Traditional and Modern Biomedical Prospecting: Part I—the History: Sustainable Exploitation of Biodiversity (Sponges and Invertebrates) in the Adriatic Sea in Rovinj (Croatia)

Nature, especially the marine environment, provides the most effective drugs used in human therapy. Among the metazoans, the marine sponges (phylum Porifera), which are sessile filter feeders, produce the most potent and highly selective bioactive secondary metabolites. These animals (or their associated symbiotic microorganisms) synthesize secondary metabolites whose activity and selectivity has developed during their long evolutionary history (evochemistry). The exploitation of these resources has become possible due to the progress in molecular and cell biology. BIOTECmarin, the German Center of Excellence follows this rationale. In the past, these animals have been successfully and extensively utilized to isolate bioactive compounds and biomaterials for human benefit. Pharmaceuticals prepared from marine animals, primarily sponges, have been applied since ancient times (Hippocrates, Aristotle and later Plinius). It has been reported that extracts and/or components from sponges can be used for the treatment of specific diseases. For a systematic and applied-oriented exploitation, the successful development of effective compounds largely depends on quality of the institutional infrastructure of marine stations and more so on the biodiversity. The Center for Marine Research in Rovinj (Croatia) fulfils these prerequisites. Founded in 1891, this institute has to its credit major discoveries related to exploitation of secondary metabolites/biomaterials from sponges for therapeutical application and to obtain biomaterials for general wellbeing. This is the first part of a review focusing on biomedical prospecting. Here, we have mainly described the historic background. The details of techniques, substances, approaches and outlooks will be discussed in the second part

Traditional and Modern Biomedical Prospecting: Part II—the Benefits: Approaches for a Sustainable Exploitation of Biodiversity (Secondary Metabolites and Biomaterials from Sponges)

The progress in molecular and cell biology has enabled a rational exploitation of the natural resources of the secondary metabolites and biomaterials from sponges (phylum Porifera). It could be established that these natural substances are superior for biomedical application to those obtained by the traditional combinatorial chemical approach. It is now established that the basic structural and functional elements are highly conserved from sponges to the crown taxa within the Protostomia (Drosophila melanogaster and Caenorhabditis elegans) and Deuterostomia (human); therefore, it is obvious that the molecular etiology of diseases within the metazoan animals have a common basis. Hence, the major challenge for scientists studying natural product chemistry is to elucidate the target(s) of a given secondary metabolite, which is per se highly active and selective. After this step, the potential clinical application can be approached. The potential value of some selected secondary metabolites, all obtained from sponges and their associated microorganisms, is highlighted. Examples of compounds that are already in medical use (inhibition of tumor/virus growth [arabinofuranosyl cytosine and arabinofuranosyl adenine]), or are being considered as lead structures (acting as cytostatic and anti-inflammatory secondary metabolites [avarol/avarone], causing induction of apoptosis [sorbicillactone]) or as prototypes for the interference with metabolic pathways common in organisms ranging from sponges to humans (modulation of pathways activated by fungal components [aeroplysinin], inhibition of angiogenesis [2-methylthio-1,4-napthoquinone], immune modulating activity [FK506]) are discussed in this study. In addition, bioactive proteins from sponges are listed (antibacterial activity [pore-forming protein and tachylectin]). Finally, it is outlined that the skeletal elements—the spicules—serve as blueprints for new biomaterials, especially those based on biosilica, which might be applied in biomedicine. These compounds and biomaterials have been isolated/studied by members of the German Center of Excellence BIOTECmarin. The goal for the future is to successfully introduce some of these compounds in the treatment of human diseases in order to raise the public awareness on the richness and diversity of natural products, which should be sustainably exploited for human benefit

Salience-based selection: attentional capture by distractors less salient than the target

