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We develop a structural model of the global market for crude oil that for the first time explicitly allows for shocks to the speculative demand for oil as well as shocks to flow demand and flow supply. The speculative component of the real price of oil is identified with the help of data on oil inventories. Our estimates rule out explanations of the 2003–2008 oil price surge based on unexpectedly diminishing oil supplies and based on speculative trading. Instead, this surge was caused by unexpected increases in world oil consumption driven by the global business cycle. There is evidence, however, that speculative demand shifts played an important role during earlier oil price shock episodes including 1979, 1986 and 1990. Our analysis implies that additional regulation of oil markets would not have prevented the 2003–2008 oil price surge. We also show that, even after accounting for the role of inventories in smoothing oil consumption, our estimate of the short-run price elasticity of oil demand is much higher than traditional estimates from dynamic models that do not account for for the endogeneity of the price of oil.

Salinization is recognized as a threat to soil fertility worldwide. A challenge in understanding the effects of salinity on soil microbial communities is the fact that it can be difficult to disentangle the effects of salinity from those of other variables that may co-vary with salinity. Here we use a trait-based approach to identify direct effects of salinity on soil bacterial communities across two salinity gradients. Through dose–response relationships between salinity and bacterial growth, we quantified distributions of the trait salt tolerance within the communities. Community salt tolerance was closely correlated with soil salinity, indicating a strong filtering effect of salinity on the bacterial communities. Accompanying the increases in salt tolerance were consistent shifts in bacterial community composition. We identified specific bacterial taxa that increased in relative abundances with community salt tolerance, which could be used as bioindicators for high community salt tolerance. A strong filtering effect was also observed for pH across the gradients, with pH tolerance of bacterial communities correlated to soil pH. We propose phenotypic trait distributions aggregated at the community level as a useful approach to study the role of environmental factors as filters of microbial community composition.

Comprehensive genome annotation is essential to understand the impact of clinically relevant variants. However, the absence of a standard for clinical reporting and browser display complicates the process of consistent interpretation and reporting. To address these challenges, Ensembl/GENCODE 1 and RefSeq 2 launched a joint initiative, the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration, to converge on human gene and transcript annotation and to jointly define a high-value set of transcripts and corresponding proteins. Here, we describe the MANE transcript sets for use as universal standards for variant reporting and browser display. The MANE Select set identifies a representative transcript for each human protein-coding gene, whereas the MANE Plus Clinical set provides additional transcripts at loci where the Select transcripts alone are not sufficient to report all currently known clinical variants. Each MANE transcript represents an exact match between the exonic sequences of an Ensembl/GENCODE transcript and its counterpart in RefSeq such that the identifiers can be used synonymously. We have now released MANE Select transcripts for 97% of human protein-coding genes, including all American College of Medical Genetics and Genomics Secondary Findings list v3.0 (ref. 3 ) genes. MANE transcripts are accessible from major genome browsers and key resources. Widespread adoption of these transcript sets will increase the consistency of reporting, facilitate the exchange of data regardless of the annotation source and help to streamline clinical interpretation. Matched Annotation from NCBI and EMBL-EBI (MANE) delivers joint transcript sets from Ensembl/GENCODE and RefSeq for standardizing variant reporting in clinical genomics and research.

Sign restrictions on the responses generated by structural vector autoregressive models have been proposed as an alternative approach to the use of exclusion restrictions on the impact multiplier matrix. In recent years such models have been increasingly used to identify demand and supply shocks in the market for crude oil. We demonstrate that sign restrictions alone are insufficient to infer the responses of the real price of oil to such shocks. Moreover, the conventional assumption that all admissible models are equally likely is routinely violated in oil market models, calling into question the use of posterior median responses to characterize the responses to structural shocks. When combining sign restrictions with additional empirically plausible bounds on the magnitude of the short-run oil supply elasticity and on the impact response of real activity, however, it is possible to reduce the set of admissible model solutions to a small number of qualitatively similar estimates. The resulting model estimates are broadly consistent with earlier results regarding the relative importance of demand and supply shocks for the real price of oil based on structural vector autoregressive (VAR) models identified by exclusion restrictions, but imply very different dynamics from the posterior median responses in VAR models based on sign restrictions only.

We aimed to determine the relationship between biochar properties and colonisation of roots by arbuscular mycorrhizal (AM) fungi in agricultural soil. We used a range of biochars that differed in pH, water holding capacity, C, N and P concentrations to investigate interactions between biochar and AM fungi. A glasshouse experiment was conducted with subterranean clover and wheat, amended separately with 34 sources of biochar (applied at 1% w/w), to investigate potential responses in a phosphorus (P) deficient agricultural soil. Plant growth responses to biochar ranged from positive to negative and were dependent on biochar P concentration, available soil P and AM root colonisation. The higher the nutrient P concentration in biochar, the lower was AM colonisation. Growth responses of wheat and clover to the application of various biochars were mostly positive, and their growth was correlated, but biochar contributions to soil fertility varied with biochar properties. When nutrient concentrations are higher in biochars, especially for P and N, plants can gain access to nutrients via the plant roots and mycorrhizal hyphae. Thus biochar amendments can increase both plant nutrient uptake and crop production in nutrient deficient soil.

Extracellular vesicles (EVs) are increasingly being recognized as mediators of intercellular signaling via the delivery of effector molecules. Interestingly, certain types of EVs are also capable of inducing therapeutic responses. For these reasons, the therapeutic potential of EVs is a topic of intense research, both in the context of drug delivery and regenerative medicine. However, to fully utilize EVs for therapeutic purposes, an improved understanding of the mechanisms by which they function would be highly advantageous. Here, the current state of knowledge regarding the cellular uptake and trafficking of EVs is reviewed, along with a consideration of how these pathways potentially influence the functions of therapeutic EVs. Furthermore, the natural cell-targeting abilities, biodistribution profiles, and pharmacokinetics of exogenously administered EVs, along with the components responsible for these features are discussed. An overview of the potential clinical applications and preclinical examples of their successful use is also provided. Finally, examples of EV modifications that have successfully been employed to improve their therapeutic characteristics receive a particular focus. We suggest that, in addition to investigation of EV cell targeting and routes of uptake, future research into the routes of intracellular trafficking in recipient cells is required to optimally utilize EVs for therapeutic purposes. Therapeutics: Helping vesicles to deliver drugs inside cells An increased understanding of how extracellular vesicles (EVs) enter cells and deliver molecules will enable promising new therapies, according to researchers in the Netherlands, UK and France. EVs are liquid-filled sacs secreted by cells that transport proteins, lipids and RNA between cells, and therefore have potential for delivering drugs. Pieter Vader at UMC Utrecht and co-workers review recent research into EVs, focusing on how EVs are distributed around the body, and how they target and enter cells. However, there is little known about EV biology once they are inside cells, and it is likely that many EVs simply degrade without delivering their cargo. Further research in this area could help identify features that improve cargo escape from EVs, thus ensuring that future therapies can be effective.

Burnout is prevalent in medicine and has been further amplified by the COVID-19 pandemic. Strategies must be developed to reduce burnout by addressing a culture of wellness, efficiency of practice, and resiliency. The entire health-care community has a role in addressing burnout and promoting well-being.

Long-term manure application is recognized as an efficient management practice to enhance soil organic carbon (SOC) accumulation and nitrogen (N) mineralization capacity. A field study was established in 1979 to understand the impact of long-term manure and/or chemical fertilizer application on soil fertility in a continuous maize cropping system. Soil samples were collected from field plots in 2012 from 9 fertilization treatments (M0CK, M0N, M0NPK, M30CK, M30N, M30NPK, M60CK, M60N, and M60NPK) where M0, M30, and M60 refer to manure applied at rates of 0, 30, and 60 t ha(-1) yr(-1), respectively; CK indicates no fertilizer; N and NPK refer to chemical fertilizer in the forms of either N or N plus phosphorus (P) and potassium (K). Soils were separated into three particle-size fractions (2000-250, 250-53, and <53 μm) by dry- and wet-sieving. A laboratory incubation study of these separated particle-size fractions was used to evaluate the effect of long-term manure, in combination with/without chemical fertilization application, on the accumulation and mineralization of SOC and total N in each fraction. Results showed that long-term manure application significantly increased SOC and total N content and enhanced C and N mineralization in the three particle-size fractions. The content of SOC and total N followed the order 2000-250 μm > 250-53 μm > 53 μm fraction, whereas the amount of C and N mineralization followed the reverse order. In the <53 μm fraction, the M60NPK treatment significantly increased the amount of C and N mineralized (7.0 and 10.1 times, respectively) compared to the M0CK treatment. Long-term manure application, especially when combined with chemical fertilizers, resulted in increased soil microbial biomass C and N, and a decreased microbial metabolic quotient. Consequently, long-term manure fertilization was beneficial to both soil C and N turnover and microbial activity, and had significant effect on the microbial metabolic quotient.

Plants rapidly release photoassimilated carbon (C) to the soil via direct root exudation and associated mycorrhizal fungi, with both pathways promoting plant nutrient availability. This study aimed to explore these pathways from the root's vascular bundle to soil microbial communities. Using nanoscale secondary ion mass spectrometry (NanoSIMS) imaging and¹³C‐phospho‐ and neutral lipid fatty acids, we traced in‐situ flows of recently photoassimilated C of¹³CO₂‐exposed wheat (Triticum aestivum) through arbuscular mycorrhiza (AM) into root‐ and hyphae‐associated soil microbial communities. Intraradical hyphae of AM fungi were significantly¹³C‐enriched compared to other root‐cortex areas after 8 h of labelling. Immature fine root areas close to the root tip, where AM features were absent, showed signs of passive C loss and co‐location of photoassimilates with nitrogen taken up from the soil solution. A significant and exclusively fresh proportion of¹³C‐photosynthates was delivered through the AM pathway and was utilised by different microbial groups compared to C directly released by roots. Our results indicate that a major release of recent photosynthates into soil leave plant roots via AM intraradical hyphae already upstream of passive root exudations. AM fungi may act as a rapid hub for translocating fresh plant C to soil microbes.

Rare diseases, an emerging global public health priority, require an evidence-based estimate of the global point prevalence to inform public policy. We used the publicly available epidemiological data in the Orphanet database to calculate such a prevalence estimate. Overall, Orphanet contains information on 6172 unique rare diseases; 71.9% of which are genetic and 69.9% which are exclusively pediatric onset. Global point prevalence was calculated using rare disease prevalence data for predefined geographic regions from the ‘Orphanet Epidemiological file’ (http://www.orphadata.org/cgi-bin/epidemio.html). Of the 5304 diseases defined by point prevalence, 84.5% of those analysed have a point prevalence of <1/1 000 000. However 77.3–80.7% of the population burden of rare diseases is attributable to the 4.2% (n = 149) diseases in the most common prevalence range (1–5 per 10 000). Consequently national definitions of ‘Rare Diseases’ (ranging from prevalence of 5 to 80 per 100 000) represent a variable number of rare disease patients despite sharing the majority of rare disease in their scope. Our analysis yields a conservative, evidence-based estimate for the population prevalence of rare diseases of 3.5–5.9%, which equates to 263–446 million persons affected globally at any point in time. This figure is derived from data from 67.6% of the prevalent rare diseases; using the European definition of 5 per 10 000; and excluding rare cancers, infectious diseases, and poisonings. Future registry research and the implementation of rare disease codification in healthcare systems will further refine the estimates.