Suchergebnisse

Funding: We would like to thank our group for critical reading of the manuscript. This work was supported by Fundação para a Ciência e a Tecnologia (FCT) through projects EXPL/BEXBCM/0379/2013 and PTDC/BIA-CEL/29765/2017. H.M. was supported by a PhD fellowship from FCT (PD/BD/114118/2015), and D.C.B. by the FCT Investigator Program (IF/00501/2014/CP1252/ CT0001). This article is supported by the LYSOCIL project. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 811087. ; The mechanisms by which the pigment melanin is transferred from melanocytes and processed within keratinocytes to achieve skin pigmentation remain ill-characterized. Nevertheless, several models have emerged in the past decades to explain the transfer process. Here, we review the proposed models for melanin transfer in the skin epidermis, the available evidence supporting each one, and the recent observations in favor of the exo/phagocytosis and shed vesicles models. In order to reconcile the transfer models, we propose that different mechanisms could co-exist to sustain skin pigmentation under different conditions. We also discuss the limited knowledge about melanin processing within keratinocytes. Finally, we pinpoint new questions that ought to be addressed to solve the long-lasting quest for the understanding of how basal skin pigmentation is controlled. This knowledge will allow the emergence of new strategies to treat pigmentary disorders that cause a significant socio-economic burden to patients and healthcare systems worldwide and could also have relevant cosmetic applications. ; publishersversion ; published

Funding: This study was supported by Fundaçã o para a Ciência e Tecnologia (FCT): C.E. was supported by a post-doctoral fellowship (SFRH/BPD/78491/2011), L.B.-L. by a PhD fellowship (SFRH/BD/131938/2017) and D.C.B. by the FCT Investigator Program (IF/00501/2014/CP1252/CT0001). This work was developed with the support from the research infrastructure PPBI-POCI-01-0145-FEDER-022122, co-financed by FCT (Portugal) and Lisboa2020, under the PORTUGAL2020 agreement (European Regional Development Fund). This article was supported by the LYSOCIL project. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 811087. Deposited in PMC for immediate release. ; Lysosomes are dynamic organelles, capable of undergoing exocytosis. This process is crucial for several cellular functions, namely plasma membrane repair. Nevertheless, the molecular machinery involved in this process is poorly understood. Here, we identify Rab11a and Rab11b as regulators of calcium-induced lysosome exocytosis. Interestingly, Rab11-positive vesicles transiently interact with lysosomes at the cell periphery, indicating that this interaction is required for the last steps of lysosome exocytosis. Additionally, we found that the silencing of the exocyst subunit Sec15, a Rab11 effector, impairs lysosome exocytosis, suggesting that Sec15 acts together with Rab11 in the regulation of lysosome exocytosis. Furthermore, we show that Rab11 binds the guanine nucleotide exchange factor for Rab3a (GRAB) and also Rab3a, which we described previously as a regulator of the positioning and exocytosis of lysosomes. Thus, our study identifies new players required for lysosome exocytosis and suggest the existence of a Rab11-Rab3a cascade involved in this process. ; publishersversion ; published

Funding: The authors would like to thank the scientific and technical assistance from the CEDOC Cell Culture, Flow Cytometry and Microscopy facilities. We also thank the Electron Microscopy Facility of Instituto Gulbenkian de Ciência for technical assistance. The authors also thank Dorothy Bennett and Elena Sviderskaya (St. George's University of London, UK), Susana Lopes (CEDOC, NOVA Medical School) and Paulo Matos (National Health Institute Doutor Ricardo Jorge, Portugal) for the kind gift of reagents and Paulo Matos also for expert advice. This article was supported by the LYSOCIL project. This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 811087. This article was also supported by Fundaçao para a Ciência e a Tecnologia ˜ (FCT), Portugal through grant PTDC/BIA-CEL/29765/2017, PhD fellowships to HM, MVN, LBL and LCC (PD/BD/114118/2015, PD/BD/137442/2018, SFRH/BD/131938/2017 and 2020.8812.BD, respectively), the FCT Investigator Program to DCB (IF/00501/2014/ CP1252/CT0001), and FCT Unit iNOVA4Health – UIDB/04462/2020 and UIDP/04462/2020, a programme financially supported by FCT / Ministério da Ciência, Tecnologia e Ensino Superior, through national funds. ; In the skin epidermis, melanin is produced and stored within melanosomes in melanocytes, and then transferred to keratinocytes. Different models have been proposed to explain the melanin transfer mechanism, which differ essentially in how melanin is transferred - either in a membrane-bound melanosome or as a melanosome core, i.e., melanocore. Here, we investigated the endocytic route followed by melanocores and melanosomes during internalization by keratinocytes, by comparing the uptake of melanocores isolated from the supernatant of melanocyte cultures, with melanosomes isolated from melanocytes. We show that inhibition of actin dynamics impairs the uptake of both melanocores and melanosomes. Moreover, depletion of critical proteins involved in actin-dependent uptake mechanisms, ...

8021-00425B) to JSA, by a postdoctoral fellowship from FCT (SFRH/BPD/32323/2006) to CS and by iNOVA4Health—UID/Multi/ 04462/2013, a program financially supported by FCT/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement. This article is supported by the LYSOCIL project. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 811087. ; Rab and Arl guanine nucleotide-binding (G) proteins regulate trafficking pathways essential for the formation, function and composition of primary cilia, which are sensory devices associated with Sonic hedgehog (Shh) signalling and ciliopathies. Here, using mammalian cells and zebrafish, we uncover ciliary functions for Rab35, a multitasking G protein with endocytic recycling, actin remodelling and cytokinesis roles. Rab35 loss via siRNAs, morpholinos or knockout reduces cilium length in mammalian cells and the zebrafish left-right organiser (Kupffer's vesicle) and causes motile cilia-associated left-right asymmetry defects. Consistent with these observations, GFP-Rab35 localises to cilia, as do GEF (DENND1B) and GAP (TBC1D10A) Rab35 regulators, which also regulate ciliary length and Rab35 ciliary localisation. Mammalian Rab35 also controls the ciliary membrane levels of Shh signalling regulators, promoting ciliary targeting of Smoothened, limiting ciliary accumulation of Arl13b and the inositol polyphosphate 5-phosphatase (INPP5E). Rab35 additionally regulates ciliary PI(4,5)P2 levels and interacts with Arl13b. Together, our findings demonstrate roles for Rab35 in regulating cilium length, function and membrane composition and implicate Rab35 in pathways controlling the ciliary levels of Shh signal regulators. ; publishersversion ; published

Spanish Ministry of Economy and Competitiveness [CSD2008-00077, CTM2016-78853-R]; European Union, Horizon 2020 [817806, 817578]

Funding: We thank Liliana Bento for valuable assistance in formatting the manuscript. This article was supported by the LYSOCIL project. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 811087. CGA has funding from Maratona da Saúde 2016 and Fundaçao para a Ciência e a Tecnologia ˜ , I.P. (CEECIND/00410/2017). FMP is a Wellcome Investigator in Science and a Royal Society Wilson merit award holder. ; Since the discovery of lysosomes more than 70 years ago, much has been learned about the functions of these organelles. Lysosomes were regarded as exclusively degradative organelles, but more recent research has revealed that they play essential roles in several other cellular functions, such as nutrient sensing, intracellular signalling, and metabolism. Methodological advances played a key part in generating our current knowledge about the biology of this multifaceted organelle. In this review, we cover current methods used to analyse lysosome morphology, positioning, motility, and function. We highlight the principles behind these methods, the methodological strategies, and their advantages and limitations. To extract accurate information and avoid misinterpretations, we discuss the best strategies to identify lysosomes and assess their characteristics and functions. With this review, we aim to stimulate an increase in the quantity and quality of research on lysosomes and further ground-breaking discoveries on an organelle that continues to surprise and excite cell biologists. ; publishersversion ; published

Telemetry is a key, widely used tool to understand marine megafauna distribution, habitat use, behavior, and physiology; however, a critical question remains: "How many animals should be tracked to acquire meaningful data sets?" This question has wide-ranging implications including considerations of statistical power, animal ethics, logistics, and cost. While power analyses can inform sample sizes needed for statistical significance, they require some initial data inputs that are often unavailable. To inform the planning of telemetry and biologging studies of marine megafauna where few or no data are available or where resources are limited, we reviewed the types of information that have been obtained in previously published studies using different sample sizes. We considered sample sizes from one to >100 individuals and synthesized empirical findings, detailing the information that can be gathered with increasing sample sizes. We complement this review with simulations, using real data, to show the impact of sample size when trying to address various research questions in movement ecology of marine megafauna. We also highlight the value of collaborative, synthetic studies to enhance sample sizes and broaden the range, scale, and scope of questions that can be answered. ; A. M. M. Sequeira was supported by an ARC Grant (DE170100841), and the Australian Institute of Marine Science, G.C. Hays by the Bertarelli Foundation as part of the Bertarelli Programme in Marine Science, and H. J. Calich by an Australian Government RTP scholarship at UWA. Workshop funding was granted to M. Thums, A. M. M. Sequeira, and C. M. Duarte by the UWA Oceans Institute, the Australian Institute of Marine Science, and the Office of Sponsored Research at King Abdullah University of Science and Technology (KAUST).

