A breathing zirconium metal-organic framework with reversible loss of crystallinity by correlated nanodomain formation

The isoreticular analogue of the metal-organic framework UiO-66(Zr), synthesized with the flexible trans-1,4-cyclohexanedicarboxylic acid as linker, shows a peculiar breathing behavior by reversibly losing long-range crystalline order upon evacuation. The underlying flexibility is attributed to a concerted conformational contraction of up to two thirds of the linkers, which breaks the local lattice symmetry. X-ray scattering data are described well by a nanodomain model in which differently oriented tetragonal-type distortions propagate over about 7-10 unit cells

Constraints on the behaviour and content of volatiles in Galápagos magmas from melt inclusions and nominally anhydrous minerals

Despite their relatively low concentration in most oceanic basalts, volatile species (e.g. H2O, CO2 and S) have a disproportionately large influence on a wide range of mantle and magmatic processes. However, constraining the concentration of H2O (and other volatiles) in basaltic magmas is not straightforward as submarine glass analyses are influenced by assimilation of hydrothermal brines, and the melt inclusion record is often reset by post-entrapment processes. Nevertheless, in this study we show that it is possible to reconstruct a detailed history of the volatile content of basaltic magmas through integration of multiple discreet volatile records and careful consideration of secondary processes. We present new analyses of volatiles in olivine-hosted melt inclusions, melt embayments and nominally anhydrous minerals (NAMS, clinopyroxene and orthopyroxene) found in basalts erupted on Floreana Island in the south-eastern Galápagos Archipelago. Our results indicate that the Floreana magmas, which are characterised by the most radiogenic Pb and Sr isotope signatures in the Galápagos Archipelago, contain H2O concentrations between 0.4 and 0.8 wt% (at a melt Mg# of 0.65, where Mg# = Mg/(Mg + Fe) molar). These are marginally greater than the H2O contents of magmas beneath Fernandina in the western Galápagos Archipelago (cf. 0.2–0.7 wt% H2O at Mg# = 0.65). While the volatile content of magmas from the western archipelago follow trends defined by concurrent mixing and crystallisation, NAMs from Floreana reveal the presence of rare, volatile-rich magmas (~2 wt% H2O) that form as a consequence of reactive porous flow in mush-dominated magmatic systems beneath the south-eastern Galápagos. Furthermore, the Floreana magmas have similar H2O/light Rare Earth Element ratios to basalts from the western Galápagos but contain F/Nd and Cl/K ratios that are ~2 – 3 times greater, indicating that the mantle source of the Floreana lavas might represent an important halogen reservoir in the Galápagos mantle plume

Development and refinement of a technique for short-term intravascular auricular vein catheter placement in mature sows

Intravenous drug administration in adult swine is difficult to perform due to inaccessible superficial veins and thick subcutaneous fat layers. However, successful intravenous drug administration is critical for many biomedical applications including pharmacokinetic studies as extravascular drug administration can influence the drug’s absorption and elimination rate. The purpose of this study was to develop and refine an effective technique for indwelling auricular vein catheter placement in the conscious mature sow. We developed a protocol using a topical anesthetic cream and minimal physical restraint to place indwelling catheters in the auricular vein of six multiparous sows. This method was quick (3 min 20 s ± 8 s [mean ± SE per catheter]), effective (11/12 catheters successfully placed) and reliable, allowing a large drug volume (20–22 mL) to be administrated successfully during the trial without relying on prolonged restraint or general anesthesia of the sow

Intrauterine Candida albicans infection causes systemic fetal candidiasis with progressive cardiac dysfunction in a sheep model of early pregnancy

Introduction: Several recent studies have identified a potential role for intrauterine Candida albicans in adverse pregnancy outcomes, including preterm birth. There is, however, a limited understanding of the impact of intrauterine candida infection on fetal well-being in early pregnancy. Using a sheep model of early pregnancy, the aims of this study were to determine (1) the ability of experimentally induced intrauterine C albicans to infect the fetus and (2) whether C albicans exposure in early pregnancy is associated with alterations in fetal cardiac function, as measured by spectral tissue Doppler imaging analysis of fetal cardiac function. Methods: Merino ewes carrying singleton pregnancies at 89 days’ gestation (term is ∼150 days) received C albicans (n = 8) via ultrasound-guided intra-amniotic injection. Saline-exposed fetuses served as controls (n = 6). Spectral tissue Doppler imaging echocardiography and amniotic fluid collection were performed at baseline and 24 and 72 hours after intrauterine C albicans injection. Fetal tissues were collected at postmortem for analysis of infection and inflammation. Results: Relative to saline control, intrauterine C albicans infection resulted in pronounced increases in amniotic fluid tumor necrosis factor α (TNF-α; P < .05) and cytokine/chemokine messenger RNA (interleukin [IL] 1β, IL-6, TNF-α, and monocyte chemoattractant protein 1; P < .05) in the fetal myocardium, lung, skin, and liver at 72 and 96 hours postinfection. Spectral tissue Doppler imaging showed diastolic dysfunction at 24 hours and severe biventricular diastolic dysfunction 72 hours postinfection. Conclusion: Intrauterine C albicans infection in a sheep model of early pregnancy causes systemic fetal candidiasis, which is associated with a robust systemic inflammatory response and progressive cardiac dysfunction detectable by spectral tissue Doppler imaging

Cryptic evolved melts beneath monotonous basaltic shield volcanoes in the Galápagos Archipelago

Funder: Jeremy Willson Charitable Trust - research grantAbstract: Many volcanoes erupt compositionally homogeneous magmas over timescales ranging from decades to millennia. This monotonous activity is thought to reflect a high degree of chemical homogeneity in their magmatic systems, leading to predictable eruptive behaviour. We combine petrological analyses of erupted crystals with new thermodynamic models to characterise the diversity of melts in magmatic systems beneath monotonous shield volcanoes in the Galápagos Archipelago (Wolf and Fernandina). In contrast with the uniform basaltic magmas erupted at the surface over long timescales, we find that the sub-volcanic systems contain extreme heterogeneity, with melts extending to rhyolitic compositions. Evolved melts are in low abundance and large volumes of basalt flushing through the crust from depth overprint their chemical signatures. This process will only maintain monotonous activity while the volume of melt entering the crust is high, raising the possibility of transitions to more silicic activity given a decrease in the crustal melt flux

Protection of the Ovine Fetal Gut against Ureaplasma-Induced Chorioamnionitis: A Potential Role for Plant Sterols

Chorioamnionitis, clinically most frequently associated with Ureaplasma, is linked to intestinal inflammation and subsequent gut injury. No treatment is available to prevent chorioamnionitis-driven adverse intestinal outcomes. Evidence is increasing that plant sterols possess immune-modulatory properties. Therefore, we investigated the potential therapeutic effects of plant sterols in lambs intra-amniotically (IA) exposed to Ureaplasma. Fetal lambs were IA exposed to Ureaplasma parvum (U. parvum, UP) for six days from 127 d–133 d of gestational age (GA). The plant sterols β-sitosterol and campesterol, dissolved with β-cyclodextrin (carrier), were given IA every two days from 122 d–131 d GA. Fetal circulatory cytokine levels, gut inflammation, intestinal injury, enterocyte maturation, and mucosal phospholipid and bile acid profiles were measured at 133 d GA (term 150 d). IA plant sterol administration blocked a fetal inflammatory response syndrome. Plant sterols reduced intestinal accumulation of proinflammatory phospholipids and tended to prevent mucosal myeloperoxidase-positive (MPO) cell influx, indicating an inhibition of gut inflammation. IA administration of plant sterols and carrier diminished intestinal mucosal damage, stimulated maturation of the immature epithelium, and partially prevented U. parvum-driven reduction of mucosal bile acids. In conclusion, we show that β-sitosterol and campesterol administration protected the fetus against adverse gut outcomes following UP-driven chorioamnionitis by preventing intestinal and systemic inflammation

Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.This work was supported by Cancer Research UK (C1094/A11728 to CMLW and NGB for the RAPPER study, C26900/A8740 to GCB, and C8197/A10865 to AMD), the Royal College of Radiologists (C26900/ A8740 to GCB), the National Institute for Health Research (GCB; no grant number), Addenbrooke's Charitable Trust (GCB; no grant number), Institute of Cancer Research (National Institute for Health Research) Biomedical Research Centre (C46/A2131 to DPD and SG), the National Institute for Health Research Cambridge Biomedical Research Centre (NGB; no grant number), UK Medical Research Council (RG70550 to LD), the Joseph Mitchell Trust (AMD; no grant number), the Experimental Cancer Medicine Centre (CMLW; no grant number), Cancer Research UK Program grant Section of Radiotherapy (C33589/ A19727 to SLG), the United States National Institutes of Health (1R01CA134444 to BSR and HO, 2P30CA014520-34 to SB, and 1K07CA187546-01A1 to SLK), the American Cancer Society (RSGT-05- 200-01-CCE to BSR), the U.S. Department of Defense (PC074201 to BSR and HO), Mount Sinai Tisch Cancer Institute Developmental Fund Award (BSR; no grant number), the Instituto de Salud Carlos III (FIS PI10/00164 and PI13/02030 to AV and PI13/01136 to AC), Fondo Europeo de Desarrollo Regional (FEDER 2007–2013 to AV and AC; no grant number), Instituto de Salud Carlos III (FIS PI10/00164 and PI13/ 02030 to AV and PI13/01136 to AC), Xunta de Galicia and the European Social Fund (POS-A/2013/034 to LF), and the Alberta Cancer Board Research Initiative Program (103.0393.71760001404 to MP). AMD receives support from the REQUITE study, which is funded by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 601826. Laboratory infrastructure for the RAPPER study was funded by Cancer Research UK [C8197/A10123] and the Manchester Experimental Cancer Medicine Centre. The RAPPER cohort comprises individuals and data recruited into the RT01 and CHHiP UK radiotherapy trials. The RT01 trial was supported by the UK Medical Research Council. The CHHiP trial (CRUK/06/016) was supported by the Department of Health and Cancer Research UK (C8262/A7253); trial recruitment was facilitated within centers by the National Institute for Health Research Cancer Research Network. DPD and SLG acknowledge NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ebiom.2016.07.02

EFSUMB 2020 Proposal for a Contrast-Enhanced Ultrasound-Adapted Bosniak Cyst Categorization – Position Statement

The well-established Bosniak renal cyst classification is based on contrast-enhanced computed tomography determining the malignant potential of cystic renal lesions. Ultrasound has not been incorporated into this pathway. However, the development of ultrasound contrast agents coupled with the superior resolution of ultrasound makes it possible to redefine the imaging of cystic renal lesions. In this position statement, an EFSUMB Expert Task Force reviews, analyzes, and describes the accumulated knowledge and limitations and presents the current position on the use of ultrasound contrast agents in the evaluation of cystic renal lesions

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial

BackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n&nbsp;=&nbsp;45) or had a complex karyotype without TP53 mutation (cohort B; n&nbsp;=&nbsp;13) received entospletinib 400&nbsp;mg twice daily with decitabine 20&nbsp;mg/m2 on days 1-10 every 28&nbsp;days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2&nbsp;years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2&nbsp;months, respectively, and the median overall survival was 6.5 and 11.5&nbsp;months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need

Projecting marine mammal distribution in a changing climate

Climate-related shifts in marine mammal range and distribution have been observed in some populations; however, the nature and magnitude of future responses are uncertain in novel environments projected under climate change. This poses a challenge for agencies charged with management and conservation of these species. Specialized diets, restricted ranges, or reliance on specific substrates or sites (e.g., for pupping) make many marine mammal populations particularly vulnerable to climate change. High-latitude, predominantly ice-obligate, species have experienced some of the largest changes in habitat and distribution and these are expected to continue. Efforts to predict and project marine mammal distributions to date have emphasized data-driven statistical habitat models. These have proven successful for short time-scale (e.g., seasonal) management activities, but confidence that such relationships will hold for multi-decade projections and novel environments is limited. Recent advances in mechanistic modeling of marine mammals (i.e., models that rely on robust physiological and ecological principles expected to hold under climate change) may address this limitation. The success of such approaches rests on continued advances in marine mammal ecology, behavior, and physiology together with improved regional climate projections. The broad scope of this challenge suggests initial priorities be placed on vulnerable species or populations (those already experiencing declines or projected to undergo ecological shifts resulting from climate changes that are consistent across climate projections) and species or populations for which ample data already exist (with the hope that these may inform climate change sensitivities in less well observed species or populations elsewhere). The sustained monitoring networks, novel observations, and modeling advances required to more confidently project marine mammal distributions in a changing climate will ultimately benefit management decisions across time-scales, further promoting the resilience of marine mammal populations