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Angiogenesis, hematopoiesis and osteogenesis are fundamental processes mediating complex and essential biological functions. In the bone marrow, endothelial cells (ECs) are a principal mediator of regulatory signals that govern hematopoietic and mesenchymal stem cells. EC and osteoblast interactions and niche functions of ECs are fundamental in maintaining bone health and coordinating repair and regeneration following injury. These cellular interactions are subject to dysregulation and deterioration under stress, aging, chronic disease states and malignancy. Thus, the prospect of manipulating the bone vasculature has tremendous potential to advance therapeutic interventions for the management of bone diseases. This review discusses the current state of vascular-skeletal tissue interactions focusing on osteoblast and hematopoietic stem cells interaction with ECs.

The Chilean soapbark tree (Quillaja saponaria) produces soap-like molecules called QS saponins that are important vaccine adjuvants. These highly valuable compounds are sourced by extraction from the bark, and their biosynthetic pathway is unknown. Here, we sequenced the Q. saponaria genome. Through genome mining and combinatorial expression in tobacco, we identified 16 pathway enzymes that together enable the production of advanced QS pathway intermediates that represent a bridgehead for adjuvant bioengineering. We further identified the enzymes needed to make QS-7, a saponin with excellent therapeutic properties and low toxicity that is present in low abundance in Q. saponaria bark extract. Our results enable the production of Q. saponaria vaccine adjuvants in tobacco and open the way for new routes to access and engineer natural and new-to-nature immunostimulants. Saponins, a type of plant-derived glycoside, are useful in formulations including soaps, medicines, and root beer foam. Reed et al. studied how the Chilean soapbark tree (Quillaja saponaria) makes its saponins, which lend immunostimulatory activity to vaccines against shingles, malaria, and COVID-19 (see the Perspective by Chubatsu Nunes and Dang). The saponins are currently extracted from the tree?s bark. The identification of enzymes in the biosynthetic pathway opens doors to the more sustainable production of these useful adjuvants and opportunities to engineer new adjuvants. ?PJH Genome-based pathway discovery reveals the biosynthetic route to vaccine adjuvants produced by the soapbark tree.

Triterpenes with complex scaffold modifications are widespread in plants yet little is known regarding biosynthesis. Limonoids are an exemplary family that includes the bitter taste in citrus (e.g., limonin) and the active constituents in neem oil, a widely used bioinsecticide (e.g., azadirachtin). Despite limonoid commercial value, a complete biosynthetic route has not been described. Here, we report the discovery of 22 enzymes that catalyze 12 unique reactions including the 4-carbon scission and furan installation that are a signature of the limonoid family and a pair of sterol isomerases previously unknown in plants. This gene set is then used for the total biosynthesis of kihadalactone A and azadirone in a heterologous plant. These results enable access to valuable limonoids and provide a template for discovery and reconstitution of triterpene biosynthetic pathways in plants that require multiple skeletal rearrangements and oxidations.

Non-random gene organization in eukaryotes plays a significant role in genome evolution. Here, we investigate the origin of a biosynthetic gene cluster for production of defence compounds in oat—the avenacin cluster. We elucidate the structure and organisation of this 12-gene cluster, characterise the last two missing pathway steps, and reconstitute the entire pathway in tobacco by transient expression. We show that the cluster has formed de novo since the divergence of oats in a subtelomeric region of the genome that lacks homology with other grasses, and that gene order is approximately colinear with the biosynthetic pathway. We speculate that the positioning of the late pathway genes furthest away from the telomere may mitigate against a ‘self-poisoning’ scenario in which toxic intermediates accumulate as a result of telomeric gene deletions. Our investigations reveal a striking example of adaptive evolution underpinned by remarkable genome plasticity., The genomic organization and origin of the avenacin biosynthetic gene cluster remain unknown. Here, the authors assemble the genome of diploid oat Avena strigosa, reveal the structure and organization of the consecutive genes, characterize the last two missing pathway steps, and investigate the origin of the pathway in cereals.

Background: Prosthetic service development and delivery rely on data describing population needs. These needs are context-specific, but most existing data come from high-income countries or small geographic areas, which are often not comparable. This study analysed routinely collected digital patient record data at multiple time points to provide insights into characteristics of people accessing Cambodian prosthetic services. Methods: We investigated trends in birth year, sex, year and reason for limb absence, and prosthesis type, over three decades. Then, we observed data from 2005 and 2019 indicating how the population actively accessing prosthetics services has changed. Results: Temporal trends in prosthetics service user demographics corresponded with events in Cambodia's socio-political history. The predominant historical reason for limb absence prior to 2000 was weapon trauma during and following conflict. Since 2000, this was replaced by non-communicable disease and road accidents. Transtibial remained the most prevalent amputation level but transfemoral amputation had higher incidence for people with limb loss from road accidents, and people with limb loss due to disease were older. These observations are important as both transfemoral and older-aged groups experience particular rehabilitation challenges compared to the young, transtibial group. Conclusions: The study shows how standardised, routinely collected data across multiple clinics within a country can be used to characterise prosthetics service user populations and shows significant changes over time. This indicates the need to track client characteristics and provides evidence for adapting services according to population dynamics and changes in patient need.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment.RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Increased microvascular permeability to plasma proteins and neutrophil emigration are hallmarks of innate immunity and key features of numerous inflammatory disorders. Although neutrophils can promote microvascular leakage, the impact of vascular permeability on neutrophil trafficking is unknown. Here, through the application of confocal intravital microscopy, we report that vascular permeability–enhancing stimuli caused a significant frequency of neutrophil reverse transendothelial cell migration (rTEM). Furthermore, mice with a selective defect in microvascular permeability enhancement (VEC-Y685F-ki) showed reduced incidence of neutrophil rTEM. Mechanistically, elevated vascular leakage promoted movement of interstitial chemokines into the bloodstream, a response that supported abluminal-to-luminal neutrophil TEM. Through development of an in vivo cell labeling method we provide direct evidence for the systemic dissemination of rTEM neutrophils, and showed them to exhibit an activated phenotype and be capable of trafficking to the lungs where their presence was aligned with regions of vascular injury. Collectively, we demonstrate that increased microvascular leakage reverses the localization of directional cues across venular walls, thus causing neutrophils engaged in diapedesis to reenter the systemic circulation. This cascade of events offers a mechanism to explain how local tissue inflammation and vascular permeability can induce downstream pathological effects in remote organs, most notably in the lungs.

Summary Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging., Graphical abstract, Highlights • Aged mice show high levels of neutrophil reverse transendothelial migration (rTEM) • Mast cells (MC) and MC-derived CXCL1 drive neutrophil rTEM in inflamed aged tissues • Intensified endothelial ACKR1-CXCL1 axis promotes neutrophil CXCR2 internalization • Aged lungs program rTEM neutrophils toward an activated and noxious phenotype, Aging is a critical risk factor for inflammatory disorders. Barkaway, Rolas et al. show that inflamed aged tissues present a high frequency of neutrophil reverse transendothelial migration (rTEM) back into the circulation in a mast cell-dependent manner. rTEM neutrophils are retained in aged lungs and programmed toward an activated phenotype, capable of inducing tissue damage.

Summary Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial. Funding UK National Institute for Health Research Health Technology Assessment Programme.

We study a new model of quintessential inflation which is inspired by supergravity and string theory. The model features a kinetic pole, which gives rise to the inflationary plateau, and a runaway quintessential tail. We envisage a coupling between the inflaton and the Peccei-Quinn (PQ) field which terminates the roll of the runaway inflaton and traps the latter at an enhanced symmetry point (ESP), thereby breaking the PQ symmetry. The kinetic density of the inflaton is transferred to the newly created thermal bath of the hot big bang due to the decay of PQ particles. The model successfully accounts for the observations of inflation and dark energy without any fine-tuning, while also resolving the strong CP problem of QCD and generating axionic dark matter, without isocurvature perturbations. Trapping the inflaton at the ESP ensures that the model does not suffer from the infamous 5th force problem, which typically plagues quintessence., Published version, 11 pages, 4 figures

We study the formation of primordial black holes (PBHs) in the early Universe during a period of slow reheating after inflation. We demonstrate how the PBH formation mechanism may change even before the end of the matter-dominated phase and calculate the expected PBH mass function. We find that there is a threshold for the variance of the density contrast, $\sigma_c \simeq 0.05$, below which the transition occurs even before reheating, with this having important consequences for the PBH mass function. We also show that there is a maximum cut-off for the PBH mass at around $100\,M_{\odot}$, below which the subdominant radiation bath affects PBH production, making the scenario particularly interesting for the recent LIGO observations of black hole mergers., Comment: 7 pages, 5 figures. v2: added discussion and references; matches the published version

We investigate a compelling model of quintessential inflation in the context of $\alpha$-attractors, which naturally result in a scalar potential featuring two flat regions, the inflationary plateau and the quintessential tail. The "asymptotic freedom" of $\alpha$-attractors, near the kinetic poles, suppresses radiative corrections and interactions, which would otherwise threaten to lift the flatness of the quintessential tail and cause a 5th-force problem respectively. Since this is a non-oscillatory inflation model, we reheat the Universe through instant preheating. The parameter space is constrained by both inflation and dark energy requirements. We find an excellent correlation between the inflationary observables and model predictions, in agreement with the $\alpha$-attractors set-up. We also obtain successful quintessence for natural values of the parameters. Our model predicts potentially sizeable tensor perturbations (at the level of 1%) and a slightly varying equation of state for dark energy, to be probed in the near future., Comment: 15 pages, 10 figures. Appendix and additional author added

A novel inflection-point inflation model is analysed. The model considers a massless scalar field, whose self-coupling's running is stabilised by a non-renormalisable operator. The running is controlled by a fermion loop. We find that successful inflation is possible for a natural value of the Yukawa coupling $y\simeq 4\times 10^{-4}$. The necessary fine-tuning is only $\sim 10^{-6}$, which improves on the typical tuning of inflection-point inflation models, such as MSSM inflation. The model predicts a spectral index within the 1-$\sigma$ bound of the latest CMB observations, with negligible tensors ($r\sim 10^{-(9-10)}$). These results are largely independent of the order of the stabilising non-renormalisable operator., Comment: 4 pages, 1 figure. Published version

Allergen-specific responses in atopic dermatitis (AD) are skewed toward a Th2 profile. However, individuals with AD have been shown to make effective virus-specific Th1 responses, raising the possibility that the skin itself contributes to driving the AD Th2 immunophenotype. Therefore, to explore the programming of immunological sensitization by the skin, we examined the outcome of sensitization through non-lesional skin of individuals with AD and healthy controls. Volunteers (controls, AD individuals with filaggrin gene (FLG) mutations (ADFM), and AD individuals without FLG mutations (ADWT)) were sensitized by cutaneous application of 2,4-dinitrochlorobenzene (DNCB), a small, highly lipophilic chemical sensitizer. At the doses tested, DNCB showed equal penetration into skin of all groups. Clinical reactions to DNCB were significantly reduced in AD. Although both controls and AD made systemic DNCB-specific Th1 responses, these were reduced in AD and associated with significantly Th2-skewed DNCB-specific T-cell responses. Th2 skewing was seen in both ADFM and ADWT, with no difference between these groups. After 3 months, DNCB-specific Th2 responses were persistent in individuals with AD, and Th1 responses persisted in controls. These data provide evidence that when antigen penetration is not limiting, AD skin has a specific propensity to Th2 programming, suggesting the existence of altered skin immune signaling that is AD-specific and independent of FLG status.

We performed a retrospective cohort comparison study to look at the processes for concentrating geriatric resources in the acute admissions area in a general hospital in the UK and compare key outcomes. The number of consultant geriatricians and other staff working at the 'front door' - acute medical unit (AMU) and short stay ward (SSW) - was increased. We compared 'front door' outcomes with whole department outcomes in 2013 and 2014, looking at the proportion of patients discharged within 3 and 5 days of admission, the proportion discharged from the 'front door', mean lengths of stay (LOS) and readmissions within 28 days of discharge. There were 1,147 and 1,381 discharge episodes in 2013 and 2014, respectively. 'Front door' discharges rose from 36% to 46% (p