Current accounts of attentional capture predict the most salient stimulus to be invariably selected first. However, existing salience and visual search models assume noise in the map computation or selection process. Consequently, they predict the first selection to be stochastically dependent on salience, implying that attention could even be captured first by the second most salient (instead of the most salient) stimulus in the field. Yet, capture by less salient distractors has not been reported and salience-based selection accounts claim that the distractor has to be more salient in order to capture attention. We tested this prediction using an empirical and modeling approach of the visual search distractor paradigm. For the empirical part, we manipulated salience of target and distractor parametrically and measured reaction time interference when a distractor was present compared to absent. Reaction time interference was strongly correlated with distractor salience relative to the target. Moreover, even distractors less salient than the target captured attention, as measured by reaction time interference and oculomotor capture. In the modeling part, we simulated first selection in the distractor paradigm using behavioral measures of salience and considering the time course of selection including noise. We were able to replicate the result pattern we obtained in the empirical part. We conclude that each salience value follows a specific selection time distribution and attentional capture occurs when the selection time distributions of target and distractor overlap. Hence, selection is stochastic in nature and attentional capture occurs with a certain probability depending on relative salience

On numerical relativistic hydrodynamics and barotropic equations of state

The characteristic formulation of the relativistic hydrodynamic equations (Donat et al 1998 J. Comput. Phys. 146 58), which has been implemented in many relativistic hydro-codes that make use of Godunov-type methods, has to be slightly modified in the case of evolving barotropic flows. For a barotropic equation of state, a removable singularity appears in one of the eigenvectors. The singularity can be avoided by means of a simple renormalization which makes the system of eigenvectors well defined and complete. An alternative strategy for the particular case of barotropic flows is discussed.Comment: 7 pages, no figures. Accepted for publication in Class. Quantum Gra

International Consensus Conference for Advanced Breast Cancer, Lisbon 2019: ABC5 Consensus – Assessment by a German Group of Experts

The 5th International Consensus Conference for Advanced Breast Cancer (ABC5) took place on November 14–16, 2019, in Lisbon, Portugal. Its aim is to standardize the treatment of advanced breast cancer based on the available evidence and to ensure that all breast cancer patients worldwide receive adequate treatment and access to new therapies. This year, the conference focused on developments and study results in the treatment of patients with hormone receptor-positive/HER2-negative breast cancer as well as precision medicine. As in previous years, patient advocates from around the world were integrated into the ABC conference and had seats on the ABC consensus panel. In the present paper, a working group of German breast cancer experts comments on the results of the on-site ABC5 consensus votes by ABC panelists regarding their applicability for routine treatment in Germany. These comments take the recommendations of the Breast Committee of the Gynecological Oncology Working Group (Arbeitsgemeinschaft Gynäkologische Onkologie; AGO) into account. The report and assessment presented here pertain to the preliminary results of the ABC5 consensus. The final version of the statements will be published in Annals of Oncology and The Breast

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency < 0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency < 0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology

Suillus luteus methanolic extract inhibits cell growth and proliferation of a colon cancer cell line

Several edible mushrooms extracts are known to have tumor cell growth inhibitory potential. The objective of this work was to study this potential in extracts of Suillus luteus collected from the Northeast of Portugal. Various extracts were prepared and their effect on tumor cell growth was studied with the SRB assay in four human tumor cell lines: MCF-7 (breast), NCI-H460 (non-small cell lung cancer), AGS (gastric) and HCT-15 (colon). The methanolic extract of S. luteus was the most potent extract. This extract was slightly more potent in the HCT-15 cells (with mutant p53, GI(50) = 17.8 +/- 1.6 mu g/mL) than in the other cell lines tested, which suggested that its effect was not p53-dependent. Indeed, in HCT-15 cells, an increase in the levels of p53 was detected but no alterations in some of the proteins transactivated by p53 (e.g. p21 or Box) were found. The extract caused an increase in the cellular levels of p-H2A.X, which is suggestive of DNA damage. Growth inhibition in these cells was mostly due to inhibition of cell proliferation and an increase in the % of cell in the G1 phase of the cell cycle. An increase in cell death was also found, even though to very low levels. In addition, this extract was not cytotoxic to primary cultures of porcine hepatocytes (GI(50) > 400 mu g/mL). Together, these results indicate that the S. luteus methanolic extract may be an interesting source of compounds that inhibit the proliferation of tumor cells but further studies should be carried out in order to understand its potential.The authors are grateful to Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) and COMPETE/QREN/EU for the financial support to this work (research project PTDC/AGR-ALI/110062/2009) and to CIMO (strategic project PEst-OE/AGR/U10690/2011). They also thank the University of Porto and Santander Totta for financial support. J.A. Vaz thanks FCT, POPH-QREN and FSE for her grant (BD/43653/2008). G.M. Almeida is supported by FCT and the European Social Fund. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT