Longer and less overlapping food webs in anthropogenically disturbed marine ecosystems: confirmations from the past

This is the final version of the article. Available from the publisher via the DOI in this record.The human exploitation of marine resources is characterised by the preferential removal of the largest species. Although this is expected to modify the structure of food webs, we have a relatively poor understanding of the potential consequences of such alteration. Here, we take advantage of a collection of ancient consumer tissues, using stable isotope analysis and SIBER to assess changes in the structure of coastal marine food webs in the South-western Atlantic through the second half of the Holocene as a result of the sequential exploitation of marine resources by hunter-gatherers, western sealers and modern fishermen. Samples were collected from shell middens and museums. Shells of both modern and archaeological intertidal herbivorous molluscs were used to reconstruct changes in the stable isotopic baseline, while modern and archaeological bones of the South American sea lion Otaria flavescens, South American fur seal Arctocephalus australis and Magellanic penguin Spheniscus magellanicus were used to analyse changes in the structure of the community of top predators. We found that ancient food webs were shorter, more redundant and more overlapping than current ones, both in northern-central Patagonia and southern Patagonia. These surprising results may be best explained by the huge impact of western sealing on pinnipeds during the fur trade period, rather than the impact of fishing on fish populations. As a consequence, the populations of pinnipeds at the end of the sealing period were likely well below the ecosystem's carrying capacity, which resulted in a release of intraspecific competition and a shift towards larger and higher trophic level prey. This in turn led to longer and less overlapping food webs.Fundacio´n BBVA funded this research as part of the project ‘‘Efectos de la explotacio´n humana sobre depredadores apicales y la estructura de la red tro´fica del Mar Argentino durante los u´timos 6000 an˜os’’ (BIOCON08-194/09 2009-2011). Agencia Nacional de Promocio´n Cientı´fica y Tecnolo´gica (Argentina) provided additional funding through the project ‘‘Ana´lisis del uso de los recursos tro´ficos y su relacio´n con cambios en la abundancia en tres predadores tope del Mar Argentino’’. FS has been supported by an FPU Fellowship granted by the Spanish Ministerio de Educacio´n, Cultura y Deporte (AP 2009- 4573). Half of the cost of the publication of this article has been funded by the University of Barcelona. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Local Victory: Assessing Interspecific Competition in Seagrass From a Trait-Based Perspective

Tropical seagrass meadows are formed by an array of seagrass species that share the same space. Species sharing the same plot are competing for resources, namely light and inorganic nutrients, which results in the capacity of some species to preempt space from others. However, the drivers behind seagrass species competition are not completely understood. In this work, we studied the competitive interactions among tropical seagrass species of Unguja Island (Zanzibar, Tanzania) using a trait-based approach. We quantified the abundance of eight seagrass species under different trophic states, and selected nine traits related to light and inorganic nutrient preemption to characterize the functional strategy of the species (leaf maximum length and width, leaves per shoot, leaf mass area, vertical rhizome length, shoots per meter of ramet, rhizome diameter, roots per meter of ramet, and root maximum length). From the seagrass abundance we calculated the probability of space preemption between pairs of seagrass species and for each individual seagrass species under the different trophic states. Species had different probabilities of space preemption, with the climax species Thalassodendron ciliatum, Enhalus acoroides, Thalassia hemprichii, and the opportunistic Cymodocea serrulata having the highest probability of preemption, while the pioneer and opportunistic species Halophila ovalis, Syringodium isoetifolium, Halodule uninervis, and Cymodocea rotundata had the lowest. Traits determining the functional strategy showed that there was a size gradient across species. For two co-occurring seagrass species, probability of preemption was the highest for the larger species, it increased as the size difference between species increased and was unaffected by the trophic state. Competitive interactions among seagrass species were asymmetrical, i.e., negative effects were not reciprocal, and the driver behind space preemption was determined by plant size. Seagrass space preemption is a consequence of resource competition, and the probability of a species to exert preemption can be calculated using a trait-based approach

SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane \u3b1-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure-function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport

An in silico structural approach to critical quality attributes assessment of biopharmaceutical products

