89 research outputs found
Inhibition of mitochondrial dynamics preferentially targets pancreatic cancer cells with enhanced tumorigenic and invasive potential
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis de-pends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. In-terestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potentialThis research was funded by the Pancreatic Cancer Research Fund, 2015 Award Round
(P.S., C.H.); the European Communityâs Seventh Framework Programme (FP7/2007-2013) under
grant agreement n 602783 (CAM-PaC) (C.H.), theWorldwide Cancer Research Charity together with
FundaciĂłn CientĂfica AsociaciĂłn Española contra el CĂĄncer (FCAECC) (19-0250) (P.S.); A Fero Foundation
grant and a Coordinated grant (GC16173694BARB) from the Fundación Asociación Española
Contra el CĂĄncer (AECC) (B.S.J.); and the Instituto de Salud Carlos III through the Miguel Servet
Program (CP16/00121) and Fondo de Investigaciones Sanitarias (PI17/00082) (both co-financed by
European funds (FSE: âEl FSE invierte en tu futuroâ and FEDER: âUna manera de hacer Europa,â
respectively) (P.S.
A Genotyping Study in Benin Comparing the Carriage of Plasmodium falciparum Infections Before Pregnancy and in Early Pregnancy: Story of a Persistent Infection
BACKGROUND: Malaria infections in the first trimester of pregnancy are frequent and deleterious for both mother and child health. To investigate if these early infections are newly acquired or already present in the host, we assessed whether parasites detected before pregnancy and those detected in early pregnancy are the same infection. METHODS: We used data from the preconceptional "RECIPAL" study (Benin, 2014-2017). Sixty-three pregnant women of 411 included who had a malaria infection detected by quantitative polymerase chain reaction both before pregnancy and at the first antenatal care (ANC) visit were selected for this study. Two highly polymorphic markers, msp-2 and glurp, and a fragment-analysis method were used to enumerate the Plasmodium falciparum genotypes and to quantify their proportions within isolates. An infection was considered as persistent when identical msp-2 and glurp genotypes were found in the corresponding prepregnancy and early-pregnancy samples. RESULTS: The median time between the 2 malaria screenings was 3 months. The median gestational age at the first ANC visit was 6.4 weeks. Most infections before pregnancy were submicroscopic infections. Based on both msp-2 and glurp genotyping, the infection was similar before and in early pregnancy in 46% (29/63) of cases. CONCLUSIONS: Almost half of P. falciparum infections detected in the first trimester originate before pregnancy. Protecting young women from malaria infection before pregnancy might reduce the prevalence of malaria in early pregnancy and its related poor maternal and birth outcomes.Impact du paludisme prĂ©coce au cours de la grossesse sur la croissance fĆtale au BĂ©ni
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Inflation and Dark Energy from spectroscopy at z > 2
The expansion of the Universe is understood to have accelerated during two
epochs: in its very first moments during a period of Inflation and much more
recently, at z < 1, when Dark Energy is hypothesized to drive cosmic
acceleration. The undiscovered mechanisms behind these two epochs represent
some of the most important open problems in fundamental physics. The large
cosmological volume at 2 < z < 5, together with the ability to efficiently
target high- galaxies with known techniques, enables large gains in the
study of Inflation and Dark Energy. A future spectroscopic survey can test the
Gaussianity of the initial conditions up to a factor of ~50 better than our
current bounds, crossing the crucial theoretical threshold of
of order unity that separates single field and
multi-field models. Simultaneously, it can measure the fraction of Dark Energy
at the percent level up to , thus serving as an unprecedented test of
the standard model and opening up a tremendous discovery space
HNF1α inhibition triggers epithelial-mesenchymal transition in human liver cancer cell lines
<p>Abstract</p> <p>Background</p> <p>Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and ÎČ-fibrinogen. Biallelic inactivating mutations of <it>HNF1A </it>have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA.</p> <p>Methods</p> <p>We transfected hepatoma cell lines HepG2 and Hep3B with siRNA targeting HNF1α and obtained a strong inhibition of HNF1α expression. We then looked at the phenotypic changes by microscopy and studied changes in gene expression using qRT-PCR and Western Blot.</p> <p>Results</p> <p>Hepatocytes transfected with HNF1α siRNA underwent severe phenotypic changes with loss of cell-cell contacts and development of migration structures. In HNF1α-inhibited cells, hepatocyte and epithelial markers were diminished and mesenchymal markers were over-expressed. This epithelial-mesenchymal transition (EMT) was related to the up regulation of several EMT transcription factors, in particular <it>SNAIL </it>and <it>SLUG</it>. We also found an overexpression of TGFÎČ1, an EMT initiator, in both cells transfected with HNF1α siRNA and H-HCA. Moreover, TGFÎČ1 expression is strongly correlated to HNF1α expression in cell models, suggesting regulation of TGFÎČ1 expression by HNF1α.</p> <p>Conclusion</p> <p>Our results suggest that HNF1α is not only important for hepatocyte differentiation, but has also a role in the maintenance of epithelial phenotype in hepatocytes.</p
Reading tea leaves worldwide: decoupled drivers of initial litter decomposition massâloss rate and stabilization
The breakdown of plant material fuels soil functioning and biodiversity. Currently, process understanding of global decomposition patterns and the drivers of such patterns are hampered by the lack of coherent largeâscale datasets. We buried 36,000 individual litterbags (tea bags) worldwide and found an overall negative correlation between initial massâloss rates and stabilization factors of plantâderived carbon, using the Tea Bag Index (TBI). The stabilization factor quantifies the degree to which easyâtoâdegrade components accumulate during earlyâstage decomposition (e.g. by environmental limitations). However, agriculture and an interaction between moisture and temperature led to a decoupling between initial massâloss rates and stabilization, notably in colder locations. Using TBI improved massâloss estimates of natural litter compared to models that ignored stabilization. Ignoring the transformation of dead plant material to more recalcitrant substances during earlyâstage decomposition, and the environmental control of this transformation, could overestimate carbon losses during early decomposition in carbon cycle models
COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study
Background:
The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms.
Methods:
International, prospective observational study of 60â109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms.
Results:
âTypicalâ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (â€â18 years: 69, 48, 23; 85%), older adults (â„â70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each Pâ<â0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country.
Interpretation:
This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men
Understanding today's convergent news media consumption through a triple articulation lens
Today's news media environment is becoming increasingly pervasive and ubiquitous. As such, it becomes quite hard for communication researchers to approach the apparent complexity of media consumers\' everyday practices. In older days, media environments were rather straight forward, whereas today, due to the increasing trend of technological convergence, this media environment is rendered tremendously complex and hard to grasp; the boundaries between media and the ways we use them have collided (Jenkins, 2006) or liquefied (Deuze, 2011). Right now, various technological objects are used to consume a myriad of news materials, either in audiovisual or written form. Moreover, this consumption is nested in every possible scene of the everyday, as well in spatial as in social terms. Hence, we rather live in media than with media (Deuze, 2011), which brings about an abundance of possible news media repertoires. In this paper, we demonstrate a novel methodological approach to grasp this complexity in news consumption. Its theoretical foundations lie within domestication theory (Silverstone & Haddon, 1996), which represents the so-called ethnographic turn in audience research. Rather than just centring on media texts, it also incited to take into account contextual surrounding of media consumption, especially within the perimeter of the everyday. One of the major attractors of is the recognition of media meanings as derived from two distinct articulations: the affording objects on the one hand, and the media text itself on the other hand. Although context has always been of the utmost importance, domestication scholars often lost themselves in overly contextual descriptions, basically ignoring these texts and objects. In a recent theoretical and methodological account, Courtois et al. (in press) propose a triple articulation as a framework to study convergent media consumption, addressing equal weights to object, text and socio-spatial context meanings. In fact, socio-spatial context is conceived as a specific articulation because these meaningful circumstances constantly change throughout the day. As such, it has become one of the three crucial interacting components that direct people's meaning making process when it comes to their media consumption. The proposed methodology entails a semi-structured face-to-face interview based on photo-elicited card sorts of objects, texts and socio-spatial context. It is directed towards uncovering the influence each articulation exercises in making up the overall meaning of media consumption. More specifically, it allows uncovering the specific roles of objects, texts and socio-spatial contexts in diverse media consumption repertoires. The results clearly show that each of the proposed articulation plays crucial roles in understanding why people use the news media in the way they do: although each articulation has the potential to affect meaning, it is clear that there is a deepening divide between news media consumers. Nonetheless, drawing upon insights in the everyday, this paper for instance helps to understand why some certain proportion of consumers stick to traditional news media repertoires, while others fully embrace modern technological means like smartphones, in a wide array of contexts
Challenging Google Search filter bubbles in social and political information: Disconforming evidence from a digital methods case study
© 2018 Elsevier Ltd This article engages in the debate on supposed online âfilter bubblesâ by analysing a panel of Google usersâ search results on a standardized set of socio-politically themed search queries. In general, the query results appear to be dominated by mainstream media sources, followed at a large distance by civil society and government resources. By means of mixed model regression analyses, with the prominence of different source types in the search results as dependent variables, it was tested whether search results vary across Google Search users. The results indicate that the inclusion of participants as a random effect does not explain variance when controlling for the different query keywords and the time at which the queries were ran. Hence, this study does not support the occurrence of âfilter bubblesâ in Google Search results in the context of social and political information.status: publishe
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