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Abstract Recent genomic analyses have revealed that microbial communities are predominantly composed of persistent, sequence-discrete species and intraspecies units (genomovars), but the mechanisms that create and maintain these units remain unclear. By analyzing closely-related isolate genomes from the same or related samples and identifying recent recombination events using a novel bioinformatics methodology, we show that high ecological cohesiveness coupled to frequent-enough and unbiased (i.e., not selection-driven) horizontal gene flow, mediated by homologous recombination, often underlie these diversity patterns. Ecological cohesiveness was inferred based on greater similarity in temporal abundance patterns of genomes of the same vs. different units, and recombination was shown to affect all sizable segments of the genome (i.e., be genome-wide) and have two times or greater impact on sequence evolution than point mutations. These results were observed in both Salinibacter ruber, an environmental halophilic organism, and Escherichia coli, the model gut-associated organism and an opportunistic pathogen, indicating that they may be more broadly applicable to the microbial world. Therefore, our results represent a departure compared to previous models of microbial speciation that invoke either ecology or recombination, but not necessarily their synergistic effect, and answer an important question for microbiology: what a species and a subspecies are.

Abstract Immunological diseases are typically heterogeneous in clinical presentation, severity and response to therapy. Biomarkers of immune diseases often reflect this variability, especially compared to their regulated behaviour in health. This leads to a common difficulty that frustrates biomarker discovery and interpretation – namely, unequal dispersion of immune disease biomarker expression between patient classes necessarily limits a biomarker’s informative range. To solve this problem, we introduce dataset restriction, a procedure that splits datasets into classifiable and unclassifiable samples. Applied to synthetic flow cytometry data, restriction identifies biomarkers that are otherwise disregarded. In advanced melanoma, restriction finds biomarkers of immune-related adverse event risk after immunotherapy and enables us to build multivariate models that accurately predict immunotherapy-related hepatitis. Hence, dataset restriction augments discovery of immune disease biomarkers, increases predictive certainty for classifiable samples and improves multivariate models incorporating biomarkers with a limited informative range. This principle can be directly extended to any classification task.

Patients present a wide range of clinical severities in response severe acute respiratory syndrome coronavirus 2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein–protein interaction analysis indicated that early-responding cytotoxic natural killer cells were associated with an effective clearance of the virus and a less severe outcome. This innate immune response was associated with the activation of select cytokine–cytokine receptor pathways and robust Th1/Th2 cell differentiation profiles. In contrast, severely ill patients exhibited a dysregulation between innate and adaptive responses affiliated with divergent Th1/Th2 profiles and negative outcomes. This knowledge forms the basis of clinical triage that may be used to preemptively detect high-risk patients before life-threatening outcomes ensue.

Summary: Cultivated meat has the potential to revolutionize food production, but its progress is hindered by fundamental shortcomings of mammalian cells with respect to industrial-scale bioprocesses. Here, we discuss the essential role of cell line engineering in overcoming these limitations, highlighting the balance between the benefits of enhanced cellular traits and the associated regulatory and consumer acceptance challenges. We believe that careful selection of cell engineering strategies, including both genetic and non-genetic modifications, can address this trade-off and is essential to advancing the field.

Abstract Inflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the gastrointestinal tract associated with multiple pathogenic factors, including dysregulation of the immune response. Effector CD4+ T cells and regulatory CD4+ T cells (Treg) are central players in maintaining the balance between tolerance and inflammation. Interestingly, genetic modifications in these cells have been implicated in regulating the commitment of specific phenotypes and immune functions. However, the transcriptional program controlling the pathogenic behavior of T helper cells in IBD progression is still unknown. In this study, we aimed to find master transcription regulators controlling the pathogenic behavior of effector CD4+ T cells upon gut inflammation. To achieve this goal, we used an animal model of IBD induced by the transfer of naïve CD4+ T cells into recombination-activating gene 1 (Rag1) deficient mice, which are devoid of lymphocytes. As a control, a group of Rag1 −/− mice received the transfer of the whole CD4+ T cells population, which includes both effector T cells and Treg. When gut inflammation progressed, we isolated CD4+ T cells from the colonic lamina propria and spleen tissue, and performed bulk RNA-seq. We identified differentially up- and down-regulated genes by comparing samples from both experimental groups. We found 532 differentially expressed genes (DEGs) in the colon and 30 DEGs in the spleen, mostly related to Th1 response, leukocyte migration, and response to cytokines in lamina propria T-cells. We integrated these data into Gene Regulatory Networks to identify Master Regulators, identifying four up-regulated master gene regulators (Lef1, Dnmt1, Mybl2, and Jup) and only one down-regulated master regulator (Foxo3). The altered expression of master regulators observed in the transcriptomic analysis was confirmed by qRT-PCR analysis and found an up-regulation of Lef1 and Mybl2, but without differences on Dnmt1, Jup, and Foxo3. These two master regulators have been involved in T cells function and cell cycle progression, respectively. We identified two master regulator genes associated with the pathogenic behavior of effector CD4+ T cells in an animal model of IBD. These findings provide two new potential molecular targets for treating IBD.

Abstract Taphonomic works aim at discovering how paleontological and archaeofaunal assemblages were formed. They also aim at determining how hominin fossils were preserved or destroyed. Hominins and other mammal carnivores have been co-evolving, at least during the past two million years, and their potential interactions determined the evolution of human behavior. In order to understand all this, taxon-specific carnivore agency must be effectively identified in the fossil record. Until now, taphonomists have been able to determine, to some degree, hominin and carnivore inputs in site formation, and their interactions in the modification of part of those assemblages. However, the inability to determine agency more specifically has hampered the development of taphonomic research, whose methods are virtually identical to those used several decades ago (lagged by a high degree of subjectivity). A call for more objective and agent-specific methods would be a major contribution to the advancement of taphonomic research. Here, we present one of these advances. The use of computer vision (CV) on a large data set of images of tooth marks has enabled the objective discrimination of taxon-specific carnivore agency up to 88% of the testing sample. We highlight the significance of this method in an interdisciplinary interplay between traditional taphonomic-paleontological analysis and artificial intelligence-based computer science. The new questions that can be addressed with this will certainly bring important changes to several ideas on important aspects of the human evolutionary process.

Individuals with neurodevelopmental disorders exhibit overlapping emotional, somatosensory and motor deficits. Although brain processes underlying these impairments have been extensively studied in a separate way, the brain interaction of these inputs is an innovative line of research. Here we present a new EEG methodology for exploring the interactive brain activity of sensorimotor and affective stimuli. The task consists in presenting affective stimuli of different modalities (e.g. affective pictures, affective touch) while simultaneously an arthromotor performs passive joint movements, unseen by the participant. Participants were then required to press one of two buttons to indicate if their joint position agreed with a picture shown in a screen. Pilot data of electroencephalography recordings revealed distinct somatosensory event-related potentials (SEP) when movement was subsequent to affective stimuli, compared to neutral stimuli, as well as a differentiation of SEPs for different neurodevelopmental conditions. Behavioral responses further showed that children with cerebral palsy had more errors to identify their hand position when they were exposed to affective stimuli. This paradigm is a valuable tool to explore the modulative influence of emotion in the sensorimotor brain processing of different populations with joint emotional and sensorimotor impairments, such as children with neurodevelopmental disorders or patients with stroke. • This method allows exploring the interaction between affective and sensoriomotor inputs in an EEG paradigm.

Abstract The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value

Abstract Since the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination.

Serine protease inhibitors (serpins) include thousands of structurally conserved proteins playing key roles in many organisms. Mutations affecting serpins may disturb their conformation, leading to inactive forms. Unfortunately, conformational consequences of serpin mutations are difficult to predict. In this study, we integrate experimental data of patients with mutations affecting one serpin with the predictions obtained by AlphaFold and molecular dynamics. Five SERPINC1 mutations causing antithrombin deficiency, the strongest congenital thrombophilia were selected from a cohort of 350 unrelated patients based on functional, biochemical, and crystallographic evidence supporting a folding defect. AlphaFold gave an accurate prediction for the wild-type structure. However, it also produced native structures for all variants, regardless of complexity or conformational consequences in vivo. Similarly, molecular dynamics of up to 1000 ns at temperatures causing conformational transitions did not show significant changes in the native structure of wild-type and variants. In conclusion, AlphaFold and molecular dynamics force predictions into the native conformation at conditions with experimental evidence supporting a conformational change to other structures. It is necessary to improve predictive strategies for serpins that consider the conformational sensitivity of these molecules.

Abstract In this study, local tsunami hazard due to seismic sources is evaluated in a stochastic framework. Several assumptions such as static passive generation, constant rake angle and source centroid (among others) are relaxed. Spatial uncertainties are modeled in a large set of scenarios. The proposed methodology is easy to implement and can be combined with other types of sources or hazards. Application in the Kuril-Kamchatkah trench shows a straightforward use of our methodology, producing simple hazard maps, which can be replicated in any region of the world.

Genetic associations with severe COVID-19 have been discovered, but epigenetic associations are not as well described. Here, the authors perform a genome-wide epigenetic analysis of COVID-19 patients, discovering an interaction between environmental exposure, genetics, and epigenetics which might play a role in severe disease.

The genetic architecture underlying Sjögren’s syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.

We are at a time of considerable growth in transcriptomics studies and subsequent in silico analysis. RNA sequencing (RNA-Seq) is the most widely used approach to analyse the transcriptome and is integrated in many studies. The processing of transcriptomic data typically requires a noteworthy number of steps, statistical knowledge, and coding skills, which are not accessible to all scientists. Despite the development of a plethora of software applications over the past few years to address this concern, there is still room for improvement. Here we present DEVEA, an R shiny application tool developed to perform differential expression analysis, data visualization and enrichment pathway analysis mainly from transcriptomics data, but also from simpler gene lists with or without statistical values. The intuitive and easy-to-manipulate interface facilitates gene expression exploration through numerous interactive figures and tables, and statistical comparisons of expression profile levels between groups. Further meta-analysis such as enrichment analysis is also possible, without the need for prior bioinformatics expertise. DEVEA performs a comprehensive analysis from multiple and flexible data sources representing distinct analytical steps. Consequently, it produces dynamic graphs and tables, to explore the expression levels and statistical results from differential expression analysis. Moreover, it generates a comprehensive pathway analysis to extend biological insights. Finally, a complete and customizable HTML report can be extracted to enable the scientists to explore results beyond the application. DEVEA is freely accessible at https://shiny.imib.es/devea/ and the source code is available on our GitHub repository https://github.com/MiriamRiquelmeP/DEVEA.

Abstract This study aimed to examine the association between meeting 24-h movement guidelines and cardiometabolic health in Chilean adults. We used cross-sectional data of 2618 adults from the Chilean National Health Survey 2016–2017. Meeting the 24-h movement guidelines was defined as ≥ 600 MET-min/week of physical activity; ≤ 8 h/day of sitting time; and 7 to 9 h/day of sleep duration. Cardiometabolic health indicators were body mass index, waist circumference, high triglycerides, high blood pressure, type 2 diabetes, metabolic syndrome, and risk of cardiovascular disease in a 10-year period. Meeting none out of three 24-h movement guidelines (vs all three) was associated with higher odds of overweight/obesity (OR 1.67; 95%CI 1.45 to 1.89), high waist circumference (1.65; 1.40 to 1.90), hypertension (2.88; 2.23 to 3.53), type 2 diabetes (1.60; 1.26 to 1.94), metabolic syndrome (1.97; 1.54 to 2.40) and risk of cardiovascular disease (1.50; 1.20, 1.80). Meeting one guideline (vs three) was associated with higher odds of five of out seven cardiometabolic indicators. Our study found that the composition of movement behaviors within a 24-h period may have important implications for cardiometabolic health.

Se analiza el interés de los científicos en compartir datos de investigación con base en el ethos de la ciencia de Robert K. Merton. Se revisaron treinta documentos científicos, resultado de búsquedas en bases de datos como Scopus y Web of Science; el análisis interpretativo del contenido se realizó con el programa ATLAS.ti. Entre los hallazgos destacan diversos factores asociados a la negación de los científicos para compartir datos en la ciencia. Asimismo, se encontraron otros posicionamientos que promueven una concientización a favor de distribuirlos, pues el bien común está por encima de los intereses particulares. Finalmente, se constata que el ethos es una propuesta apropiada para examinar el interés de los investigadores en la distribución de datos de investigación.

Single spikes can trigger repeatable firing sequences in cortical networks. The mechanisms that support reliable propagation of activity from such small events and their functional consequences remain unclear. By constraining a recurrent network model with experimental statistics from turtle cortex, we generate reliable and temporally precise sequences from single spike triggers. We find that rare strong connections support sequence propagation, while dense weak connections modulate propagation reliability. We identify sections of sequences corresponding to divergent branches of strongly connected neurons which can be selectively gated. Applying external inputs to specific neurons in the sparse backbone of strong connections can effectively control propagation and route activity within the network. Finally, we demonstrate that concurrent sequences interact reliably, generating a highly combinatorial space of sequence activations. Our results reveal the impact of individual spikes in cortical circuits, detailing how repeatable sequences of activity can be triggered, sustained, and controlled during cortical computations.

Abstract Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

Oxidative stress is a major risk factor that causes osteocyte cell death and bone loss. Prior studies primarily focus on the function of cell surface expressed Cx43 channels. Here, we reported a new role of mitochondrial Cx43 (mtCx43) and hemichannels (HCs) in modulating mitochondria homeostasis and function in bone osteocytes under oxidative stress. In murine long bone osteocyte-Y4 cells, the translocation of Cx43 to mitochondria was increased under H2O2-induced oxidative stress. H2O2 increased the mtCx43 level accompanied by elevated mtCx43 HC activity, determined by dye uptake assay. Cx43 knockdown (KD) by the CRISPR-Cas9 lentivirus system resulted in impairment of mitochondrial function, primarily manifested as decreased ATP production. Cx43 KD had reduced intracellular reactive oxidative species levels and mitochondrial membrane potential. Additionally, live-cell imaging results demonstrated that the proton flux was dependent on mtCx43 HCs because its activity was specifically inhibited by an antibody targeting Cx43 C-terminus. The co-localization and interaction of mtCx43 and ATP synthase subunit F (ATP5J2) were confirmed by Förster resonance energy transfer and a protein pull-down assay. Together, our study suggests that mtCx43 HCs regulate mitochondrial ATP generation by mediating K+, H+, and ATP transfer across the mitochondrial inner membrane and the interaction with mitochondrial ATP synthase, contributing to the maintenance of mitochondrial redox levels in response to oxidative stress.

Early events during axolotl limb regeneration include an immune response and the formation of a wound epithelium. These events are linked to a clearance of damaged tissue prior to blastema formation and regeneration of the missing structures. Here, we report the resorption of calcified skeletal tissue as an active, cell-driven, and highly regulated event. This process, carried out by osteoclasts, is essential for a successful integration of the newly formed skeleton. Indeed, the extent of resorption is directly correlated with the integration efficiency, and treatment with zoledronic acid resulted in osteoclast function inhibition and failed tissue integration. Moreover, we identified the wound epithelium as a regulator of skeletal resorption, likely releasing signals involved in recruitment/differentiation of osteoclasts. Finally, we reported a correlation between resorption and blastema formation, particularly, a coordination of resorption with cartilage condensation. In sum, our results identify resorption as a major event upon amputation, playing a critical role in the overall process of skeletal regeneration.

Euphausiids (hereafter “krill”) are one of the main components of the pelagic communities of the Humboldt Current System (HCS). Their community dynamics have been well studied in central-southern Chile where upwelling is strongly seasonal, but little is known about the permanent-upwelling area of the HCS, which yields the largest fishery in the world, the Peruvian anchovy. We applied hierarchical generalized additive models with environmental and biological predictors to determine the main drivers of krill abundance, adjusting species-specific functions. We used a time series of 16 bi-annual surveys to study annual, seasonal, and spatial scales of variability of the four numerically dominant taxa: Euphausia mucronata (Humboldt krill), E. eximia, Stylocheiron affine, and Nematoscelis spp. The spatial pattern of the Humboldt krill (the dominant species) proved it is an upwelling-associated species, with higher abundances within 10 km from the coast. The other 3 taxa showed opposite spatial patterns with higher abundances offshore. The main covariates explaining krill abundances were the depth of the upper limit of the oxygen minimum zone (dOMZ) and the mean temperature of the water column. Humboldt krill was negatively correlated to both drivers, and the opposite effect was observed for the other taxa. Although many krill species are metabolically adapted to cope with the severe hypoxic conditions of this system, the Humboldt krill was the only species with higher modeled abundances when dOMZ was shallower. Chlorophyll-a remained high during all sampling periods, and it was an insignificant predictor for all taxa, suggesting food is not a limitation for krill in this highly productive system. The acoustic biomass of the Peruvian anchovy had a negative non-linear effect on the abundances of the Humboldt krill, and higher Humboldt krill abundances were found in areas with no anchovy hotspots. Our results indicate that krill in this system are susceptible to changes in temperature, oxygen, and upwelling conditions. Extreme events (e.g. heatwaves and ENSO events) are expected to increase in frequency and intensity, while climate change scenarios show a potential intensification of upwelling. These conditions could lead to distribution displacements and alter trophic interactions by modifying the distribution and biomass of the predator.

Abstract Humans are unique in their diet, physiology and socio-reproductive behavior compared to other primates. They are also unique in the ubiquitous adaptation to all biomes and habitats. From an evolutionary perspective, these trends seem to have started about two million years ago, coinciding with the emergence of encephalization, the reduction of the dental apparatus, the adoption of a fully terrestrial lifestyle, resulting in the emergence of the modern anatomical bauplan, the focalization of certain activities in the landscape, the use of stone tools, and the exit from Africa. It is in this period that clear taphonomic evidence of a switch in diet with respect to Pliocene hominins occurred, with the adoption of carnivory. Until now, the degree of carnivorism in early humans remained controversial. A persistent hypothesis is that hominins acquired meat irregularly (potentially as fallback food) and opportunistically through klepto-foraging. Here, we test this hypothesis and show, in contrast, that the butchery practices of early Pleistocene hominins (unveiled through systematic study of the patterning and intensity of cut marks on their prey) could not have resulted from having frequent secondary access to carcasses. We provide evidence of hominin primary access to animal resources and emphasize the role that meat played in their diets, their ecology and their anatomical evolution, ultimately resulting in the ecologically unrestricted terrestrial adaptation of our species. This has major implications to the evolution of human physiology and potentially for the evolution of the human brain.

Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

Abstract We estimated the proportion and number of deaths from non-communicable diseases (NCD) attributable to high body mass index (BMI) in Chile in 2018. We used data from 5927 adults from a 2016–2017 Chilean National Health Survey to describe the distribution of BMI. We obtained the number of deaths from NCD from the Ministry of Health. Relative risks (RR) and 95% confidence intervals per 5 units higher BMI for cardiovascular disease, cancer, and respiratory disease were retrieved from the Global BMI Mortality Collaboration meta-analyses. The prevalences of overweight and obesity were 38.9% and 39.1%, respectively. We estimated that reducing population-wide BMI to a theoretical minimum risk exposure level (mean BMI: 22.0 kg/m2; standard deviation: 1) could prevent approximately 21,977 deaths per year (95%CI 13,981–29,928). These deaths represented about 31.6% of major NCD deaths (20.1–43.1) and 20.4% of all deaths (12.9–27.7) that occurred in 2018. Most of these preventable deaths were from cardiovascular diseases (11,474 deaths; 95% CI 7302–15,621), followed by cancer (5597 deaths; 95% CI 3560–7622) and respiratory disease (4906 deaths; 95% CI 3119–6684). A substantial burden of NCD deaths was attributable to high BMI in Chile. Policies and population-wide interventions are needed to reduce the burden of NCD due to high BMI in Chile.

Sjögren’s syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

Misiam is a modern wildebeest-dominated accumulation situated in a steep ravine covered with dense vegetation at Olduvai Gorge (Tanzania). It is interpreted here as a leopard lair to which carcasses have been transported for several years. Felid-specific bone damage patterns, felid-typical skeletal part profiles, taxonomic specialization and the physical presence of leopards observed by the authors show that leopards at Misiam can be specialized medium-sized carcass accumulators. Hyenas also intervened at intervals in the modification of the retrieved faunal assemblage. This makes Misiam a carnivore palimpsest. Here, we additionally show that leopards only transport and accumulate carcasses on occasions, that they can seem highly specialized despite being dietary generalists, and that such a behaviour may be prompted by seasonal competition or during the breeding season or both. Misiam is the first open-air leopard lair with a dense bone accumulation reported. There, leopards engaged in intensive accumulation of carcasses during the wet season, when the southern Serengeti short-grass plains undergo the effect of the famous wildebeest migration and this migratory species reaches the gorge. The ecological importance of this behaviour and its relevance as a proxy for reconstructing prehistoric carnivore behaviours are discussed.

The high mountain segments of the valleys of the southernmost Atacama Desert of Chile present Late Quaternary glacial landforms that developed in already incised valleys. Glacier advances and deglaciation have left a geomorphic imprint in the southernmost Atacama Desert. In this work, the glacial landforms of the Encierro River Valley (29.1°S–69.9°W) have been revisited and new detailed geomorphological mapping is provided. This work also includes new 10Be exposure ages from moraine boulders and one age from an ice-molded bedrock surface. The former glacier of the El Encierro valley extended 16 km down the valley during the last local glacial maximum recorded by a terminal moraine (ENC 1a) with an exposure age of ∼40 ka. Four inboard moraine arcs were deposited upstream in telescopic patterns (ENC 1b–d), whose exposure ages range between ∼25 and ∼33 ka (ENC 1d). Exposure ages between ∼17–24 ka on lateral moraines (ENC 1L) developed during the later ice recession of the ENC 1 drift. Thus, the ice mostly disappeared in the main valley before ∼18 ka, as is also supported by the exposure age obtained from an ice-molded bedrock surface. Seven kilometers up the valley from the ENC 1, the ENC 2a–d moraine arcs correspond to a small ice advance by ∼17–20 ka. The last glacial advance (ENC 2), which occurred after deglaciation of the last local glacial maximum (ENC 1), coincides with the start of the Heinrich Stadial Event 1 (HS1; 18–14.5 ka), which is thought to play a direct role in the last glacial termination in the Andes.

Abstract Ecologists study how populations are regulated, while scientists studying biological pest control apply population regulation processes to reduce numbers of harmful organisms: an organism (a natural enemy) is used to reduce the population density of another organism (a pest). Finding an effective biological control agent among the tens to hundreds of natural enemies of a pest is a daunting task. Evaluation criteria help in a first selection to remove clearly ineffective or risky species from the list of candidates. Next, we propose to use an aggregate evaluation criterion, the pest kill rate, to compare the pest population reduction capacity of species not eliminated during the first selection. The pest kill rate is the average daily lifetime killing of the pest by the natural enemy under consideration. Pest kill rates of six species of predators and seven species of parasitoids of Tuta absoluta were calculated and compared. Several natural enemies had pest kill rates that were too low to be able to theoretically reduce the pest population below crop damaging densities. Other species showed a high pest reduction capacity and their potential for practical application can now be tested under commercial crop production conditions.

The authors show that the pathogen Staphylococcus aureus induces a distinct airway immunometabolic response, dominated by release of itaconate. This metabolite, in turn, potentiates extracellular polysaccharide synthesis and biofilm formation in S. aureus, which may facilitate chronic infection.

Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4+ effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.

Imaging of low-mass exoplanets can be achieved once the thermal background in the mid-infrared (MIR) wavelengths can be mitigated. Here, the authors present a ground-based MIR observing approach enabling imaging low-mass temperate exoplanets around nearby stars.

Mechanical stimulation, such as physical exercise, is essential for bone formation and health. Here, we demonstrate the critical role of osteocytic Cx43 hemichannels in anabolic function of bone in response to mechanical loading. Two transgenic mouse models, R76W and Δ130–136, expressing dominant-negative Cx43 mutants in osteocytes were adopted. Mechanical loading of tibial bone increased cortical bone mass and mechanical properties in wild-type and gap junction-impaired R76W mice through increased PGE2, endosteal osteoblast activity, and decreased sclerostin. These anabolic responses were impeded in gap junction/hemichannel-impaired Δ130–136 mice and accompanied by increased endosteal osteoclast activity. Specific inhibition of Cx43 hemichannels by Cx43(M1) antibody suppressed PGE2 secretion and impeded loading-induced endosteal osteoblast activity, bone formation and anabolic gene expression. PGE2 administration rescued the osteogenic response to mechanical loading impeded by impaired hemichannels. Together, osteocytic Cx43 hemichannels could be a potential new therapeutic target for treating bone loss and osteoporosis.

The Cueva de Ardales is a hugely important Palaeolithic site in the south of the Iberian Peninsula owing to its rich inventory of rock art. From 2011–2018, excavations were carried out in the cave for the first time ever by a Spanish-German research team. The excavation focused on the entrance area of the cave, where the largest assemblage of non-figurative red paintings in the cave is found. A series of 50 AMS dates from the excavations prove a long, albeit discontinuous, occupation history spanning from the Middle Palaeolithic to the Neolithic. The dating of the Middle Palaeolithic layers agrees with the U/Th dating of some red non-figurative paintings in the entrance area. In addition, a large assemblage of ochre lumps was discovered in the Middle Palaeolithic layers. Human visits of the cave in the Gravettian and Solutrean can be recognized, but evidence from the Aurignacian and Magdalenian cannot be confirmed with certainty. The quantity and nature of materials found during the excavations indicate that Cueva de Ardales was not a campsite, but was mainly visited to carry out non-domestic tasks, such as the production of rock art or the burial of the dead.

Background Pharmaceutical care has been implemented and regulated differently across Europe with no consensus among countries in relation with professional competencies and especially on nurse prescribing. Demophac Project funded by the European Commission aims to develop a Pan-European Pharmaceutical Care Model with collaboration of 14 partner teams across Europe including Spain where nurse prescribing is starting its implementation at regional level. The aim of the study was to increase understanding of the role of nurses in Pharmaceutical care in Spain after the Nurse Prescribing Regulation approved in 2018 throughout exploring the views and expectations of health professionals involved in the representative settings. Methods and findings In depth interviews were conducted in a structure previously agreed by the European Demophac partnership around four topics associated with the Nursing ideal role in pharmaceutical care and the ideal interaction with other healthcare professionals. A grounded-theory approach based on Corbin & Strauss was conducted to interpret collected data from the Spanish most representative settings (primary care, specialized care and residential care for older population). Participants were health professionals involved in pharmaceutical care that accepted to participate (nurses (n = 7), physicians (n = 8) and pharmacists (n = 9)). A pharmaceutical care comprehensive model for the Spanish context considering the recently approved Nurse Prescribing role and the interprofessional collaboration and communication was developed towards facilitating the understanding in such context and the contribution to the unified European Demophac Framework. Conclusions Nurses are primarily responsible for population’s Pharmaceutical Care while other professionals pivot on them to provide quality healthcare on a multidisciplinary level. Nurse prescribing may contribute efficiently to the Spanish Health System though more consensus in terms of nurses’ training nationwide and enhancement in communication among different professionals within healthcare organizations is required to achieve adequate integrated care into practice.

BackgroundPharmaceutical care has been implemented and regulated differently across Europe with no consensus among countries in relation with professional competencies and especially on nurse prescribing. Demophac Project funded by the European Commission aims to develop a Pan-European Pharmaceutical Care Model with collaboration of 14 partner teams across Europe including Spain where nurse prescribing is starting its implementation at regional level. The aim of the study was to increase understanding of the role of nurses in Pharmaceutical care in Spain after the Nurse Prescribing Regulation approved in 2018 throughout exploring the views and expectations of health professionals involved in the representative settings.Methods and findingsIn depth interviews were conducted in a structure previously agreed by the European Demophac partnership around four topics associated with the Nursing ideal role in pharmaceutical care and the ideal interaction with other healthcare professionals. A grounded-theory approach based on Corbin & Strauss was conducted to interpret collected data from the Spanish most representative settings (primary care, specialized care and residential care for older population). Participants were health professionals involved in pharmaceutical care that accepted to participate (nurses (n = 7), physicians (n = 8) and pharmacists (n = 9)). A pharmaceutical care comprehensive model for the Spanish context considering the recently approved Nurse Prescribing role and the interprofessional collaboration and communication was developed towards facilitating the understanding in such context and the contribution to the unified European Demophac Framework.ConclusionsNurses are primarily responsible for population's Pharmaceutical Care while other professionals pivot on them to provide quality healthcare on a multidisciplinary level. Nurse prescribing may contribute efficiently to the Spanish Health System though more consensus in terms of nurses' training nationwide and enhancement in communication among different professionals within healthcare organizations is required to achieve adequate integrated care into practice.

The Cueva de Ardales is a hugely important Palaeolithic site in the south of the Iberian Peninsula owing to its rich inventory of rock art. From 2011-2018, excavations were carried out in the cave for the first time ever by a Spanish-German research team. The excavation focused on the entrance area of the cave, where the largest assemblage of non-figurative red paintings in the cave is found. A series of 50 AMS dates from the excavations prove a long, albeit discontinuous, occupation history spanning from the Middle Palaeolithic to the Neolithic. The dating of the Middle Palaeolithic layers agrees with the U/Th dating of some red non-figurative paintings in the entrance area. In addition, a large assemblage of ochre lumps was discovered in the Middle Palaeolithic layers. Human visits of the cave in the Gravettian and Solutrean can be recognized, but evidence from the Aurignacian and Magdalenian cannot be confirmed with certainty. The quantity and nature of materials found during the excavations indicate that Cueva de Ardales was not a campsite, but was mainly visited to carry out non-domestic tasks, such as the production of rock art or the burial of the dead.

Monitoring vegetation disturbances using long remote sensing time series is crucial to support environmental management, biodiversity conservation, and adaptation strategies to climate change from global to local scales. However, it is difficult to assess whether a remotely detected vegetation disturbance is critical or not, since available operational remote sensing methods deliver only maps of the vegetation anomalies but not maps of how “uncommon” or “extreme” the detected anomalies are based on the available records of the reference period. In this technical note, we present a new release of the probabilistic method and its implementation, the npphen R package, designed to detect not only vegetation anomalies from remotely sensed vegetation indices, but also to quantify the position of the anomalous observations within the historical frequency distribution of the phenological annual records. This version of the R package includes two new key functions to detect and map extreme vegetation anomalies: ExtremeAnom and ExtremeAnoMap. The npphen package allows remote sensing users to detect vegetation changes for a wide range of ecosystems, taking advantage of the flexibility of kernel density estimations to account for any shape of annual phenology and its variability through time. It provides a uniform statistical framework to study all types of vegetation dynamics, contributing to global monitoring efforts such as the GEO-BON Essential Biodiversity Variables.

Nature–inspired computing is a promising field of artificial intelligence. This area is mainly devoted to designing computational models based on natural phenomena to address complex problems. Nature provides a rich source of inspiration for designing smart procedures capable of becoming powerful algorithms. Many of these procedures have been successfully developed to treat optimization problems, with impressive results. Nonetheless, for these algorithms to reach their maximum performance, a proper balance between the intensification and the diversification phases is required. The intensification generates a local solution around the best solution by exploiting a promising region. Diversification is responsible for finding new solutions when the main procedure is trapped in a local region. This procedure is usually carryout by non-deterministic fundamentals that do not necessarily provide the expected results. Here, we encounter the stagnation problem, which describes a scenario where the search for the optimum solution stalls before discovering a globally optimal solution. In this work, we propose an efficient technique for detecting and leaving local optimum regions based on Shannon entropy. This component can measure the uncertainty level of the observations taken from random variables. We employ this principle on three well–known population–based bio–inspired optimization algorithms: particle swarm optimization, bat optimization, and black hole algorithm. The proposal’s performance is evidenced by solving twenty of the most challenging instances of the multidimensional knapsack problem. Computational results show that the proposed exploration approach is a legitimate alternative to manage the diversification of solutions since the improved techniques can generate a better distribution of the optimal values found. The best results are with the bat method, where in all instances, the enhanced solver with the Shannon exploration strategy works better than its native version. For the other two bio-inspired algorithms, the proposal operates significantly better in over 70% of instances.

Summary: Emerging evidence challenges the lens as an immune-privileged organ. Here, we provide a direct mechanism supporting a role of macrophages in lens capsule rupture repair. Posterior lens capsule rupture in a connexin 50 and aquaporin 0 double-knockout mouse model resulted in lens tissue extrusion into the vitreous cavity with formation of a “tail-like” tissue containing delayed regressed hyaloid vessels, fibrotic tissue and macrophages at postnatal (P) 15 days. The macrophages declined after P 30 days with M2 macrophages detected inside the lens. By P 90 days, the “tail-like” tissue completely disappeared and the posterior capsule rupture was sealed with thick fibrotic tissue. Colony-stimulating factor 1 (CSF-1) accelerated capsule repair, whereas inhibition of the CSF-1 receptor delayed the repair. Together, these results suggest that lens posterior rupture leads to the recruitment of macrophages delivered by the regression delayed hyaloid vessels. CSF-1-activated M2 macrophages mediate capsule rupture repair and development of fibrosis.

Hyphae are a major innovation in fungi associated with transitions to multicellularity. Here, Kiss and colleagues use comparative genomic analyses to reconstruct the evolutionary origins of hyphae and the molecular evolution of hypha morphogenesis genes.

In the fecal immunological test, a suitable cut-off value may be selected to classify results as either positive or negative. Our aim is to estimate the optimal cut-off value for detecting colorectal cancer in different age and sex groups. This is a multicentric retrospective cohort study of participants in CRC screening programs with FIT between 2006 and 2012. A total of 545,505 participations were analyzed. Cancers diagnosed outside of the program were identified after a negative test result (IC_test) up until 2014. The Wilcoxon test was used to compare fecal hemoglobin levels. ROC curves were used to identify the optimal cut-off value for each age and sex group. Screening program results were estimated for different cut-off values. The results show that the Hb concentration was higher in colorectal cancer (average = 179.6μg/g) vs. false positives (average = 55.2μg/g), in IC_test (average = 3.1μg/g) vs. true negatives (average = 0μg/g), and in men (average = 166.2μg/g) vs. women (average = 140.2μg/g) with colorectal cancer. The optimal cut-off values for women were 18.3μg/g (50-59y) and 14.6μg/g (60-69y), and 16.8μg/g (50-59y) and 19.9μg/g (60-69y) for men. Using different cut-off values for each age and sex group lead to a decrease in the IC_test rate compared to the 20μg/g cut-off value (from 0.40‰ to 0.37‰) and an increase in the false positive rate (from 6.45% to 6.99%). Moreover, test sensitivity improved (90.7%), especially in men and women aged 50-59y (89.4%; 90%) and women aged 60-69y (90.2%). In conclusion, the optimal cut-off value varies for different sex and age groups and the use of an optimal cut-off value for each group improves sensitivity and leads to a small decrease in IC_tests, but also to a larger increase in false positives.

ObjectivesTo understand healthcare professionals' experiences and perceptions of nurses' potential or ideal roles in pharmaceutical care (PC).DesignQualitative study conducted through semi-structured in-depth interviews.SettingBetween December 2018 and October 2019, interviews were conducted with healthcare professionals of 14 European countries in four healthcare settings: hospitals, community care, mental health and long-term residential care.ParticipantsIn each country, pharmacists, physicians and nurses in each of the four settings were interviewed. Participants were selected on the basis that they were key informants with broad knowledge and experience of PC.Data collection and analysisAll interviews were conducted face to face. Each country conducted an initial thematic analysis. Consensus was reached through a face-to-face discussion of all 14 national leads.Results340 interviews were completed. Several tasks were described within four potential nursing responsibilities, that came up as the analysis themes, being: 1) monitoring therapeutic/adverse effects of medicines, 2) monitoring medicines adherence, 3) decision making on medicines, including prescribing 4) providing patient education/information. Nurses' autonomy varied across Europe, from none to limited to a few tasks and emergencies to a broad range of tasks and responsibilities. Intended level of autonomy depended on medicine types and level of education. Some changes are needed before nursing roles can be optimised and implemented in practice. Lack of time, shortage of nurses, absence of legal frameworks and limited education and knowledge are main threats to European nurses actualising their ideal role in PC.ConclusionsEuropean nurses have an active role in PC. Respondents reported positive impacts on care quality and patient outcomes when nurses assumed PC responsibilities. Healthcare professionals expect nurses to report observations and assessments. This key patient information should be shared and addressed by the interprofessional team. The study evidences the need of a unique and consensus-based PC framework across Europe.

Monitoring ground layer biomass, and therefore forage availability, is important for managing large, vertebrate herbivore populations for conservation. Remote sensing allows for frequent observations over broad spatial scales, capturing changes in biomass over the landscape and through time. In this study, we explored different satellite-derived vegetation indices (VIs) for their utility in estimating understorey biomass in semi-arid woodlands of south-eastern Australia. Relationships between VIs and understorey biomass data have not been established in these particular semi-arid communities. Managers want to use forage availability to inform cull targets for western grey kangaroos (Macropus fuliginosus), to minimise the risk that browsing poses to regeneration in threatened woodland communities when grass biomass is low. We attempted to develop relationships between VIs and understorey biomass data collected over seven seasons across open and wooded vegetation types. Generalised Linear Mixed Models (GLMMs) were used to describe relationships between understorey biomass and VIs. Total understorey biomass (live and dead, all growth forms) was best described using the Tasselled Cap (TC) greenness index. The combined TC brightness and Modified Soil Adjusted Vegetation Index (MSAVI) ranked best for live understorey biomass (all growth forms), and grass (live and dead) biomass was best described by a combination of TC brightness and greenness indices. Models performed best for grass biomass, explaining 70% of variation in external validation when predicting to the same sites in a new season. However, we found empirical relationships were not transferrable to data collected from new sites. Including other variables (soil moisture, tree cover, and dominant understorey growth form) improved model performance when predicting to new sites. Anticipating a drop in forage availability is critical for the management of grazing pressure for woodland regeneration, however, predicting understorey biomass through space and time is a challenge. Whilst remotely sensed VIs are promising as an easily-available source of vegetation information, additional landscape-scale data are required before they can be considered a cost-efficient method of understorey biomass estimation in this semi-arid landscape.

Many bridges and other structures worldwide present a lack of maintenance or a need for rehabilitation. The first step in the rehabilitation process is to perform a bridge inspection to know the bridge′s current state. Routine bridge inspections are usually based only on visual recognition. In this paper, a methodology for bridge inspections in communication routes using images acquired by unmanned aerial vehicle (UAV) flights is proposed. This provides access to the upper parts of the structure safely and without traffic disruptions. Then, a standardized and systematized novel image acquisition protocol is applied for data acquisition. Afterwards, the images are studied by civil engineers for damage identification and description. Then, specific structural inspection forms are completed using the acquired information. Recommendations about the need of new and more detailed inspections should be included at this stage when needed. The suggested methodology was tested on two railway bridges in France. Image acquisition of these structures was performed using an UAV for its ability to provide an expert assessment of the damage level. The main advantage of this method is that it makes it possible to safely accurately identify diverse damages in structures without the need for a specialised engineer to go to the site. Moreover, the videos can be watched by as many engineers as needed with no personal movement. The main objective of this work is to describe the systematized methodology for the development of bridge inspection tasks using a UAV system. According to this proposal, the in situ inspection by a specialised engineer is replaced by images and videos obtained from an UAV flight by a trained flight operator. To this aim, a systematized image/videos acquisition method is defined for the study of the morphology and typology of the structural elements of the inspected bridges. Additionally, specific inspection forms are proposed for every type of structural element. The recorded information will allow structural engineers to perform a postanalysis of the damage affecting the bridges and to evaluate the subsequent recommendations.

Gastric cancer (GC) is a significant cancer-related cause of death worldwide. The most used chemotherapeutic regimen in GC is based on platinum drugs such as cisplatin (CDDP). However, CDDP resistance reduces advanced GC survival. In vitro drug-resistant cell model would help in the understanding of molecular mechanisms underlying this drug-resistance phenomenon. The aim of this study was to characterize new models of CDDP-resistant GC cell lines (AGS R-CDDP and MKN-28 R-CDDP) obtained through a stepwise increasing drug doses method, in order to understand the molecular mechanisms underlying chemoresistance as well as identify new therapeutic targets for the treatment of GC. Cell viability assays, cell death assays and the expression of resistance molecular markers confirmed that AGS R-CDDP and MKN-28 R-CDDP are reliable CDDP-resistant models. RNA-seq and bioinformatics analyses identified a total of 189 DEGs, including 178 up-regulated genes and 11 down-regulated genes, associated mainly to molecular functions involved in CDDP-resistance. DEGs were enriched in 23 metabolic pathways, among which the most enriched was the inflammation mediated by chemokine and cytokine signaling pathway. Finally, the higher mRNA expression of SERPINA1, BTC and CCL5, three up-regulated DEGs associated to CDDP resistance found by RNA-seq analysis was confirmed. In summary, this study showed that AGS R-CDDP and MKN-28 R-CDDP are reliable models of CDDP resistance because resemble many of resistant phenotype in GC, being also useful to assess potential therapeutic targets for the treatment of gastric cancers resistant to CDDP. In addition, we identified several DEGs associated with molecular functions such as binding, catalytic activity, transcription regulator activity and transporter activity, as well as signaling pathways associated with inflammation process, which could be involved in the development of CDDP resistance in GC. Further studies are necessary to clarify the role of inflammatory processes in GC resistant to CDDP and these models could be useful for these purposes.

Alterations in the cortico-cerebellar-thalamic-cortical circuit might underlie the diversity of symptoms in schizophrenia. However, molecular changes in cerebellar neuronal circuits, part of this network, have not yet been fully determined. Using LC-MS/MS, we screened altered candidates in pooled grey matter of cerebellum from schizophrenia subjects who committed suicide (n = 4) and healthy individuals (n = 4). Further validation by immunoblotting of three selected candidates was performed in two cohorts comprising schizophrenia (n = 20), non-schizophrenia suicide (n = 6) and healthy controls (n = 21). We found 99 significantly altered proteins, 31 of them previously reported in other brain areas by proteomic studies. Transport function was the most enriched category, while cell communication was the most prevalent function. For validation, we selected the vacuolar proton pump subunit 1 (VPP1), from transport, and two EF-hand calcium-binding proteins, calmodulin and parvalbumin, from cell communication. All candidates showed significant changes in schizophrenia (n = 7) compared to controls (n = 7). VPP1 was altered in the non-schizophrenia suicide group and increased levels of parvalbumin were linked to antipsychotics. Further validation in an independent cohort of non-suicidal chronic schizophrenia subjects (n = 13) and non-psychiatric controls (n = 14) showed that parvalbumin was increased, while calmodulin was decreased in schizophrenia. Our findings provide evidence of calcium-binding protein dysregulation in the cerebellum in schizophrenia, suggesting an impact on normal calcium-dependent synaptic functioning of cerebellar circuits. Our study also links VPP1 to suicide behaviours, suggesting a possible impairment in vesicle neurotransmitter refilling and release in these phenotypes.

BackgroundGlobally, tobacco consumption continues to cause a huge burden of preventable diseases. Chile has been leading the tobacco burden ranking in the Latin American region for the last ten years; it has currently a 33. 3% prevalence of current smokers.MethodsA microsimulation economic model was developed within the framework of a multi-country project in order to estimate the burden attributable to smoking in terms of morbidity, mortality, disability-adjusted life-years (DALYs), and direct costs of care. We also modelled the impact of increasing cigarettes' taxes on this burden.ResultsIn Chile, 16,472 deaths were attributable to smoking in 2017, which represent around 16% of all deaths. This burden corresponds to 416,445 DALYs per year. The country's health system spends 1.15 trillion pesos annually (in Dec 2017 CLP, approx. U$D 1.8 billion) in health care treatment of illnesses caused by smoking. If the price of tobacco cigarettes was to be raised by 50%, around 13,665 deaths and 360,476 DALYs from smoking-attributable diseases would be averted in 10 years, with subsequent savings on health care costs, and increased tax revenue collection. In Chile, the tobacco tax collection does not fully cover the direct healthcare costs attributed to smoking.ConclusionDespite a reduction observed on smoking prevalence between 2010 (40.6%) and 2017 (33.3%), this study shows that the burden of disease, and the economic toll due to smoking, remain high. As we demonstrate, a rise in the price of cigarettes could lead to a significant reduction of this burden, averting deaths and disability, and reducing healthcare spending.