\u201cQuality by design\u201d (QbD) is a key approach in modern pharmaceutical development, applied during the development, the manufacturing and the whole life cycle of the product, included the post approval phase, for assuring the quality in terms of efficacy and safety. In detail, QbD process includes the critical quality attributes (CQAs) assessment, providing a comprehensive understanding of the product itself and the manufacturing process. CQAs are defined as \u201call the physical, chemical, biological, or microbiological properties or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality\u201d (ICH Q8). They have a potential impact on bioactivity, PK, immunogenicity and safety and are associated with the drug substance and drug product. In the context of biotechnological products, the introduction of a structural investigation in an early identification of potential CQAs (pCQAs) can be very useful to QbD approach. Identification of pCQAs of biomolecules can lead the characterization process during the development phase in order to ensure the desired drug quality profile. Monoclonal antibodies (mAbs), fusion proteins and antibody-drug conjugates (ADC) represent one of the most innovative class of biopharmaceuticals, due to their ability to specifically recognize unique epitopes inducing specific therapeutic responses. CQAs assessment for these biopharmaceuticals is a complex analysis due to the lack of structural information. Actually, there is only one fully-crystallized human IgG1 (PDB entry: 1HZH) and, in absence of whole structures, it is challenging to understand the impact of structural insights on the therapeutic response. On these basis, the purpose of this study was to develop an in silico strategy to build the atomistic model of the whole structure of an IgG1, focusing on lambda and kappa light chains. To reach this goal, we used a structural chimeric approach that, using the Homology Modeling (HM) tool by MOE software, allowed us to build the full atomistic model of two therapeutic and commercially available IgG1: adalimumab (kappa chain) and avelumab (lambda chain). This allowed us to investigate structural differences between two isotypes, kappa and lambda, and understand the impact of these different characteristics on the antibody structure and function. Our results try to fill the gap between biological and structural properties on biotechnological products, created by lack of full immunoglobulin crystal structures. Moreover, this innovative structural approach can be used in CQAs assessment during the pharmaceutical development and production phases, giving an important resource to pharmaceutical companies. DISCLOSURES Merck Serono, Guidonia Montecelio-Rome, Italy is an affiliate of Merck KGaA, Darmstadt, Germany. Please note that avelumab has been approved in various countries for the treatment of metastatic Merkel cell carcinoma and in the US for treatment of advanced urothelial carcinoma progressed after platinum-containing treatment

Reliability analysis of a timber truss system subjected to decay

Assessing the safety of existing timber structures is of paramount importance for taking reliable decisions on repair actions and their extent. The results obtained through semi-probabilistic methods are unrealistic, as the partial safety factors present in codes are calibrated considering the uncertainty exhibited by new structures. In order to overcome these limitations, and also to include the e ects of decay in the safety analysis, probabilistic methods, based on Monte-Carlo simulation are applied here to assess the safety of existing timber structures. In particular, the impact of decay on structural safety is analyzed and discussed using a simple structural model, similar to that used for current semi-probabilistic analysis.Fundação para a Ciência e a Tecnologia (FCT

Surface Plasmon Resonance as a Tool for Ligand Binding Investigation of Engineered GPR17 Receptor, a G Protein Coupled Receptor Involved in Myelination

The aim of this study was to investigate the potential of surface plasmon resonance (SPR) spectroscopy for the measurement of real-time ligand-binding affinities and kinetic parameters for GPR17, a G protein-coupled receptor (GPCR) of major interest in medicinal chemistry as potential target in demyelinating diseases. The receptor was directly captured, in a single-step, from solubilized membrane extracts on the sensor chip through a covalently bound anti-6x-His-antibody and retained its ligand binding activity for over 24h. Furthermore, our experimental setup made possible, after a mild regeneration step, to remove the bound receptor without damaging the antibody, and thus to reuse many times the same chip. Two engineered variants of GPR17, designed for crystallographic studies, were expressed in insect cells, extracted from crude membranes and analyzed for their binding with two high affinity ligands: the antagonist Cangrelor and the agonist Asinex 1. The calculated kinetic parameters and binding constants of ligands were in good agreement with those reported from activity assays and highlighted a possible functional role of the N-terminal residues of the receptor in ligand recognition and binding. Validation of SPR results was obtained by docking and molecular dynamics of GPR17-ligands interactions and by functional in vitro studies. The latter allowed us to confirm that Asinex 1 behaves as GPR17 receptor agonist, inhibits forskolin-stimulated adenylyl cyclase pathway and promotes oligodendrocyte precursor cell maturation and myelinating ability

