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Background Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab.Methods In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety.Results Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported.Conclusions Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile.Trial registration number NCT03212404.

La contribution relative de l’usage des antibiotiques en production animale sur la baisse de l’efficacité des antibiotiques utilisés en médecine humaine reste mal documentée, mais l’importance de ce problème de santé publique requiert de réduire leur usage. Le plan Ecoantibio 1, mis en œuvre entre 2012 et 2016, consiste en une approche volontaire coordonnée par le Ministère de l’Agriculture afin de limiter l’usage des antibiotiques dans les filières d’élevage. Ce plan, ainsi que l’ensemble des initiatives privées et publiques mises en place sur cette période ont permis une réduction massive de l’usage des antibiotiques. L’évaluation rétrospective présentée ici identifie les effets socio-économiques, aux niveaux individuels et structurels, de ce plan sur la filière porcine française, perçue comme forte utilisatrice d’antibiotiques. Pour ce faire, une enquête a été conduite auprès des parties prenantes. Les impacts socio-économiques du plan Ecoantibio 1 apparaissent modérés, au niveau des changements de pratiques, des transformations structurelles, et des effets économiques. Ce plan s’est inséré dans une dynamique professionnelle, amorcée par d’autres politiques publiques et des initiatives privées. D’un point de vue technique, la plupart des alternatives aux antibiotiques existaient avant la mise en œuvre du plan, comme la vaccination ou la biosécurité. Les relations entre parties prenantes de la filière porcine ont été soit peu impactées, soit renforcées. Enfin, ce plan n’a pas eu d’impact significatif sur la croissance des porcs ni sur les revenus des différents acteurs. In fine, le plan Ecoantibio 1 est venu confirmer la dynamique déjà à l’œuvre, tout en donnant une assise règlementaire à des pratiques déjà en place.

A reference genome sequence for Pseudotsuga menziesii var. menziesii (Mirb.) Franco (Coastal Douglas-fir) is reported, thus providing a reference sequence for a third genus of the family Pinaceae. The contiguity and quality of the genome assembly far exceeds that of other conifer reference genome sequences (contig N50 = 44,136 bp and scaffold N50 = 340,704 bp). Incremental improvements in sequencing and assembly technologies are in part responsible for the higher quality reference genome, but it may also be due to a slightly lower exact repeat content in Douglas-fir vs. pine and spruce. Comparative genome annotation with angiosperm species reveals gene-family expansion and contraction in Douglas-fir and other conifers which may account for some of the major morphological and physiological differences between the two major plant groups. Notable differences in the size of the NDH-complex gene family and genes underlying the functional basis of shade tolerance/intolerance were observed. This reference genome sequence not only provides an important resource for Douglas-fir breeders and geneticists but also sheds additional light on the evolutionary processes that have led to the divergence of modern angiosperms from the more ancient gymnosperms.

This article presents the results of measurements of the braking efficiency of vehicles adapted to be operated by drivers with motor dysfunctions. In such cars, the braking system is extended with an adaptive device that allows braking with the upper limb. This device applies pressure to the original brake in the car. The braking force and thus its efficiency depend on the mechanical ratio in the adapting device. In addition, braking performance depends on the sensitivity of the car’s original braking system and the maximum force that a disabled person can exert on the handbrake lever. Such a person may have limited power in the upper limbs. The force exerted by the driver can also be influenced by the position of the driver’s seat in relation to the handbrake lever. This article describes the research aimed at understanding the influence of the above-mentioned factors on the car braking performance. As a part of the analysis of the test results, a mathematical function was proposed that allows a parametric description of the braking efficiency index on the basis of data on the braking system, adaptation device, driver’s motor limitations, and the position of the driver’s seat. The information presented in this article can be used for the preliminary selection of adaptive devices to the needs of a given driver with a disability and to the vehicle construction.