A new family of inflationary models is introduced and analysed. The behaviour of the parameters characterising the models suggest preferred values, which generate the most interesting testable predictions. Results are further improved if late reheating and/or a subsequent period of thermal inflation is taken into account. Specific model realisations consider a sub-Planckian inflaton variation or a potential without fine-tuning of mass scales, based on the Planck and grand unified theory scales. A toy model realisation in the context of global and local supersymmetry is examined and results fitting the Planck observations are determined., Comment: 14 pages, 5 figures

Minimal hybrid inflation in supergravity has been ruled out by the 2015 Planck observations because the spectral index of the produced curvature perturbation falls outside observational bounds. To resurrect the model, a number of modifications have been put forward but many of them spoil the accidental cancellation that resolves the eta-problem and require complicated Kahler constructions to counterbalance the lost cancellation. In contrast, in this paper the model is rendered viable by supplementing the scenario with a brief period of thermal inflation, which follows the reheating of primordial inflation. The scalar field responsible for thermal inflation requires a large non-zero vacuum expectation value (VEV) and a flat potential. We investigate the VEV of such a flaton field and its subsequent effect on the inflationary observables. We find that, for large VEV, minimal hybrid inflation in supergravity produces a spectral index within the 1-sigma Planck bound and a tensor-to-scalar ratio which may be observable in the near future. The mechanism is applicable to other inflationary models., Comment: 9 pages, 1 figure, published version

A novel approach to quintessential inflation model building is studied, within the framework of $\alpha$-attractors, motivated by supergravity theories. Inflationary observables are in excellent agreement with the latest CMB observations, while quintessence explains the dark energy observations without any fine-tuning. The model is kept intentionally minimal, avoiding the introduction of many degrees of freedom, couplings and mass scales. In stark contrast to $\Lambda$CDM, for natural values of the parameters, the model attains transient accelerated expansion, which avoids the future horizon problem, while it maintains the field displacement mildly sub-Planckian such that the flatness of the quintessential tail is not lifted by radiative corrections and violations of the equivalence principle (fifth force) are under control. In particular, the required value of the cosmological constant is near the eletroweak scale. Attention is paid to the reheating of the Universe, which avoids gravitino overproduction and respects nucleosynthesis constraints. Kination is treated in a model independent way. A spike in gravitational waves, due to kination, is found not to disturb nucleosynthesis as well., Comment: 21 pages, 4 figures, published version

Older people presenting to the acute medical unit (AMU) in our hospital were traditionally triaged to acute medicine (ACM), discharged after shorter stay (

Wheat is a widely grown food crop that suffers major yield losses due to attack by pests and pathogens. A better understanding of biotic stress responses in wheat is thus of major importance. The recently assembled bread wheat genome coupled with extensive transcriptomic resources provides unprecedented new opportunities to investigate responses to pathogen challenge. Here, we analyze gene coexpression networks to identify modules showing consistent induction in response to pathogen exposure. Within the top pathogen-induced modules, we identify multiple clusters of physically adjacent genes that correspond to six pathogen-induced biosynthetic pathways that share a common regulatory network. Functional analysis reveals that these pathways, all of which are encoded by biosynthetic gene clusters, produce various different classes of compounds—namely, flavonoids, diterpenes, and triterpenes, including the defense-related compound ellarinacin. Through comparative genomics, we also identify associations with the known rice phytoalexins momilactones, as well as with a defense-related gene cluster in the grass model plant Brachypodium distachyon . Our results significantly advance the understanding of chemical defenses in wheat and open up avenues for enhancing disease resistance in this agriculturally important crop. They also exemplify the power of transcriptional networks to discover the biosynthesis of chemical defenses in plants with large, complex genomes.

Wheat is one of the most widely grown food crops in the world. However, it succumbs to numerous pests and pathogens that cause substantial yield losses. A better understanding of biotic stress responses in wheat is thus of major importance. Here we identify previously unknown pathogen-induced biosynthetic pathways that produce a diverse set of molecules, including flavonoids, diterpenes and triterpenes. These pathways are encoded by six biosynthetic gene clusters and share a common regulatory network. We further identify associations with known or novel phytoalexin clusters in other cereals and grasses. Our results significantly advance the understanding of chemical defenses in wheat and open up new avenues for enhancing disease resistance in this agriculturally important crop.