Effect of Alloying Elements in Melt Spun Mg-alloys for Hydrogen Storage

In this paper we report the effect of alloying elements on hydrogen storage properties of melt-spun Mg-based alloys. The base alloys Mg90Si10, Mg90Cu10, Mg65Cu35 (at%) were studied. We also investigated the effect of rare earths (using MM: mischmetal) and Al in Mg65Cu25Al10, Mg65Cu25MM10 and Mg65Cu10Al15MM10 alloys. All the melt-spun alloys without MM show a crystalline structure, and the Mg65Cu25MM10 and Mg65Cu10Al15MM10 alloys showed an amorphous and partially amorphous structure respectively. At 350˚C all the alloys had a crystalline structure during the hydrogen absorption-desorption tests. It was observed that Si and Cu in the binaries alloys hindered completely the activation of the hydrogen absorption. The partial substitution of Cu by MM or Al allowed activation. The combined substitution of Cu by MM and Al showed the best results with the fastest absorption and desorption kinetics, which suggests that this combination can be used for new Mg-alloys to improve hydrogen storage properties

Donor Lymphocyte Infusions After Allogeneic Stem Cell Transplantation in Acute Leukemia: A Survey From the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6\u201373.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55\u20133,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or 654 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III\u2013IV graft versus host disease (GVHD) (3%), grade III\u2013IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32\u20131,390) from the first DLI. With a median follow-up of 461 days (2\u20133,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation

The Impact of Graft CD3 Cell/Regulatory T Cell Ratio on Acute Graft-versus-Host Disease and Post-Transplantation Outcome: A Prospective Multicenter Study of Patients with Acute Leukemia Undergoing Allogeneic Peripheral Blood Stem Cell Transplantation

Although it is well known that tumor site- or bone marrow-infiltrating regulatory T cells (Tregs) might be correlated with worse outcomes in solid tumors and acute leukemias by promoting immune surveillance escape, their contribution to the immediate post-allogeneic transplantation phase by peripheral blood (PB) allografts remains unclear. Moreover, the Treg content in stem cells harvested from PB has been suggested to be correlated with acute graft versus-host-disease (aGVHD) and immunologic recovery after allogeneic PB stem cell transplantation (allo-PBSCT). This study aimed to investigate the impact of the graft content of Tregs, as graft CD3+/Tregs ratio (gCD3/TregsR), on acute GVHD and post-allo-PBSCT outcomes. We prospectively enrolled 94 consecutive patients at 9 Italian centers of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) with acute myelogenous (n = 71; 75%) or lymphoblastic (n = 23; 25%) leukemia in complete remission who underwent matched related donor (n = 35; 37%) or unrelated donor (n = 59; 63%) allo-PBSCT. The median graft CD3+ cell, Treg, and gCD3/TregsR values were 196 × 106/kg body weight (range, 17 to 666 × 106/kg), 3 × 106/kg (range, 0.1 to 35 × 106/kg), and 71 (range, 1 to 1883), respectively. The discriminatory power of the gCD3/TregsR value to predict grade ≥II aGVHD was assessed by estimating the area under the receiver operating characteristic (ROC) curve (AUC). Any grade and grade ≥II aGVHD occurred in 24 (26%) and 17 (18%) allo-PBSCT recipients, respectively. By ROC analysis, AUC (0.74; 95% confidence interval [CI], 0.608 to 0.866; P =.002) identified 70 as the optimal gCD3/TregsR cutoff value predicting the appearance of grade ≥II aGVHD with 76% sensitivity and 71% specificity. Patients were subdivided into a high (ROC curve value ≥70) gCD3/TregsR group (HR; n = 48) and a low (ROC curve value <70) gCD3/TregsR group (LR; n = 46). The incidence of grade II-IV aGVHD was lower in the LR group compared with the HR group (9% [4 of 46] versus 27% [13 of 48]) in both univariate analysis (odds ratio [OR], 4.8; 95% CI, 1.44 to 16.17; P =.015) and multivariate analysis (OR, 5.0; 95% CI, 1.34 to 18.93; P =.017), whereas no differences were documented taking into account aGVHD of any grade. The overall survival, disease-free survival, nonrelapse mortality, and relapse rates at 2 and 3 years were 61% and 54%, 62% and 55%, 15% and 23%, and 27% and 30%, respectively. Of note, gCD3/TregsR did not significantly correlate with relapse (P =.135). Taken together, our data from this prospective multicenter study confirm the value of Tregs in preventing aGVHD while maintaining the graft-versus-leukemia effect. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc