Tissue separation in Hydra: Involvement of a Rho dependent pathway and the organization of actomyosin complexes during final bud detachment

Tissue separation is an essential process during embryonic development. The underlying mechanism is highly conserved and mostly controlled by apical constriction of cells. It requires a rearrangement of the actin cytoskeleton and the asymmetric establishment of cortical actomyosin complexes. These actomyosin complexes are essential for cell shape changes, morphogenesis, boundary formation and tissue separation. In adult Hydra, morphogenesis is well observable during the asexual budding process. Various receptor systems are involved and FGFR signaling controls bud detachment in which intact epithelia separate from each other without a wound. This morphogenetic process is regulated by bifunctional epitheliomuscle cells which have to ensure movement and morphogenetic processes. The knowledge of intracellular signaling pathways targeting these processes in Hydra was limited and its elucidation is the main subject of my thesis. A candidate signaling pathway through Rho, ROCK and myosin II was identified which controls bud base constriction and therewith also bud detachment. Gene expression analysis confirmed that candidate genes of an FGFR-coupled pathway are expressed in overlapping regions undergoing morphogenesis. In addition, pharmacological inhibition of any component of the pathway prevented bud detachment and led to stable non-detaching, Y-shaped phenotypes. Accompanying bud detachment, a strong accumulation of F-actin in the constricting cells at the bud base was detected which undergo dynamic cell shape changes. In parallel the myosin regulatory light chain (MLC) was phosphorylated (pMLC20) at the late bud base. The MLC signal was detected by gene expression data and antibody staining in all morphogenetic active regions. The pMLC20 antibody revealed the phosphorylated protein in the basal contractile processes of ectodermal epitheliomuscle cells which control body movement as well as the essential constriction of the bud base. Here, pMLC20 was detected in the apical and basolateral compartments of a small cell population. Pharmacological inhibition revealed that MLC phosphorylation occurs in distinct subcellular compartments during movement and morphogenesis and is controlled by at least two independent pathways. During contraction of the basal cell protrusions (movement) MLC is mainly phosphorylated by myosin light chain kinase (MLCK). In contrast, apical and cortical MLC phosphorylation is stimulated via a Rho-ROCK pathway during morphogenesis in constricting cells of the bud base. The present data provide a new, complex picture of the function of epitheliomuscle cells with Rho-dependent phosphorylation of MLC in bud morphogenesis and a housekeeping function fulfilled by MLCK in the normal basal contractility of ectodermal epitheliomuscle cells during body movement

Financing Quality Education for All

In OECD countries the average expenditure on primary and secondary education institutions is about 3.5% of GDP. The investment in education has large implications for economic development and the proper functioning of democratic institutions, as well as overall well-being. However, clear consensus and guidance on which system leads to the best educational outcomes is lacking. This volume describes the resource allocation for compulsory and special needs education for a selection of well-performing countries and regions on PISA tests. By studying the funding systems in well-performing countries and regions the authors identify the elements in the respective funding systems that are associated with best outcomes and have the ideal characteristics to pursue particular goals of education systems such as equity and efficiency. The funding methods of primary and secondary education as well as special needs education are covered

The Rise of Certificate Transparency and Its Implications on the Internet Ecosystem

In this paper, we analyze the evolution of Certificate Transparency (CT) over time and explore the implications of exposing certificate DNS names from the perspective of security and privacy. We find that certificates in CT logs have seen exponential growth. Website support for CT has also constantly increased, with now 33% of established connections supporting CT. With the increasing deployment of CT, there are also concerns of information leakage due to all certificates being visible in CT logs. To understand this threat, we introduce a CT honeypot and show that data from CT logs is being used to identify targets for scanning campaigns only minutes after certificate issuance. We present and evaluate a methodology to learn and validate new subdomains from the vast number of domains extracted from CT logged certificates.Comment: To be published at ACM IMC 201

Packed to the Brim: Investigating the Impact of Highly Responsive Prefixes on Internet-wide Measurement Campaigns

Internet-wide scans are an important tool to evaluate the deployment of services. To enable large-scale application layer scans, a fast, stateless port scan (e.g., using ZMap) is often performed ahead of time to collect responsive targets. It is a common expectation that port scans on the entire IPv4 address space provide a relatively unbiased view as they cover the complete address space. Previous work, however, has found prefixes where all addresses share particular properties. In IPv6, aliased prefixes and fully responsive prefixes, i.e., prefixes where all addresses are responsive, are a well-known phenomenon. However, there is no such in-depth analysis for prefixes with these responsiveness patterns in IPv4. This paper delves into the underlying factors of this phenomenon in the context of IPv4 and evaluates port scans on a total of 161 ports (142 TCP & 19 UDP ports) from three different vantage points. To account for packet loss and other scanning artifacts, we propose the notion of a new category of prefixes, which we call highly responsive prefixes (HRPs). Our findings show that the share of HRPs can make up 70 % of responsive addresses on selected ports. Regarding specific ports, we observe that CDNs contribute to the largest fraction of HRPs on TCP/80 and TCP/443, while TCP proxies emerge as the primary cause of HRPs on other ports. Our analysis also reveals that application layer handshakes to targets outside HRPs are, depending on the chosen service, up to three times more likely to be successful compared to handshakes with targets located in HRPs. To improve future scanning campaigns conducted by the research community, we make our study's data publicly available and provide a tool for detecting HRPs. Furthermore, we propose an approach for a more efficient, ethical, and sustainable application layer target selection

Monitoring der Sustainable Development Goals auf kommunaler Ebene und die Bedeutung von Flächenindikatoren

Nachhaltigkeitsprozesse der Vereinten Nationen haben für Kommunen spätestens seit Verabschiedung der Agenda 21 eine hohe Relevanz. Mit dem SDG 11 und anderen (Unter-)Zielen, die zur nachhaltigen Stadt- und Gemeindeentwicklung beitragen sollen, wurde ihnen explizit eine entscheidende Rolle zugesprochen. Gleichwohl beziehen sich die 17 SDGs, die 169 Unterziele und die zugehörigen Indikatoren zur Erfolgskontrolle der globalen Ziele auf die nationale Ebene und benötigen somit Übertragungs- und Anpassungsleistungen für die kommunale Ebene. Im Rahmen der Arbeitsgruppe „SDG-Indikatoren für Kommunen“ hat das Deutsche Institut für Urbanistik im Auftrag und gemeinsam mit der Bertelsmann Stiftung und den kommunalen Spitzenverbänden (Deutscher Städtetag, Deutscher Städte-und Gemeindebund, Deutscher Landkreistag), dem Bundesinstitut für Bau-, Stadt- und Raumforschung (BBSR), der Servicestelle Kommunen in der Einen Welt (SKEW) und weiteren begleitenden Gremien ein umfassendes Monitoring zum Status quo der SDGs auf kommunaler Ebene erarbeitet. Die inhaltliche Weiterentwicklung des ersten Indikatorenkatalogs von 2018 erfolgte nun auf Basis von Praxis-Erprobungen und umfassenden Evaluationen. Die Bewertung der gesammelten und entwickelten 120 Indikatoren stellte dabei in einigen Themenbereichen wie der Flächennutzung eine Herausforderung dar, die Diskrepanzen der Relevanz von SDGs je nach Perspektive und Ebene offenbaren

Integrated results from the COPERNICUS and GALILEO studies.

OBJECTIVES: To report on the efficacy and safety of intravitreal aflibercept in patients with macular edema secondary to central retinal vein occlusion (CRVO) in an integrated analysis of COPERNICUS and GALILEO. PATIENTS AND METHODS: Patients were randomized to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until week 24. From week 24 to week 52, all intravitreal aflibercept-treated patients in both studies and sham-treated patients in COPERNICUS were eligible to receive intravitreal aflibercept based on prespecified criteria. In GALILEO, sham-treated patients continued to receive sham treatment through week 52. RESULTS: At week 24, mean gain in best-corrected visual acuity and mean reduction in central retinal thickness were greater for intravitreal aflibercept-treated patients compared with sham, consistent with individual trial results. At week 52, after 6 months of intravitreal aflibercept as-needed treatment in COPERNICUS, patients originally randomized to sham group experienced visual and anatomic improvements but did not improve to the extent of those initially treated with intravitreal aflibercept, while the sham group in GALILEO did not improve over week 24 mean best-corrected visual acuity scores. Ocular serious adverse events occurred in CONCLUSION: This analysis of integrated data from COPERNICUS and GALILEO confirmed that intravitreal aflibercept is an effective treatment for macular edema following CRVO

FGFR-ERK signaling is an essential component of tissue separation

AbstractFormation of a constriction and tissue separation between parent and young polyp is a hallmark of the Hydra budding process and controlled by fibroblast growth factor receptor (FGFR) signaling. Appearance of a cluster of cells positive for double phosphorylated ERK (dpERK) at the late separation site indicated that the RAS/MEK/ERK pathway might be a downstream target of the Hydra Kringelchen FGFR. In fact, inhibition of ERK phosphorylation by the MEK inhibitor U0126 reversibly delayed bud detachment and prevented formation of the dpERK-positive cell cluster indicating de novo-phosphorylation of ERK at the late bud base. In functional studies, a dominant-negative Kringelchen FGFR prevented bud detachment as well as appearance of the dpERK-positive cell cluster. Ectopic expression of full length Kringelchen, on the other hand, induced a localized rearrangement of the actin cytoskeleton at sites of constriction, localized ERK-phosphorylation and autotomy of the body column. Our data suggest a model in which (i) the Hydra FGFR targets, via an unknown pathway, the actin cytoskeleton to induce a constriction and (ii) FGFR activates MEK/ERK signaling at the late separation site to allow tissue separation

What lies beneath: Hydra provides cnidarian perspectives into the evolution of FGFR docking proteins

Across the Bilateria, FGF/FGFR signaling is critical for normal development, and in both Drosophila and vertebrates, docking proteins are required to connect activated FGFRs with downstream pathways. While vertebrates use Frs2 to dock FGFR to the RAS/MAPK or PI3K pathways, the unrelated protein, downstream of FGFR (Dof/stumps/heartbroken), fulfills the corresponding function in Drosophila. To better understand the evolution of the signaling pathway downstream of FGFR, the available sequence databases were screened to identify Frs2, Dof, and other key pathway components in phyla that diverged early in animal evolution. While Frs2 homologues were detected only in members of the Bilateria, canonical Dof sequences (containing Dof, ankyrin, and SH2/SH3 domains) were present in cnidarians as well as bilaterians (but not in other animals or holozoans), correlating with the appearance of FGFR. Although these data suggested that Dof coupling might be ancestral, gene expression analysis in the cnidarian Hydra revealed that Dof is not upregulated in the zone of strong FGFRa and FGFRb expression at the bud base, where FGFR signaling controls detachment. In contrast, transcripts encoding other, known elements of FGFR signaling in Bilateria, namely the FGFR adaptors Grb2 and Crkl, which are acting downstream of Dof (and Frs2), as well as the guanyl nucleotide exchange factor Sos, and the tyrosine phosphatase Csw/Shp2, were strongly upregulated at the bud base. Our expression analysis, thus, identified transcriptional upregulation of known elements of FGFR signaling at the Hydra bud base indicating a highly conserved toolkit. Lack of transcriptional Dof upregulation raises the interesting question, whether Hydra FGFR signaling requires either of the docking proteins known from Bilateria

Evaluating the Impact of Intravitreal Aflibercept on Diabetic Retinopathy Progression in the VIVID-DME and VISTA-DME Studies

Purpose To evaluate the impact of intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Tarrytown, NY) versus laser on progression of diabetic retinopathy (DR) severity in Intravitreal Aflibercept Injection in Vision Impairment due to DME (VIVID-DME) and Study of Intravitreal Aflibercept Injection in Patients with Diabetic Macular Edema (VISTA-DME). Design Secondary and exploratory analyses of 2 phase 3, randomized, controlled studies. Participants All patients with a baseline Diabetic Retinopathy Severity Scale (DRSS) score based on fundus photograph (full analysis), patients who progressed to proliferative DR (PDR) (safety analysis) in VIVID-DME (n = 403) and VISTA-DME (n = 459), or both. Methods We randomized patients with diabetic macular edema (DME) to intravitreal aflibercept 2 mg every 4 weeks (2q4), intravitreal aflibercept 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation at baseline and sham injections at every visit. Main Outcome Measures Proportions of patients with 2-step or more and 3-step or more improvements from baseline in DRSS score, who progressed to PDR, and who underwent panretinal photocoagulation (PRP). Results Among patients with an assessable baseline DRSS score, most showed moderately severe or severe nonproliferative DR. The proportions of patients treated with 2q4, 2q8, and laser with a 2-step or more improvement in DRSS score at week 100 were 29.3%, 32.6%, and 8.2%, respectively, in VIVID-DME and 37.0%, 37.1%, and 15.6%, respectively, in VISTA-DME; the proportions with a 3-step or more improvement in DRSS score were 7.3%, 2.3%, and 0%, respectively, and 22.7%, 19.9%, and 5.2%, respectively. Fewer patients in the 2q4 and 2q8 groups versus the laser group progressed to PDR at week 100 in VISTA-DME (1.5% and 2.2% vs. 5.3%) and VIVID-DME (3.2% and 2.0% vs. 12.3%). The proportions of patients who underwent PRP were 2.9%, 0.7%, and 4.5%, respectively, in VIVID-DME and 1.9%, 0.7%, and 5.2%, respectively, in VISTA-DME. The most frequent serious ocular adverse event at week 100 was cataract (pooled intravitreal aflibercept, 1.7% of patients; laser, 3.5% of patients). Conclusions These analyses demonstrate the benefit of intravitreal aflibercept over laser with respect to DR progression, suggesting a benefit on DME, and on underlying DR

Sustainable Development

The emergence of a global and technological world and the accelerating dissemination of technology does not only give rise to technological, economic, social, environmental, political and educational tasks. Significant philosophical questions, epistemic reflections and cultural debates result and have to be pushed forward. To move sustainable development from a political mission statement and scientific challenge into everyday life we have to shift our focus of attention to those who are driving a non-sustainable development: human beings and their societal and cultural conditions and interactions. Ultimately not the ecological footprint is the core challenge, but we and those who are leaving this footprint. The idea of the present volume of Sustainable Development - Relationships to Culture, Knowledge and Ethics was developed in the course of the international conference “Sustainability 2010: The Cultural Dimension”, which took place in July 2010 in Berlin. The aim of this book is to provide discussions about cultural, epistemic and ethical implications of contemporary changes and emerging challenges on an interdisciplinary and international level