Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells

Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress

Meme-ingful Analysis: Enhanced Understanding of Cyberbullying in Memes Through Multimodal Explanations

Internet memes have gained significant influence in communicating political, psychological, and sociocultural ideas. While memes are often humorous, there has been a rise in the use of memes for trolling and cyberbullying. Although a wide variety of effective deep learning-based models have been developed for detecting offensive multimodal memes, only a few works have been done on explainability aspect. Recent laws like "right to explanations" of General Data Protection Regulation, have spurred research in developing interpretable models rather than only focusing on performance. Motivated by this, we introduce {\em MultiBully-Ex}, the first benchmark dataset for multimodal explanation from code-mixed cyberbullying memes. Here, both visual and textual modalities are highlighted to explain why a given meme is cyberbullying. A Contrastive Language-Image Pretraining (CLIP) projection-based multimodal shared-private multitask approach has been proposed for visual and textual explanation of a meme. Experimental results demonstrate that training with multimodal explanations improves performance in generating textual justifications and more accurately identifying the visual evidence supporting a decision with reliable performance improvements.Comment: EACL202

Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury Role of Human CD34+ Cells Deficient in MicroRNA-377

AbstractBackgroundMicroRNA (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress.ObjectivesThe aim of this study was to explore the role of miR in human CD34+ cell (hCD34+) dysfunction in vivo after transplantation into the myocardium under ischemia-reperfusion (I-R) conditions.MethodsIn response to inflammatory stimuli, the miR array profile of endothelial progenitor cells was analyzed using a polymerase chain reaction–based miR microarray. miR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF). We investigated the effect of miR-377 inhibition on an hCD34+ cell angiogenic proteome profile in vitro and on cardiac repair and function after I-R injury in immunodeficient mice.ResultsThe miR array data from endothelial progenitor cells in response to inflammatory stimuli indicated changes in numerous miR, with a robust decrease in the levels of miR-377. Human cardiac biopsies from patients with HF showed significant increases in miR-377 expression compared with nonfailing control hearts. The proteome profile of hCD34+ cells transfected with miR-377 mimics showed significant decrease in the levels of proangiogenic proteins versus nonspecific control–transfected cells. We also validated that serine/threonine kinase 35 is a target of miR-377 using a dual luciferase reporter assay. In a mouse model of myocardial I-R, intramyocardial transplantation of miR-377 silenced hCD34+ cells in immunodeficient mice, promoting neovascularization (at 28 days, post–I-R) and lower interstitial fibrosis, leading to improved left ventricular function.ConclusionsThese findings indicate that HF increased miR-377 expression in the myocardium, which is detrimental to stem cell function, and transplantation of miR-377 knockdown hCD34+ cells into ischemic myocardium promoted their angiogenic ability, attenuating left ventricular remodeling and cardiac fibrosis

NanoDCFH-DA: a silica based nanostructured fluorogenic probe for the detection of reactive oxygene species

A biocompatible fluorescent nanoprobe for the detection of reactive oxygen species in biological systems has been designed, synthesized and characterized, circumventing some of the limitations of the molecular probe diacetyl 2',7'-dihidrochlorodihydrofluorescein (DCFH-DA). It has been synthesized the nanoparticulate forme of DCFH-DA by convalently attaching the widely used fluorescent probe DCFH-DA to a mesoporous silica nanoparticle though a linker, The reactivity of nanoDCFH-DA has been tested toward several reactive oxygen species. In addition, it has been proven to slow down DCFH-DA reaction with molecular oxygen and it hampers from interactions with proteins. As a final piece of evidence, in vitro studies showed that the nanoprobe is internalized HeLa cancer cells, thus being capable of detecting intracellularly generated reactive oxygen species. To sum up, it can be stated that nanoDCFH-DA overcomes two major problems of free DCFH-DA, namely oxidation of the probe by air and interaction with proteins in biological systems. This 'nano' approach has thus proven useful to extend the utility of an existing and valuable fluorescent probe to complex biological systems

Insights into Chagas treatment based on the potential of bacteriocin AS-48

Chagas disease caused by the protozoan parasite Trypanosoma cruzi represents a significant public health problem in Latin America, affecting around 8 million cases worldwide. Nowadays is urgent the identification of new antichagasic agents as the only therapeutic options available, Nifurtimox and Benznidazole, are in use for>40 years, and present high toxicity, limited efficacy and frequent treatment failures in the chronic phase of the disease. Recently, it has been described the antiparasitic effect of AS-48, a bacteriocin produced by Enterococcus faecalis, against Trypanosoma brucei and Leishmania spp. In this work, we have demonstrated the in vitro potential of the AS-48 bacteriocin against T. cruzi. Interesting, AS-48 was more effective against the three morphological forms of different T. cruzi strains, and displayed lower cytotoxicity than the reference drug Benznidazole. In addition, AS-48 combines the criteria established as a potential antichagasic agent, resulting in a promising therapeutic alternative. According to the action mechanism, AS-48 trypanocidal activity could be explained in a mitochondrion-dependent manner through a reactive oxygen species production and mitochondrial depolarization, causing a fast and severe bioenergetic collapse.This work was supported by the Spanish Ministry of Economy and Competitiveness [grant numbers SAF2013-48971-C2-1-R, CSD2010- 00065], both including funds from the European Regional Development Fundings (ERDF), and the Ministry of Education of Spain [RM-E, grant number FPU14/01537]

Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts

<p>Abstract</p> <p>Background</p> <p>NF-κB is a survival signaling transcription factor complex involved in the malignant phenotype of many cancers, including squamous cell carcinomas (SCC). The citrus coumarin, auraptene (AUR), and the ethno-medicinal ginger (Alpinia galanga) phenylpropanoid, 1'-acetoxychavicol acetate (ACA), were previously shown to suppress 12-<it>O</it>-tetradecanoylphorbol-13-acetate (TPA) induced mouse skin tumor promotion. The goal of the present study was to determine whether AUR and ACA are effective either alone or in combination with all-<it>trans </it>retinoic acid (ATRA) for suppressing SCC tumor growth.</p> <p>Methods</p> <p>We first determined the effects of orally administered ACA (100 mg/kg bw) and AUR (200 mg/kg bw) on lipopolysaccharide (LPS)-induced NF-κB activation in NF-κB-RE-luc (Oslo) luciferase reporter mice. Dietary administration of AUR and ACA ± ATRA was next evaluated in a xenograft mouse model. Female SCID/bg mice were fed diets containing the experimental compounds, injected with 1 × 10⁶SRB12-p9 cells s.c., palpated and weighed twice a week for 28 days following injection.</p> <p>Results</p> <p>Both ACA and AUR suppressed LPS-induced NF-κB activation in the report mice. In the xenograft model, AUR (1000 ppm) and ACA (500 ppm) modestly suppressed tumor volume. However, in combination with ATRA at 5, 10, and 30 ppm, ACA 500 ppm significantly inhibited tumor volume by 56%, 62%, and 98%, respectively. The effect of ATRA alone was 37%, 33%, and 93% inhibition, respectively. AUR 1000 ppm and ATRA 10 ppm were not very effective when administered alone, but when combined, strongly suppressed tumor volume by 84%.</p> <p>Conclusions</p> <p>Citrus AUR may synergize the tumor suppressive effects of ATRA, while ACA may prolong the inhibitory effects of ATRA. Further studies will be necessary to determine whether these combinations may be useful in the control of human SCC.</p

The mediational role of physical activity, social contact and stroke on the association between age, education, employment and dementia in an Asian older adult population

BACKGROUND: Our study aimed to investigate the pathways by which socio-demographic factors, modifiable health and lifestyle risk factors influence each other, and subsequently, lead to dementia. METHODS: We used data from the Well-being of the Singapore Elderly study, a nationally representative survey of the older adult population aged 60 years and above in Singapore. Dementia diagnosis was established using 10/66 dementia criteria. Structural equation modelling (SEM) without latent variable was applied to confirm the hypothesized model. RESULTS: The results of SEM supported the hypothesized model (χ (2) = 14.999, df = 10, p = 0.132). The final model showed that those aged 75–84 years and 85 years and over (vs. 60–74 years), having no formal education, who had completed primary or secondary education (vs. completed tertiary), who were homemakers and retired (vs. paid work), and with a history of stroke were directly associated with higher odds of having dementia, while those who had more frequent contact with friends and neighbors as well as being physically active were directly associated with lower odds of having dementia diagnosis. The study also found that physical activity, more frequent contact with friends and stroke played a significant role as mediators in these relationships. The overall pathways model explained 57.7% of the variance in dementia. CONCLUSION: Our results suggest that physical activity, social contact and stroke were potential mediators in the relationship between age, education, employment and dementia. Intervention programmes focusing on physical activity such as exercise and social contact may be useful in reducing the risk of dementia among older adults