EMT- and MET-related processes in nonepithelial tumors:Importance for disease progression, prognosis, and therapeutic opportunities

The epithelial-to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment-derived stimuli that provoke EMT-like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal-to-epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/ PMET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets

Three-dimensional culture models to study glioblastoma:current trends and future perspectives

International audienc

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines

Associated factors for maternal-foetal complications in pregnant women with sickle cell disease at the departmental University Hospital of Borgou and Alibori (Benin)

Background: Sickle cell disease is one of the most common genetic disorders in the world, with a high prevalence in Africa. It is a pathology that threatens the maternal-fetal prognosis in case of pregnancy. The objective of this study was to describe the maternal-foetal complications and to identify the factors associated with maternal-foetal complications in sickle cell pregnant women (SP).Methods: This was a descriptive cross-sectional study with retrospective data collection over a period of 4 years (01 January 2015 to 31 August 2019). The study population was All SP who had given birth in the maternity ward of the UH of Borgou/Alibori.Results: We recorded 130 SP out of 10087 admissions, either a frequency of 1.3%. There were 119/130 exploitable files. Maternal complications during pregnancy were: vaso-occlusive crises 79%; severe anaemia 27.7%; hyponatremia 10.1%; vasculo-renal syndromes 18.4%; infections 74.8%. The foetal complications during pregnancy were: Preterm births 38.6%, in utero deaths 17.6%, low birth weight 54.7%. Early neonatal mortality was 8.4% (8/95). There was a 4.2% (5/119) of maternal deaths. Low educational level of the SP, SS genotype, insufficient antenatal follow-up and antenatal follow-up outside the specialized center for the care of sickle cell pregnant women (SCCSP) were the factors associated with maternal-foetal complications in the SP.Conclusions: The association of pregnancy and sickle cell disease is frequent in West Africa, particularly in Benin, and is characterised by numerous maternal-foetal complications that are associated with certain factors

A 24 hour naproxen dose on gastrointestinal distress and performance during cycling in the heat

Using a double-blind, randomized and counterbalanced, cross-over design, we assessed naproxen's effects on gastrointestinal (GI) distress and performance in eleven volunteers (6 male, 5 female). Participants completed 4 trials: 1) placebo and ambient); 2) placebo and heat; 3) naproxen and ambient; and 4) naproxen and heat. Independent variables were one placebo or 220 mg naproxen pill every 8 h (h) for 24 h and ambient (22.7 ± 1.8°C) or thermal environment (35.7 ± 1.3°C). Participants cycled 80 min at a steady heart rate then 10 min for maximum distance. Perceived exertion was measured throughout cycling. Gastrointestinal distress was assessed pre-, during, post-, 3 h post-, and 24 h post-cycling using a GI index for upper, lower, and systemic symptoms. No statistically significant differences occurred between conditions at any time for GI symptoms or perceived exertion, distance, or heart rate during maximum effort. A 24 h naproxen dose did not significantly affect performance or cause more frequent or serious GI distress when participants were euhydrated and cycling at moderate intensity in a thermal environment

Physiological consequences of rising water salinity for a declining freshwater turtle.

Sea-level rise, drought and water diversion can all lead to rapid salinization of freshwater habitats, especially in coastal areas. Increased water salinities can in turn alter the geographic distribution and ecology of freshwater species including turtles. The physiological consequences of salinization for freshwater turtles, however, are poorly known. Here, we compared the osmoregulatory response of two geographically separate populations of the freshwater Western Pond Turtle (Actinemys marmorata)-a species declining across its range in western North America-to three constant salinities: 0.4 ppt, 10 ppt and 15 ppt over 2 weeks. We found that turtles from a coastal estuarine marsh population regulated their plasma osmolality at lower levels than their conspecifics from an inland freshwater creek population 45 km away. Plasma osmolalities were consistently lower in estuarine marsh turtles than the freshwater creek turtles over the entire 2-week exposure to 10 ppt and 15 ppt water. Furthermore, estuarine marsh turtles maintained plasma osmolalities within 1 SD of their mean field osmolalities over the 2-week exposure, whereas freshwater creek turtles exceeded their field values within the first few days after exposure to elevated salinities. However, individuals from both populations exhibited body mass loss in 15 ppt water, with significantly greater loss in estuarine turtles. We speculate that the greater ability to osmoregulate by the estuarine marsh turtles may be explained by their reduced feeding and drinking in elevated salinities that was not exhibited by the freshwater creek population. However, due to mass loss in both populations, physiological and behavioural responses exhibited by estuarine marsh turtles may only be effective adaptations for short-term exposures to elevated salinities, such as those from tides and when traversing saline habitats, and are unlikely to be effective for long-term exposure to elevated salinity as is expected under sea-level rise

Origin of Complexity in Hemoglobin Evolution

Most proteins associate into multimeric complexes with specific architectures, which often have functional properties such as cooperative ligand binding or allosteric regulation. No detailed knowledge is available about how any multimer and its functions arose during evolution. Here we use ancestral protein reconstruction and biophysical assays to elucidate the origins of vertebrate hemoglobin, a heterotetramer of paralogous α- and β-subunits that mediates respiratory oxygen transport and exchange by cooperatively binding oxygen with moderate affinity. We show that modern hemoglobin evolved from an ancient monomer and characterize the historical “missing link” through which the modern tetramer evolved—a noncooperative homodimer with high oxygen affinity that existed before the gene duplication that generated distinct α- and β-subunits. Reintroducing just two post-duplication historical substitutions into the ancestral protein is sufficient to cause strong tetramerization by creating favorable contacts with more ancient residues on the opposing subunit. These surface substitutions markedly reduce oxygen affinity and even confer cooperativity because an ancient linkage between the oxygen binding site and the multimerization interface was already an intrinsic feature of the protein’s structure. Our findings establish that evolution can produce new complex molecular structures and functions via simple genetic mechanisms that recruit existing biophysical features into higher-level architectures. The interfaces that hold molecular complexes together typically involve sterically tight, electrostatically complementary interactions among many amino acids. Similarly, allostery and cooperativity usually depend on numerous residues that connect surfaces to active sites. The acquisition of such complicated machinery would seem to require elaborate evolutionary pathways. The classical explanation of this process, by analogy to the evolution of morphological complexity, is that multimerization conferred or enhanced beneficial functions, allowing selection to drive the many substitutions required to build and optimize new interfaces. Whether this account accurately describes the evolution of any natural molecular complex requires a detailed reconstruction of the historical steps by which it evolved. Hemoglobin (Hb) is a useful model for this purpose, because the structural mechanisms that mediate its multimeric assembly, cooperative oxygen binding, and allosteric regulation are well established. Moreover, its subunits descend by duplication and divergence from the same ancestral proteins, so their history can be reconstructed in a single analysis. Despite considerable speculation, virtually nothing is known about the evolutionary origin of Hb’s heterotetrameric architecture and the functions that depend on it

Demystifying incentives in the consensus computer

Cryptocurrencies like Bitcoin and the more recent Ethereum system allow users to specify scripts in transactions and contracts to support applications beyond simple cash transactions. In this work, we analyze the extent to which these systems can enforce the correct semantics of scripts. We show that when a script execution requires nontrivial computation effort, practical attacks exist which either waste miners\u27 computational resources or lead miners to accept incorrect script results. These attacks drive miners to an ill-fated choice, which we call the {\em verifier\u27s dilemma}, whereby rational miners are well-incentivized to accept unvalidated blockchains. We call the framework of computation through a scriptable cryptocurrency a consensus computer and develop a model that captures incentives for verifying computation in it. We propose a resolution to the verifier\u27s dilemma which incentivizes correct execution of certain applications, including outsourced computation, where scripts require minimal time to verify. Finally we discuss two distinct, practical implementations of our consensus computer in real cryptocurrency networks like Ethereum