Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis

Healthy living on a healthy planet - Summary

Unsere Lebensweise macht krank und zerstört die natürlichen Lebensgrundlagen. In der Vision „Gesund leben auf einer gesunden Erde“ werden menschliche Lebensbereiche – Ernähren, Bewegen, Wohnen – gesund und umweltverträglich gestaltet sowie planetare Risiken – Klimawandel, Biodiversitätsverlust, Verschmutzung – bewältigt. Gesundheitssysteme nutzen ihre transformativen Potenziale, Bildung und Wissenschaft befördern gesellschaftliche Veränderungen. Die Vision ist nur mit internationaler Kooperation realisierbar und erfordert eine globale Dringlichkeitsgovernance.Our lifestyle is making us ill and is destroying the natural life-support systems. In the vision of ‘healthy living on a healthy planet’, human spheres of life – what we eat, how we move, where we live – are designed to be both healthy and environmentally compatible, and planetary risks – climate change, biodiversity loss, pollution – have been overcome. Health systems harness their transformative potential; education and science promote societal change. The vision can only be realized with international cooperation and requires what the WBGU terms global urgency governance

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Examiner

The goal of this thesis was to evaluate alternatives to the Wawo face recog nition (fr) library, used by the company CodeMill AB in an application for video-based fr, implemented as a plugin to the media asset management sys tem Vidispine. The aim was to improve the fr performance of the application, and the report tried to compare the performance of recent versions of Open Source Biometrics Recognition (OpenBR) and Open Source Computer Vision (OpenCV) to Wawo. For comparison of the fr systems, roc curves and area under roc curves (auc) metrics were used. Two di erent test videos were used: one simpler shot with webcam and one excerpt from a tv music show. The results are somewhat inconclusive; the Wawo system had technical di culties with the biggest test case. However, it performed better than OpenBR in the two other cases (comparing auc values), which leads to the conclusion that Wawo would have outperformed the other systems for all test cases if it had worked. Finally

Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells

The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2-deficient cells. In contrast, here we show that inhibiting ROCK in BRCA2-deficient cells triggers SL independently from acute replication stress. Such SL is preceded by polyploidy and binucleation resulting from cytokinesis failure. Such initial mitosis abnormalities are followed by other M-phase defects, including anaphase bridges and abnormal mitotic figures associated with multipolar spindles, supernumerary centrosomes and multinucleation. SL was also triggered by inhibiting Citron Rho-interacting kinase, another enzyme that, similarly to ROCK, regulates cytokinesis. Together, these observations demonstrate that cytokinesis failure triggers mitotic abnormalities and SL in BRCA2-deficient cells. Furthermore, the prevention of mitotic entry by depletion of Early mitotic inhibitor 1 (EMI1) augmented the survival of BRCA2-deficient cells treated with ROCK inhibitors, thus reinforcing the association between M-phase and cell death in BRCA2-deficient cells. This novel SL differs from the one triggered by PARPi and uncovers mitosis as an Achilles heel of BRCA2-deficient cells.Fil: Siri, Sebastian Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Martino, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Calzetta, Nicolás Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Paviolo, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Garro, Cintia Araceli. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Pansa, Maria Florencia. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Carbajosa González, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Brown, Aaron C.. Maine Medical Center Research Institute; Estados UnidosFil: Bocco, Jose Luis. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gloger, Israel. GlaxoSmithKline-Trust in Science; Estados UnidosFil: Drewes, Gerard. GlaxoSmithKline-Trust in Science; Estados UnidosFil: Madauss, Kevin P.. GlaxoSmithKline-Trust in Science; Estados UnidosFil: Soria, Gastón. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

See (n)One, Do (n)One, Teach (n)One: Reality of Surgical Resident Training in Germany

Introduction!#!Due to technological changes, working time restrictions and the creation of specialized centers, surgical training has changed. A competence-based learning technique of surgical skills is the sub-step practice approach, which has been proven important in nationwide opinion surveys. The aim of this prospective multi-center trial was to determine the status quo of the sub-step concept in Germany.!##!Methods!#!Over 6 months, the voluntarily participating centers evaluated the following index procedures: laparoscopic cholecystectomy (LCHE), laparoscopic and open sigmoid resection, minimally invasive inguinal hernia repair, thyroid resection and pylorus-preserving pancreaticoduodenectomy (PPPD). Patients with private insurance were excluded. The detailed sub-steps were documented as well as the reason why these were not performed. In addition, an online survey regarding the sub-step concept was performed before and after the study.!##!Results!#!In total, 21 centers included 2969 surgical procedures in 2018 for final analyses. While 24.4% of the procedures were performed by residents, sub-steps were performed in 22.2%. LCHE was most often performed completely by residents (43.3%), and PPPD revealed the highest rate of performed sub-steps (43.3%). Reasons for not assisting sub-steps to residents were often organizational and other reasons. After an initial increase, the number of performed sub-steps decreased significantly during the second half of the survey. The opinion survey revealed a high importance of the sub-step concept. The number of resident procedures was overestimated, and the number of performed sub-steps was underestimated. After the study, these estimations were more realistic.!##!Conclusion!#!Even though the sub-step practice concept is considered highly important for surgical education, it needs to be put into practice more consequently. The current data suggest a low participation of surgical residents in the operating room, although the participating hospitals are most likely highly interested in surgical education, hence their voluntary participation. Conceptual changes and a control of surgical education are needed