary development of elevated soil temperatures. This study examines the hypothesis that heating Cr(III)-Fe(III) (oxy)hydroxides at temperatures which occur in surface soils during fires can drive rapid oxidation of Cr(III) to hazardous Cr(VI). To test this, poorly-ordered Cr(III)x-Fe(III)1-x (oxy)hydroxides, with x spanning 0.1 to 0.9, were heated at up to 800 °C for 2 h. Heating at 400-800 °C produced a highly crystalline hematite-eskolaite solid-solution (FeIII2-nCrIIInO3, where n ranges from 0 to 2). Chromium K-edge X-ray absorption spectroscopy showed that during heating up to ∼40% of the initial Cr(III) was oxidized to Cr(VI), with the greatest extent of Cr(VI) formation occurring at 200-400 °C. At these temperatures, a substantial proportion (17%-70%) of the newly-formed Cr(VI) was exchangeable (i.e. extracted by a pH 7.2, 10 mM PO43- solution). This suggests that much of the Cr(VI) formed by heating of Cr(III)x-Fe(III)1-x (oxy)hydroxides at 200-400 °C is likely to be relatively mobile in fire-impacted soils. The results of this study provide new insights into a potentially-important pathway for the in-situ formation of Cr(VI) in soil.

GlycA is a novel composite biomarker of systemic inflammation reflecting posttranslational glycosylation of acute phase reactants. GlycA has been associated with coronary artery calcium, cardiovascular disease (CVD) events and mortality. Vascular calcifications outside of the coronary arteries are risk markers of CVD and mortality. Whether GlycA is linked to extra-coronary calcifications (ECC) is not well established.

Substance use has a tremendous impact on the burden of disease. This is particularly true in the Eastern Mediterranean region (EMR), where many countries serve as suppliers of drugs. As risk perception and frequency of use are inversely correlated, targeting perception during adolescence becomes essential for prevention. In this study, we systematically reviewed the literature on attitudes, beliefs, and knowledge of substance use amongst youth in the EMR.

Human Cytomegalovirus (HCMV) is an opportunistic pathogen that causes substantial disease in neonates and immunocompromised individuals. Reverse genetic analysis of the HCMV genome is a powerful tool to dissect the roles that various viral genes play during infection. However, genetic engineering of HCMV is hampered by both the large size of the HCMV genome and HCMV's slow replication cycle. Currently, most laboratories that genetically engineer HCMV employ Bacterial Artificial Chromosome (BAC) mediated recombineering, which is a relatively lengthy process. We explored an alternative method of producing recombinant HCMV using the CRISPR/Cas9 system. We employed both homologous recombination (HR) and Non-homologous end-joining (NHEJ)-based methods, and find that each approach is capable of efficiently mutating the HCMV genome, with optimal efficiencies of 42% and 81% respectively. Our results suggest that CRISPR-mediated genomic engineering of HCMV is competitive with BAC-mediated recombineering and provide a framework for using CRISPR/Cas9 for mutational analysis of the HCMV genome.

Resting-state networks (RSNs; groups of regions consistently co-activated without an explicit task) are hugely influential in modern brain research. Despite this popularity, the link between specific RSNs and their functions remains elusive, limiting the impact on cognitive neuroscience (where the goal is to link cognition to neural systems). Here we present a series of logical steps to formally test the relationship between a coherent RSN with a cognitive domain. This approach is applied to a challenging and significant test-case; extracting a recently-proposed semantic RSN, determining its relation with a well-known RSN, the default mode network (DMN), and assessing their roles in semantic cognition. Results showed the DMN and semantic network are two distinct coherent RSNs. Assessing the cognitive signature of these spatiotemporally coherent networks directly (and therefore accounting for overlapping networks) showed involvement of the proposed semantic network, but not the DMN, in task-based semantic cognition. Following the steps presented here, researchers could formally test specific hypotheses regarding the function of RSNs, including other possible functions of the DMN.

Recognizing and distinguishing the emotional states of those around us is crucial for adaptive social behavior. Previous work has shown that damage to the ventromedial frontal lobe (VMF) impairs recognition of subtle emotional facial expressions and affects fixation patterns to face stimuli. However, whether this relates to deficits in acquiring or interpreting facial expression information remains unclear. We tested 37 patients with frontal lobe damage, including 17 subjects with VMF lesions, in a series of emotion recognition tasks with different gaze manipulations. Subjects were asked to rate neutral, subtle and extreme emotional expressions while freely examining faces, while instructed to look only at the eyes, and in a gaze-contingent condition that required top-down direction of eye movements to reveal the stimulus. People with VMF damage were worse at detecting subtle disgust during free viewing and confused extreme emotional expressions more than healthy controls. However, fixation patterns did not differ systematically between groups during free or gaze-contingent viewing conditions. Moreover, instruction to fixate only the eyes did not improve the performance of VMF damaged subjects. These data argue that VMF is not necessary for normal fixations to emotional face stimuli, and that impairments in emotion recognition after VMF damage do not stem from impaired information gathering, as indexed by patterns of fixation.

The γc family of cytokines comprising interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-2 is an important group of 4-helix bundle cytokines that signals through receptors incorporating the common gamma chain (γc). These cytokines are involved in lymphocyte biology and their specific functions are contingent on binding to cognate receptor chains. Here, we examined the structural relationships between γc cytokines, aiming to understand the basis for receptor chain usage and sharing. To that end, we obtained tertiary structures of human and mouse γc cytokines plus two other related cytokines, IL-13 and TSLP, which share receptors with IL-4 and IL-7, respectively. Subsequently, we compared the cytokine 3D-structures introducing a structural similarity score that grouped γc cytokines in a manner that mirrored the relationships dictated by receptor sharing. Unlike previously thought, we identified that IL-9 is more closely related to IL-2 and IL-15 than to IL-7, which is actually the most distant member of the γc family of cytokines. Moreover, we found that all the members of the γc family of cytokines share the topology of short-chain 4-helix bundle cytokines but IL-7 that with TSLP has the topology of long-chain 4-helix bundle cytokines. We also carried out Maximun-Likehood and Bayesian phylogenetic analyses that supported these results at the amino acid sequence level. Overall, our findings are of paramount relevance to understand receptor sharing among γc cytokines and can lead to the discovery of new cytokine receptor partners.

Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with an unknown etiology. Increased oxidative stress and mitochondrial dysfunction are thought to be involved in its pathogenesis. However, the effect of the AluYb8MUTYH polymorphism on IPF is not known.