Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for ...cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.
The evolution of ocean temperature measurement systems is presented with a focus on the development and accuracy of two critical devices in use today (expendable bathythermographs and ...conductivity‐temperature‐depth instruments used on Argo floats). A detailed discussion of the accuracy of these devices and a projection of the future of ocean temperature measurements are provided. The accuracy of ocean temperature measurements is discussed in detail in the context of ocean heat content, Earth's energy imbalance, and thermosteric sea level rise. Up‐to‐date estimates are provided for these three important quantities. The total energy imbalance at the top of atmosphere is best assessed by taking an inventory of changes in energy storage. The main storage is in the ocean, the latest values of which are presented. Furthermore, despite differences in measurement methods and analysis techniques, multiple studies show that there has been a multidecadal increase in the heat content of both the upper and deep ocean regions, which reflects the impact of anthropogenic warming. With respect to sea level rise, mutually reinforcing information from tide gauges and radar altimetry shows that presently, sea level is rising at approximately 3 mm yr−1 with contributions from both thermal expansion and mass accumulation from ice melt. The latest data for thermal expansion sea level rise are included here and analyzed.
Key Points
Oceanographic techniques and analysis have improved over many decades
These improvements allow more accurate Earth‐energy balance estimates
Understanding of ocean heat content and sea‐level rise has also increased
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If ...left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.
In a world of shrinking habitats and increasing competition for natural resources, potentially dangerous predators bring the challenges of coexisting with wildlife sharply into focus. Through ...interdisciplinary collaboration among authors trained in the humanities, social sciences, and natural sciences, we reviewed current approaches to mitigating adverse human-predator encounters and devised a vision for future approaches to understanding and mitigating such encounters. Limitations to current approaches to mitigation include too much focus on negative impacts; oversimplified equating of levels of damage with levels of conflict; and unsuccessful technical fixes resulting from failure to engage locals, address hidden costs, or understand cultural (nonscientific) explanations of the causality of attacks. An emerging interdisciplinary literature suggests that to better frame and successfully mitigate negative human-predator relations conservation professionals need to consider dispensing with conflict as the dominant framework for thinking about human-predator encounters; work out what conflicts are really about (they may be human-human conflicts); unravel the historical contexts of particular conflicts; and explore different cultural ways of thinking about animals. The idea of cosmopolitan natures may help conservation professionals think more clearly about human-predator relations in both local and global context. These new perspectives for future research practice include a recommendation for focused interdisciplinary research and the use of new approaches, including human-animal geography, multispecies ethnography, and approaches from the environmental humanities notably environmental history. Managers should think carefully about how they engage with local cultural beliefs about wildlife, work with all parties to agree on what constitutes good evidence, develop processes and methods to mitigate conflicts, and decide how to monitor and evaluate these. Demand for immediate solutions that benefit both conservation and development favors dispute resolution and technical fixes, which obscures important underlying drivers of conflicts. If these drivers are not considered, well-intentioned efforts focused on human-wildlife conflicts will fail. En un mundo en el que los hábitats se reducen y la competencia por los recursos naturales incrementa, los depredadores potencialmente peligrosos resaltan pronunciadamente la dificultad de coexistir con la vida silvestre. Por medio de la colaboración interdisciplinaria entre autores preparados en las humanidades, las ciencias sociales y las ciencias naturales revisamos las estrategias actuales para mitigar los encuentros adversos entre depredadores y humanos y diseñamos una visión para estrategias futuras para entender y mitigar dichos encuentros. Las limitaciones de las estrategias actuales para la mitigación incluyen demasiado enfoque sobre los impactos negativos; la equiparación demasiado simplificada de los niveles de daño con los niveles del conflicto; y los arreglos técnicos infructuosos que resultan del fracaso por involucrar a los locales, hablar sobre los costos ocultos o entender las explicaciones culturales (no científicas) de la causalidad de los ataques. La literatura interdisciplinaria emergente sugiere que para enmarcar de mejor manera y mitigar exitosamente las relaciones negativas entre humanos y depredadores, los profesionales de la conservación necesitan considerar dispensar el conflicto como el marco de trabajo dominante para pensar sobre los encuentros entre humanos y depredadores; descifrar de qué se tratan realmente los conflictos (pueden ser conflictos humano - humano); aclarar los contextos históricos de conflictos particulares; y explorar las diferentes formas culturales de pensar sobre los animales. La idea de naturalezas cosmopolitas puede ayudar a los profesionales de la conservación a pensar de manera más clara sobre las relaciones humano - depredador en el contexto global y en el local. Estas nuevas perspectivas para la futura investigación de la práctica incluyen una recomendación para la investigación interdisciplinaria enfocada y el uso de nuevas estrategias, incluidas la geografía humano - animal, la etnografía de varias especies y estrategias de las humanidades ambientales, notablemente la historia ambiental. Los manejadores deberían pensar cuidadosamente sobre cómo se involucran con las creencias de los locales acerca de la vida silvestre, trabajar con todos los actores para acordar qué constituye una buena evidencia, desarrollar procesos y métodos para mitigar los conflictos, y decidir cómo monitorear y evaluarlos. La demanda por soluciones inmediatas que benefician tanto a la conservación como al desarrollo favorece a la resolución de disputas y a los arreglos técnicos, lo que hace a un lado a importantes conductores subyacentes de los conflictos. Si no son considerados estos conductores, los esfuerzos bien intencionados enfocados en los conflictos humano - vida silvestre fracasarán.
Predators may influence their prey populations not only through direct lethal effects, but also through indirect behavioral changes. Here, we combined spatiotemporal fine-scale data from GPS radio ...collars on lions with habitat use information on 11 African herbivores in Hwange National Park (Zimbabwe) to test whether the risk of predation by lions influenced the distribution of herbivores in the landscape. Effects of long-term risk of predation (likelihood of lion presence calculated over four months) and short-term risk of predation (actual presence of lions in the vicinity in the preceding 24 hours) were contrasted. The long-term risk of predation by lions appeared to influence the distributions of all browsers across the landscape, but not of grazers. This result strongly suggests that browsers and grazers, which face different ecological constraints, are influenced at different spatial and temporal scales in the variation of the risk of predation by lions. The results also show that all herbivores tend to use more open habitats preferentially when lions are in their vicinity, probably an effective anti-predator behavior against such an ambush predator. Behaviorally induced effects of lions may therefore contribute significantly to structuring African herbivore communities, and hence possibly their effects on savanna ecosystems.
The negative effect of increasing atmospheric nitrogen (N) pollution on grassland biodiversity is now incontrovertible. However, the recent introduction of cleaner technologies in the UK has led to ...reductions in the emissions of nitrogen oxides, with concomitant decreases in N deposition. The degree to which grassland biodiversity can be expected to 'bounce back' in response to these improvements in air quality is uncertain, with a suggestion that long-term chronic N addition may lead to an alternative low biodiversity state. Here we present evidence from the 160-year-old Park Grass Experiment at Rothamsted Research, UK, that shows a positive response of biodiversity to reducing N addition from either atmospheric pollution or fertilizers. The proportion of legumes, species richness and diversity increased across the experiment between 1991 and 2012 as both wet and dry N deposition declined. Plots that stopped receiving inorganic N fertilizer in 1989 recovered much of the diversity that had been lost, especially if limed. There was no evidence that chronic N addition has resulted in an alternative low biodiversity state on the Park Grass plots, except where there has been extreme acidification, although it is likely that the recovery of plant communities has been facilitated by the twice-yearly mowing and removal of biomass. This may also explain why a comparable response of plant communities to reduced N inputs has yet to be observed in the wider landscape.
Context.
Controversial studies on the jet collimation profile of BL Lacertae (BL Lac), the eponymous blazar of the BL Lac objects class, complicate the scenario in this already puzzling class of ...objects. Understanding the jet geometry in connection with the jet kinematics and the physical conditions in the surrounding medium is fundamental for better constraining the formation, acceleration, and collimation mechanisms in extragalactic jets.
Aims.
With the aim of investigating the jet geometry in the innermost regions of the BL Lac jet, and resolving the controversy, we explore the radio jet in this source using high-resolution millimeter-wave VLBI data.
Methods.
