Origin and spread of human mitochondrial DNA haplogroup U7

Human mitochondrial DNA haplogroup U is among the initial maternal founders in Southwest Asia and Europe and one that best indicates matrilineal genetic continuity between late Pleistocene hunter-gatherer groups and present-day populations of Europe. While most haplogroup U subclades are older than 30 thousand years, the comparatively recent coalescence time of the extant variation of haplogroup U7 (~16–19 thousand years ago) suggests that its current distribution is the consequence of more recent dispersal events, despite its wide geographical range across Europe, the Near East and South Asia. Here we report 267 new U7 mitogenomes that – analysed alongside 100 published ones – enable us to discern at least two distinct temporal phases of dispersal, both of which most likely emanated from the Near East. The earlier one began prior to the Holocene (~11.5 thousand years ago) towards South Asia, while the later dispersal took place more recently towards Mediterranean Europe during the Neolithic (~8 thousand years ago). These findings imply that the carriers of haplogroup U7 spread to South Asia and Europe before the suggested Bronze Age expansion of Indo-European languages from the Pontic-Caspian Steppe region

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer, studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory, a versatile observatory designed to address the Hot and Energetic Universe science theme, selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), it aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR, browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters. Finally we briefly discuss on the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, and touch on communication and outreach activities, the consortium organisation, and finally on the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. (abridged).Comment: 48 pages, 29 figures, Accepted for publication in Experimental Astronomy with minor editin

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory. Athena is a versatile observatory designed to address the Hot and Energetic Universe science theme, as selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), X-IFU aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over a hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR (i.e. in the course of its preliminary definition phase, so-called B1), browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters, such as the instrument efficiency, spectral resolution, energy scale knowledge, count rate capability, non X-ray background and target of opportunity efficiency. Finally, we briefly discuss the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, touch on communication and outreach activities, the consortium organisation and the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. The X-IFU will be provided by an international consortium led by France, The Netherlands and Italy, with ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Poland, Spain, Switzerland, with additional contributions from the United States and Japan.The French contribution to X-IFU is funded by CNES, CNRS and CEA. This work has been also supported by ASI (Italian Space Agency) through the Contract 2019-27-HH.0, and by the ESA (European Space Agency) Core Technology Program (CTP) Contract No. 4000114932/15/NL/BW and the AREMBES - ESA CTP No.4000116655/16/NL/BW. This publication is part of grant RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. This publication is part of grant RTI2018-096686-B-C21 and PID2020-115325GB-C31 funded by MCIN/AEI/10.13039/501100011033

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr

The Multifaceted Role of Extracellular Vesicles in Glioblastoma: microRNA Nanocarriers for Disease Progression and Gene Therapy

Glioblastoma (GB) is the most aggressive form of brain cancer in adults, characterized by poor survival rates and lack of effective therapies. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally through specific pairing with target messenger RNAs (mRNAs). Extracellular vesicles (EVs), a heterogeneous group of cell-derived vesicles, transport miRNAs, mRNAs and intracellular proteins, and have been shown to promote horizontal malignancy into adjacent tissue, as well as resistance to conventional therapies. Furthermore, GB-derived EVs have distinct miRNA contents and are able to penetrate the blood–brain barrier. Numerous studies have attempted to identify EV-associated miRNA biomarkers in serum/plasma and cerebrospinal fluid, but their collective findings fail to identify reliable biomarkers that can be applied in clinical settings. However, EVs carrying specific miRNAs or miRNA inhibitors have great potential as therapeutic nanotools in GB, and several studies have investigated this possibility on in vitro and in vivo models. In this review, we discuss the role of EVs and their miRNA content in GB progression and resistance to therapy, with emphasis on their potential as diagnostic, prognostic and disease monitoring biomarkers and as nanocarriers for gene therapy

Enhancing the Antioxidant Potential of <i>Weissella confusa</i> PP29 Probiotic Media through Incorporation of <i>Hibiscus sabdariffa</i> L. Anthocyanin Extract

