CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Ecological filtering shapes the impacts of agricultural deforestation on biodiversity.

The biodiversity impacts of agricultural deforestation vary widely across regions. Previous efforts to explain this variation have focused exclusively on the landscape features and management regimes of agricultural systems, neglecting the potentially critical role of ecological filtering in shaping deforestation tolerance of extant species assemblages at large geographical scales via selection for functional traits. Here we provide a large-scale test of this role using a global database of species abundance ratios between matched agricultural and native forest sites that comprises 71 avian assemblages reported in 44 primary studies, and a companion database of 10 functional traits for all 2,647 species involved. Using meta-analytic, phylogenetic and multivariate methods, we show that beyond agricultural features, filtering by the extent of natural environmental variability and the severity of historical anthropogenic deforestation shapes the varying deforestation impacts across species assemblages. For assemblages under greater environmental variability-proxied by drier and more seasonal climates under a greater disturbance regime-and longer deforestation histories, filtering has attenuated the negative impacts of current deforestation by selecting for functional traits linked to stronger deforestation tolerance. Our study provides a previously largely missing piece of knowledge in understanding and managing the biodiversity consequences of deforestation by agricultural deforestation.

Case report emphasize pearls of duodenal perforation.

INTRODUCTION: Isolated duodenal perforation secondary to trauma is a rare abdominal surgical condition, with a questionable surgical approach depending on the case. PRESENTATION OF CASE: This is a case report of a 27-year-old male patient who presented with a free perforation in the posterior wall of the third portion of the duodenal frame and secondary retropneumoperitoneum without injuring any contiguous organ, after a medium-impact blunt abdominal trauma during a soccer game. DISCUSSION: A laparotomy was performed, followed by duodenorraphy with Connell-Mayo suture and Lambert suture using vascular prolene in two planes. A nasogastric tube was placed up to the jejunum, and a Jackson-Pratt drain was placed in close to the duodenum next to the sutures. During hospitalization was found a positive bacterial culture of the peritoneal fluid hence received antibiotics, without complication. CONCLUSION: It is essential to make a timely diagnosis with its respective individualized surgical approach and it must be managed as an emergency surgical procedure.

Genetic mapping of maize metabolites using high-throughput mass profiling.

Plant metabolites are the basis of human nutrition and have biological relevance in ecology. Farmers selected plants with favorable characteristics since prehistoric times and improved the cultivars, but without knowledge of underlying mechanisms. Understanding the genetic basis of metabolite production can facilitate the successful breeding of plants with augmented nutritional value. To identify genetic factors related to the metabolic composition in maize, we generated mass profiles of 198 recombinant inbred lines (RILs) and their parents (B73 and Mo17) using direct-injection electrospray ionization mass spectrometry (DLI-ESI MS). Mass profiling allowed the correct clustering of samples according to genotype. We quantified 71 mass features from grains and 236 mass features from leaf extracts. For the corresponding ions, we identified tissue-specific metabolic 'Quantitative Trait Loci' (mQTLs) distributed across the maize genome. These genetic regions could regulate multiple metabolite biosynthesis pathways. Our findings demonstrate that DLI-ESI MS has sufficient analytical resolution to map mQTLs. These identified genetic loci will be helpful in metabolite-focused maize breeding. Mass profiling is a powerful tool for detecting mQTLs in maize and enables the high-throughput screening of loci responsible for metabolite biosynthesis.

Are birds more afraid in urban parks or cemeteries? A Latin American study contrasts with results from Europe.

The escape behaviour, measured as flight initiation distance (FID; the distance at which individuals take flight when approached by a potential predator, usually a human in the study systems), is a measure widely used to study fearfulness and risk-taking in animals. Previous studies have shown significant differences in the escape behaviour of birds inhabiting cemeteries and urban parks in European cities, where birds seem to be shyer in the latter. We collected a regional dataset of the FID of birds inhabiting cemeteries and parks across Latin America in peri-urban, suburban and urban parks and cemeteries. FIDs were recorded for eighty-one bird species. Mean species-specific FIDs ranged from 1.9 to 19.7 m for species with at least two observations (fifty-seven species). Using Bayesian regression modelling and controlling for the phylogenetic relatedness of the FID among bird species and city and country, we found that, in contrast to a recent publication from Europe, birds escape earlier in cemeteries than parks in the studied Latin American cities. FIDs were also significantly shorter in urban areas than in peri-urban areas and in areas with higher human density. Our results indicate that some idiosyncratic patterns in animal fearfulness towards humans may emerge among different geographic regions, highlighting difficulties with scaling up and application of regional findings to other ecosystems and world regions. Such differences could be associated with intrinsic differences between the pool of bird species from temperate European and mostly tropical Latin American cities, characterized by different evolutionary histories, but also with differences in the historical process of urbanization.

Association of the Surgical Technique With the Structural Valve Deterioration of a Bioprosthesis: A Prospective Cohort Study.

The Trifecta aortic valve is a prosthesis with externally mounted leaflets and a stent which may be deformed during implant. Our aim was to know if the use of the holder as a protection device during the knotting has an impact on the incidence of structural valve deterioration (SVD) or endocarditis. Prospective cohort study where all patients who underwent aortic valve replacement with a Trifecta aortic valve between 2013 and 2018 were included. The use of the holder as a protection device was collected in a database. Propensity-score matched methods were used and analyses were based on competing events. Death without SVD or prosthesis replacement not due to SVD was considered competing events. 782 patients were included, 352 pairs after the matching. Rates of SVD at 5 and 8 years were 5.8% (95% CI 3.5-8.7) and 13.6% (95% CI 9.2-18.9) in the group without holder and 2.3% (95% CI 1-4.5) and 7% (95% CI 4.2-10.8) in the group with holder; sHR = 0.49 (95% CI 0.27-0.86; P = 0.015). The risk of endocarditis at 8 years was 4.8% (95% CI 2.8-7.4) in the group without holder and 2.3% (95% CI 1.1-4.3) in the group with holder, sHR = 0.49 (95% CI 0.21-1.15, P = 0.1). The use of holder as a protection device during the knotting of the Trifecta aortic valve is associated with less risk of SVD.

Applicability of a Material Constitutive Model Based on a Transversely Isotropic Behaviour for the Prediction of the Mechanical Performance of Multi Jet Fusion Printed Polyamide 12 Parts.

Multi Jet Fusion (MJF), an innovative additive manufacturing (AM) technique in the field of Powder Bed Fusion (PBF) developed by Hewlett-Packard (HP) Inc. (Palo Alto, CA, USA), has been designed to produce polymer parts using thermoplastic-based powders, primarily focusing on polyamide 12 (PA12). Employing a layer-by-layer approach, MJF enables the rapid production of intricate components, reportedly up to 10 times faster than other AM processes. While the mechanical properties of MJF-printed PA12 and the impact of build orientation on those properties have already been explored in various studies, less attention has been given to the mechanical performance of MJF-printed PA12 components under complex loads and accurate predictive models. This contribution aims to assess the applicability of a constitutive model based on a transversely isotropic behaviour under linear elastic deformation for predicting the mechanical response of MJF-printed PA12 parts through numerical simulations. Both uniaxial tensile and shear tests were carried out on printed samples to determine the elastic properties of MJF-printed PA12, with additional testing on printed complex handle-shaped parts. Finally, a numerical model was developed to simulate the mechanical tests of the handles. Results from tests on printed samples showed that MJF-printed PA12, to some extent, behaves as a transversely isotropic material. Furthermore, using a constitutive model that assumes a transversely isotropic behaviour under linear elastic deformation for predicting the mechanical response of MJF-printed PA12 parts in numerical simulations could be a reasonable approach, provided that the material stress levels remain within the linear range. However, the particularities of the stress-strain curve of MJF-printed PA12 complicate determining the elasticity-to-plasticity transition point.

Allele-specific Expression Reveals Multiple Paths to Highland Adaptation in Maize.

Maize is a staple food of smallholder farmers living in highland regions up to 4,000 m above sea level worldwide. Mexican and South American highlands are two major highland maize growing regions, and population genetic data suggest the maize's adaptation to these regions occurred largely independently, providing a case study for convergent evolution. To better understand the mechanistic basis of highland adaptation, we crossed maize landraces from 108 highland and lowland sites of Mexico and South America with the inbred line B73 to produce F1 hybrids and grew them in both highland and lowland sites in Mexico. We identified thousands of genes with divergent expression between highland and lowland populations. Hundreds of these genes show patterns of convergent evolution between Mexico and South America. To dissect the genetic architecture of the divergent gene expression, we developed a novel allele-specific expression analysis pipeline to detect genes with divergent functional cis-regulatory variation between highland and lowland populations. We identified hundreds of genes with divergent cis-regulation between highland and lowland landrace alleles, with 20 in common between regions, further suggesting convergence in the genes underlying highland adaptation. Further analyses suggest multiple mechanisms contribute to this convergence in gene regulation. Although the vast majority of evolutionary changes associated with highland adaptation were region specific, our findings highlight an important role for convergence at the gene expression and gene regulation levels as well.

Genome sequencing reveals evidence of adaptive variation in the genus Zea.

Maize is a globally valuable commodity and one of the most extensively studied genetic model organisms. However, we know surprisingly little about the extent and potential utility of the genetic variation found in wild relatives of maize. Here, we characterize a high-density genomic variation map from 744 genomes encompassing maize and all wild taxa of the genus Zea, identifying over 70 million single-nucleotide polymorphisms. The variation map reveals evidence of selection within taxa displaying novel adaptations. We focus on adaptive alleles in highland teosinte and temperate maize, highlighting the key role of flowering-time-related pathways in their adaptation. To show the utility of variants in these data, we generate mutant alleles for two flowering-time candidate genes. This work provides an extensive sampling of the genetic diversity of Zea, resolving questions on evolution and identifying adaptive variants for direct use in modern breeding.

Thermal Water Prospection with UAV, Low-Cost Sensors and GIS. Application to the Case of La Hermida.

The geothermal resource is one of the great sources of energy on the planet. The conventional prospecting of this type of energy is a slow process that requires a great amount of time and significant investments. Nowadays, geophysical techniques have experienced an important evolution due to the irruption of UAVs, which combined with infrared sensors can provide great contributions in this field. The novelty of this technology involves the lack of tested methodologies for their implementation in this type of activities. The research developed is focused on the proposal of a methodology for the exploration of hydrothermal resources in an easy, economic, and rapid way. The combination of photogrammetry techniques with visual and thermal images taken with UAVs allows the generation of temperature maps or thermal orthomosaics, which analyzed with GIS tools permit the quasi-automatic identification of zones of potential geothermal interest along rivers or lakes. The proposed methodology has been applied to a case study in La Hermida (Cantabria, Spain), where it has allowed the identification of an effluent with temperatures close to 40 °C, according to the verification measurements performed on the geothermal interest area. These results allow validation of the potential of the method, which is strongly influenced by the particular characteristics of the study area.

An adaptive teosinte mexicana introgression modulates phosphatidylcholine levels and is associated with maize flowering time.

Native Americans domesticated maize (Zea mays ssp. mays) from lowland teosinte parviglumis (Zea mays ssp. parviglumis) in the warm Mexican southwest and brought it to the highlands of Mexico and South America where it was exposed to lower temperatures that imposed strong selection on flowering time. Phospholipids are important metabolites in plant responses to low-temperature and phosphorus availability and have been suggested to influence flowering time. Here, we combined linkage mapping with genome scans to identify High PhosphatidylCholine 1 (HPC1), a gene that encodes a phospholipase A1 enzyme, as a major driver of phospholipid variation in highland maize. Common garden experiments demonstrated strong genotype-by-environment interactions associated with variation at HPC1, with the highland HPC1 allele leading to higher fitness in highlands, possibly by hastening flowering. The highland maize HPC1 variant resulted in impaired function of the encoded protein due to a polymorphism in a highly conserved sequence. A meta-analysis across HPC1 orthologs indicated a strong association between the identity of the amino acid at this position and optimal growth in prokaryotes. Mutagenesis of HPC1 via genome editing validated its role in regulating phospholipid metabolism. Finally, we showed that the highland HPC1 allele entered cultivated maize by introgression from the wild highland teosinte Zea mays ssp. mexicana and has been maintained in maize breeding lines from the Northern United States, Canada, and Europe. Thus, HPC1 introgressed from teosinte mexicana underlies a large metabolic QTL that modulates phosphatidylcholine levels and has an adaptive effect at least in part via induction of early flowering time.

Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis.

PURPOSE: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. PATIENTS AND METHODS: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). RESULTS: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Demonstration of local adaptation in maize landraces by reciprocal transplantation.

Populations are locally adapted when they exhibit higher fitness than foreign populations in their native habitat. Maize landrace adaptations to highland and lowland conditions are of interest to researchers and breeders. To determine the prevalence and strength of local adaptation in maize landraces, we performed a reciprocal transplant experiment across an elevational gradient in Mexico. We grew 120 landraces, grouped into four populations (Mexican Highland, Mexican Lowland, South American Highland, South American Lowland), in Mexican highland and lowland common gardens and collected phenotypes relevant to fitness and known highland-adaptive traits such as anthocyanin pigmentation and macrohair density. 67k DArTseq markers were generated from field specimens to allow comparisons between phenotypic patterns and population genetic structure. We found phenotypic patterns consistent with local adaptation, though these patterns differ between the Mexican and South American populations. Quantitative trait differentiation (Q ST) was greater than neutral allele frequency differentiation (F ST) for many traits, signaling directional selection between pairs of populations. All populations exhibited higher fitness metric values when grown at their native elevation, and Mexican landraces had higher fitness than South American landraces when grown in these Mexican sites. As environmental distance between landraces' native collection sites and common garden sites increased, fitness values dropped, suggesting landraces are adapted to environmental conditions at their natal sites. Correlations between fitness and anthocyanin pigmentation and macrohair traits were stronger in the highland site than the lowland site, supporting their status as highland-adaptive. These results give substance to the long-held presumption of local adaptation of New World maize landraces to elevation and other environmental variables across North and South America.

Penicillin-Binding Proteins, ß-Lactamases, and ß-Lactamase Inhibitors in ß-Lactam-Producing Actinobacteria: Self-Resistance Mechanisms.

The human society faces a serious problem due to the widespread resistance to antibiotics in clinical practice. Most antibiotic biosynthesis gene clusters in actinobacteria contain genes for intrinsic self-resistance to the produced antibiotics, and it has been proposed that the antibiotic resistance genes in pathogenic bacteria originated in antibiotic-producing microorganisms. The model actinobacteria Streptomyces clavuligerus produces the ß-lactam antibiotic cephamycin C, a class A ß-lactamase, and the ß lactamases inhibitor clavulanic acid, all of which are encoded in a gene supercluster; in addition, it synthesizes the ß-lactamase inhibitory protein BLIP. The secreted clavulanic acid has a synergistic effect with the cephamycin produced by the same strain in the fight against competing microorganisms in its natural habitat. High levels of resistance to cephamycin/cephalosporin in actinobacteria are due to the presence (in their ß-lactam clusters) of genes encoding PBPs which bind penicillins but not cephalosporins. We have revised the previously reported cephamycin C and clavulanic acid gene clusters and, in addition, we have searched for novel ß-lactam gene clusters in protein databases. Notably, in S. clavuligerus and Nocardia lactamdurans, the ß-lactamases are retained in the cell wall and do not affect the intracellular formation of isopenicillin N/penicillin N. The activity of the ß-lactamase in S. clavuligerus may be modulated by the ß-lactamase inhibitory protein BLIP at the cell-wall level. Analysis of the ß-lactam cluster in actinobacteria suggests that these clusters have been moved by horizontal gene transfer between different actinobacteria and have culminated in S. clavuligerus with the organization of an elaborated set of genes designed for fine tuning of antibiotic resistance and cell wall remodeling for the survival of this Streptomyces species. This article is focused specifically on the enigmatic connection between ß-lactam biosynthesis and ß-lactam resistance mechanisms in the producer actinobacteria.

ROOT PENETRATION INDEX 3, a major quantitative trait locus associated with root system penetrability in Arabidopsis.

