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The core diagram of a double Lie algebroid consists of the core of the double Lie algebroid, together with the two core-anchor maps to the sides of the double Lie algebroid. If these two core-anchors are surjective, then the double Lie algebroid and its core diagram are called transitive. This paper establishes an equivalence between transitive double Lie algebroids, and transitive core diagrams over a fixed base manifold. In other words, it proves that a transitive double Lie algebroid is completely determined by its core diagram.
The comma double Lie algebroid associated to a morphism of Lie algebroids is defined. If the latter morphism is one of the core-anchors of a transitive core diagram, then the comma double algebroid can be quotiented out by the second core-anchor, yielding a transitive double Lie algebroid, which is the one that is equivalent to the transitive core diagram.
Brown's and Mackenzie's equivalence of transitive core diagrams (of Lie groupoids) with transitive double Lie groupoids is then used in order to show that a transitive double Lie algebroid with integrable sides and core is automatically integrable to a transitive double Lie groupoid.
Land-use intensification is a major driver of biodiversity loss. However, understanding how different components of land use drive biodiversity loss requires the investigation of multiple trophic levels across spatial scales. Using data from 150 agricultural grasslands in central Europe, we assess the influence of multiple components of local- and landscape-level land use on more than 4,000 above- and belowground taxa, spanning 20 trophic groups. Plot-level land-use intensity is strongly and negatively associated with aboveground trophic groups, but positively or not associated with belowground trophic groups. Meanwhile, both above- and belowground trophic groups respond to landscape-level land use, but to different drivers: aboveground diversity of grasslands is promoted by diverse surrounding land-cover, while belowground diversity is positively related to a high permanent forest cover in the surrounding landscape. These results highlight a role of landscape-level land use in shaping belowground communities, and suggest that revised agroecosystem management strategies are needed to conserve whole-ecosystem biodiversity.
We compared the feasibility of 4 cytomegalovirus (CMV)- and Aspergillus-reactive T-cell immunoassay protocols in allogenic stem cell transplant recipients. While enzyme-linked immunospot performed best overall, logistically advantageous whole blood–based assays performed comparably in patients with less severe lymphocytopenia. CMV-induced interferon-gamma responses correlated strongly across all protocols and showed high concordance with serology.
Co-occurrence patterns of tree-related microhabitats: A method to simplify routine monitoring
(2021)
A Tree-related Microhabitat (TreM) is a distinct, well-delineated morphological singularity occurring on living or standing dead trees, which constitutes a crucial substrate or life site for various species. TreMs are widely recognized as key features for biodiversity. Current TreM typology identifies 47 TreM types according to their morphology and their associated taxa. In order to provide a range of resolutions and make the typology more user-friendly, these 47 TreM types have been pooled into 15 groups and seven forms. Depending on the accuracy required and the time available, a user can now choose to describe TreMs at resolution levels corresponding to type, group or form. Another way to more easily record TreMs during routine management work would be to use co-occurrence patterns to reduce the number of observed TreMs required. Based on a large international TreM database (2052 plots; 70,958 individual trees; 78 tree species), we evaluated both the significance and the magnitude of TreM co-occurrence on living trees for 11 TreM groups. We highlighted 33 significant co-occurrences for broadleaves and nine for conifers. Bark loss, rot hole, crack and polypore had the highest number of positive co-occurrences (N = 8) with other TreMs on broadleaves; bark loss (N = 4) had the highest number for conifers. We found mutually exclusive occurrences only for conifers: Exposed Heartwood excluded both dendrotelm and sap run. Among the four variables we tested for their positive contribution to significant co-occurrences, tree diameter at breast height was the most consistent. Based on our results and practical considerations, we selected three TreM groups for broadleaves, and nine for conifers, and formed useful short lists to reduce the number of TreM groups to assess during routine forest management work in the field. In addition, detecting potential similarities or associations between TreMs has potential theoretical value, e.g. it may help researchers identify common factors favouring TreM formation or help managers select trees with multiple TreMs as candidates for retention.
The Cambrian is anomalous among geological systems as many reports divide it into three divisions of indeterminate rank. This use of “lower”, “middle”, and “upper” has been a convenient way to subdivide the Cambrian despite agreement it consists of four global series. Traditional divisions of the system into regional series (Lower, Middle, Upper) reflected local biotic developments not interprovincially correlatable with any precision. However, use of “lower”, “middle”, and “upper” is unsatisfactory. These adjectives lack standard definition, evoke the regional series, and are misused. Notably, there is an almost 50 year use of three Cambrian subsystems and a 1997 proposal to divide the Avalonian and global Cambrian into four series and three subsystems. The global series allow proposal of three formal subsystems: a ca. 32.6 Ma Lower Cambrian Subsystem (Terreneuvian and Series 2/proposed Lenaldanian Series), a ca. 9.8 Ma Middle, and a ca. 10 Ma Upper Cambrian Subsystem (=Furongian Series). Designations as “Lower Cambrian Subsystem” or “global Lower Cambrian” distinguish the new units from such earlier units as “Lower Cambrian Series” and substitute for the de facto subsystem terms “lower”, “middle”, and “upper”. Cambrian subsystems are comparable to the Carboniferous’ Lower (Mississippian) and Upper (Pennsylvanian) Subsystems.
Engineering non-linear hybrid light-matter states in tailored lattices is a central research strategy for the simulation of complex Hamiltonians. Excitons in atomically thin crystals are an ideal active medium for such purposes, since they couple strongly with light and bear the potential to harness giant non-linearities and interactions while presenting a simple sample-processing and room temperature operability. We demonstrate lattice polaritons, based on an open, high-quality optical cavity, with an imprinted photonic lattice strongly coupled to excitons in a WS2 monolayer. We experimentally observe the emergence of the canonical band-structure of particles in a one-dimensional lattice at room temperature, and demonstrate frequency reconfigurability over a spectral window exceeding 85 meV, as well as the systematic variation of the nearest-neighbour coupling, reflected by a tunability in the bandwidth of the p-band polaritons by 7 meV. The technology presented in this work is a critical demonstration towards reconfigurable photonic emulators operated with non-linear photonic fluids, offering a simple experimental implementation and working at ambient conditions.
Several hypotheses explain the prevalence of undifferentiated sex chromosomes in poikilothermic vertebrates. Turnovers change the master sex determination gene, the sex chromosome or the sex determination system (e.g. XY to WZ). Jumping master genes stay main triggers but translocate to other chromosomes. Occasional recombination (e.g. in sex-reversed females) prevents sex chromosome degeneration. Recent research has uncovered conserved heteromorphic or even homomorphic sex chromosomes in several clades of non-avian and non-mammalian vertebrates. Sex determination in sturgeons (Acipenseridae) has been a long-standing basic biological question, linked to economical demands by the caviar-producing aquaculture. Here, we report the discovery of a sex-specific sequence from sterlet (Acipenser ruthenus). Using chromosome-scale assemblies and pool-sequencing, we first identified an approximately 16 kb female-specific region. We developed a PCR-genotyping test, yielding female-specific products in six species, spanning the entire phylogeny with the most divergent extant lineages (A. sturio, A. oxyrinchus versus A. ruthenus, Huso huso), stemming from an ancient tetraploidization. Similar results were obtained in two octoploid species (A. gueldenstaedtii, A. baerii). Conservation of a female-specific sequence for a long period, representing 180 Myr of sturgeon evolution, and across at least one polyploidization event, raises many interesting biological questions. We discuss a conserved undifferentiated sex chromosome system with a ZZ/ZW-mode of sex determination and potential alternatives.
This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
As yet, there are still no evidence-based clinical diagnostic and management guidelines for ambulatory single-channel EMG devices, like the BUTLER® GrindCare® (GrindCare), that are used in patients with sleep bruxism. Therefore, a consensus meeting was organised with GrindCare developers, researchers, and academic and non-academic clinicians experienced with the use of ambulatory EMG devices. The aim of the meeting was to discuss and develop recommendations for clinical guidelines for GrindCare usage, based on the existing clinical and research experience of the consensus meeting's participants. As an important outcome of the consensus meeting, clinical guidelines were proposed in which an initial 2-week baseline phase with the device in its inactive (non-stimulus) mode for habituation and assessment of the number of jaw-muscle activities is followed by a 4-week active phase with contingent electrical stimuli suppressing the jaw-muscle activities. As to avoid the commonly reported reduction in sensitivity to the stimuli, a 2-week inactive phase is subsequently installed, followed by a repetition of active and inactive phases until a lasting reduction in the number of jaw-muscle activities and/or associated complaints has been achieved. This proposal has the characteristics of a single-patient clinical trial. From a research point of view, adoption of this approach by large numbers of GrindCare users creates a great opportunity to recruit relatively large numbers of study participants that follow the same protocol.
Impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of CMV reactivation and associated complications in solid-organ transplantation. Reliably assessing CMV-CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T-Track® CMV, a novel IFN-γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE-I CMV proteins, to monitor CMV-CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate-risk renal transplant recipients. CMV-CMI, CMV viral load, and clinical complications were monitored over 6 months post-transplantation. Ninety-five percent and 88–92% ELISpot assays were positive pre- and post-transplantation, respectively. CMV-specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65-specific response was ninefold higher in patients with self-clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T-Track® CMV is a highly sensitive IFN-γ ELISpot assay, suitable for the immunomonitoring of CMV-seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV-related clinical complications (ClinicalTrials.gov Identifier: NCT02083042).
A stimulus (conditioned stimulus, CS) associated with an appetitive unconditioned stimulus (US) acquires positive properties and elicits appetitive conditioned responses (CR). Such associative learning has been examined extensively in animals with food as the US, and results are used to explain psychopathologies (e.g., substance-related disorders or obesity). Human studies on appetitive conditioning exist, too, but we still know little about generalization processes. Understanding these processes may explain why stimuli not associated with a drug, for instance, can elicit craving. Forty-seven hungry participants underwent an appetitive conditioning protocol during which one of two circles with different diameters (CS+) became associated with an appetitive US (chocolate or salty pretzel, according to participants’ preference) but never the other circle (CS−). During generalization, US were delivered twice and the two CS were presented again plus four circles (generalization stimuli, GS) with gradually increasing diameters from CS− to CS+. We found successful appetitive conditioning as reflected in appetitive subjective ratings (positive valence, higher contingency) and physiological responses (startle attenuation and larger skin conductance responses) to CS+ versus CS−, and, importantly, both measures confirmed generalization as indicated by generalization gradients. Small changes in CS-US contingency during generalization may have weakened generalization processes on the physiological level. Considering that appetitive conditioned responses can be generalized to non-US-associated stimuli, a next important step would be to investigate risk factors that mediate overgeneralization.
We develop a model of oligopoly competition involving innovation effort, market entry and production flexibility under demand uncertainty. Several heterogeneous firms make efforts to develop new prototypes; if they succeed, they hold a shared option to enter a new market under stochastic demand. We derive analytic results for the Markov perfect equilibrium accounting for development effort, market entry and production decisions and complement these by numerical analyses. Firm value—which embeds real options—is not convex increasing in demand but exhibits “competitive waves” due to market entries by rivals. A firm with a development advantage (“innovator”) exerts greater innovation effort if the market is a niche, whereas another benefiting from economies of scale (“incumbent”) invests more if the market is larger. Positive externalities benefit the incumbent in the development stage, whereas the innovator is better off in counteracting negative externalities. Demand volatility raises firm incentives to innovate as it enhances the value of firm market‐entry and production flexibility.
During drought, abscisic acid (ABA) induces closure of stomata via a signaling pathway that involves the calcium (Ca2+)-independent protein kinase OST1, as well as Ca2+-dependent protein kinases. However, the interconnection between OST1 and Ca2+ signaling in ABA-induced stomatal closure has not been fully resolved.
ABA-induced Ca2+ signals were monitored in intact Arabidopsis leaves, which express the ratiometric Ca2+ reporter R-GECO1-mTurquoise and the Ca2+-dependent activation of S-type anion channels was recorded with intracellular double-barreled microelectrodes.
ABA triggered Ca2+ signals that occurred during the initiation period, as well as in the acceleration phase of stomatal closure. However, a subset of stomata closed in the absence of Ca2+ signals. On average, stomata closed faster if Ca2+ signals were elicited during the ABA response. Loss of OST1 prevented ABA-induced stomatal closure and repressed Ca2+ signals, whereas elevation of the cytosolic Ca2+ concentration caused a rapid activation of SLAC1 and SLAH3 anion channels.
Our data show that the majority of Ca2+ signals are evoked during the acceleration phase of stomatal closure, which is initiated by OST1. These Ca2+ signals are likely to activate Ca2+-dependent protein kinases, which enhance the activity of S-type anion channels and boost stomatal closure.
