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To contend with the diversity and ubiquity of bacteriophages and other mobile genetic elements, bacteria have developed an arsenal of immune defence mechanisms. Bacterial defences include CRISPR–Cas, restriction–modification and a growing list of mechanistically diverse systems, which constitute the bacterial ‘immune system’. As a response, bacteriophages and mobile genetic elements have evolved direct and indirect mechanisms to circumvent or block bacterial defence pathways and ensure successful infection. Recent advances in methodological and computational approaches, as well as the increasing availability of genome sequences, have boosted the discovery of direct inhibitors of bacterial defence systems. In this Review, we discuss methods for the discovery of direct inhibitors, their diverse mechanisms of action and perspectives on their emerging applications in biotechnology and beyond.

People with bipolar disorder (BD) have an increased risk of premature mortality and the respiratory mortality rate is higher than those of the general population. To date, however, the evidence on respiratory disease in this population has not been meta-analyzed. We systematically review and meta-analyze the frequency of respiratory diseases in patients with BD and to compare prevalence and odds ratio (OR) with the general population. The systematic literature search was conducted in Pubmed, PsycINFO, Scielo and Scopus, with snowball search of reference and citation lists. Inclusion criteria were studies reporting diagnoses of respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), pneumonia, lung cancer and tuberculosis) in people with BD according to operationalized criteria and where possible, control group. Of the 2158 articles screened, 20 including 962,352 people with BD and 37,340,405 control group, met the inclusion criteria. In people with BD, the prevalence of COPD was 9.14% (95%CI: 6.61–12.5%), asthma 6.4% (95%CI: 4.56–8.91%), pneumonia 2.78% (95%CI: 2.51–3.08%) and lung cancer 0.44% (95%CI:0.23–0.84%). Compared to the general population, people with BD had significantly higher rates of COPD (OR: 1.73; 95% CI: 1.40–2.14), showing an increased rate in younger and female patients; asthma (OR: 1.91, 95% CI: 1.25–2.94), with a greater rate in younger patients; and pneumonia (OR: 2.82, 95% CI: 1.33–5.99). In the first meta-analysis on the topic, BD was associated with an increased risk of respiratory illness versus the general population. In COPD and asthma, young people and women are at particular risk. Prevention programs are urgently needed.

The Single Supervisory Mechanism (SSM) is a relatively recent and remarkable piece of institutional architecture at the core of the Banking Union. The vast powers conferred on the ECB under the SSM, the complexity of coordination and the sensitive nature of some decisions allocated to the EU level make accountability a key requisite for the system’s success. Some of the provisions applicable provide a solid foundation for a system of strong accountability. Recently, the need to offer a credible response to climate change risks have added additional challenges to ECB accountability under the SSM. Accordingly, there is room to improve the system to effectively counterbalance the powers given to the SSM to increase their accountability at the European level without undermining their independence and within the boundaries of the current legal framework.

Within the institutional architecture for financial supervision within the EU, courts coexist with quasi-courts, i. e., review bodies like the ESAs Joint Board of Appeal, the SSM’s Administrative Board of Review (ABoR) and the SRB’s Appeal Panel. This has parallels e. g. US Administrative Law Judges (ALJs). Some argue that this flight away from courts is justified because administrative law and procedure are more flexible. Yet administrative mechanisms are deceptively simple. This paper offers a cautionary tale about the complexities of all quasi-judicial arrangements and their competing and complementary role with courts and presents an analysis of the European framework from both a functional and a comparative perspective.

Many bacteria use CRISPR–Cas systems to combat mobile genetic elements, such as bacteriophages and plasmids1. In turn, these invasive elements have evolved anti-CRISPR proteins to block host immunity2,3. Here we unveil a distinct type of CRISPR–Cas Inhibition strategy that is based on small non-coding RNA anti-CRISPRs (Racrs). Racrs mimic the repeats found in CRISPR arrays and are encoded in viral genomes as solitary repeat units4. We show that a prophage-encoded Racr strongly inhibits the type I-F CRISPR–Cas system by interacting specifically with Cas6f and Cas7f, resulting in the formation of an aberrant Cas subcomplex. We identified Racr candidates for almost all CRISPR–Cas types encoded by a diverse range of viruses and plasmids, often in the genetic context of other anti-CRISPR genes5. Functional testing of nine candidates spanning the two CRISPR–Cas classes confirmed their strong immune inhibitory function. Our results demonstrate that molecular mimicry of CRISPR repeats is a widespread anti-CRISPR strategy, which opens the door to potential biotechnological applications6.

To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae.

On 30 January 2020, the Court of Justice of the European Union (CJEU) delivered its judgment in the Case C 394/18 I.G.I. Srl v. Maria Grazia Cicenia et al.The case offers an interpretation of the Directive on corporate divisions in a case that fell outside its scope, and a delicate balancing act between the need to protect legal certainty in corporate divisions, and the need to respect Private Law remedies enshrined in domestic civil codes. The CJEU ruled that the rules of the Sixth Council Directive 82/891/EEC did not preclude the creditors of a company being divided from bringing an actio paulianaagainst the corporate division, in order to obtain a declaration that the division does not have effects against them, nor did it preclude them from bringing enforcement proceedings against the assets transferred to the newly formed company.

Letter to the Editor

Scientifically robust analysis of trade-offs for onshore gas activity can inform the design of strategies for socially acceptable and efficient use of energy resources. Here, we present lessons from a portfolio of research spanning three States and different industry stages conducted as part of the Gas Industry Social and Environmental Research Alliance (GISERA). Considering the effects of onshore gas development on regional economies, an important lesson is to look at net changes, considering decreases as well as increases in economic activity. In Queensland, where competing claims about employment effects were raised in public debates, measuring reduced agricultural employment in addition to increases to the number of jobs in other sectors were crucial to providing a balanced analysis. Another lesson is to take a broad view of economic dimensions beyond employment and income. Our research shifted the public debate when we demonstrated that the construction phase in Queensland improved youth retention, gender balance and skill levels. Another lesson is that economic effects of gas development (positive or negative) can occur before stakeholders expect them. In New South Wales, we observed that the exploration phase had a significant positive effect on income (but not employment). A further lesson is that effects differ between domestic and export markets. Research from South Australia has demonstrated that the potential regional benefits of gas development substantially depend on meeting the energy needs of other local industries such as manufacturing. These lessons can inform public debate and policy settings and help balance different priorities such as energy needs, regional development and environmental sustainability.

AbstractThe Atlantic Motorway, AP-9, crosses the Vigo estuary in Spain by means of a 400 m span cable-stayed bridge with a composite deck over the Rande Strait. This bridge was built between 1973 and 1977, and opened to traffic in 1981. In 2006, the average daily traffic reached 55 000 vehicles, close to its effective capacity, and therefore resulted in frequent traffic congestion conditions. To increase the bridge’s traffic capacity, feasibility studies were carried out. After technical, aesthetic and economic comparative analyses, the most favourable solution found was a widening project. The widening solution consists of two new external composite decks positioned along both the outer sides of the existing deck next to the main piers. This system, a worldwide pioneer, will allow bridge-widening works without either interrupting the traffic on the existing bridge or affecting the Vigo estuary, a very valuable zone from a natural environmental and landscape perspective.

Background: Arthroscopic rotator cuff repairs are associated with moderate-to-severe pain. Opioids are not the first line for postsurgical pain control due to their potential misuse and side effects. Transdermal buprenorphine represents an alternative for multimodal postoperative pain control.Methods: This was a single-centre, prospective longitudinal exploratory study of patients undergoing arthroscopic rotator cuff repairs managed with multimodal analgesia with transdermal buprenorphine. Patients were followed-up by telephone at eight time points, assessing pain levels, rescue analgesics requirement and side effects.Findings: Twenty-five patients with an average age of 63.4 ± 8.2 were included. Fourteen patients were ⩾65 years. Pain levels were similar among age groups at all time points, with no pain or mild pain (visual analogue scale 1–4) in most patients. The most frequent side effects were dizziness and somnolence.Conclusion: Transdermal buprenorphine provided a sustained analgesic effect after an arthroscopic rotator cuff repair during the acute postsurgical period. It showed a similar safety profile among younger and older patients.

While understanding the genetic underpinnings of osteogenesis has far-reaching implications for skeletal diseases and evolution, a comprehensive characterization of the osteoblastic regulatory landscape in non-mammalian vertebrates is still lacking. Here, we compared the ATAC-Seq profile of Xenopus tropicalis(Xt) osteoblasts to a variety of non mineralizing control tissues, and identified osteoblast-specific nucleosome free regions (NFRs) at 527 promoters and 6747 distal regions. Sequence analyses, Gene Ontology, RNA-Seq and ChIP-Seq against four key histone marks confirmed that the distal regions correspond to bona fideosteogenic transcriptional enhancers exhibiting a shared regulatory logic with mammals. We report 425 regulatory regions conserved with human and globally associated to skeletogenic genes. Of these, 35 regions have been shown to impact human skeletal phenotypes by GWAS, including one trps1enhancer and the runx2promoter, two genes which are respectively involved in trichorhinophalangeal syndrome type I and cleidocranial dysplasia. Intriguingly, 60 osteoblastic NFRs also align to the genome of the elephant shark, a species lacking osteoblasts and bone tissue. To tackle this paradox, we chose to focus on dlx5because its conserved promoter, known to integrate regulatory inputs during mammalian osteogenesis, harbours an osteoblast-specific NFR in both frog and human. Hence, we show that dlx5is expressed in Xtand elephant shark odontoblasts, supporting a common cellular and genetic origin of bone and dentine. Taken together, our work (i) unravels the Xtosteogenic regulatory landscape, (ii) illustrates how cross-species comparisons harvest data relevant to human biology and (iii) reveals that a set of genes including bnc2, dlx5, ebf3, mir199a, nfia, runx2and zfhx4drove the development of a primitive form of mineralized skeletal tissue deep in the vertebrate lineage.

Magnetotactic bacteria synthesize a chain of magnetic nanoparticles, called magnetosome chain, used to align and swim along the geomagnetic field lines. In particular, Magnetospirillum gryphiswaldensebiomineralize magnetite, Fe3O4. Growing this species in a Co-supplemented medium, Co-doped magnetite is obtained, tailoring in this way the magnetic properties of the magnetosome chain. Combining structural and magnetic techniques such as transmission electron microscopy, energy-dispersive x-ray spectroscopy, X-ray absorption near edge structure, and X-ray magnetic circular dichroism, we determine that ∼1% of Co2+substitutes Fe2+located in octahedral places in the magnetite, thus increasing the coercive field. In the framework of the Stoner–Wohlfarth model, we have analyzed the evolution of the hysteresis loops as a function of temperature determining the different magnetic anisotropy contributions and their evolution with temperature. In contrast with the control magnetosome chains, whose effective anisotropy is uniaxial in the whole temperature range from 300 to 5 K, the effective anisotropy of Co-doped magnetosome chains changes appreciably with temperature, from uniaxial down to 150 K, through biaxial down to 100 K, to triaxial below 100 K.

Quantifying the role of sediment trapping by dams is important due to its control on fluvial and coastal geomorphology, aquatic ecology, water quality, and human water uses. Sediment trapping behind dams is a major source of bias in large‐scale hydrogeomorphic models, hindering robust analyses of anthropogenic influences on sediment fluxes in freshwater and coastal systems. This study focuses on developing a new reservoir trapping efficiency (Te) parameter to account for the impacts of dams in hydrological models. This goal was achieved by harnessing a novel remote sensing data product which offers high‐resolution and spatially continuous maps of suspended sediment concentration across the Contiguous United States (CONUS). Validation of remote sensing‐derived surface sediment fluxes against USGS depth‐averaged sediment fluxes showed that this remote sensing data set can be used to calculate Tewith high accuracy (R2= 0.98). Tecalculated for 222 dams across the CONUS, using incoming and outgoing sediment fluxes from their reservoirs, range from 0.13% to 98.3% with a mean of 45.8%. Contrary to the previous understanding that large reservoirs have larger Te, remote sensing data show that large reservoirs can have a wide range of Tevalues. A suite of 22 explanatory variables were used to develop an empirical Temodel. The strongest model predicts Teusing four variables: incoming sediment flux, outgoing water discharge, reservoir length, and reservoir storage. A global model was also developed using explanatory variables obtained from a global dam database. Remote sensing‐derived surface river sediment fluxes align well with depth‐averaged river sediment fluxes with a simple adjustment factorReservoir sediment trapping efficiency (Te) was calculated using remote sensing sediment data to develop Contiguous United States and global TemodelsRemote sensing shows large reservoirs having a wide range of Te, contrary to the previous claims that Teis very large for large reservoirs Remote sensing‐derived surface river sediment fluxes align well with depth‐averaged river sediment fluxes with a simple adjustment factor Reservoir sediment trapping efficiency (Te) was calculated using remote sensing sediment data to develop Contiguous United States and global Temodels Remote sensing shows large reservoirs having a wide range of Te, contrary to the previous claims that Teis very large for large reservoirs

We hereby present experimental and theoretical insights on the use of biomineralized magnetite nanoparticles, called magnetosomes, as heat nanoinductors in the magnetic hyperthermia technique. The heating efficiency or specific absorption rate of magnetosomes extracted from Magnetospirillum gryphiswaldensebacteria and immersed in water and agarose gel, was directly determined from the hysteresis loops obtained at different frequencies and magnetic field amplitudes. We demonstrate that heat production of magnetosomes can be predicted in the framework of the Stoner–Wohlfarth theory of uniaxial magnetic anisotropy subjected to significant dipolar interactions, which can be described in terms of an interaction anisotropy superimposed to that of each particle. Based on these findings, we propose optimal magnetic field amplitude and frequency values in order to maximize the heat production while keeping the undesired eddy current effects below safe and tolerable limits. The efficiency of magnetosomes as heat generators and their impact on cell viability has been checked in macrophage cells. Our results clearly indicate that the hyperthermia treatment causes both cell death and inhibition of cell proliferation. Specifically, only 36% of the treated macrophages remained alive 2 h after alternating magnetic field exposure, and 24 h later the percentage fell to 22%.

La displasia septóptica es un síndrome congénito poco común, que engloba varias entidades, caracterizadas por alteraciones del septo pelúcido, hipotálamo, hipófisis y estructuras ópticas.

Prokaryotic adaptation is strongly influenced by the horizontal acquisition of beneficial traits via mobile genetic elements (MGEs), such as viruses and plasmids. However, MGEs can also impose a fitness cost due to their often parasitic nature and differing evolutionary trajectories. In response, prokaryotes have evolved diverse immune mechanisms against MGEs. Recently, our understanding of the abundance and diversity of prokaryotic immune systems has greatly expanded. These defence systems can degrade the invading genetic material, inhibit genome replication or trigger abortive infection, leading to population protection. In this review, we highlight these strategies, focusing on the most recent discoveries. The study of prokaryotic defences not only sheds light on microbial evolution but also uncovers novel enzymatic activities with promising biotechnological applications.

The building described hereunder is an example of the importance of early stage cooperation between the architectural and structural engineering teams in establishing design guidelines that capitalise on the full potential of architectural forms to maximise structural effectiveness and minimise the impact on functionality. One such guideline is the “megastructure” concept, whereby the overall shape of a building is used to generate a large-scale structural member. The solution for the iconic element of the design at issue (a huge curved cantilever) was to optimise façade and structural slab performance by eschewing additional elements (such as diaphragm walls, masts or tie beams) that would affect the aesthetics of the building exteriors or constitute an invasion of the indoor space.

El edificio de que es objeto el presente artículo es un ejemplo de cómo una temprana colaboración entre los equipos de Arquitectura y Estructuras permite la aplicación de pautas de diseño que aprovechan la potencialidad de la forma arquitectónica para lograr estructuras de máxima eficacia y mínima afección a la funcionalidad.

Con algunas diferencias menores en el mundo prevalecen dos estrategias paradigmáticas compatibles con el empuje de la globalización. Una está basada en la expansión del crédito como sustituto de la inversión y del empleo en la tarea de armonizar oferta y demanda agregadas en cada país. La brecha resultante entre ambas variables, se cubre con importaciones, creando desequilibrios en el comercio internacional y en su financiamiento. La segunda opción está diseñada para cubrir las deficiencias en la demanda interna, exportando, esto es, usando el poder de compra de otros países. Dichas estrategias tienen la evidente ventaja política de eludir por un tiempo difíciles cuestiones distributivas. En la actualidad, sin embargo, ambas se tornan obsoletas ante los cambios de circunstancias y ante los desajustes mundiales atribuibles a su aplicación. Hay enormes desigualdades en la distribución de los beneficios del intercambio y también entre los recibidos por el capital y el trabajo. Esos desajustes se traducen en disímbolos problemas políticos y económicos entre países y regiones que hacen difícil encontrar respuestas comunes, prontas, a la crisis económica global y a la reconstrucción obligada del orden económico internacional.

The Orona Zero building is considered to be the most emblematic building of a new business and research campus under development by Orona Company at Hernani, Spain. This building would be the new headquarters of the company.The building has a layout consisting of an inclined ring, partially embedded in the ground, that provides great dynamism to the iconic picture of the building. This ring has an outer diameter of 90 m, an inner diameter of 45 m, and a height of 16 m; and its outer part cantilevers from the ground approximately 30 m, this being the most significant element of the project.The structure of the building has been designed, from the very beginning, in close cooperation between the architectural team and the structural engineers, in a very interactive workflow. This collaborative work has made it possible to achieve a noncanonic building with a reasonably efficient structural system, thanks to the consideration of structural issues in the first stages of the project: structural use of the inner and outer facades of the building, geometric standardization of the whole building to ease fabrication and construction, use of building's floors as diaphragms, and structural "flanges" of the structural facade.The result of this process may serve as an example of overcoming the structural challenges in designing an efficient structural system in a non-conventional building taking the advantage of its own form and in a nonintrusive way.

Madrid Stadium, completed and assigned to athletics in 1992, consists of a single grandstand of large seating capacity. In 2004, the City Council of Madrid undertook the development of an expansion project for this site to convert this into a football stadium with a capacity for 70 000 spectators. The design of the stadium also took into account the possibility of transforming the structure and facilities of the building for use as an athletics stadium should the city of Madrid host Olympic Games in the future.The foundation is made up of castin-place executed piles, with up to 1500 mm diameter and 40 m length. Integrity tests were done. Micropiles were necessary to reinforce the current stadium's foundation to bear the loads arising from the new structure.The structure of the new stadium is mainly composed of radially placed rigid frame structures that together with the existing grandstand resulted in a completely closed stadium. Precast concrete steppings are placed over these rigid frame structures. Beneath these elements there are reinforced-concrete or post-tensioned slabs that define the building's floors. The entire structure is surrounded by perimeter walls that constitute the building enclosure.Finally, the stadium is covered with a roof structure executed with a heavy lifting system, consisting of pairs of radial pre-stressed cables connecting the outer compression ring with the inner tension ring and covering the stands with pre-stressed textile membranes.

AbstractThe Orona Zero building is considered to be the most emblematic building of a new business and research campus under development by Orona Company at Hernani, Spain. This building would be the new headquarters of the company.The building has a layout consisting of an inclined ring, partially embedded in the ground, that provides great dynamism to the iconic picture of the building. This ring has an outer diameter of 90 m, an inner diameter of 45 m, and a height of 16 m; and its outer part cantilevers from the ground approximately 30 m, this being the most significant element of the project.The structure of the building has been designed, from the very beginning, in close cooperation between the architectural team and the structural engineers, in a very interactive workflow. This collaborative work has made it possible to achieve a noncanonic building with a reasonably efficient structural system, thanks to the consideration of structural issues in the first stages of the project: structural use of the inner and outer facades of the building, geometric standardization of the whole building to ease fabrication and construction, use of building’s floors as diaphragms, and structural “flanges” of the structural facade.The result of this process may serve as an example of overcoming the structural challenges in designing an efficient structural system in a non-conventional building taking the advantage of its own form and in a nonintrusive way.

AbstractMadrid Stadium, completed and assigned to athletics in 1992, consists of a single grandstand of large seating capacity. In 2004, the City Council of Madrid undertook the development of an expansion project for this site to convert this into a football stadium with a capacity for 70 000 spectators. The design of the stadium also took into account the possibility of transforming the structure and facilities of the building for use as an athletics stadium should the city of Madrid host Olympic Games in the future.The foundation is made up of castin-place executed piles, with up to 1500 mm diameter and 40 m length. Integrity tests were done. Micropiles were necessary to reinforce the current stadium’s foundation to bear the loads arising from the new structure.The structure of the new stadium is mainly composed of radially placed rigid frame structures that together with the existing grandstand resulted in a completely closed stadium. Precast concrete steppings are placed over these rigid frame structures. Beneath these elements there are reinforced-concrete or post-tensioned slabs that define the building’s floors. The entire structure is surrounded by perimeter walls that constitute the building enclosure.Finally, the stadium is covered with a roof structure executed with a heavy lifting system, consisting of pairs of radial pre-stressed cables connecting the outer compression ring with the inner tension ring and covering the stands with pre-stressed textile membranes.

Madrid Stadium, completed and assigned to athletics in 1992, consists of a single grandstand of large seating capacity. In 2004, the City Council of Madrid undertook the development of an expansion project for this site to convert this into a football stadium with a capacity for 70 000 spectators. The design of the stadium also took into account the possibility of transforming the structure and facilities of the building for use as an athletics stadium should the city of Madrid host Olympic Games in the future.The foundation is made up of castin-place executed piles, with up to 1500 mm diameter and 40 m length. Integrity tests were done. Micropiles were necessary to reinforce the current stadium's foundation to bear the loads arising from the new structure.The structure of the new stadium is mainly composed of radially placed rigid frame structures that together with the existing grandstand resulted in a completely closed stadium. Precast concrete steppings are placed over these rigid frame structures. Beneath these elements there are reinforced-concrete or post-tensioned slabs that define the building's floors. The entire structure is surrounded by perimeter walls that constitute the building enclosure.Finally, the stadium is covered with a roof structure executed with a heavy lifting system, consisting of pairs of radial pre-stressed cables connecting the outer compression ring with the inner tension ring and covering the stands with pre-stressed textile membranes.

The Orona Zero building is considered to be the most emblematic building of a new business and research campus under development by Orona Company at Hernani, Spain. This building would be the new headquarters of the company.The building has a layout consisting of an inclined ring, partially embedded in the ground, that provides great dynamism to the iconic picture of the building. This ring has an outer diameter of 90 m, an inner diameter of 45 m, and a height of 16 m; and its outer part cantilevers from the ground approximately 30 m, this being the most significant element of the project.The structure of the building has been designed, from the very beginning, in close cooperation between the architectural team and the structural engineers, in a very interactive workflow. This collaborative work has made it possible to achieve a noncanonic building with a reasonably efficient structural system, thanks to the consideration of structural issues in the first stages of the project: structural use of the inner and outer facades of the building, geometric standardization of the whole building to ease fabrication and construction, use of building's floors as diaphragms, and structural "flanges" of the structural facade.The result of this process may serve as an example of overcoming the structural challenges in designing an efficient structural system in a non-conventional building taking the advantage of its own form and in a nonintrusive way.