Marine plastic pollution is worse than expected, and we are starting to realize its full extent and severity. Solving the plastic pollution problem is not easy, as it requires the action and commitment of all sectors of our society. With a coastline extending over 4,000 km (from 18 degrees S to 56 degrees S), Chile is a maritime country, and since plastics are potentially harmful for marine and coastal ecosystems, food security, and public health, plastic pollution is a real threat. Chile is the sixth-largest exporter of seafood (fish, invertebrates, and algae) in the world, but the extent of plastic contamination of marine organisms, its potential effects on commercial species and aquaculture, and its subsequent effects on human health are mostly unknown. Chile has recently introduced some legislation to prevent plastics from reaching the environment and the coastal ocean. Governmental and non-governmental organizations have joined an informal alliance to take action against plastic pollution, both at a national and regional level, but stronger involvement of producers and commerce is required for effective measures. Chilean scientists working on plastic pollution have created the Scientific Plastic Pollution Alliance of Chile network, aiming to promote collaborative and coordinated research focused on this pollutant. The wide geographical extent of Chile, with researchers working in diverse ecosystems, provides a unique opportunity to better understand the consequences of one of the most recent and severe threats to biodiversity. Rather than solely presenting the plastic pollution problem from the scientific perspective, this paper includes views from different sectors of society. Mitigating plastic pollution is exceptionally complex, with this study highlighting the importance of local engagement, media, solving social inequities, new legislation, and law enforcement in order to advance on decreasing plastic pollution from a country-wide perspective.

Biotechnological drugs have become a fundamental resource for the treatment of rheumatic patients. Patent expiry of some of these drugs created the opportunity for biopharmaceutical manufacturers to develop biosimilar drugs intended to be as efficacious as the originator product but with a lower cost to healthcare systems. Due to the complex manufacturing process and highly intricate structure of biologicals, a biosimilar can never be an exact copy of its reference product. Consequently, regulatory authorities issued strict preclinical and clinical guidelines to ensure safety and efficacy equivalence and, in September 2013, the biosimilar of infliximab was the first biosimilar monoclonal antibody to be authorized for use in the European Union. The current document is a position statement of the "Sociedade Portuguesa de Reumatologia" (Portuguese Society of Rheumatology) on the use of biosimilar drugs in rheumatic diseases. Two systematic literature reviews were performed, one concerning clinical trials and the other one concerning international position papers on biosimilars. The results were presented and discussed in a national meeting and a final position document was discussed, written and approved by Portuguese rheumatologists. Briefly, this position statement is contrary to automatic substitution of the originator by the biosimilar, defends either a different INN or the prescription by brand name, supports that switching between biosimilars and the originator molecule should be done after at least 6 months of treatment and based on the attending physician decision and after adequate patient information, recommends the registration of all biosimilar treated patients in Reuma.pt for efficacy, safety and immunogenicity surveillance, following the strategy already ongoing for originators, and opposes to extrapolation of indications approved to the originator to completely different diseases and/or age groups without adequate pre-clinical, safety or efficacy data. ; info:eu-repo/semantics/publishedVersion

We summarize some of the past year's most important findings within climate change-related research. New research has improved our understanding about the remaining options to achieve the Paris Agreement goals, through overcoming political barriers to carbon pricing, taking into account non-CO2 factors, a well-designed implementation of demand-side and nature-based solutions, resilience building of ecosystems and the recognition that climate change mitigation costs can be justified by benefits to the health of humans and nature alone. We consider new insights about what to expect if we fail to include a new dimension of fire extremes and the prospect of cascading climate tipping elements. Technical summary. A synthesis is made of 10 topics within cli- mate research, where there have been significant advances since January 2020. The insights are based on input from an inter- national open call with broad disciplinary scope. Findings include: (1) the options to still keep global warming below 1.5 °C; (2) the impact of non-CO2 factors in global warming; (3) a new dimension of fire extremes forced by climate change; (4) the increasing pressure on interconnected climate tipping elements; (5) the dimensions of climate justice; (6) political chal- lenges impeding the effectiveness of carbon pricing; (7) demand- side solutions as vehicles of climate mitigation; (8) the potentials and caveats of nature-based solutions; (9) how building resili- ence of marine ecosystems is possible; and (10) that the costs of climate change mitigation policies can be more than justified by the benefits to the health of humans and nature. Social media summary. How do we limit global warming to 1.5 °C and why is it crucial? See highlights of latest climate science.

Background: The COVID-19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 weeks of peak disruption due to COVID-19. Methods: A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β-regression model was used to estimate 12-week cancellation rates for 190 countries. Elective surgical case-mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country-level surgical volumes. The 12-week cancellation rates were then applied to these figures to calculate the total number of cancelled operations. Results: The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID-19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12-week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID-19 disruption. Conclusion: A very large number of operations will be cancelled or postponed owing to disruption caused by COVID-19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely.