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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.

Aim: This study was aimed at evaluating the anticancer potential of curcumin-loaded poly(lactic-co-glycolic acid) (PLGA) based nanoparticles (NPs) in MDA-MB231 human breast cancer cells. Methods: Curcumin-loaded PLGA NPs were developed using a modified solvent evaporation technique. Physical characterization was performed on the formulated NPs. Furthermore, in vitro experiments were conducted to study the biological activity of the curcumin-loaded NPs. Results: Curcumin-loaded PLGA NPs demonstrated high encapsulation efficiency and sustained payload release. Moreover, the NPs exhibited a significant reduction in cell viability, cell migration and cell invasion in the MDA-MB231 cells. Conclusion: The study revealed that the formulated curcumin-loaded PLGA NPs possessed significant anti-metastatic properties. The findings showcased the possible potential of curcumin-loaded NPs in the management of debilitating conditions such as cancer. In addition, this study could form the basis for further research and advancements in this area.

Breast cancer; Cancer Càncer de mama; Càncer Cáncer de mama; Cáncer The METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine. Funding provided by Celldex Therapeutics, Inc.

Carbon dioxide and hydrocarbon gases including methane, ethane, propane, and produced gas (69.5/21/9.5 mol ratio of methane/ethane/propane) were used to recover oil from rock samples collected in t...

A systematic study of alluaudite, hagendorfite, and varulite was done using single-crystal X-ray diffraction, powder diffraction, and electron probe microanalysis of samples from 12 separate localities. The crystal structures of the representative alluaudite and hagendorfite samples were refined to R1 indices of 3.7 and 1.8%, respectively, using a Siemens P4 automated four-circle diffractometer equipped with a graphite monochromator and MoKα X-radiation. These samples and several others were analyzed with an electron microprobe to study variations in chemical composition. For the single-crystal analyses, the resulting unit formulae are (Na0.11□0.89)(Na0.59Mn0.27Ca0.14)Mn1.00(Fe3+1.64Al0.24Mg0.13)(PO4)3 for alluaudite, (Na0.79□0.21)(Na0.81Mn2+0.19)(Mn0.70Fe2+0.30)(Fe2+1.72Mg0.27Al0.01)(PO4)3 for hagendorfite, and (Na0.84□0.16)(Na0.71Ca0.23□0.06)Mn1.00(Fe3+0.89Fe2+0.68Mn0.42Mg0.01)(PO4)3 for varulite. Originally, a nomenclature scheme was proposed for the alluaudite-group minerals that was based on sequentially distributing the cations in the cell according to increasing polyhedron size, matching that size with increasing ionic radii of the cations. For alluaudite, the structural formula was written as X(2)4X(1)4M(1)4M(2)8(PO4)12, with the sites ordered in decreasing size of the discrete polyhedra. Later, the formula [A(2)A(2)'A(2)”2][A(1)A(1)'A(1)”2]M(1)M(2)2(PO4)3 was proposed, which takes into account the distinct crystallographic sites in the channels of the structure. More recently there has been a revision to the nomenclature of the group. The simplified structural formula for the alluaudite-type is now A(2)'A(1)M(1)M(2)2(TO4)3; the new nomenclature scheme has been adopted by the Commission on New Minerals, Nomenclature and Classification of the International Mineralogical Association (IMA-CNMNC), based on the contents of the M(1) and M(2) octahedral sites, and the results are reviewed here. Compounds belonging to the alluaudite structural family have been the focus of synthetic mineral studies for decades owing to the open-framework architecture and their unique physical properties. Improvements in synthesis methods have allowed researchers to substitute a wide range of elements into the alluaudite structure.

Background Agricultural insect pests frequently exhibit geographic variation in levels of insecticide resistance, which are often presumed to be due to the intensity of insecticide use for pest management. However, regional differences in the evolution of resistance to novel insecticides suggests that other factors are influencing rates of adaptation. We examined median lethal concentration (LC50 ) bioassay data spanning 15 years and six insecticides (abamectin, imidacloprid, spinosad, cyantraniliprole, chlorantraniliprole, and metaflumizone) for evidence of regional differences in Leptinotarsa decemlineata baseline sensitivity to insecticides as they became commercially available. Results We consistently found that larvae from Colorado potato beetle populations from the northwestern USA had the highest baseline sensitivity to novel insecticides, while populations from the eastern USA had the lowest. Comparisons of gene expression between populations from these regions revealed constitutively elevated expression of an array of detoxification genes in the East, but no evidence of additional induction when exposed to imidacloprid. Conclusions Our results suggest a mechanism for geographic variation in rates of adaptation to insecticides, whereby baseline levels of gene expression determine a population's response to novel insecticides. These findings have implications for the regional development of insecticide resistance management strategies and for the fundamental question of what determines the rate of adaptation to insecticides. © 2020 Society of Chemical Industry.

A structure hierarchy is developed for chain-, ribbon- and tube-silicate based on the connectedness of one-dimensional polymerisations of (TO4)n−tetrahedra, where T = Si4+plus P5+, V5+, As5+, Al3+, Fe3+, B3+, Be2+, Zn2+and Mg2+. Such polymerisations are described by ageometrical repeat unit(with ngtetrahedra) and atopological repeat unit(or graph) (with ntvertices). The connectivity of the tetrahedra (vertices) in the geometrical (topological) repeat units is denoted by the expressioncTr(cVr) wherecis the connectivity (degree) of the tetrahedron (vertex) andris the number of tetrahedra (vertices) of connectivity (degree)cin the repeat unit. ThuscTr=1Tr12Tr23Tr34Tr4(cVr=1Vr12Vr23Vr34Vr4) represents all possible connectivities (degrees) of tetrahedra (vertices) in the geometrical (topological) repeat units of such one-dimensional polymerisations. We may generate all possiblecTr(cVr) expressions for chains (graphs) with tetrahedron (vertex) connectivities (degrees)c= 1 to 4 wherer= 1 tonby sequentially increasing the values ofcandr, and by ranking them accordingly. The silicate (sensu lato) units of chain-, ribbon- and tube-silicate minerals are identified and associated with the relevantcTr(cVr) symbols. Following description and association with the relevantcTr(cVr) symbols of the silicate units in all chain-, ribbon- and tube-silicate minerals, the minerals are arranged into decreasing O:T ratio from 3.0 to 2.5, an arrangement that reflects their increasing structural connectivity. Considering only the silicate component, the compositional range of the chain-, ribbon- and tube-silicate minerals strongly overlaps that of the sheet-silicate minerals. Of the chain-, ribbon- and tube-silicates and sheet silicates with the same O:T ratio, some have the samecVrsymbols (vertex connectivities) but the tetrahedra link to each other in different ways and are topologically different. The abundance of chain-, ribbon- and tube-silicate minerals decreases as O:T decreases from 3.0 to 2.5 whereas the abundance of sheet-silicate minerals increases from O:T = 3.0 to 2.5 and decreases again to O:T = 2.0. Some of the chain-, ribbon- and tube-silicate minerals have more than one distinct silicate unit: (1) vinogradovite, revdite, lintisite (punkaruaivite) and charoite have mixed chains, ribbons and/or tubes; (2) veblenite, yuksporite, miserite and okenite have clusters or sheets in addition to chains, ribbons and tubes. It is apparent that some chain-ribbon-tube topologies are favoured over others as of the ~450 inosilicate minerals, ~375 correspond to only four topologically unique graphs, the other ~75 minerals correspond to ~46 topologically unique graphs.

Mg migration in oxide spinels is impeded by strong affinity between divalent Mg and oxygen, suggesting a necessity of exploring new chemistry of solid lattices for functional Mg-ion electrode mater...

BackgroundThe prognosis is poor for children and adolescents with recurrent osteosarcoma (OS). Glycoprotein non-metastatic B (gpNMB) is a glycoprotein highly expressed in OS cells. We conducted a phase II study of glembatumumab vedotin (GV), a fully human IgG2 monoclonal antibody (CR011) against gpNMB conjugated to the microtubule inhibitor, monomethyl auristatin E.Patients and methodsPatients aged ≥12 years and

Tamboite (x = 3; y = 2) and metatamboite (x = 3; y = 0), Fe3+3(SO4)(Te4+O3)3(Te4+O(OH)2)(OH)(H2O)x{H2O}y, are new tellurite minerals from the Tambo mine, Coquimbo Province, Chile. The two minerals transform to each other reversibly with changes in ambient humidity. They occur as pale-yellow clusters of radiating fiber bundles on the surface of a compact aggregate of silicified tuff. Tamboite and metatamboite are optically biaxial, and their calculated mean index of refraction is greater than 1.80. The calculated densities are 3.648 g/cm3 for tamboite and 4.053 g/cm3 for metatamboite. Tamboite and metatamboite are monoclinic, space group P21/c, Z = 4. Unit-cell parameters for tamboite are a 16.879(10), b 7.310(4), c 16.666(9) Å, β 108.857(11)°, V 1958(3) Å3; for metatamboite they are a 14.395(5), b 7.296(4), c 16.411(6) Å, β 98.909(10)°, V 1703(2) Å3. Chemical analysis by electron microprobe gave the empirical cations [calculated on the basis of 22 anions pfu with OH = 3 and H2O = 5 pfu (tamboite) or H2O = 3 pfu (metatamboite)] as (Fe3+3.10Al0.15)Σ3.25(S6+0.75Se6+0.05)Σ0.80Te4+4.11. The seven strongest lines in the X-ray powder diffraction patterns [listed as d (Å), I, (hkl)] are as follows: metatamboite: 14.221, 100, (100); 2.874, 13, ; 3.140, 12, (221); 3.423, 11, ; 3.400, 11, (312); 3.012, 11, ; 4.054, 9, ; tamboite: 16.068, 100, (100); 3.425, 9, ; 2.999, 8, ; 3.171, 6, (221); 2.853, 5, ; 4.153, 4, ; 3.943, 4, (004).The crystal structures were solved by direct methods and refined to R1 indices of 4.3 and 3.0%. The structures consist of virtually identical ferric-sulfate-tellurite-hydrate slabs that are constructed from strands of ferric-sulfate-hydrate polyhedra linked by Te4+ cations. In metatamboite, the slabs are linked directly by hydrogen bonds whereas in tamboite, interslab linkage occurs by hydrogen bonds through interstitial {H2O}4 clusters known as Ci cyclic tetramers. Exposure of a crystal to a desiccant at room temperature resulted in a third variant (x = 2; y = 0) with the structural formula Fe3+2Fe2+(SO3(OH))(Te4+O3)3(Te4+O(OH)2)(OH)(H2O)x, space group P21/c, Z = 4, a 16.879(10), b 7.310(4), c 16.666(9) Å, β 108.857(11)°, V 1958(3) Å3, calculated density 4.176 g/cm3. This lower-hydrate variant has less cation-bonded (H2O) than metatamboite and tamboite, and the ferric-sulfate-tellurite-hydrate slabs are polymerized to form a framework structure. Attempts to transform the lower hydrate back to tamboite or metatamboite at room temperature and elevated humidity were unsuccessful.

Davidbrownite-(NH4), (NH4,K)5(V4+O)2(C2O4)[PO2.75(OH)1.25]4·3H2O, is a new mineral species from the Rowley mine, Maricopa County, Arizona, USA. It occurs in an unusual bat-guano-related, post-mining assemblage of phases that include a variety of vanadates, phosphates, oxalates and chlorides, some containing NH4+. Other secondary minerals found in association with davidbrownite-(NH4) are antipinite, fluorite, mimetite, mottramite, quartz, rowleyite, salammoniac, struvite, vanadinite, willemite and wulfenite. Crystals of davidbrownite-(NH4) are light green–blue needles or narrow blades up to ~0.2 mm long. The streak is white, the lustre is vitreous, Mohs hardness isca. 2, tenacity is brittle and fracture is splintery. There are two good cleavages in the [010] zone, probably {100} and {001}. The measured density is 2.12(2) g cm–3. Davidbrownite-(NH4) is optically biaxial (+) with α = 1.540(2), β = 1.550(5) and γ = 1.582(2) (white light); 2V = 58.5(5)°; moderater>vdispersion; and orientationZ=bandY≈a. Pleochroism:X= pale blue,Y= nearly colourless,Z= light blue; andY 2σIreflections) consists of a chain structural unit with the formula {(V4+O)2(C2O4)[PO2.75(OH)1.25]4}5–, and a disordered interstitial complex containing five large monovalent cations (NH4+and K+) and three H2O groups pfu. Strong hydrogen bonds form links within and between the chains.

An innovative sampling method was developed that allowed crude oil hydrocarbons dissolved in the upper gas-rich phase to be collected and quantitatively measured while maintaining constant reservoir conditions of 15.6 MPa and 42 °C. Crude oil was allowed to come to equilibrium with the injected gas phase (ca. 1/1 vol ratio) prior to collecting the dissolved hydrocarbons via a heated flow restrictor and analyzing them using high-resolution gas chromatography. As solvents, the three fluids’ efficacy parallel their minimum miscibility pressures (MMPs) for the test crude oil. Methane (MMP = 28.1 MPa) was a very poor hydrocarbon solvent, and was only able to dissolve ca. 18 mg oil/g methane. In contrast, CO2 (MMP = 9.68 MPa) dissolved up to 133 mg oil/g CO2 and ethane (MMP = 5.27 MPa) dissolved 722 mg oil/g ethane. Sequential collections of the dissolved oil hydrocarbons in the gas-dominated phase showed progressively lower concentrations for ethane and CO2, which demonstrated that liquid/liquid partitioning (and not saturation solubility) between the gas-dominated and oil-dominated phases controls the amounts of dissolved hydrocarbons. Thus, the lower the ratio of injected ethane or CO2 to the bulk crude oil, the higher the dissolved hydrocarbon concentrations. Both methane and CO2 showed a bias against dissolving heavier hydrocarbons. Methane was only capable of dissolving the lightest hydrocarbons (up to about C12), while CO2 preferentially dissolved light and middle hydrocarbons (up to about C16), leaving a residual oil rich in higher molecular weight hydrocarbons with significantly higher viscosity and density (lower API gravity) than the original unexposed crude oil. In contrast, ethane was capable of efficiently dissolving the entire range of hydrocarbons, with only a small bias against the heavier hydrocarbons. These lab studies show that, at the constant reservoir pressure and temperature used, ethane is a far superior hydrocarbon solvent for crude oil hydrocarbons than CO2, while CO2 is far superior to methane. Thus, ethane may ultimately yield higher oil recovery efficiencies (used either instead of CO2 or after a CO2 flood), while reducing the deposition of paraffinic and other higher molecular weight hydrocarbons in the reservoir.

Lepageite, a new arsenite-antimonite mineral, was discovered in a granitic pegmatite hosted by serpentinites of the Szklary massif, Lower Silesia, southwest Poland. Lepageite is a primary mineral formed during injection of an evolved LCT-type melt related to anatectic processes within the metasedimentary-metavolcanic complex of the nearby Góry Sowie Block, ~380 Ma, into serpentinite of the Szklary massif and its contamination by fluid-mobile serpentinite-hosted elements, among others As and Sb, transported in the form of H2AsO3− and HSbO2 species at pH ≈ 9–11 and a low redox potential of –0.7 to –0.3 V.

Six-coordinate titanium(IV) N,N-dialkylmonothiocarbamate complexes Ti(R2mtc)2Cl2 (R = Me, Et, i-Pr, or i-Bu) have been prepared in excellent yield by reaction of titanium(IV) chloride with stoichiometric amounts of sodium N,N-dialkylmonothiocarbamates in dichloromethane or benzene. The complexes were characterized by conductance measurements and by infrared and 1H NMR spectroscopy. The x-ray crystal structure of Ti(Me2mtc)2Cl2 was determined in order to establish the location of the sulfur atoms, which are generally cis in monothiocarbamate and monothio-β-diketonate complexes. Ti(Me2mtc)2Cl2 has a distorted octahedral structure in which the Ti(IV) atom is bonded to two cis Cl atoms and two planar, bidentate monothiocarbamate ligands. The complex exists (unexpectedly) as the C2 stereoisomer that has S atoms in trans positions.

Kidney transplantation is the optimum treatment for kidney failure in carefully selected patients. Technical surgical complications and second warm ischemic time (SWIT) increase the risk of delayed graft function (DGF) and subsequent short- and long-term graft outcomes including the need for post-transplant dialysis and graft failure. Intraoperative organ thermal regulation could reduce SWIT, minimizing surgical complications due to time pressure, and limiting graft ischemia-reperfusion injury.A novel ischemic-injury thermal protection jacket (iiPJ) was designed and fabricated in silicone composite and polyurethane (PU) elastomer prototypes. Both were compared with no thermal insulation as controls. Time to reach ischemic threshold (15°C) and thermal energy transfer were compared. A water bath model was used to examine the thermal protective properties of porcine kidneys, as a feasibility study prior to in vivo translation.In both iterations of the iiPJ, the time taken to reach the warm ischemia threshold was 35.2 ± 1.4 minutes (silicone) and 38.4 ± 3.1 minutes (PU), compared with 17.2 ± 1.5 minutes for controls (n = 5, P .001 for both comparisons). Thermal energy transfer was also found to be significantly less for both iiPJ variants compared with controls. There was no significant difference between the thermal performance of the 2 iiPJ variants.Protection from SWIT by using a protective insulation jacket is feasible. With clinical translation, this novel strategy could facilitate more optimal surgical performance and reduce transplanted organ ischemia-reperfusion injury, in particular the SWIT, potentially affecting delayed graft function and long-term outcomes.

We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho-hydroxy β-oxidized atorvastatin. Atorvastatin and M1 pharmacokinetics and inflammatory markers were assessed in C57BL6/J mice given atorvastatin 5 mg/kg/day or 10 mg/kg/day, as a single dose or for 21 days, with or without 10 µL or 30 µL mineral oil. No consistent differences in plasma exposure of atorvastatin or M1 were observed in mice after single or repeat dosing of atorvastatin with or without mineral oil. However, mice administered atorvastatin 10 mg/kg with 30 µL mineral oil for 21 days had significantly increased plasma levels of serum amyloid A (mean 9.6 µg/mL vs 7.9 µg/mL without mineral oil; p0.01) and significantly increased proportions of C62L

The structure hierarchy hypothesis states thatstructures may be ordered hierarchically according to the polymerisation of coordination polyhedra of higher bond-valence. A hierarchical structural classification is developed for sheet-silicate minerals based on the connectedness of the two-dimensional polymerisations of (TO4) tetrahedra, where T = Si4+plus As5+, Al3+, Fe3+, B3+, Be2+, Zn2+and Mg2+. Two-dimensional nets and oikodoméic operations are used to generate the silicate (sensu lato) structural units of single-layer, double-layer and higher-layer sheet-silicate minerals, and the interstitial complexes (cation identity, coordination number and ligancy, and the types and amounts of interstitial (H2O) groups) are recorded. Key aspects of the silicate structural unit include: (1) the type of plane net on which the sheet (or parent sheet) is based; (2) the u (up) and d (down) directions of the constituent tetrahedra relative to the plane of the sheet; (3) the planar or folded nature of the sheet; (4) the layer multiplicity of the sheet (single, double or higher); and (5) the details of the oikodoméic operations for multiple-layer sheets. Simple 3-connected plane nets (such as 63, 4.82and 4.6.12) have the stoichiometry (T2O5)n(Si:O = 1:2.5) and are the basis of most of the common rock-forming sheet-silicate minerals as well as many less-common species. Oikodoméic operations, e.g. insertion of 2- or 4-connected vertices into 3-connected plane nets, formation of double-layer sheet-structures by (topological) reflection or rotation operations, affect the connectedness of the resulting sheets and lead to both positive and negative deviations from Si:O = 1:2.5 stoichiometry. Following description of the structural units in all sheet-silicate minerals, the minerals are arranged into decreasing Si:O ratio from 3.0 to 2.0, an arrangement that reflects their increasing structural connectivity. Considering the silicate component of minerals, the range of composition of the sheet silicates completely overlaps the compositional ranges of framework silicates and most of the chain-ribbon-tube silicates.

Ethyl formate (EF) is a Generally Recognised As Safe (GRAS) alternative to methyl bromide, with potential to control surface pests on New Zealand avocados before export. "Hass" avocados, two-spotted spider mites (TSM) and oleander scale (OS) insects were fumigated with 1.2% EF (240 g VAPORMATE™/m3) at 6 °C for 1, 2 or 4 h. Fruit were then stored at 5 °C for 3 weeks before external and internal fruit quality assessment. Survival of pest species was assessed 1 or 7 days later. Fumigation with 1.2% EF + 10% CO2 for 2 or 4 h controlled all life stages of non-diapausing TSM and all life stages of OS, apart from crawlers (0.3-0.7% survivorship). Diapausing TSM were harder to control (17% ± 4.8% mortality; 4-h treatment). Ethyl formate treatment resulted in damage to avocado skins (41% ± 5.3% – 91% ± 2.0%), and an increase in vascular browning and rots. The EF fumigations of avocado fruit at doses used here have potential to control non-diapausing mites and scale insects, but treated fruit were of unacceptable quality. Future studies could examine whether prior cool storage could reduce fruit damage.