Bacillus anthracis, the causative agent of anthrax in humans, livestock, and wildlife, exists in a community with hundreds of other species of bacteria in the environment. Work on the genetics of these communities has shown that B. anthracis shares a high percentage of chromosomal genes with both B. thuringiensis and B. cereus, and that phenotypic differences among these bacteria can result from extra-chromosomal DNA in the form of plasmids. We developed a simple hypothetical individual-based model to simulate the likelihood of detecting plasmids with genes encoding anthrax toxins within bacterial communities composed of B. anthracis, B. thuringiensis, and B. cereus, and the surrounding matrix of extra-cellular polymeric substances. Simulation results suggest the horizontal transfer of plasmids with genes encoding anthrax toxins among Bacillus species persisting outside the host could function as a proximate factor triggering anthrax outbreaks.

The work presents a simulation model of a “driver–automation–autonomous vehicles–road” system which is the basis for synthesis of automatic gear shift control system. The mathematical description makes use of physical quantities which characterise driving torque transformation from the combustion engine to the car driven wheels. The basic components of the model are algorithms for the driver’s action logic in controlling motion velocity, logic of gear shift control functioning regarding direction and moment of switching, for determining right-hand side of differential equations and for motion quality indicators. The model is realised in a form of an application software package, comprising sub-programmes for input data, for computerised motion simulation of cars with mechanical and hydro-mechanical – automatically controlled – transmission systems and for models of characteristic car routes.

In this paper, we studied some ferroelectric properties of archetypal oxide uniaxial ferroelectric single crystals of Pb5Ge3O11 modified by Ba ions. They include dielectric, DSC, ferroelectric polarization, and electrocaloric effect (ECE) measurements. The measurements show that increasing Ba doping considerably influences all the measured parameters, mainly by lowering the Curie temperature, gradually diffusing the phase transition, and decreasing values of polarization as well as the coercive field. The decrease in overall ECE is influenced by decreasing polarization. Compared with the pure PGO single crystals, this decrease is from 1.2 K to 0.2 K. However, the effect of diffusing the phase transition increases the range of its occurrence (up to 30 K), which might be beneficial in applications.

Background and study aims Anticoagulation (AC) and antiplatelet (AP) therapy may increase the risk of gastrointestinal bleeding after double balloon enteroscopy (DBE); however, limited data are currently available regarding the incidence. The aim of this study was to assess the incidence and clinical characteristics of post-DBE bleeding in patients on AC and AP therapy. Patients and methods The medical records of patients who underwent DBE between 2009 and 2013 at Mayo Clinic, Florida, were retrospectively reviewed. Patients were divided into three groups: 1) continued AP therapy; 2) AC therapy; and 3) neither AP nor AC at the time of DBE. Follow-up data were collected at 60 days and 1 year. Results A total of 683 patients were identified; 43 on AC, 183 on AP and 457 not on AP or AC therapy. The most common indication for DBE was obscure gastrointestinal bleeding in the groups on and not on AP (85.3 % vs 70.9 %, P 3 and indication for DBE of GI bleeding were independent risk factors for post-DBE bleeding within 1 year. Conclusions Continued antiplatelet use at the time of DBE was not an independent risk factor for bleeding post-DBE at 60 days or 1 year of follow up.

Abstract Background Invasions by non-native plants contribute to loss of ecosystem biodiversity and productivity, modification of biogeochemical cycles, and inhibition of natural regeneration of native species. Japanese stiltgrass (Microstegium vimineum (Trin.) A. Campus) is one of the most prevalent invasive grasses in the forestlands of Tennessee, United States. We measured the extent of invasion, identified potential factors affecting invasion, and quantified the relative importance of each factor. We analyzed field data collected by the Forest Inventory and Analysis Program of the U.S. Forest Service to measure the extent of invasion from 2005 to 2011 and identified potential factors affecting invasion during this period using boosted regression trees. Results Our results indicated that presence of Japanese stiltgrass on sampled plots increased 50% (from 269 to 404 plots) during the time period. The probability of invasion was correlated with one landscape condition (elevation) (20.5%) and five forest features (including tree species diversity, basal area, stand age, site productivity, and natural regeneration) (79.5%). Boosted regression trees identified the most influential (highly correlated) variables as tree species diversity (30.7%), basal area (22.9%), elevation (20.5%), and stand age (16.7%). Our results suggest that Japanese stiltgrass is likely to continue its invasion in Tennessee forests. Conclusions The present model, in addition to correlating the probability of Japanese stiltgrass invasions with current climatic conditions and landscape attributes, could aid in the on-going development of control strategies for confronting Japanese stiltgrass invasions by identifying vulnerable areas that might emerge as a result of likely changes in climatic conditions and land use patterns.

A reference genome sequence for Pseudotsuga menziesii var. menziesii (Mirb.) Franco (Coastal Douglas-fir) is reported, thus providing a reference sequence for a third genus of the family Pinaceae. The contiguity and quality of the genome assembly far exceeds that of other conifer reference genome sequences (contig N50 = 44,136 bp and scaffold N50 = 340,704 bp). Incremental improvements in sequencing and assembly technologies are in part responsible for the higher quality reference genome, but it may also be due to a slightly lower exact repeat content in Douglas-fir vs. pine and spruce. Comparative genome annotation with angiosperm species reveals gene-family expansion and contraction in Douglas-fir and other conifers which may account for some of the major morphological and physiological differences between the two major plant groups. Notable differences in the size of the NDH-complex gene family and genes underlying the functional basis of shade tolerance/intolerance were observed. This reference genome sequence not only provides an important resource for Douglas-fir breeders and geneticists but also sheds additional light on the evolutionary processes that have led to the divergence of modern angiosperms from the more ancient gymnosperms.

Oksana Gorobets,1,2 Svitlana Gorobets,1 Marceli Koralewski3 1National Technical University of Ukraine (Igor Sikorsky Kyiv Polytechnic Institute), 2Institute of Magnetism, National Academy of Sciences, Kiev, Ukraine; 3Faculty of Physics, Adam Mickiewicz University, Poznan, Poland Abstract: The discovery of biogenic magnetic nanoparticles (BMNPs) in the human brain gives a strong impulse to study and understand their origin. Although knowledge of the subject is increasing continuously, much remains to be done for further development to help our society fight a number of pathologies related to BMNPs. This review provides an insight into the puzzle of the physiological origin of BMNPs in organisms of all three domains of life: prokaryotes, archaea, and eukaryotes, including humans. Predictions based on comparative genomic studies are presented along with experimental data obtained by physical methods. State-of-the-art understanding of the genetic control of biomineralization of BMNPs and their properties are discussed in detail. We present data on the differences in BMNP levels in health and disease (cancer, neurodegenerative disorders, and atherosclerosis), and discuss the existing hypotheses on the biological functions of BMNPs, with special attention paid to the role of the ferritin core and apoferritin. Keywords: biogenic magnetic nanoparticles, biomineralization, ferritin, magnetoferritin, genetic control, neurodegenerative disorders, cancer

Invasive plants decrease biodiversity, modify vegetation structure, and inhibit growth and reproduction of native species. Japanese honeysuckle (Lonicera japonica Thunb.) is the most prevalent invasive vine in the forestlands of eastern Texas. Hence, we aimed to identify potential factors influencing the distribution of the species, quantify the relative importance of each factor, and test possible management strategies. We analyzed an extensive dataset collected as part of the Forest Inventory and Analysis Program of the United States Department of Agriculture (USDA) Forest Service to quantify the range expansion of Japanese honeysuckle in the forestlands of eastern Texas from 2006 to 2011. We then identified potential factors influencing the likelihood of presence of Japanese honeysuckle using boosted regression trees. Our results indicated that the presence of Japanese honeysuckle on sampled plots almost doubled during this period (from 352 to 616 plots), spreading extensively, geographically. The probability of invasion was correlated with variables representing landscape conditions, climatic conditions, forest features, disturbance factors, and forest management activities. Habitats most at risk to invasion under current conditions occurred primarily in northeastern Texas, with a few invasion hotspots in the south. Estimated probabilities of invasion were reduced most by artificial site regeneration, with habitats most at risk again occurring primarily in northeastern Texas.

Celem artykułu jest przedstawienie zagadnienia podstawy przetwarzania danych w celach marketingowych przez przedsiębiorców telekomunikacyjnych. Główny problem dotyczy stosunku przepisów sektorowych, jakimi są przepisy prawa telekomunikacyjnego do przepisów ogólnych wynikających z ustawy o ochronie danych osobowych. Zagadnienie to wymaga analizy kolizji norm, do której dochodzi pomiędzy tymi ustawami, w szczególności ustalenia treści normy kolizyjnej zawartej w art. 5 ustawy o ochronie danych osobowych, stanowiącym podstawę wyznaczania relacji przepisów ogólnych i sektorowych w tym zakresie.

Artykuł omawia warunki prawne świadczenia usług opartych na przetwarzaniu danych geograficznych (Location Based Services LBS). Wskazuje w jaki sposób pozyskiwane są dane o położeniu geograficznym urządzeń mobilnych, bez których świadczenie usług LBS nie byłoby możliwe. Artykuł identyfikuje i omawia zależności pomiędzy sposobem pozyskiwania danych o położeniu geograficznym a regulacjami prawnymi, które mają zastosowanie do danego przypadku.

Prolonged physical exercise is associated with several immunological changes, e.g. increase in proinflammatory cytokines, changes in the white blood count etc. Great discrepancies exist with regard to the exercise- induced influence on serum immunoglobulin and neopterin values. One explanation could be the shifts in plasma volume (PV) during and after exercise which might influence plasma concentrations of these parameters. Therefore we investigated the consequences of a marathon race in a homogenous group of experienced runners on plasma volume shifts, serum Immunglobulin and neopterin concentrations. Plasma values with and without correction for plasma volume shifts were compared. PV was significantly diminished after the race (-8.4%) followed by a rise 34h after finish (+8.5%). Serum immunoglobulin IgG, IgA and IgM were increased within the first hours postmarathon and normalized in the recovery period. When chages in PV were considered, only IgA rose significantly. Serum neopterin remained unchanged after the marathon independently whether corrected for PV changes or not. We conclude that the increase in immunoglobulins in our study was mainly the consequence of plasma volume changes. Since neopterin was unchanged we have at least in our study no evidence for exercise-induced activation of the cellular immune system.

Economic costs associated with the invasion of nonnative species are of global concern. We estimated expected costs of Chinese tallow (Triadica sebifera (L.) Small) invasions related to timber production in southern U.S. forestlands under different management strategies. Expected costs were confined to the value of timber production losses plus costs for search and control. We simulated management strategies including (1) no control (NC), and control beginning as soon as the percentage of invaded forest land exceeded (2) 60 (Low Control), (3) 25 (Medium Control), or (4) 0 (High Control) using a spatially-explicit, stochastic, bioeconomic model. With NC, simulated invasions spread northward and westward into Arkansas and along the Gulf of Mexico to occupy ≈1.2 million hectares within 20 years, with associated expected total costs increasing exponentially to ≈$300 million. With LC, MC, and HC, invaded areas reached ≈275, 34, and 2 thousand hectares after 20 years, respectively, with associated expected costs reaching ≈$400, $230, and $200 million. Complete eradication would not be cost-effective; the minimum expected total cost was achieved when control began as soon as the percentage of invaded land exceeded 5%. These results suggest the importance of early detection and control of Chinese tallow, and emphasize the importance of integrating spread dynamics and economics to manage invasive species.

Despite significant advances in high-throughput DNA sequencing, many important species remain understudied at the genome level. In this study we addressed a question of what can be predicted about the genome-wide characteristics of less studied species, based on the genomic data from completely sequenced species. Using NCBI databases we performed a comparative genome-wide analysis of such characteristics as alternative splicing, number of genes, gene products and exons in 36 completely sequenced model species. We created statistical regression models to fit these data and applied them to loblolly pine (Pinus taeda L.), an example of an important species whose genome has not been completely sequenced yet. Using these models, the genome-wide characteristics, such as total number of genes and exons, can be roughly predicted based on parameters estimated from available limited genomic data, e.g. exon length and exon/gene ratio.