Lactic acid bacteria (LAB) produce important metabolites during fermentation processes, such as exopolysaccharides (EPS), which represent powerful natural antioxidants. On the other hand, H. sabdariffa L. anthocyanin extracts protect LAB and support their development. This study uncovers for the first time, the antioxidant profile of Weissella confusa PP29 probiotic media and focuses on elevating its impressive antioxidant attributes by synergistically integrating H. sabdariffa L. anthocyanin extract. The multifaceted potential of this innovative approach is explored and the results are remarkable, allowing us to understand the protective capacity of the fermented product on the intestinal mucosa. The total phenolic content was much lower at the end of the fermentation process compared to the initial amount, confirming their LAB processing. The DPPH radical scavenging and FRAP of the fermented products were higher compared to ascorbic acid and antioxidant extracts, while superoxide anion radical scavenging and lipid peroxidation inhibitory activity were comparable to that of ascorbic acid. The antioxidant properties of the fermented products were correlated with the initial inoculum and anthocyanin concentrations. All these properties were preserved for 6 months, demonstrating the promising efficacy of this enriched medium, underlining its potential as a complex functional food with enhanced health benefits

Dextran Formulations as Effective Delivery Systems of Therapeutic Agents

Dextran is by far one of the most interesting non-toxic, bio-compatible macromolecules, an exopolysaccharide biosynthesized by lactic acid bacteria. It has been extensively used as a major component in many types of drug-delivery systems (DDS), which can be submitted to the next in-vivo testing stages, and may be proposed for clinical trials or pharmaceutical use approval. An important aspect to consider in order to maintain high DDS&rsquo; biocompatibility is the use of dextran obtained by fermentation processes and with a minimum chemical modification degree. By performing chemical modifications, artefacts can appear in the dextran spatial structure that can lead to decreased biocompatibility or even cytotoxicity. The present review aims to systematize DDS depending on the dextran type used and the biologically active compounds transported, in order to obtain desired therapeutic effects. So far, pure dextran and modified dextran such as acetalated, oxidised, carboxymethyl, diethylaminoethyl-dextran and dextran sulphate sodium, were used to develop several DDSs: microspheres, microparticles, nanoparticles, nanodroplets, liposomes, micelles and nanomicelles, hydrogels, films, nanowires, bio-conjugates, medical adhesives and others. The DDS are critically presented by structures, biocompatibility, drugs loaded and therapeutic points of view in order to highlight future therapeutic perspectives

Dextran Formulations as Effective Delivery Systems of Therapeutic Agents

Dextran is by far one of the most interesting non-toxic, bio-compatible macromolecules, an exopolysaccharide biosynthesized by lactic acid bacteria. It has been extensively used as a major component in many types of drug-delivery systems (DDS), which can be submitted to the next in-vivo testing stages, and may be proposed for clinical trials or pharmaceutical use approval. An important aspect to consider in order to maintain high DDS’ biocompatibility is the use of dextran obtained by fermentation processes and with a minimum chemical modification degree. By performing chemical modifications, artefacts can appear in the dextran spatial structure that can lead to decreased biocompatibility or even cytotoxicity. The present review aims to systematize DDS depending on the dextran type used and the biologically active compounds transported, in order to obtain desired therapeutic effects. So far, pure dextran and modified dextran such as acetalated, oxidised, carboxymethyl, diethylaminoethyl-dextran and dextran sulphate sodium, were used to develop several DDSs: microspheres, microparticles, nanoparticles, nanodroplets, liposomes, micelles and nanomicelles, hydrogels, films, nanowires, bio-conjugates, medical adhesives and others. The DDS are critically presented by structures, biocompatibility, drugs loaded and therapeutic points of view in order to highlight future therapeutic perspectives

Strategy Based on Michael Addition Reaction for the Development of Bioinspired Multilayered and Multiphasic 3D Constructs

The high incidence of osteochondral defects has increased the interest in the development of improved repairing alternatives, with tissue engineering being considered a promising approach. The hierarchical, complex structure of osteochondral tissue requires the design of a biomimetic multilayered scaffold. Here, a multilayered and multiphasic 3D macroporous structure was achieved at subzero temperature by the Michael addition reaction of amino functionalities of collagen with acryloyl groups of a bifunctionalized poly(ε-caprolactone). This green approach has been successfully applied to crosslink layers of different composition, both for their efficient sequential formation and connection. Polyethylenimine functionalized nano-hydroxyapatite (nHApLPEI) was added to the bottom layer. The resulting hybrid cryogels were characterized by morphology, equilibrium swelling ratios, compressive strength analysis, and MTS assay. They presented good stability, integrity, and biocompatibility. The results revealed that the properties of the prepared constructs may be tuned by varying the composition, number, and thickness of the layers. The Young modulus values were between 3.5 ± 0.02 and 10.5 ± 0.6 kPa for the component layers, while for the multilayered structures they were more than 7.3 ± 0.2 kPa. The equilibrium swelling ratio varied between 4.6 and 14.2, with a value of ~10.5 for the trilayered structure, correlated with the mean pore sizes (74–230 µm)