Ethyl formate (EF) is used as a fumigant against insect pests on many commodities. Delivery of EF uses a carrier gas, usually carbon dioxide (CO2), to reduce its flammability. However, CO2 is expensive and can only be delivered relatively slowly. Nitrogen (N2) has been proposed as an alternative. The efficacy of EF delivered using CO2 or N2, was evaluated at 5 and 15˚C, against two important postharvest pests of kiwifruit (greedy scale (Hemiberlesia rapax, Hemiptera: Diaspididae) and obscure mealybug (Pseudococcus viburni, Hemiptera: Pseudococcidae). Mortalities of both insect species were higher in the presence of CO2 than N2. There was a strong interaction with treatment temperature: N2 at 5˚C resulted in low mortality across both species. Greedy scale was more susceptible to EF than obscure mealybug across all treatments. Nitrogen as a carrier gas for EF substantially lowered the efficacy of EF as an insecticidal fumigant, relative to CO2. This is hypothesised to be caused by differing respiration rates across temperatures and CO2 concentrations. Solutions for rapid CO2 delivery should be explored over further trials with N2 at low temperatures.

Two new minerals of the graftonite group, graftonite-(Mn), ideallyM(1)MnM(2),M(3)Fe2(PO4)2, and graftonite-(Ca), ideallyM(1)CaM(2),M(3)Fe2(PO4)2, were discovered in phosphate nodules of two beryl–columbite–phosphate pegmatites at Lutomia and Michałkowa, respectively, in the Góry Sowie Block, Lower Silesia, southwest Poland. Graftonite-(Mn) is pinkish brown, whereas graftonite-(Ca) shows more brownish colouration. Both minerals have a vitreous lustre, a good cleavage observed along (010) and irregular fracture; both are transparent and neither of them is fluorescent. They are brittle and have a Mohs hardness of ~5. The minerals are non-pleochroic, colourless in all orientations, biaxial (+), with mean refractive indices α = 1.710(2) and 1.690(2), β = 1.713(2) and 1.692(2), and γ = 1.725(2) and 1.710(5), respectively. With complete order of Ca at theM(1) site, the formulae of the holotype crystals areM(1)(Mn0.70Ca0.30)M(2),M(3)(Fe1.34Mn0.60Mg0.06Zn0.01)Σ3(PO4)2for graftonite-(Mn) andM(1)(Ca0.98Mn0.02)M(2),M(3)(Fe1.38Mn0.56Mg0.05)Σ3(PO4)2for graftonite-(Ca). Both crystal chemistry and crystal-structure refinement (R1= 2.34 and 1.63%, respectively) indicate that theM(1) site is occupied dominantly by Mn in graftonite-(Mn) and by Ca in graftonite-(Ca), and theM(2) andM(3) sites are occupied by Fe2+and Mn2+, with Fe2+dominant over Mn2+at the aggregateM(2) +M(3) sites. Graftonite-(Mn) and graftonite-(Ca) are isostructural with graftonite,M(1)FeM(2),M(3)Fe2(PO4)2(monoclinic system; space-group symmetryP21/c), with the unit-cell parametersa= 8.811(2) Å,b= 11.494(2) Å,c= 6.138(1) Å, β = 99.23(3)° and V = 613.5(4) Å3, anda= 8.792(2) Å,b= 11.743(2) Å,c= 6.169(1) Å, β = 99.35(3)° andV= 628.5(1) Å3, respectively. The densities calculated on the basis of molar weights and unit-cell volumes are 3.793 g/cm3for graftonite-(Mn) and 3.592 g/cm3for graftonite-(Ca). The eight strongest lines in powder X-ray diffraction patterns on the basis of single-crystal data are, respectively [d, Å,I(hkl)]: 2.874, 100, (230 + 040); 2.858, 79, (221); 3.506, 73, (130); 2.717, 79, ($\bar{3}$11); 2.952, 55, (131); 2.916, 53, ($\bar{1}$12); 2.899, 44, (300); 3.016, 35, ($\bar{1}$02); and 3.654, 100, (130); 2.979, 85, (221); 3.014, 77, (230); 3.042, 76, (040 +$\bar{1}$12); 2.834, 68, ($\bar{3}$11); 3.097, 57, (131); 3.133, 56, ($\bar{1}$02); 2.542, 30, (311). Both minerals are common primary phosphates in phosphate nodules, occurring as lamellar intergrowths with sarcopside ± triphylite/lithiophilite, products of exsolution from a (Li,Ca)-rich graftonite-like parent phase crystallized at high temperature from P-bearing hydrosaline melts.

The mechanical behavior of carbonate-bearing fluorapatite (CFAP) (with up to 5.5 wt% CO3) was investigated at high pressure up to 7 GPa. The incorporation of carbonate in CFAP samples was investigated by FTIR spectroscopy. The chemical formulae and cell parameters are Ca4.90Fe0.04 (PO4)2.87 (CO3)0.13 F1.23 and a = 9.3527(1), c = 6.8752(1) A, V = 520.83(1) A3 for the FOW CFAP (Fowey Consols area, UK), and Ca4.97Sr0.03 (PO4)2.55 (CO3)0.45 F1.42 and a = 9.3330(1), c = 6.8984(1) A, V = 520.38(1) A3 for the FRA CFAP (Framont region, France). Preliminary characterization at ambient conditions was done by single-crystal X-ray diffraction study. The structure refinements, in space group P63/m, confirm a type-B substitution of the phosphate (PO4)3− group by the carbonate ion (CO3)2−. The site occupancies for the C atom are 0.04 for FOW and 0.11 for FRA CFAP, in quite good agreement with the 1.6 and 5.5 wt% CO3 amount obtained by analytical methods. Single-crystal high-pressure XRD study on the two type-B CFAP samples was performed. The FOW and FRA crystals were mounted concurrently in a ETH-type DAC and cell parameters were determined at 26 different pressures up to 6.86 GPa at room T. The variation with pressure of the unit-cell parameters and volume shows no discontinuity that could be related to any possible phase transition in the P range investigated. The linear compressibility coefficients are βa = 3.63 × 10−3 GPa−1 and βc = 2.47 × 10−3 GPa−1 for FOW, and βa = 3.67 × 10−3 GPa−1 and βc = 2.65 × 10−3 GPa−1 for FRA, giving an axial anisotropy of βa:βc = 1.47:1 and 1.38:1, respectively. The P-V data were fitted by a second-order Birch–Murnaghan EoS and the resulting BM2-EoS coefficients are V0 = 519.81(7) A3, KT0 = 92.1(3) GPa for FOW, and V0 = 518.95(9) A3, KT0 = 89.1(4) GPa for FRA CFAP. The results obtained indicate that a 5.5 wt% CO3 content (type-B) reduces the isothermal bulk modulus by about 9%.

In this work we report on a complete crystal-chemical characterization of a near end-member riebeckite from Malawi, and use the available data to critically compare information obtained from different analytical methods. The sample occurs as well-formed and very large single crystals in pegmatitic rocks. Accurate site-populations were determined by combining single-crystal structure refinement and electron microprobe analysis (EMPA). The Fe3+/Fe2+ ratio was obtained from Mössbauer spectroscopy. Lithium was quantified by Laser Ablation Inductively Coupled Plasma Mass Spectroscopy (LA-ICP-MS).Fourier-Transform Infrared (FTIR) spectra, collected both on powders and single crystals, are presented and discussed. FTIR spectra in the NIR region are also presented for the first time for this amphibole. The FTIR data are compatible with complete local ordering of A cations close to F, and complete Fe2+/Mg disorder at M(1,3). Polarized Raman-scattering data collected from single crystals confirm this conclusion. In addition, it was found that FTIR data collected on powders provide the best agreement with the site occupancies derived from chemical (EMPA and LA-ICP-MS) and crystal-chemical data, possibly because they do not depend on experimental issues such as orientation and polarization.