Soil mechanical impedance precludes root penetration, confining root system development to shallow soil horizons where mobile nutrients are scarce. Using a two-phase-agar system, we characterized Arabidopsis responses to low and high mechanical impedance at three root penetration stages. We found that seedlings whose roots fail to penetrate agar barriers show a significant reduction in leaf area, root length, and elongation zone and an increment in root diameter, while those capable of penetrating show only minor morphological effects. Analyses using different auxin-responsive reporter lines, exogenous auxins, and inhibitor treatments suggest that auxin responsiveness and PIN-mediated auxin distribution play an important role in regulating root responses to mechanical impedance. The assessment of 21 Arabidopsis accessions revealed that primary root penetrability varies widely among accessions. To search for quantitative trait loci (QTLs) associated to root system penetrability, we evaluated a recombinant inbred population derived from Landsberg erecta (Ler-0, with a high primary root penetrability) and Shahdara (Sha, with a low primary root penetrability) accessions. QTL analysis revealed a major-effect QTL localized in chromosome 3, ROOT PENETRATION INDEX 3 (q-RPI3), which accounted for 29.98% (logarithm of odds=8.82) of the total phenotypic variation. Employing an introgression line (IL-321) with a homozygous q-RPI3 region from Sha in the Ler-0 genetic background, we demonstrated that q-RPI3 plays a crucial role in root penetrability. This multiscale study reveals new insights into root plasticity during the penetration process in hard agar layers, natural variation, and genetic architecture behind primary root penetrability in Arabidopsis.

Tuberculosis endobronquial / Endobronchial Tuberculosis

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[Translated article] Endobronchial Tuberculosis / Tuberculosis endobronquial

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A B73×Palomero Toluqueño mapping population reveals local adaptation in Mexican highland maize.

Generations of farmer selection in the central Mexican highlands have produced unique maize varieties adapted to the challenges of the local environment. In addition to possessing great agronomic and cultural value, Mexican highland maize represents a good system for the study of local adaptation and acquisition of adaptive phenotypes under cultivation. In this study, we characterize a recombinant inbred line population derived from the B73 reference line and the Mexican highland maize variety Palomero Toluqueño. B73 and Palomero Toluqueño showed classic rank-changing differences in performance between lowland and highland field sites, indicative of local adaptation. Quantitative trait mapping identified genomic regions linked to effects on yield components that were conditionally expressed depending on the environment. For the principal genomic regions associated with ear weight and total kernel number, the Palomero Toluqueño allele conferred an advantage specifically in the highland site, consistent with local adaptation. We identified Palomero Toluqueño alleles associated with expression of characteristic highland traits, including reduced tassel branching, increased sheath pigmentation and the presence of sheath macrohairs. The oligogenic architecture of these three morphological traits supports their role in adaptation, suggesting they have arisen from consistent directional selection acting at distinct points across the genome. We discuss these results in the context of the origin of phenotypic novelty during selection, commenting on the role of de novo mutation and the acquisition of adaptive variation by gene flow from endemic wild relatives.

Energetic optimization of an autonomous mobile socially assistive robot for autism spectrum disorder.

The usage of socially assistive robots for autism therapies has increased in recent years. This novel therapeutic tool allows the specialist to keep track of the improvement in socially assistive tasks for autistic children, who hypothetically prefer object-based over human interactions. These kinds of tools also allow the collection of new information to early diagnose neurodevelopment disabilities. This work presents the integration of an output feedback adaptive controller for trajectory tracking and energetic autonomy of a mobile socially assistive robot for autism spectrum disorder under an event-driven control scheme. The proposed implementation integrates facial expression and emotion recognition algorithms to detect the emotions and identities of users (providing robustness to the algorithm since it automatically generates the missing input parameters, which allows it to complete the recognition) to detonate a set of adequate trajectories. The algorithmic implementation for the proposed socially assistive robot is presented and implemented in the Linux-based Robot Operating System. It is considered that the optimization of energetic consumption of the proposal is the main contribution of this work, as it will allow therapists to extend and adapt sessions with autistic children. The experiment that validates the energetic optimization of the proposed integration of an event-driven control scheme is presented.