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BackgroundThis study investigated the cost-effectiveness of vitamin D3 supplementation in older adults in Ireland, with year-round vitamin D deficiency (serum 25-hydroxyvitamin D concentration MethodsThree age groups were investigated: (1) ≥50 years, (2) ≥60 years and (3) ≥70 years. Based on the clinical literature, vitamin D3 supplementation may: (1) decrease all-cause mortality by 7% and (2) reduce hip fractures by 16% and non-hip fractures by 20%. A discount rate of 4% was applied to life years and quality-adjusted life years (QALYs) gained, and healthcare costs. The annual healthcare costs per patient used in the model are based on the average annual health resource use over the 5-year time horizon of the model.ResultsThe cost/QALY estimates in all three age groups are below the usually acceptable cost-effectiveness threshold of €20 000/QALY. The most cost-effective and least costly intervention was in adults ≥70 years. For this age group, the average annual costs and outcomes would be approximately €5.6 million, 1044 QALYs gained, with a cost/QALY of approximately €5400. The results are most sensitive to the mortality risk reduction following vitamin D3 supplementation.ConclusionThe cost-effectiveness of vitamin D3 supplementation is most robust in adults ≥70 years. Clinical uncertainty in the magnitude of the benefits of vitamin D3 supplementation could be further addressed by means of: (1) performing a clinical research study or (2) conducting a pilot/regional study, prior to reaching a decision to invest in a nationwide programme.

Objective: To evaluate neurodevelopmental status among children with inherited cholestatic liver diseases with native liver and variables predictive of impairment. Methods: Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85–99, 70–84, 1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ. Conclusions: Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions.

Background & Aims Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. Methods Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. Results Of 177 patients, 169 (95.5%) were PI-naive. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. Conclusion Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. Lay summary Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. Clinical trial number NCT03092375 .

Methcathinone (MCAT) is a psychostimulant of abuse that can cause both persistent striatal dopaminergic and serotonergic, as well as hippocampal serotonergic, deficits. Evidence suggests that the rapid effects of stimulants that are structurally and mechanistically similar to MCAT on monoamine transporter function may contribute to the abuse liability and/or persistent monoaminergic deficits caused by these agents. Thus, effects of MCAT on 1) striatal dopamine (DA) transporter (DAT); and 2) striatal and hippocampal serotonin transporter (SERT) function, as determined in tissues from adult male rats, were assessed. As reported previously, a single administration of MCAT rapidly (within 1 hr) decreases striatal [3 H]DA uptake. Similarly, incubation of rat synaptosomes with MCAT at 37℃ (but not 4˚C) decreased striatal [3 H]DA uptake. Incubation with MCAT likewise decreased [3 H]5HT but not vesicular [3 H]DA uptake. MCAT incubation in vitro was without effect on [3 H]DA uptake in striatal synaptosomes prepared from MCAT-treated rats. The decrease in [3 H]DA uptake caused by MCAT incubation: (a) reflected a decrease in Vmax , with minimal change in Km , and (b) was attenuated by co-incubation with the cell-permeable calcium chelator, N,N'-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]-1,1'-bis[(acetyloxy)methyl] ester-glycine (BAPTA-AM), as well as the non-selective protein kinase-C (PKC) inhibitors bisindolylmaleimide-1 (BIM-1) and 2-[1-3(Aminopropyl)indol-3-yl]-3(1-methyl-1H-indol-3-yl)maleimide (or Bisindolylmaleimide VIII; Ro-31-7549). Taken together, these results suggest that in vitro MCAT incubation may model important aspects of MCAT administration in vivo, and that calcium and PKC contribute to the in vitro effects of MCAT on DAT.

Production of neutral beams consisting of the mixed hydrogen isotopes is of interest for the purposes of diagnostics, since it enables us to study the relaxation process of fast ions trapped in plasma using the neutron diagnostics. In addition, the injection of mixed deuterium–tritium beams for heating and sustaining the plasma could greatly simplify the expensive systems for isotope separation in fusion reactors. In this work, the Doppler spectroscopy technique is used to experimentally determine the fractional content of ions with different masses in the ion source beam consisting of the mixed hydrogen isotopes (hydrogen–deuterium beam). The experience acquired in this field is proposed to be further used to optimize the conditions for plasma generation in the ion source in order to obtain an ion beam with the mixed isotope composition and specific characteristics required for various applications.

The mammalian membrane‐bound O‐acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small‐molecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel small‐molecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structure‐activity relationship investigation identified single enantiomer IMP‐1575, the most potent HHAT inhibitor reported to‐date, and guided design of photocrosslinking probes that maintained HHAT‐inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small‐molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed by kinetic analysis. Our results provide an optimal HHAT tool inhibitor IMP‐1575 (K i=38 nM) and a strategy for mapping small molecule interaction sites in MBOATs., Structure‐activity relationship analysis of Hedgehog acyltransferase (HHAT) inhibitors allowed rational design of photochemical probes for HHAT. Probe photocrosslinking identified the first small‐molecule inhibitor binding site in HHAT and revealed the inhibitory mechanism, providing an optimal HHAT tool inhibitor IMP‐1575 (K i=38 nM) for future studies.

Cirrus clouds composed of small ice crystals are often the first solid matter encountered by sunlight as it streams into Earth’s atmosphere. A broad array of recent research has emphasized that photon-particle scattering calculations are very sensitive to ice particle morphology, complexity, and surface roughness. Uncertain variations in these parameters have major implications for successfully parameterizing the radiative ramifications of cirrus clouds in climate models. To date, characterization of the microscale details of cirrus particle morphology has been limited by the particles’ inaccessibility and technical difficulty in capturing imagery with sufficient resolution. Results from a new experimental system achieve much higher resolution images of cirrus ice particles than existing airborne particle imaging systems. The novel system (Ice Cryo-Encapsulation by Balloon, ICE-Ball) employs a balloon-borne payload with environmental sensors and hermetically-sealed cryo-encapsulation cells. The payload captures ice particles from cirrus clouds, seals them, and returns them via parachute for vapor-locked transfer onto a cryo-scanning electron microscopy stage (cryo-SEM). From 2016–2019, the ICE-Ball system has successfully yielded high resolution particle images on nine cirrus-penetrating flights. On several flights, including one highlighted here in detail, thousands of cirrus particles were retrieved and imaged, revealing unanticipated particle morphologies, extensive habit heterogeneity, multiple scales of mesoscale roughening, a wide array of embedded aerosol particles, and even greater complexity than expected.

Ten infrequently monitored antibiotics in biosolids were examined in archived American sewage sludges (n = 79) collected as part of the 2006/2007 U.S. Environmental Protection Agency (EPA) Targeted National Sewage Sludge Survey. This study inspected the occurrence of amoxicillin, ampicillin, erythromycin, furazolidone [proxy metabolite: 3-(2-nitrobenzylidenamino)-2-oxazolidinone (NP-AOZ)], nalidixic acid, oxolinic acid, oxytetracycline, spiramycin, sulfadimidine, and sulfadimethoxine in sewage sludges after nearly a decade in frozen storage. Six antibiotics were detected at the following average concentrations (ng/g dry weight): amoxicillin (1.0), nalidixic acid (19.1), oxolinic acid (2.7), erythromycin (0.6), oxytetracycline (4.5), and ampicillin (14.8). The remaining four were not detected in any samples (

Purpose To assess the dietary intake, nutrition knowledge and hydration status of Irish Gaelic footballers. Method One hundred and sixty-eight male club/county level Irish Gaelic footballers (median [IQR]; age 23 years [20.0, 27.0]; height 1.79 m [1.74, 1.84]; body mass 78.0 kg [73.5, 84.8]) participated in this cross-sectional study. Dietary intake was assessed using a 4-day semi-quantitative food record, with the application of Goldberg cut-offs to define acceptable reporters (n = 62). Nutrition knowledge was assessed using the validated Nutrition for Sport Knowledge Questionnaire in a sub-group of athletes (n = 24), while hydration status was measured using urine specific gravity pre-exercise (USG) in 142 athletes. Results Dietary analysis indicated an energy deficit at the group level (485 kcal [IQR 751,6]) (p p p p Conclusions Our findings suggest that Irish Gaelic footballers have sub-optimal dietary practices and lack nutrition knowledge. Individualised nutrition support may benefit these athletes to meet their nutrition requirements, to support health and performance.

Hyperpolarization-activated cation-nonselective (HCN) channels regulate electrical activity in the brain and heart in a cAMP-dependent manner. The voltage-gating of these channels is mediated by a transmembrane (TM) region but is additionally regulated by direct binding of cAMP to a cyclic nucleotide-binding (CNB) fold in the cytoplasmic C-terminal region. Cyclic AMP potentiation has been explained by an autoinhibition model which views the unliganded CNB fold as an inhibitory module whose influence is disrupted by cAMP binding. However, the HCN2 subtype uses two other CNB fold-mediated mechanisms called open-state trapping and Quick-Activation to respectively slow the deactivation kinetics and speed the activation kinetics, against predictions of an autoinhibition model. To test how these multiple mechanisms are influenced by the TM region, we replaced the TM region of HCN2 with that of HCN4. This HCN4 TM-replacement preserved cAMP potentiation but augmented the magnitude of autoinhibition by the unliganded CNB fold; it moreover disrupted open-state trapping and Quick-Activation so that autoinhibition became the dominant mechanism contributed by the C-terminal region to determine kinetics. Truncation within the CNB fold partially relieved this augmented autoinhibition. This argues against the C-terminal region acting like a portable module with consistent effects on TM regions of different subtypes. Our findings provide evidence that functional interactions between the HCN2 TM region and C-terminal region govern multiple CNB fold-mediated mechanisms, implying that the molecular mechanisms of autoinhibition, open-state trapping, and Quick-Activation include participation of TM region structures. Electronic supplementary material The online version of this article (10.1007/s00232-020-00111-8) contains supplementary material, which is available to authorized users.

The complex trans-[(2,9-dipyridyl-1,10-phenanthroline)(CH3CN)2Ru](OTf)2 was synthesized and tested as a homogeneous hydrodeoxygenation catalyst for the conversion of biomass-derived furfuryl alcoho...

Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS‐related cholestasis. Two hundred and ninety‐three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z‐scores of

The air tolerant precatalyst, [Rh(L)(NBD)]Cl ([1]Cl) [L = κ3-(iPr2PCH2CH2)2NH, NBD = norbornadiene], mediates the selective synthesis of N-methylpolyaminoborane, (H2BNMeH)n, by dehydropolymerization of H3B·NMeH2. Kinetic, speciation, and DFT studies show an induction period in which the active catalyst, Rh(L)H3 (3), forms, which sits as an outer-sphere adduct 3·H3BNMeH2 as the resting state. At the end of catalysis, dormant Rh(L)H2Cl (2) is formed. Reaction of 2 with H3B·NMeH2 returns 3, alongside the proposed formation of boronium [H2B(NMeH2)2]Cl. Aided by isotopic labeling, Eyring analysis, and DFT calculations, a mechanism is proposed in which the cooperative “PNHP” ligand templates dehydrogenation, releasing H2B═NMeH (ΔG‡calc = 19.6 kcal mol–1). H2B═NMeH is proposed to undergo rapid, low barrier, head-to-tail chain propagation for which 3 is the catalyst/initiator. A high molecular weight polymer is formed that is relatively insensitive to catalyst loading (Mn ∼71 000 g mol–1; Đ, of ∼ 1.6). The molecular weight can be controlled using [H2B(NMe2H)2]Cl as a chain transfer agent, Mn = 37 900–78 100 g mol–1. This polymerization is suggested to arise from an ensemble of processes (catalyst speciation, dehydrogenation, propagation, chain transfer) that are geared around the concentration of H3B·NMeH2. TGA and DSC thermal analysis of polymer produced on scale (10 g, 0.01 mol % [1]Cl) show a processing window that allows for melt extrusion of polyaminoborane strands, as well as hot pressing, drop casting, and electrospray deposition. By variation of conditions in the latter, smooth or porous microstructured films or spherical polyaminoboranes beads (∼100 nm) result.

Treatment of vascular disease, from peripheral ischemia to coronary heart disease (CHD), is poised for transformation with the introduction of transient implants designed to "scaffold" regeneration of blood vessels and ultimately leave nothing behind. Improved materials could expand the use of these devices. Here, we examine one of the leading polymers for bioresorbable scaffolds (BRS), polylactide (PLA), as the matrix of nanocomposites with tungsten disulfide (WS2) nanotubes (WSNT), which may provide mechanical reinforcement and enhance radio-opacity. We evaluate in vitro cytotoxicity using vascular cells, flow-induced crystallization and radio-opacity of PLA-WSNT nanocomposites at low WSNT concentration. A small amount of WSNT (0.1 wt%) can effectively promote oriented crystallization of PLA without compromising molecular weight. And radio-opacity improves significantly: as little as 0.5 to 1 wt% WSNT doubles the radio-opacity of PLA-WSNT relative to PLA at 17 keV. The results suggest that a single component, WSNT, has the potential to increase the strength of BRS to enable thinner devices and increase radio-opacity to improve intraoperative visualization. The in vitro toxicity results indicate that PLA-WSNT nanocomposites are worthy of investigation in vivo. Although substantial further preclinical studies are needed, PLA-WSNT nanocomposites may provide a complement of material properties that may improve BRS and expand the range of lesions that can be treated using transient implants. STATEMENT OF SIGNIFICANCE: Bioresorbable Scaffolds (BRSs) support regeneration of arteries without permanent mechanical constraint. Poly-L-lactide (PLLA) is the structural material of the first approved BRS for coronary heart disease (ABSORB BVS), withdrawn due to adverse events in years 1-3. Here, we examine tungsten disulfide (WS2) nanotubes (WSNT) in PLA to address two contributors to early complications: (1) reinforce PLLA (enable thinner BRS), and (2) increase radiopacity (provide intraoperative visibility). For BRS, it is significant that WSNT disperse, remain dispersed, reduce friction and improve mechanical properties without additional chemicals or surface modifications. Like WS2 nanospheres, bare WSNT and PLA-WSNT nanocomposites show low cytotoxicity in vitro. PLA-WSNT show enhanced flow-induced crystallization relative to PLA, motivating future study of the processing behavior and strength of these materials.

Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091, a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclinical studies demonstrated BIB091 to be a high potency molecule with good drug-like properties and a safety/tolerability profile suitable for clinical development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.

We aimed to understand the contemporary changes in the characteristics and the determinants of outcomes among simultaneous liver-kidney transplantation (SLKT) recipients at 6 liver transplantation centers in the United States. We retrospectively enrolled SLKT recipients between 2002 and 2017 in the US Multicenter SLKT Consortium. We analyzed time-related trends in recipient characteristics and outcomes with linear regression and nonparametric methods. Clustered Cox regression determined the factors associated with 1-year and overall survival. We enrolled 572 patients. We found significant changes in the clinical characteristics of SLKT recipients: as compared with 2002, recipients in 2017 were older (59 versus 52years; P&nbsp

As neurons establish extensive connections throughout the central nervous system, the transport of cargo along the microtubule network of the axon is crucial for differentiation and homeostasis. Specifically, building blocks such as membrane and cytoskeletal components, organelles, transmembrane receptors, adhesion molecules, and peptide neurotransmitters all require proper transport to the presynaptic compartment. Here, we identify a novel complex regulating vesicular endoplasmic reticulum transport in neurites, composed of CLN6: an ER-associated protein of relatively unknown function implicated in CLN6-Batten disease; CRMP2: a tubulin binding protein important in regulating neurite microtubule dynamics; and KLC4: a classic transport motor protein. We show that this “CCK” complex allows ER-derived vesicles to migrate to the distal end of the axon, aiding in proper neurite outgrowth and arborization. In the absence of CLN6, the CCK complex does not function effectively, leading to reduced vesicular transport, stunted neurite outgrowth, and deficits in CRMP2 binding to other protein partners. Treatment with a CRMP2 modulating compound, lanthionine ketimine ester, partially restores these deficits in CLN6-deficient mouse neurons, indicating that stabilization of CRMP2 interacting partners may prove beneficial in lieu of complete restoration of the CCK complex. Taken together, these findings reveal a novel mechanism of ER-derived vesicle transport in the axon and provide new insights into therapeutic targets for neurodegenerative disease.

INTRODUCTION AND OBJECTIVE:Abiraterone acetate (AA) has proven survival benefit for patients with metastatic hormone sensitive prostate cancer (mHSPC) and metastatic castrate resistant prostate can...

Bone marrow adipocytes accumulate with age and in diverse disease states. However, their origins and adaptations in these conditions remain unclear, impairing our understanding of their context-specific endocrine functions and relationship with surrounding tissues. In this study, by analyzing bone and adipose tissues in the lipodystrophic ‘fat-free’ mouse, we define a novel, secondary adipogenesis pathway that relies on the recruitment of adiponectin-negative stromal progenitors. This pathway is unique to the bone marrow and is activated with age and in states of metabolic stress in the fat-free mouse model, resulting in the expansion of bone marrow adipocytes specialized for lipid storage with compromised lipid mobilization and cytokine expression within regions traditionally devoted to hematopoiesis. This finding further distinguishes bone marrow from peripheral adipocytes and contributes to our understanding of bone marrow adipocyte origins, adaptations, and relationships with surrounding tissues with age and disease.

A multi-disciplinary expert group met to discuss vitamin D deficiency in the UK and strategies for improving population intakes and status. Changes to UK Government advice since the 1st Rank Forum on Vitamin D (2009) were discussed, including rationale for setting a reference nutrient intake (10 µg/d; 400 IU/d) for adults and children (4+ years). Current UK data show inadequate intakes among all age groups and high prevalence of low vitamin D status among specific groups (e.g. pregnant women and adolescent males/females). Evidence of widespread deficiency within some minority ethnic groups, resulting in nutritional rickets (particularly among Black and South Asian infants), raised particular concern. Latest data indicate that UK population vitamin D intakes and status reamain relatively unchanged since Government recommendations changed in 2016. Vitamin D food fortification was discussed as a potential strategy to increase population intakes. Data from dose–response and dietary modelling studies indicate dairy products, bread, hens’ eggs and some meats as potential fortification vehicles. Vitamin D3 appears more effective than vitamin D2 for raising serum 25-hydroxyvitamin D concentration, which has implications for choice of fortificant. Other considerations for successful fortification strategies include: (i) need for ‘real-world’ cost information for use in modelling work; (ii) supportive food legislation; (iii) improved consumer and health professional understanding of vitamin D’s importance; (iv) clinical consequences of inadequate vitamin D status and (v) consistent communication of Government advice across health/social care professions, and via the food industry. These areas urgently require further research to enable universal improvement in vitamin D intakes and status in the UK population.

A comprehensive review of indigenous knowledge about a traditional Cape, San and Khoi food item called anise root or anyswortel (genus Annesorhiza) is presented. The first accurate record was by Thunberg in 1772 at the Berg River near Vlermuisdrift (now Bridgetown) in the Western Cape and applied to A. grandiflora. Four species have recorded food uses as root vegetables (A. grandiflora, A. macrocarpa, A. nuda and an as yet undescribed species from Namaqualand) and two species (A. nuda and A. flagellifolia) as leaf vegetables. Essential oils of this genus were studied for the first time. Hydro-distilled oil from the fleshy roots, leaves and fruits of three species recorded as edible (A. grandiflora, A. macrocarpa and A. nuda) were chemically characterized using GC–MS and NMR spectroscopy. Noteworthy differences were found between plant parts as well as species. Estragole and a small amount of anethole occur in the roots of A. nuda (but not in any of the other two species). The major components of A. grandiflora fruits were dillapiole, nothoapiole and limonene, while elemicin was identified in the roots of the same species. Fruits of A. macrocarpa contained methyleugenol, the leaves ethyl-benzenes and α-terpineol, whereas the roots yielded nerolidol and an unidentified sesquiterpene. In contrast, leaves and roots of A. nuda were quite similar with the exception of the occurrence of estragole and anethole in roots only and not in the leaves. This partially explains the reported anise flavor of the edible roots of this species. The main compound of both roots and leaves of A. nuda was butan-2-yl (2Z)-3-(methylsulfanyl) prop-2-enoate, a new trans-β-methylthioacrylate derivative. This α, β-unsaturated methylsulfanyl ester, colloquially named (−)-nudaic ester, was characterized and assigned using 2D-NMR spectroscopy. The pronounced chemical differences between the examined species require further chemosystematic studies and the differences between roots, leaves and fruits may reflect the distinct vegetative (winter) and reproductive (summer) growth phases in these summer-deciduous plants.

Reports of imidazoliumionic liquids (ILs) with at least one benzylic substituent bound to the imidazolium cation are far less common than the ubiquitous 1-alkyl-3-methylimidazolium ILs ([Cnmim][X])...

One- ( C V1 ) and two-phase ( C V2 ) liquid + vapor equilibrium isochoric heat capacities, densities ( ρ S ), and phase-transition temperatures ( T S ) of 2-propanol were measured in the critical region. Measurements were made in the immediate vicinity of the liquid–gas phase transition and critical point in order to accurately determine the locus of phase-transition properties ( T S , ρ S , C V1 , and C V2 ). Additional measurements were made over an extended temperature range from (317 to 525) K for 9 liquid and 3 vapor isochores between (234 and 697) kg⋅m−3 at pressure up to 6.5 MPa. The measurements were performed using a high-temperature, high-pressure, nearly constant-volume adiabatic piezo-calorimeter. The standard uncertainty of the density, temperature, and isochoric heat capacity ( C V ) measurements is estimated to be 0.1%, 0.02 K, and 1.5%, respectively. The measured one- ( C V1 ) and two-phase ( C V2 ) isochoric heat capacities along the critical isochore and the saturated liquid ( ρ S ' ) and vapor ( ρ S '' ) densities near the critical point were used to derive theoretically meaningful asymptotic critical amplitudes ( A 0 ± and B 0 ) and related amplitudes for other properties ( Γ 0 + , D 0 , ξ 0 ) and their universal relations, A 0 + / A 0 - , A 0 + Γ 0 + B 0 2 , α A 0 + Γ 0 + B 0 - 2 , D 0 Γ 0 + B 0 δ - 1 , ξ 0 α A 0 + v C 1 / 3 and the asymmetric parameters a 3 and b 2 of the coexistence curve singular diameter. Experimental two-phase heat capacities C V2 as a function of specific volume V , along various isotherms, were used to calculate second temperature derivatives of vapor pressure d 2 P S d T 2 and chemical potential d 2 μ d T 2 and to estimate the value of the Yang-Yang anomaly strength parameter R μ for 2-propanol. The relative contributions of the vapor pressure, C VP = V C T d 2 P S d T 2 , and the chemical potential, C V μ = - T d 2 μ d T 2 , to the measured total two-phase C V2 were estimated.

Aims Regional human immunodeficiency virus (HIV) prevalence rates are high in people with history of injection drug use, including those managed with maintenance opioids. Fostemsavir (FTR) is an oral prodrug of temsavir, a first-in-class attachment inhibitor that binds HIV-1 gp120, preventing initial HIV attachment and entry into host immune cells. Here we determine the impact of FTR on the pharmacokinetics of opioids methadone (MET: R-, S- and total) or buprenorphine and norbuprenorphine (BUP and norBUP) when coadministered. Methods Study 206216 (NCT02666001) was a Phase I, open-label study, assessing the effect of FTR 600 mg (extended-release formulation) twice daily on pharmacokinetics of MET or BUP and norBUP, in non-HIV-infected participants on stable maintenance therapy with MET (40-120 mg; n = 16) or BUP plus naloxone (8-24 mg plus 2-6 mg; n = 16); pharmacodynamic response was assessed using standard opioid rating scales. Results Following coadministration with FTR, dose-normalized MET (R-, S- and total) exposures (maximum concentration in plasma, area under the plasma concentration-time curve over the dosing interval and concentration in plasma at 24 hours) increased 9-15% and BUP and norBUP exposures increased 24-39%. The 90% confidence interval ranges for MET (1.01-1.21) and BUP and norBUP (1.03-1.69) were within respective no-effect ranges (0.7-1.43 and 0.5-2.0). Opioid pharmacodynamic scores were similar with and without MET/BUP with no symptoms of withdrawal/overdose; no new safety signal for FTR when combined with a stable opioid regimen. Conclusions FTR did not impact MET and had no clinically significant impact on BUP pharmacokinetics. Standardized assessments of opioid pharmacodynamics were unchanged throughout FTR administration with MET or BUP. FTR can be administered with MET or BUP without dose adjustment.

Abdominal aortic aneurysm (AAA) is an important cause of death in older adults, which has no current drug therapy. Inflammation and abnormal redox status are believed to be key pathogenic mechanisms for AAA. In light of evidence correlating inflammation with aberrant fatty acid profiles, this study compared erythrocyte fatty acid content in 43 AAA patients (diameter 3.0–4.5 cm) and 52 healthy controls. In addition, the effect of omega-3 PUFA (n-3 PUFA) supplementation on erythrocyte fatty acid content was examined in a cohort of 30 AAA patients as part of a 12 week randomized placebo-controlled clinical trial. Blood analyses identified associations between AAA and decreased linoleic acid (LA), and AAA and increased Δ6-desaturase activity and biosynthesis of arachidonic acid (AA) from LA. Omega-3 PUFA supplementation (1.5 g DHA + 0.3 g EPA/day) decreased red blood cell distribution width (14.8 ± 0.4% to 13.8 ± 0.2%; P = 0.003) and levels of pro-inflammatory n-6 PUFAs (AA, 12.46 ± 0.23% to 10.14 ± 0.3%, P < 0.001; adrenic acid, 2.12 ± 0.13% to 1.23 ± 0.09%; P < 0.001). In addition, Δ-4 desaturase activity increased (DHA/docosapentaenoic acid ratio, 1.85 ± 0.14 to 3.93 ± 0.17; P < 0.001) and elongase 2/5 activity decreased (adrenic acid/AA ratio, 0.17 ± 0.01 to 0.12 ± 0.01; P < 0.01) following supplementation. The findings suggest that n-3 PUFAs improve fatty acid profiles and ameliorate factors associated with inflammation in AAA patients.

Thermodynamic properties (isochoric heat capacity, critical and phase transition temperatures, pressure and thermal-pressure coefficient) of a nanofluid (2-propanol + TiO2) were experimentally studied near the critical point of the pure base fluid (2-propanol). Measurements were made using a high-temperature, high-pressure, nearly constant-volume adiabatic piezo-calorimeter that was designed for simultaneous measurements of caloric ( C V V T ) and density ( PVT ) properties of fluids along the near-critical isochores as a function of temperature in the two-phase and single-phase regions. The standard uncertainty of the density, temperature, pressure, thermal-pressure coefficient, and heat capacity measurements is estimated to be 0.1%, 0.02 K, 0.5%, 1.0%, and 1.5%, respectively. The measurements were made along a selected near-critical isochore of 282.68 kg·m−3 for a concentration of 0.132 mass fraction of TiO2 in the temperature range from (314 to 511) K. The measured C V and critical temperature data were interpreted in terms of finite-size scaling theory of critical phenomena for fluids confined in the finite-size media. The influence of finite size on the thermodynamic properties of the near- and supercritical fluid has been studied, along with thermal instability of the nanofluid (2-propanol + TiO2) at high temperatures (around 500 K).

Dietary lipid supplementation can reduce de novo lipogenesis and increase intramuscular fat content of pork simultaneously, and vitamin E supplementation can increase the oxidative stability of pork. A total of 96 pigs (Yorkshire) were used to investigate the effect of dietary lipid (0 or 1% flaxseed oil + 1, 3, or 5% poultry fat for diets supplemented with lipids) and vitamin E (11 or 220 IU/kg) supplementation in a 4 × 2 factorial arrangement of treatments on growth performance, serum metabolites, and carcass traits of finisher pigs, and physical characteristics of pork. Forty-eight pens containing 2 gilts or 2 castrated males per pen were randomly assigned to 8 diets with 3 gilt pens and 3 castrated male pens per treatment. Pigs were switched from finisher-1 [initial body weight (BW): 54.3 ± 3.4 kg] to finisher-2 diets when the average pen BW reached 84.1 ± 4.0 kg. Standardized ileal digestible Lys and Ca and P were adjusted with the DE content accordingly to maintain constant Lys, Ca, and P to DE ratios. Pigs were harvested when they reached the target BW of 110.0 ± 3.0 kg. There were no lipid x vitamin E interactions in growth performance. As dietary lipids increased from 0 to 6%, average daily feed intake decreased linearly (P

Background The conserved NDR-family kinase Sid2p localizes to the contractile ring during fission yeast cytokinesis to promote ring constriction, septation, and completion of cell division. Previous studies have found that the Type 2 interphase node proteins Blt1p and Gef2p contribute to localization of Sid2p and its regulatory protein Mob1p at the division site. However, their relative contributions and whether they operate in the same or parallel pathways has been unclear. In this study, we quantify the respective roles of Blt1p and Gef2p in Sid2p/Mob1p recruitment and characterize the effect of single and double deletion mutants on contractile ring dynamics and completion of cell division. Results Using quantitative confocal fluorescence microscopy, we measured Sid2p and Mob1p recruitment to the division site in blt1∆, gef2∆, and blt1∆/gef2∆ mutant cells. We observed an equivalent decrease in Sid2p/Mob1p localization for both single and double mutants. Though assembly of the contractile ring is normal in these mutants, the reduction in Sid2p/Mob1p at the division site delayed the onset of contractile ring constriction and completion of division. We quantified localization of Blt1p and Gef2p at the medial cortex throughout the cell cycle and found that Blt1p localization to interphase nodes and the contractile ring is independent of Gef2p. However, Gef2p localization to the contractile ring is decreased in blt1∆ mutants. Conclusions Blt1p and Gef2p work in the same pathway, rather than in parallel, to localize the NDR-family kinase Sid2p and its regulatory partner Mob1p to the division site, thereby promoting timely completion of cell division. Future studies are necessary to understand how additional fission yeast cytokinesis proteins work with these Type 2 interphase node components to promote Sid2p/Mob1p recruitment. Electronic supplementary material The online version of this article (10.1186/s12860-018-0182-z) contains supplementary material, which is available to authorized users.

In recent years increasing aquaculture production combined with a high variance in availability and cost of fishmeal and fish oil commodities, has led to a need to identify alternative source materials for protein and the polyunsaturated fatty acids (PUFAs) which fish oil is prized for containing. Chloroplasts are the organelles in plants’ leaves where many of the valuable nutrients, fatty acids (FAs), amino acids, vitamins and pigments, are synthesised. Chloroplasts could be incorporated into fish diets either retained in, or liberated from, plant cells. In this study zebrafish were fed with seven different diets individually; fish was fed with reducing fishmeal levels (10, 20 or 50%) by either spinach leaf powder (SLP) or a chloroplast rich fraction (CRF) prepared by an established method to recover chloroplasts. Both SLP and CRF had a positive impact on growth, taste response, whole fishFA composition, and carotenoid profile. Fish fed with CRF diets showed significantly (P≤0.05) greater α-linolenic (C18:3 n-3) and hexadecatrienoic (C16:3) acids content than those of SLP and the control. Hexadecanoic acid (C16:3) is a unique FA in the galactolipids of the chloroplast; its presence in zebrafish tissues proves that zebrafish digest and absorb chloroplast galactolipids. Lutein profile of eggs produced by zebrafish fed with CRF diet was significantly (P≤0.05) higher than that of SLP and control. Alterations in egg colour were also noted, warranting further investigations of diet impacts on fish fecundity, embryo fertility, hatch rate and larval survival.

A highly accurate and versatile fluorescence polarisation assay for any enzyme adding or removing lipid posttranslational modifications, with the potential to accelerate drug discovery against these targets., Posttranslational attachment of lipids to proteins is important for many cellular functions, and the enzymes responsible for these modifications are implicated in many diseases, from cancer to neurodegeneration. Lipid transferases and hydrolases are increasingly tractable therapeutic targets, but present unique challenges for high-throughput biochemical enzyme assays which hinder development of new inhibitors. We present Acylation-coupled Lipophilic Induction of Polarisation (Acyl-cLIP) as the first universally applicable biochemical lipidation assay, exploiting the hydrophobic nature of lipidated peptides to drive a polarised fluorescence readout. Acyl-cLIP allows sensitive, accurate, real-time measurement of S- or N-palmitoylation, N-myristoylation, S-farnesylation or S-geranylgeranylation. Furthermore, it is applicable to transfer and hydrolysis reactions, and we demonstrate its extension to a high-throughput screening format. We anticipate that Acyl-cLIP will greatly expedite future drug discovery efforts against these challenging targets.

A two-photon absorbing (2PA) red emitter group was chemically conjugated onto amphiphilic poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) copolymers, and further grafted with cyclo (Arg-Gly-Asp) (cRGD) peptide to form micelle 1. Micelle 1 with cRGD targeting groups were used for targeted bioimaging. For comparison, micelle 2 without the cRGD targeting groups were also prepared and investigated. The micelles were characterized using dynamic light scattering (DLS), showing average diameters of around 77 nm. The cRGD targeting group is known to bind specifically with α(v)β(3) integrin in cancer cells. In this study, α(v)β(3) integrin overexpressed human glioblastoma U87MG cell line and α(v)β(3) integrin deficient human cervical cancer HeLa cell line were chosen. Results showed that the cRGD targeting group enhanced the cellular uptake efficiency of the micelles significantly in α(v)β(3) integrin rich U87MG cells. Higher temperature (37 °C versus 4 °C) and calcium ions (with 3M calcium chloride in the cell culture medium versus no addition of calcium ions) enhanced the cellular uptake efficiency, suggesting that the uptake of the micelles is through the endocytosis pathway in cells. A 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay was used to evaluate the cytotoxicity of the micelles and no significant cytotoxicity was observed. The BTD-containing two-photon absorbing emitter in the micelles showed a two-photon absorbing cross-section of 236 GM (1GM = 1 × 10(−50) cm(4) s photon(−1) molecule(−1)) at 820 nm, which is among the highest values reported for red 2PA emitters. Because of the two-photon absorbing characteristics, micelle 1 was successfully used for two-photon fluorescence imaging targeted to U87MG cells under a two-photon fluorescence microscope. This study is the first report regarding the targeted imaging of a specific cancer cell line (herein, U87MG) using the BTD-conjugated-fluorophore-containing block copolymers.

Vibrio vulnificus, a gram-negative bacterium, is the leading cause of seafood-borne illnesses and mortality in the United States. Previous studies have identified metabolites 2-C-methylerythritol 4-phosphate (MEP) as being essential for V. vulnificus growth and function. It was shown that 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) is a critical enzyme in the viability of V. vulnificus, and many other bacteria, as it catalyzes the rearrangement of 1-deoxy-D-xylulose-5-phosphate (Dxp) to 2-C-methylerythritol 4-phosphate (MEP) within the MEP pathway, found in plants and bacteria. The MEP pathway produces the isoprenoids, isopentenyl diphosphate and dimethylallyl pyrophosphate. In this study, we produced and structurally characterized V. vulnificus Dxr. The enzyme forms a dimeric assembly and contains a metal ion in the active site. Protein produced in Escherichia coli co-purifies with Mg2+ ions, however the Mg2+ cations may be substituted with Mn2+, as both of these metals may be utilized by Dxrs. These findings will provide a basis for the design of Dxr inhibitors that may find application as antimicrobial compounds.

AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRAS(G12D) increased lung tumour burden and reduced survival in Kras(LSLG12D/+)/AMPKα(fl/fl) mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.

The relative oral bioavailability and dermal absorption of chemical substances from environmental media are key factors that are needed to accurately estimate site-specific risks and manage human exposures. This study evaluated the in vivo relative oral bioavailability and in vitro dermal absorption of several polycyclic aromatic hydrocarbons (PAHs) found in soils collected from two formerly used Department of Defense sites impacted by weathered fragments of clay shooting targets. Concentrations of individual carcinogenic PAHs in the ≤250 μm fraction of soil ranged from approximately 0.1 to 100 mg/kg. A novel sample preparation method was developed to produce accurate and precise test diets for oral studies. The resulting test diets showed consistent concentrations of PAHs in soil- and soil-extract-amended diets and a consistent PAH concentration profile. Mean oral relative bioavailability factors (RBAFs) and dermal absorption fractions (ABSd) for benzo(a)pyrene ranged from 8 to 14% and 0.58 to 1.3%, respectively. Using the RBAF and ABSd values, measured here, for benzo(a)pyrene in USEPA's regional screening level equations yields concentrations for residential soils that are approximately eight times higher than those when default values are used (e.g., 9.6 vs 1.2 mg/kg at a target excess risk of 1 × 10-5).

Summary Small-cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, has limited treatment options beyond platinum-based chemotherapy, whereafter acquired resistance is rapid and common. By analyzing expression data from SCLC tumors, patient-derived models, and established cell lines, we show that the expression of TIAM1, an activator of the small GTPase RAC1, is associated with a neuroendocrine gene program. TIAM1 depletion or RAC1 inhibition reduces viability and tumorigenicity of SCLC cells by increasing apoptosis associated with conversion of BCL2 from its pro-survival to pro-apoptotic function via BH3 domain exposure. This conversion is dependent upon cytoplasmic translocation of Nur77, an orphan nuclear receptor. TIAM1 interacts with and sequesters Nur77 in SCLC cell nuclei and TIAM1 depletion or RAC1 inhibition promotes Nur77 translocation to the cytoplasm. Mutant TIAM1 with reduced Nur77 binding fails to suppress apoptosis triggered by TIAM1 depletion. In conclusion, TIAM1-RAC1 signaling promotes SCLC cell survival via Nur77 nuclear sequestration., Graphical abstract, Highlights • TIAM1 is upregulated in neuroendocrine compared to non-neuroendocrine SCLC cells • TIAM1-RAC1 inhibition decreases SCLC cell viability by increasing apoptosis • TIAM1 interacts with and maintains Nur77 nuclear localization • TIAM1-RAC1 inhibition causes Nur77 relocalization and pro-apoptotic BCL2 conversion, Payapilly, Guilbert et al. identify TIAM1, a selective activator of the small GTPase RAC1, as a gene product upregulated in neuroendocrine SCLC cells. They show that depletion of TIAM1 or RAC1 inhibition leads to SCLC cell apoptosis through cytoplasmic translocation of the orphan nuclear receptor Nur77 and pro-apoptotic BCL2 conformational change.

The mammalian membrane-bound O-acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small-molecule inhibition is elusive. This study reports development of a photochemical probe to interrogate the small-molecule binding site in the human MBOAT Hedgehog acyltransferase (HHAT) based on HHAT inhibitor RUSKI-201. Structure-activity relationship investigation identified the improved enantiomeric inhibitor IMP-1575, which is the most potent HHAT inhibitor reported to-date, and guided rational design of a photocrosslinking probe that maintained HHAT-inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small-molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed via kinetic analysis. Our results provide an optimal HHAT inhibitor IMP-1575 (Ki = 38 nM) and a strategy for mapping of interaction sites in MBOATs.

In the present study, the simultaneous and accurate determination of liquid viscosity and surface tension of the n-alkanes n-hexane (n-C(6)H(14)), n-octane (n-C(8)H(18)), n-decane (n-C(10)H(22)), and n-hexadecane (n-C(16)H(34)) by surface light scattering (SLS) in thermodynamic equilibrium is demonstrated. Measurements have been performed over a wide temperature range from 283.15 K up to 473.15 K for n-C(6)H(14), 523.15 K for n-C(8)H(18), and 573.15 K for n-C(10)H(22) as well as n-C(16)H(34). The liquid dynamic viscosity and surface tension data with average total measurement uncertainties (k = 2) of (2.0 and 1.7) % agree with the available literature and contribute to a new database at high temperatures. Over the entire temperature range, a Vogel-type equation for the dynamic viscosity and a modified van der Waals equation for the surface tension represent the measured data for the four n-alkanes within experimental uncertainties. By also considering our former SLS data for n-dodecane (n-C(12)H(26)) and n-octacosane (n-C(28)H(58)), empirical models for the liquid viscosity and surface tension of n-alkanes were developed as a function of temperature and carbon number covering values between 6 and 28. Agreement between these models and reference correlations for further selected n-alkanes which were not included in the development procedure was found.

This article is the first of three projected IUPAC Technical Reports resulting from IUPAC Project 2011-037-2-100 (Reference Materials for Phase Equilibrium Studies). The goal of this project is to select reference systems with critically evaluated property values for the validation of instruments and techniques used in phase equilibrium studies of mixtures. This report proposes seven systems for liquid–liquid equilibrium studies, covering the four most common categories of binary mixtures: aqueous systems of moderate solubility, non-aqueous systems, systems with low solubility, and systems with ionic liquids. For each system, the available literature sources, accepted data, smoothing equations, and estimated uncertainties are given.

Although theoretical models highlight the role of coping motivations in promoting co-development of depression and alcohol use, few longitudinal studies have examined such processes across early adulthood. The current study examined the role of coping in the association between depression and alcohol use across late adolescence and early adulthood. A control sample of adolescents (N = 498) from a longitudinal prevention trial completed the Brief Symptom Inventory, Life Events Coping Inventory, and a self-report survey on alcohol use at ages 17, 22, and 23, as well as the Composite International Diagnostic Interview at age 28-30. Path analyses integrated self-report and diagnostic measures. Although gender differences were observed in mean levels of depression, alcohol use, and the use of substances to cope, we did not find gender differences in structural relations across these domains over time. Substance use coping served as an intervening pathway in the association between alcohol use and depression both at the symptom level from age 17 to 23, and in predicting longer term diagnostic outcomes at ages 28-30. Depressive symptoms in early adulthood were indirectly related to major depressive disorder (MDD) through two independent paths, including the stability of depressive symptoms over time, and through the influence of depression on increasing the tendency to use substances to cope with stress. Our results underscore that coping effects provide unique predictive power across developmental transitions, over and above the stability of depressive symptoms and alcohol use, underscoring coping motives as a promising intervention target that may prevent co-occurring depression and substance use. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The detonation of a helium shell on top of a carbon-oxygen white dwarf has been argued as a potential explosion mechanism for type Ia supernovae (SNe~Ia). The ash produced during helium shell burning can lead to light curves and spectra that are inconsistent with normal SNe~Ia, but may be viable for some objects showing a light curve bump within the days following explosion. We present a series of radiative transfer models designed to mimic predictions from double detonation explosion models. We consider a range of core and shell masses, and systematically explore multiple post-explosion compositions for the helium shell. We find that a variety of luminosities and timescales for early light curve bumps result from those models with shells containing $^{56}$Ni, $^{52}$Fe, or $^{48}$Cr. Comparing our models to SNe~Ia with light curve bumps, we find that these models can reproduce the shapes of almost all of the bumps observed, but only those objects with red colours around maximum light ($B-V \gtrsim 1$) are well matched throughout their evolution. Consistent with previous works, we also show that those models in which the shell does not contain iron-group elements provide good agreement with normal SNe~Ia of different luminosities from shortly after explosion up to maximum light. While our models do not amount to positive evidence in favour of the double detonation scenario, we show that provided the helium shell ash does not contain iron-group elements, it may be viable for a wide range of normal SNe~Ia., Comment: 21 pages, 25 figures, 1 table. Accepted for publication in MNRAS. Model light curves available at https://github.com/MarkMageeAstro/TURTLS-Light-curves

Small cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, has limited treatment options beyond platinum-based chemotherapy, whereafter acquired resistance is rapid and common. By analysing expression data from SCLC tumours, patient-derived models and established cell lines, we discovered that expression of TIAM1, an activator of the small GTPase RAC1, is associated with a neuroendocrine gene program. TIAM1 depletion or RAC1 inhibition reduced viability and tumorigenicity of SCLC cells by increasing apoptosis associated with conversion of BCL2 from its pro-survival to pro-apoptotic function via BH3 domain exposure. This conversion depended upon cytoplasmic translocation of Nur77, an orphan nuclear receptor. TIAM1 interacts with and sequesters Nur77 in SCLC cell nuclei and TIAM1 depletion or RAC1 inhibition promoted Nur77 translocation to the cytoplasm. Mutant TIAM1 with reduced Nur77 binding failed to suppress apoptosis provoked by TIAM1 depletion. In conclusion, TIAM1-RAC1 signalling is required for SCLC cell survival via nuclear sequestration of Nur77.