A conserved regulatory program drives emergence of the lateral plate mesoderm

Cardiovascular cell lineages emerge with kidney, smooth muscle, and limb skeleton progenitors from the lateral plate mesoderm (LPM). How the LPM emerges during development and how it has evolved to form key lineages of the vertebrate body plan remain unknown. Here, we captured LPM formation by transgenic in toto imaging and lineage tracing using the first pan-LPM enhancer element from the zebrafish gene draculin (drl). drl LPM enhancer-based reporters are specifically active in LPM-corresponding territories of several chordate species, uncovering a universal LPM-specific gene program. Distinct from other mesoderm, we identified EomesA, FoxH1, and MixL1 with BMP/Nodal-controlled Smad activity as minimally required factors to drive drl-marked LPM formation. Altogether, our work provides a developmental and mechanistic framework for LPM emergence and the in vitro differentiation of cardiovascular cell types. Our findings suggest that the LPM may represent an ancient cell fate domain that predates ancestral vertebrates

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

Aronia melanocarpa juice induces a redox-sensitive p73-related caspase 3-dependent apoptosis in human leukemia cells

Polyphenols are natural compounds widely present in fruits and vegetables, which have antimutagenic and anticancer properties. The aim of the present study was to determine the anticancer effect of a polyphenol-rich Aronia melanocarpa juice (AMJ) containing 7.15 g/L of polyphenols in the acute lymphoblastic leukemia Jurkat cell line, and, if so, to clarify the underlying mechanism and to identify the active polyphenols involved. AMJ inhibited cell proliferation, which was associated with cell cycle arrest in G(2)/M phase, and caused the induction of apoptosis. These effects were associated with an upregulation of the expression of tumor suppressor p73 and active caspase 3, and a downregulation of the expression of cyclin B1 and the epigenetic integrator UHRF1. AMJ significantly increased the formation of reactive oxygen species (ROS), decreased the mitochondrial membrane potential and caused the release of cytochrome c into the cytoplasm. Treatment with intracellular ROS scavengers prevented the AMJ-induced apoptosis and upregulation of the expression of p73 and active caspase 3. The fractionation of the AMJ and the use of identified isolated compounds indicated that the anticancer activity was associated predominantly with chlorogenic acids, some cyanidin glycosides, and derivatives of quercetin. AMJ treatment also induced apoptosis of different human lymphoblastic leukemia cells (HSB-2, Molt-4 and CCRF-CEM). In addition, AMJ exerted a strong pro-apoptotic effect in human primary lymphoblastic leukemia cells but not in human normal primary T-lymphocytes. Thus, the present findings indicate that AMJ exhibits strong anticancer activity through a redox-sensitive mechanism in the p53-deficient Jurkat cells and that this effect involves several types of polyphenols. They further suggest that AMJ has chemotherapeutic properties against acute lymphoblastic leukemia by selectively targeting lymphoblast-derived tumor cells

The force of the sign. Terrorism as a symbolic phenomenon

Seit der radikalen Änderung der weltpolitischen Lage durch das Selbstmordattentat islamistischer Terroristen auf die Supermacht U.S.A. am 11.9.01 versucht die Weltöffentlichkeit, dem Phänomen des Terrorismus durch die verschiedensten Erklärungsstrategien Herr zu werden. Man führt den Kampf der Kulturen oder Religionen an, verweist auf die Ausbeutung der Peripherie des kapitalistischen Weltsystems durch den Hegemon U.S.A. oder pathologisiert bzw. dämonisiert die Taten der Terroristen. Uns scheinen diese Erklärungsstrategien den Machtkonstellationen der postmodernen Gesellschaften nicht gerecht zu werden, da sie ein zentrales soziales Phänomen der vergangenen Jahrzehnte nicht beachten: das Unbehagen an der pluralistischen Gesellschaft und der konsensuell-repräsentativen Demokratie. Um dieses Unbehagen angemessen beschreiben zu können, wollen wir uns ihm aus einer zeichentheoretischen Perspektive nähern, die soziale Formationen nicht durch (kooperative) Arbeit determiniert sieht, sondern durch die Instanz des Codes. Für Jean Baudrillard ist die Wahl des Ziels der beiden Türme bedeutend, die sich wechselseitig reflektieren und das System nach allen Seiten hin abschließen. Mit ihnen wurde das neuralgische Zentrum des Systems getroffen, das sich auf einem binären Code gründet. Die Twintowers bedeuteten nicht nur das Ende jedweder originalen Referenz, sondern auch den Abschluss des Bezeichneten durch die Wiederholung des Zeichens. Der Code führt eine symbolische Verteilung der gesellschaftlichen Körper durch und zielt auf eine möglichst genaue Übereinstimmung der Gemeinschaft mit sich selbst gemäß eines arithmetischen und geometrischen Kalküls. Die integrative Kraft dieses auf dem Identitätsprinzip basierenden Systems scheint immer häufiger nicht mehr in der Lage zu sein, das negative Potential antagonistischer Strategien binden zu können, die in Form von zivilem Ungehorsam, Politik von Minoritäten oder terroristischen Akten die symbolische Ordnung der westlichen Gesellschaften unterhöhlen. In diesem Tagungsband diskutieren wir das Ausmaß der Krise der konsensuellen Demokratie und ihrer Institutionen. Die Aufsätze behandeln folgende Themen: • Die Krise der pluralistischen Gesellschaft: Wie verständlich ist das kulturelle, politische und religiöse Unbehagen am westlichen Wertekanon? • Die Funktion der Medien in der konsensuellen Demokratie; die gesellschaftliche Wirkung der medialen Reproduktion terroristischer Akte; das Bild des Terrorismus in der Populärkultur • Ästhetischer Terror: Die Vernichtung von Sinn und Bedeutung in der zeitgenössischen Kunst und Kunsttheorie • Die politische Logik des Terrorismus (Ziele, Bedingungen u. Legitimität des Terrorismus in Abgrenzung zu alternativen politischen Ausdrucksformen wie z.B. dem zivilen Ungehorsam; die Bedeutung des terroristischen Opfertodes) • Geschichte des Terrorismus (speziell der Terrorismus der RAF) • Terror als irrationale Gewalt (der ontologische Status des Terrorismus)Since the radical changes in international politics caused by the suicide attacks on the USA by Islamic terrorists on the 11th of September in 2001, the world public tries to grasp the phenomenon of „Terrorism“ through different explanatory strategies. These include referring to the clash of cultures and of religions, to the exploitation of the periphery by the capitalist system incarnated by the USA, or pathologizing as well as demonizing the deeds of the terrorists. All these explanatory attempts do not seem to do justice to the actual constellations of power in postmodern societies, because they do not take a widespread social phenomenon of the past decades in consideration: the discomfort with the pluralistic society and with the concurrent-representative democracy. In order to describe this discomfort adequately we would like to approach the phenomenon from a semiotic perspective which does not consider social formations as determined by cooperative work but rather by the authority of the code. For Jean Baudrillard the target was meaningful since the two towers not only reflect each other but also completely close the system. With them the neuralgic center which is based upon the binary code was severely hit. The twin towers not only meant the end of every original reference but also the completion of the signified by the reduplication of the sign. The code conducts a symbolic distribution of the social bodies and aims at an as accurate as possible identification of the community with itself corresponding to an arithmetic and geometric calculus. The system which is based upon the principle of identity does not seem to have the ability to integrate antagonist energies properly. So these antagonist powers undermine the symbolic order of western societies in terms of civil disobedience, politics of minorities or terroristic acts. In this conference transcript we discuss the degree of crisis of consensual democracy and ist institutions. The essays cover the following topics: • The crisis of the pluralistic society: How comprehensible and justified is the cultural, political, and religious discomfort with western values? • The function of mass media in democratic systems: What is the impact of the reproduction of terrorist acts on society? How does popular culture deal with terrorism? • Aesthetic terror: the destruction of sense and meaning in contemporary arts and art theory • The political logic of terrorism (aims, legitimacy of terrorism as opposed to other forms of opposition like civil disobedience; the meaning of the terrorist self-sacrifice death) • History of terrorism (e.g. The German terrorism of the RAF) • Terrorism as an irrational power (ontological status of terrorism

A conserved regulatory program drives emergence of the lateral plate mesoderm

Cardiovascular cell lineages emerge with kidney, smooth muscle, and limb skeleton progenitors from the lateral plate mesoderm (LPM). How the LPM emerges during development and how it has evolved to form key lineages of the vertebrate body plan remain unknown. Here, we captured LPM formation by transgenic in toto imaging and lineage tracing using the first pan-LPM enhancer element from the zebrafish gene draculin (drl). drl LPM enhancer-based reporters are specifically active in LPM-corresponding territories of several chordate species, uncovering a universal LPM-specific gene program. Distinct from other mesoderm, we identified EomesA, FoxH1, and MixL1 with BMP/Nodal-controlled Smad activity as minimally required factors to drive drl-marked LPM formation. Altogether, our work provides a developmental and mechanistic framework for LPM emergence and the in vitro differentiation of cardiovascular cell types. Our findings suggest that the LPM may represent an ancient cell fate domain that predates ancestral vertebrates

A conserved regulatory program initiates lateral plate mesoderm emergence across chordates

Cardiovascular lineages develop together with kidney, smooth muscle, and limb connective tissue progenitors from the lateral plate mesoderm (LPM). How the LPM initially emerges and how its downstream fates are molecularly interconnected remain unknown. Here, we isolate a pan-LPM enhancer in the zebrafish-specific draculin (drl) gene that provides specific LPM reporter activity from early gastrulation. In toto live imaging and lineage tracing of drl-based reporters captures the dynamic LPM emergence as lineage-restricted mesendoderm field. The drl pan-LPM enhancer responds to the transcription factors EomesoderminA, FoxH1, and MixL1 that combined with Smad activity drive LPM emergence. We uncover specific activity of zebrafish-derived drl reporters in LPM-corresponding territories of several chordates including chicken, axolotl, lamprey, Ciona, and amphioxus, revealing a universal upstream LPM program. Altogether, our work provides a mechanistic framework for LPM emergence as defined progenitor field, possibly representing an ancient mesodermal cell state that predates the primordial vertebrate embryo

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM (-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors