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The endocannabinoid system (ECS) modulates synaptic function to regulate many aspects of neurophysiology. It adapts to environmental changes and is affected by disease. Thus, the ECS presents an important target for therapeutic development. Despite recent interest in cannabinoid-based treatments, few preclinical studies are conducted in human systems. Human induced pluripotent stem cells (hiPSCs) provide one possible solution to this issue. However, it is not known if these cells have a fully functional ECS. Here we show that hiPSC-derived neuron/astrocyte cultures exhibit a complete ECS. Using Ca

Genomic expression assays provide prognostic information and guide adjuvant chemotherapy decisions for patients with estrogen receptor (ER)-positive breast cancer. Few studies have evaluated the utility of such assays for invasive lobular carcinoma (ILC). The objective of this study is to evaluate the 70-gene signature test (ST) as a prognostic and predictive tool for ILC using a national cancer database. We identified patients diagnosed with stage I–III ER-positive ILC from 2004 to 2016 using the National Cancer Database. All patients underwent 70-gene ST testing. We used the Kaplan–Meier method and Cox proportional hazard analyses to determine overall survival based on genomic risk classification. We also determined the benefit of adjuvant chemotherapy for patients with high-genomic risk ILC based on 70-gene ST testing. We identified 2610 patients with ILC who underwent 70-gene ST testing; 280 (11%) were classified as high genomic risk. Five-year overall survival rates were significantly worse for patients classified as high risk (83%) as compared with those classified as low risk (94%, p

An unprecedented amount of evidence now illuminates the phylogeny of living mammals and birds on the Tree of Life. We use this tree to measure the phylogenetic value of data typically used in paleontology (bones and teeth) from six data sets derived from five published studies. We ask three interrelated questions: 1) Can these data adequately reconstruct known parts of the Tree of Life? 2) Is accuracy generally similar for studies using morphology, or do some morphological data sets perform better than others? 3) Does the loss of non-fossilizable data cause taxa to occur in misleadingly basal positions? Adding morphology to DNA data sets usually increases congruence of resulting topologies to the well-corroborated tree, but this varies among morphological data sets. Extant taxa with a high proportion of missing morphological characters can greatly reduce phylogenetic resolution when analyzed together with fossils. Attempts to ameliorate this by deleting extant taxa missing morphology are prone to decreased accuracy due to long-branch artifacts. We find no evidence that fossilization causes extinct taxa to incorrectly appear at or near topologically basal branches. Morphology comprises the evidence held in common by living taxa and fossils, and phylogenetic analysis of fossils greatly benefits from inclusion of molecular and morphological data sampled for living taxa, whatever methods are used for phylogeny estimation. [Concatenation; fossilization; morphology; parsimony; systematics; taphonomy; total-evidence.]

Macroscelidid afrotherians and canid carnivorans possess four premolar loci, the first of which is not replaced. Previous work suggests that the first premolar in macroscelidids is a retained deciduous tooth, but in Canis it is a successional tooth with no milk precursor. We tested this contrasting interpretation of first premolar homology with data from ontogenetic anatomy and with area predictions from the inhibitory cascade (IC) model. Our results based on anatomy support previous interpretations that the functional first premolar is a retained deciduous tooth (dp1) with no successor in macroscelidids, and a successional tooth (p1) with no precursor in Canis. Hyracoids are among the few placental mammals that show replacement at the first premolar locus and show less deviation than other taxa of actual from predicted areas across the deciduous and molar toothrow. However, predicted vs. actual tooth areas can depart substantially from one another. At least without a better means of representing tooth size, the inhibitory cascade does not help to distinguish the deciduous from successional first premolar. This observation does not rule out the possibility that factors such as a size-shift within the toothrow (e.g., carnivoran carnassials) help to explain deviations from the inhibitory cascade model.

High-throughput sequencing projects generate genome-scale sequence data for species level phylogenies. However, state-of-the-art Bayesian methods for inferring timetrees are computationally limited to small datasets and cannot exploit the deluge of new genomes. In the case of mammals, molecular-clock analyses of limited datasets have produced conflicting estimates of clade ages with large uncertainties and, thus, the timescale of placental mammal evolution remains contentious. Here we develop a Bayesian molecular-clock dating approach to estimate a timetree of 4,705 mammal species integrating information from 72 mammal genomes. We show increasingly larger phylogenomic datasets produce diversification time estimates with progressively smaller uncertainties, facilitating precise tests of macroevolutionary hypotheses. For example, we confidently reject an explosive model of placental mammal origination in the Paleogene8 and show crown Placentalia originated in the Late Cretaceous with unambiguous ordinal diversification in the Paleocene/Eocene. Our new Bayesian methodology facilitates analysis of complete genomes and thousands of species within an integrated framework, making it possible to address hitherto intractable research questions on species diversifications. As such, our approach can be used to tackle other contentious cases of animal and plant diversifications that require analysis of species-level phylogenomic datasets.

Currently, a significant portion (~50%) of global warming emissions, such as CO

Competitive behaviours of plant growth promoting rhizobacteria (PGPR) are integral to their ability to colonize and persist on plant roots and outcompete phytopathogenic fungi, oomycetes and bacteria. PGPR engage in a range of antagonistic behaviours that have been studied in detail, such as the production and secretion of compounds inhibitory to other microbes. In contrast, their defensive activities that enable them to tolerate exposure to inhibitory compounds produced by their neighbours are less well understood. In this study, the genes involved in the Pseudomonas protegens Pf-5 response to metabolites from eight diverse rhizosphere competitor organisms, Fusarium oxysporum, Rhizoctonia solani, Gaeumannomyces graminis var. tritici, Pythium spinosum, Bacillus subtilis QST713, Pseudomonas sp. Q2-87, Streptomyces griseus and Streptomyces bikiniensis subspecies bikiniensi, were examined. Proximity induced excreted metabolite responses were confirmed for Pf-5 with all partner organisms through HPLC before culturing a dense Pf-5 transposon mutant library adjacent to each of these microbes. This was followed by transposon-directed insertion site sequencing (TraDIS), which identified genes that influence Pf-5 fitness during these competitive interactions. A set of 148 genes was identified that were associated with increased fitness during competition, including cell surface modification, electron transport, nucleotide metabolism, as well as regulatory genes. In addition, 51 genes were identified for which loss of function resulted in fitness gains during competition. These included genes involved in flagella biosynthesis and cell division. Considerable overlap was observed in the set of genes observed to provide a fitness benefit during competition with all eight test organisms, indicating commonalities in the competitive response to phylogenetically diverse micro-organisms and providing new insight into competitive processes likely to take place in the rhizosphere.

Genomic expression assays provide prognostic information and guide adjuvant chemotherapy decisions for patients with estrogen receptor (ER)-positive breast cancer. Few studies have evaluated the utility of such assays for invasive lobular carcinoma (ILC). The objective of this study is to evaluate the 70-gene signature test (ST) as a prognostic and predictive tool for ILC using a national cancer database.We identified patients diagnosed with stage I-III ER-positive ILC from 2004 to 2016 using the National Cancer Database. All patients underwent 70-gene ST testing. We used the Kaplan-Meier method and Cox proportional hazard analyses to determine overall survival based on genomic risk classification. We also determined the benefit of adjuvant chemotherapy for patients with high-genomic risk ILC based on 70-gene ST testing.We identified 2610 patients with ILC who underwent 70-gene ST testing; 280 (11%) were classified as high genomic risk. Five-year overall survival rates were significantly worse for patients classified as high risk (83%) as compared with those classified as low risk (94%, p 0.05). In Cox models, high genomic risk was independently associated with a significantly increased hazard of death. In our Cox models of patients who were high genomic risk, adjuvant chemotherapy was not significantly associated with improved overall survival.In this large database study, we found that the genomic risk category determined by the 70-gene ST was significantly associated with survival outcomes for patients with ILC. However, the 70-gene ST failed to predict the benefit of adjuvant chemotherapy for patients with high genomic risk.

Background: \ud In order to expand the pool of usable donors from circulatory death (DCD) there is increasing interest in normothermic regional perfusion (NRP) to assess and improve liver viability.1,2 NRP may also improve outcomes in kidney transplantation.We present our single center experience of outcomes in imported kidneys following NRP.\ud \ud Methods: \ud Data was obtained from a prospectively maintained database between December 2012 and September 2018. Primary endpoints were incidence of delayed graft function (DGF) and estimated glomerular filtration rate (eGFR).\ud \ud Results: \ud Six-hundred and thirty-two decease donor kidneys were transplanted, 229 from DCD donors, 29 of which had NRP. The DGF rate was lower for NRP versus DCD (six of 29, 20.7% vs. 70 of 200, 35.0%) with reduced duration of DGF. Multivariate analysis demonstrated transplant type to be a statistically significant independent predictor of eGFR at 7 and 14 days. Early transplant function in NRP kidneys was comparable to DBD. There were no graft losses within 30 days in the NRP group. One-year graft loss rate was 3.4% for NRP and 6.0% for standard DCD.\ud \ud Conclusion: \ud This data suggests NRP is safe, and reduces rates of DGF and improves early renal transplant function.

Schultz’s rule predicts early eruption of replacement teeth (incisors, canines, and premolars) relative to molars as growth slows and life history events take place over a greater span of time. Here, we investigate if the opposite trend might occur during the domestication process as a consequence of an accelerated life-history and driven by increased energetic needs. We provide new data on tooth eruption in four mammalian species and their domesticated forms: wolf and dog, polecat and ferret, bezoar and goat, wild boar and pig. Our results show some variation in eruption sequences between wild and domestic forms, but none that is consistent and reliably distinct from intraspecific variation. There may be variation in the absolute timing of dental eruption, but despite well documented changes across life history variables, which distinguish wild from domestic forms, eruption sequences remained constant in each wild and domestic version of the species we examined. A conserved eruption sequence is in accordance with many earlier studies, which found no evidence for Schultz’s rule in some wild clades of mammals. Phylogenetic conservation and functional factors likely play an important role in constraining patterns of growth and tooth eruption in these mammals. Furthermore, we suggest that the domestication processes started too recently for fundamental changes of tooth eruption sequences to occur.

SUMMARY Low activities of the monomeric aluminium (Al) species, Al3+, Al(OH)2+ and Al(OH)2+ in solution reduce root growth and root hair development in soybean [Glycine max (L.) Merr.]. Calcium (Ca) ameliorates to a certain extent the toxic effects of Al on root growth, but the interactive effects of Ca and Al on root hair development are not known. In the absence of added Al in solution culture, Ca concentration over the range 500–2000 μM had little effect on root growth or root hair development of soybean cv. Fitzroy. Where the sum of the activities of the monomeric Al species was 2 μM, taproot elongation and lateral root development of soybean was suppressed in solution with 500 μM Ca. The length of the root hair zone was only 10% of that in plants not exposed to Al, and scanning electron microscopy revealed a low density of root hairs. Increasing the Ca concentration to 2000 μM largely overcame these deleterious effects. The results are discussed in relation to the role of root hairs as infection sites for Bradyrhizobium, and the known effects of Al in suppressing nodulation in soybean.

Correction to: Space Sci. Rev. (2020) 216: 103 Affiliation 2 in this article is the wrong affiliation that instead should read: “Institute of Geophysics and Planetary Physics, University of California, Los Angeles, CA, USA” which should be regarded as the final version by the reader.

Gene essentiality studies have been performed on numerous bacterial pathogens, but essential gene sets have been determined for only a few plant-associated bacteria. Pseudomonas protegens Pf-5 is a plant-commensal, biocontrol bacteria that can control disease-causing pathogens on a wide range of crops. Work on Pf-5 has mostly focused on secondary metabolism and biocontrol genes, but genome-wide approaches such as high-throughput transposon mutagenesis have not yet been used in this species. Here we generated a dense P. protegens Pf-5 transposon mutant library and used transposon-directed insertion site sequencing (TraDIS) to identify 446 genes essential for growth on rich media. Genes required for fundamental cellular machinery were enriched in the essential gene set, while genes related to nutrient biosynthesis, stress responses and transport were under-represented. Comparison of the essential gene sets of Pf-5 and P. aeruginosa PA14, an opportunistic human pathogen, provides insight into the biological processes important for their different lifestyles. Key differences include cytochrome c biogenesis, formation of periplasmic disulfide bonds, lipid biosynthesis, ribonuclease activity, lipopolysaccharides and cell surface structures. Comparison of the Pf-5 in silico predicted and in vitro determined essential gene sets highlighted the essential cellular functions that are over- and underestimated by each method. Expanding essentiality studies into bacteria with a range of lifestyles can improve our understanding of the biological processes important for survival and growth in different environmental niches.ImportanceEssential genes are those crucial for survival or normal growth rates in an organism. Essential gene sets have been identified in numerous bacterial pathogens, but only a few plant-associated bacteria. Employing genome-wide approaches, such as transposon insertion sequencing, allows for the concurrent analysis of all genes of a bacterial species and rapid determination of essential gene sets. We have used transposon insertion sequencing to systematically analyze thousands of Pseudomonas protegens Pf-5 genes and gain insights into gene functions and interactions that are not readily available using traditional methods. Comparing Pf-5 essential genes with those of P. aeruginosa PA14, an opportunistic human pathogen, provides insight into differences in gene essentiality which may be linked to their different lifestyles.

Background and Aims UK NHSBT kidney matching scheme changed in September 2019, aiming to better match graft and patient survival through stratification of donors and recipients into risk quartiles. We present data on two years of transplants aiming to highlight discrepancies between our unit and the model on which the scheme is based, and the potential implications on service provision of its’ introduction. Method We reviewed all deceased donor transplants in our centre in 2015 and 2016. Recipients and donors were re-classified into the risk index quartiles and endpoint data included inpatient days in first year, 1 year eGFR, survival, imaging, and infection episodes. Comparisons were made with NHSBT literature. Results 196 deceased donor transplants were performed. Distribution of D1-4 kidneys to R1-4 recipients in our cohort did not reflect those presented in the allocation scheme models, with our population skewed toward higher risk R4 category (73.4%), including 55 D4R4 (83% of D4 kidneys), see Figure 1. 2.0% had an age difference between donor and recipient of >25years, and 12.8% 15-25 years, compared with the NHSBT proposed targets of 8% and 20% respectively. Within the R4 group, recipients receiving a D4 graft were associated with a higher rate of DGF (41.7%, vs 23.2% D1-D3 grafts, p=0.009), longer index admission (median 11 days vs 8 days, p=0.038) and more readmissions within the first post-operative year (median 18 vs 11 days, p = 0.005) – Figure 2. D4 grafts demonstrated lower mean eGFR at one year (35.7, vs. 54.8 ml/min, p Day ward attendances, bacteraemia, and CT imaging events did not differ by R or D category; D4 was associated with higher rates of transplant ultrasound (5.6 vs R1-3 4.25, p=0.009), and R4 with higher rates of urinary tract infection (3.6 vs R1-3 1.5, p=0.03). Conclusion Firstly, our transplant population is weighted to higher risk R4 recipients; secondly, intended principals of the allocation scheme are already largely being observed. Thirdly, our data does suggest that increasing R4D4 transplants will have a significant impact on transplant centres, with resource burden primarily within the first year. But despite poorer graft function, patient survival appears to be equivalent and improved matching may in the longer term reduce need for re-implantation as the scheme intends.

Currently, a significant portion (~50%) of global warming emissions, such as CO, are related to energy production and transportation. As most energy usage will be electrical (as well as transportation), the efficient management of electrical power is thus central to achieve the XXI century climatic goals. Ultra‐wide bandgap (UWBG) semiconductors are at the very frontier of electronics for energy management or energy electronics. A new generation of UWBG semiconductors will open new territories for higher power rated power electronics and solar‐blind deeper ultraviolet optoelectronics. Gallium oxide—GaO (4.5–4.9 eV), has recently emerged pushing the limits set by more conventional WBG (~3 eV) materials, such as SiC and GaN, as well as for transparent conducting oxides (TCO), such asInO, ZnO and SnO, to name a few. Indeed, GaO as the first oxide used as a semiconductor for power electronics, has sparked an interest in oxide semiconductors to be investigated (oxides represent the largest family of UWBG). Among these new power electronic materials, AlxGa1‐xO may provide high‐power heterostructure electronic and photonic devices at bandgaps far beyond all materials available today (~8 eV) or ZnGaO (~5 eV), enabling spinel bipolar energy electronics for the first time ever. Here, we review the state‐of‐the‐art and prospects of some ultra‐wide bandgap oxide semiconductor arising technologies as promising innovative material solutions towards a sustainable zero emission society., This research was funded by the French National Research Agency ANR, “Accelerating the demonstration of Gallium Oxide’s outstanding potential for Energy application” (GOPOWER), grant number Project-ANR-21-CE50-0015.

Funder: Department of Zoology, University of Cambridge, Funder: Leverhulme Trust; doi: http://dx.doi.org/10.13039/501100000275, Domestication and island evolution can lead to changes of life history along the slow-fast gradient. Shifts of life history patterns, in turn, are potentially related to alterations of patterns and timing of tooth eruption. Schultz’s rule predicts an earlier eruption of molars relative to premolars as fecundity increases during the domestication process. On the other hand, evolution on a predator-free, resource limited island might lead to a generally slow life history and delayed tooth eruption, as in the Plio-Pleistocene Balearic caprine Myotragus. In this study, we investigate tooth eruption and its relation to life history in a unique sheep population that is an example of both domestication and island evolution: the ancient and feral Soay sheep (Ovis aries) of the St. Kilda archipelago, Scotland. Tooth eruption timing and sequence is investigated in a comparative framework featuring new data on other domestic sheep (O. aries), including European mouflon (O. a. musimon), as well as wild sheep (O. vignei, O. cycloceros, O. arkal, O. orientalis, O. ammon). These data indicate that the order of eruption is similar in wild and domestic sheep, despite the fundamental life history changes that came about with domestication. However, in contrast to other domestic sheep breeds, Soay sheep erupt their teeth at an absolute older age and also tend to grow more slowly, which resembles the evolutionary trend in island-adapted Myotragus. Despite these similarities, Soay sheep do not share the slow life history pattern inferred for Myotragus, highlighting the distinctive nature of tooth eruption in Soay sheep.

International audience; Understanding the origins of morphological specializations in mammals is a key goal in evolutionary biology. It can be accomplished by studying dental homology, which is at the core of most evolutionary and developmental studies. Here, we focused on the evolution and development of the specialized dentition of hyraxes for which dental homologies have long been debated, and could have implications on early placental evolution. Specifically, we analysed dental mineralization sequences of the three living genera of hyraxes and 17 fossil species using X‐ray computed microtomography. Our results point out the labile position of vestigial upper teeth on jaw bones in extant species, associated with the frequently unusual premolar shape of deciduous canines over 50 Ma of hyracoid evolution. We proposed two evolutionary and developmental hypotheses to explain these original hyracoid dental characteristics. (a) The presence of a vestigial teeth on the maxilla in front of a complex deciduous canine could be interpreted as extra‐teeth reminiscent of early placental evolution or sirenians, an order phylogenetically close to hyracoids and showing five premolars. (b) These vestigial teeth could also correspond to third incisors with a position unusually shifted on the maxilla, which could be explained by the dual developmental origin of these most posterior incisors and their degenerated condition. This integrative study allows discussion on the current evolutionary and developmental paradigms associated with the mammalian dentition. It also highlights the importance of nonmodel species to understand dental homologies.