Pattern recognition receptors (PRRs) sense microbial patterns and activate innate immunity against attempted microbial invasions. The leucine-rich repeat receptor kinases (LRR-RK) FLS2 and EFR, and the LRR receptor protein (LRR-RP) receptors RLP23 and RLP42, respectively, represent prototypical members of these two prominent and closely related PRR families.
We conducted a survey of Arabidopsis thaliana immune signaling mediated by these receptors to address the question of commonalities and differences between LRR-RK and LRR-RP signaling.
Quantitative differences in timing and amplitude were observed for several early immune responses, with RP-mediated responses typically being slower and more prolonged than those mediated by RKs. Activation of RLP23, but not FLS2, induced the production of camalexin. Transcriptomic analysis revealed that RLP23-regulated genes represent only a fraction of those genes differentially expressed upon FLS2 activation. Several positive and negative regulators of FLS2-signaling play similar roles in RLP23 signaling. Intriguingly, the cytoplasmic receptor kinase BIK1, a positive regulator of RK signaling, acts as a negative regulator of RP-type immune receptors in a manner dependent on BIK1 kinase activity.
Our study unveiled unexpected differences in two closely related receptor systems and reports a new negative role of BIK1 in plant immunity.
The membrane-bound proton-pumping pyrophosphatase (V-PPase), together with the V-type H+-ATPase, generates the proton motive force that drives vacuolar membrane solute transport. Transgenic plants constitutively overexpressing V-PPases were shown to have improved salinity tolerance, but the relative impact of increasing PPi hydrolysis and proton-pumping functions has yet to be dissected.
For a better understanding of the molecular processes underlying V-PPase-dependent salt tolerance, we transiently overexpressed the pyrophosphate-driven proton pump (NbVHP) in Nicotiana benthamiana leaves and studied its functional properties in relation to salt treatment by primarily using patch-clamp, impalement electrodes and pH imaging.
NbVHP overexpression led to higher vacuolar proton currents and vacuolar acidification. After 3 d in salt-untreated conditions, V-PPase-overexpressing leaves showed a drop in photosynthetic capacity, plasma membrane depolarization and eventual leaf necrosis. Salt, however, rescued NbVHP-hyperactive cells from cell death. Furthermore, a salt-induced rise in V-PPase but not of V-ATPase pump currents was detected in nontransformed plants.
The results indicate that under normal growth conditions, plants need to regulate the V-PPase pump activity to avoid hyperactivity and its negative feedback on cell viability. Nonetheless, V-PPase proton pump function becomes increasingly important under salt stress for generating the pH gradient necessary for vacuolar proton-coupled Na+ sequestration.
Recent studies have revealed that some responses of fern stomata to environmental signals differ from those of their relatives in seed plants. However, it is unknown whether the biophysical properties of guard cells differ fundamentally between species of both clades.
Intracellular micro-electrodes and the fluorescent Ca2+ reporter FURA2 were used to study voltage-dependent cation channels and Ca2+ signals in guard cells of the ferns Polypodium vulgare and Asplenium scolopendrium.
Voltage clamp experiments with fern guard cells revealed similar properties of voltage-dependent K+ channels as found in seed plants. However, fluorescent dyes moved within the fern stomata, from one guard cell to the other, which does not occur in most seed plants. Despite the presence of plasmodesmata, which interconnect fern guard cells, Ca2+ signals could be elicited in each of the cells individually.
Based on the common properties of voltage-dependent channels in ferns and seed plants, it is likely that these key transport proteins are conserved in vascular plants. However, the symplastic connections between fern guard cells in mature stomata indicate that the biophysical mechanisms that control stomatal movements differ between ferns and seed plants.
Agrobacterium tumefaciens is the causal agent of crown gall disease in a wide range of plants via a unique interkingdom DNA transfer from bacterial cells into the plant genome. Agrobacterium tumefaciens is capable of transferring its T-DNA into different plant parts at different developmental stages for transient and stable transformation. However, the plant genes and mechanisms involved in these transformation processes are not well understood. We used Arabidopsis thaliana Col-0 seedlings to reveal the gene expression profiles at early time points during Agrobacterium infection. Common and differentially expressed genes were found in shoots and roots. A gene ontology analysis showed that the glucosinolate (GS) biosynthesis pathway was an enriched common response. Strikingly, several genes involved in indole glucosinolate (iGS) modification and the camalexin biosynthesis pathway were up-regulated, whereas genes in aliphatic glucosinolate (aGS) biosynthesis were generally down-regulated, on Agrobacterium infection. Thus, we evaluated the impacts of GSs and camalexin during different stages of Agrobacterium-mediated transformation combining Arabidopsis mutant studies, metabolite profiling and exogenous applications of various GS hydrolysis products or camalexin. The results suggest that the iGS hydrolysis pathway plays an inhibitory role on transformation efficiency in Arabidopsis seedlings at the early infection stage. Later in the Agrobacterium infection process, the accumulation of camalexin is a key factor inhibiting tumour development on Arabidopsis inflorescence stalks. In conclusion, this study reveals the differential roles of GSs and camalexin at different stages of Agrobacterium-mediated transformation and provides new insights into crown gall disease control and improvement of plant transformation.
Stomata control gas exchanges between the plant and the atmosphere. How natural variation in stomata size and density contributes to resolve trade-offs between carbon uptake and water loss in response to local climatic variation is not yet understood. We developed an automated confocal microscopy approach to characterize natural genetic variation in stomatal patterning in 330 fully sequenced Arabidopsis thaliana accessions collected throughout the European range of the species. We compared this to variation in water-use efficiency, measured as carbon isotope discrimination (δ13C). We detect substantial genetic variation for stomata size and density segregating within Arabidopsis thaliana. A positive correlation between stomata size and δ13C further suggests that this variation has consequences on water-use efficiency. Genome wide association analyses indicate a complex genetic architecture underlying not only variation in stomatal patterning but also to its covariation with carbon uptake parameters. Yet, we report two novel QTL affecting δ13C independently of stomatal patterning. This suggests that, in A. thaliana, both morphological and physiological variants contribute to genetic variance in water-use efficiency. Patterns of regional differentiation and covariation with climatic parameters indicate that natural selection has contributed to shape some of this variation, especially in Southern Sweden, where water availability is more limited in spring relative to summer. These conditions are expected to favour the evolution of drought avoidance mechanisms over drought escape strategies.
Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was −1.0 (interquartile range −2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].
Aims/Introduction
In the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated the effects of empagliflozin on the kidneys in Asian patients.
Materials and Methods
Participants in the EMPA-REG OUTCOME® trial were randomized (1:1:1) to empagliflozin 10 mg, 25 mg or a placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio changes, and renal safety.
Results
Of 7,020 treated patients, 1,517 (26.1%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio 0.64, 95% confidence interval 0.49–0.83), progression to macroalbuminuria (hazard ratio 0.64, 95% confidence interval 0.49–0.85) and the composite of doubling of serum creatinine, initiation of renal-replacement therapy or renal death (hazard ratio 0.48, 95% confidence interval 0.25–0.92). Furthermore, empagliflozin-treated participants showed slower eGFR decline versus placebo, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, maintained through week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population.
Conclusions
In Asian patients from the EMPA-REG OUTCOME® trial, empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings.
Aim
The aim was to identify benefit thresholds for clinical variables. We hypothesize, if variables fall below or exceed these threshold levels, systemic amoxicillin/metronidazole may contribute to reducing progression of periodontitis.
Material & Methods
This is an explorative per-protocol collective analysis (n = 345) conducted on the placebo-controlled, multi-centre ABPARO trial (ClinicalTrials.gov NCT00707369). Patients received debridement with systemic amoxicillin 500 mg/metronidazole 400 mg (3×/day, 7 days, n = 170) or placebo (n = 175) and maintenance therapy every three months. To identify thresholds, each of the following baseline characteristics was classified into two groups (≥threshold value/<threshold value): bleeding on probing, extent of pocket probing depth (PPD) ≥ 5 mm, mean clinical attachment level and age. Treatment effect (% of sites with new attachment loss ≥ 1.3 mm at 27.5 months post-treatment) was calculated.
Results
Adjunctive antimicrobials reduced median new attachment loss in patients < 55 years (5.2%), or with ≥ 35% PPD ≥ 5 mm (4.5%) or with a mean attachment level > 5 mm (5.2%) at baseline compared to the placebo (9.0%, 11.6%, and 12.5%, respectively; p < 0.005).
Conclusions
The clinical benefits of systemic amoxicillin/metronidazole may depend on periodontitis severity and patients' age.