We collect 86 GHz GMVA and 43 GHz VLBA data to obtain stacked images that we use to infer the jet collimation profile by means of two comparable methods. We analyze the kinematics at 86 GHz, and we discuss it in the context of the jet expansion. Finally, we consider a possible implication of the Bondi sphere in shaping the jet of BL Lac.
Results.
The jet in BL Lac expands with an overall conical geometry. A higher expanding rate region is observed between ∼5 and 10 pc (de-projected) from the black hole. Such a region is associated with the decrease in brightness usually observed in high-frequency VLBI images of BL Lac. The jet retrieves the original jet expansion around 17 pc, where the presence of a recollimation shock is supported by both the jet profile and the 15 GHz kinematics (MOJAVE survey). The change in the jet expansion profile occurring at ∼5 pc could be associated with a change in the external pressure at the location of the Bondi radius (∼3.3 × 10
5
R
S
).
Quantifying the content and composition of soil carbon in the laboratory is time-consuming, requires specialised equipment and is therefore expensive. Rapid, simple and low-cost accurate methods of ...analysis are required to support current interests in carbon accounting. This study was completed to develop national and state-based models capable of predicting soil carbon content and composition by coupling diffuse reflectance mid-infrared (MIR) spectra with partial least-squares regression (PLSR) analyses. Total, organic and inorganic carbon contents were determined and MIR spectra acquired for 20495 soil samples collected from 4526 locations from soil depths to 1m within Australia’s agricultural regions. However, all subsequent MIR/PLSR models were developed using soils only collected from the 0–10, 10–20 and 20–30cm depth layers. The extent of grinding applied to air-dried soil samples was found to be an important determinant of the variability in acquired MIR spectra. After standardisation of the grinding time, national MIR/PLSR models were developed using an independent test-set validation approach to predict the square-root transformed contents of total, organic and inorganic carbon and total nitrogen. Laboratory fractionation of soil organic carbon into particulate, humus and resistant forms was completed on 312 soil samples. Reliable national MIR/PLSR models were developed using cross-validation to predict the contents of these soil organic carbon fractions; however, further work is required to enhance the representation of soils with significant contents of inorganic carbon. Regional MIR/PLSR models developed for total, organic and inorganic carbon and total nitrogen contents were found to produce more reliable and accurate predictions than the national models. The MIR/PLSR approach offers a more rapid and more cost effective method, relative to traditional laboratory methods, to derive estimates of the content and composition of soil carbon and total nitrogen content provided that the soils are well represented by the calibration samples used to build the predictive models.
We report results from a deep polarization imaging of the nearby radio galaxy 3C 84 (NGC 1275). The source was observed with the Global Millimeter VLBI Array (GMVA) at 86 GHz at an ultrahigh angular ...resolution of 50 μas (corresponding to ∼200Rs). We also add complementary multiwavelength data from the Very Long Baseline Array (VLBA; 15 and 43 GHz) and from the Atacama Large Millimeter/submillimeter Array (ALMA; 97.5, 233.0 and 343.5 GHz). At 86 GHz, we measured a fractional linear polarization of ∼2% in the VLBI core region. The polarization morphology suggests that the emission is associated with an underlying limb-brightened jet. The fractional linear polarization is lower at 43 and 15 GHz (∼0.3−0.7% and <0.1%, respectively). This suggests an increasing linear polarization degree toward shorter wavelengths on VLBI scales. We also obtain a large rotation measure (RM) of ∼105–6 rad m2 in the core at ≳43 GHz. Moreover, the VLBA 43 GHz observations show a variable RM in the VLBI core region during a small flare in 2015. Faraday depolarization and Faraday conversion in an inhomogeneous and mildly relativistic plasma could explain the observed linear polarization characteristics and the previously measured frequency dependence of the circular polarization. Our Faraday depolarization modeling suggests that the RM most likely originates from an external screen with a highly uniform RM distribution. To explain the large RM value, the uniform RM distribution and the RM variability, we suggest that the Faraday rotation is caused by a boundary layer in a transversely stratified jet. Based on the RM and the synchrotron spectrum of the core, we provide an estimate for the magnetic field strength and the electron density of the jet plasma.
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