Folvikite, Sb5+Mn3+(Mg,Mn2+)10O8(BO3)4, is a new oxyborate mineral from the Kitteln mine, Värmland, Sweden, where it occurs as a primary skarn mineral embedded in calcite. It forms striated prismatic crystals up to 0.3 mm, and is black to dark reddish-brown with submetallic lustre and a reddish-brown streak. It is brittle, has a Mohs hardness of 6, and the calculated density is 4.14 g/cm3. Folvikite is biaxial with indeterminate optic sign due to pervasive twinning. The optic axial angle is 68.9(4)°. Refractive indices were not measured; the calculated mean refractive index is 1.85. Strong pleochroism was observed in plane-polarized light: AB = brown (intermediate), OB = dark brown (maximum) and ON = honey brown (minimum). Folvikite is monoclinic, space group P2, a = 5.3767(10), b = 6.2108(10), c = 10.9389(18) Å, β = 94.399(9)°, V = 364.22(16) Å3 and Z = 1. Chemical analysis by electron microprobe gave Sb2O5 18.15, MgO 24.11, MnO 29.73, Mn2O3 11.62, Al2O3 0.27, Fe2O3 0.45, B2O3 15.27, sum 99.60 wt.%. The B2O3 content was assigned as B = 4 apfu and the Mn2O3 / (MnO + Mn2O3) ratio was determined from the crystal structure. The empirical formula was normalized on the basis of 20 anions pfu: (Sb5+1.02Mn3+1.34Al0.05Fe3+0.05Mg5.46Mn2+3.82□0.26)Σ12O8(BO3)4. A simplified formula may be written as Sb5+Mn3+(Mg,Mn2+)10O8(BO3)4 with Z = 1. The crystal structure was solved by direct methods and refined to an R1 index of 4.1%. Folvikite is a member of the (3 Å) zigzag wallpaper-borate structures in which chains of edge-sharing octahedra extend along the c axis and are cross-linked by BO3 groups. There are five X sites partly occupied by Mn2+ > Mg, one octahedrally coordinated M-site occupied by Sb5+ > Mg, two M sites occupied by Mg ≥ Mn > Sb5+, two M sites occupied by Mn3+ > Mn2+, two M sites occupied by Mg > Mn2+, and one M-site occupied by Mg > □; plus two [3]-coordinated B sites occupied by B. As with the other zigzag borates, the polyhedra are arranged in F-walls, C-walls and S-columns.

Although well logs and core data show that there is significant oil content in Bakken shales, the oil transport behavior in these source rocks is still not well understood. This lack of understanding impedes the drilling and production operations in the shale members. A series of experiments were conducted to investigate the rock properties of the Bakken shales and how to extract oil from the shales using supercritical CO 2 . High-pressure mercury injection tests showed that pore throat radii are less than 10 nm for most pores in both the upper and lower Bakken samples. Such small pore sizes yield high capillary pressure in the rock and make fluid flow difficult. Total organic carbon content was measured using 180 shale samples, and kerogen was characterized by Rock-Eval pyrolysis, which indicated considerable organic carbon present (10–15 wt%) in the shales. However, oil and gas are difficult to mobilize from organic matter using conventional methods. A systematic experimental procedure was carried out to reveal the potential for extracting hydrocarbons from the shale samples using supercritical CO 2 under typical Bakken reservoir conditions (e.g., 34.5 MPa and 110 °C). Results showed that supercritical CO 2 enables extraction of a considerable portion (15–65%) of hydrocarbons from the Bakken shales within 24 h. Measurement of CO 2 adsorption isotherm showed that Bakken shale has a considerable capability to trap CO 2 (up to 17 mg/g) under a wide range of pressures. The experimental results suggest the possibility of using supercritical CO 2 injection to increase the ultimate oil recovery and store a considerable quantity of CO 2 in the Bakken Formation.

High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the development of a companion PET-based diagnostic imaging agent using 89Zr-labeled glembatumumab ([89Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [89Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [89Zr]DFO-CR011 binds specifically to gpNMB with high affinity (Kd = 25 ± 5 nM), immunoreactivity of 2.2-fold less than the native CR011, and its cellular uptake correlates with gpNMB expression (r = 0.95). In PET studies at the optimal imaging timepoint of 7 days p.i., the [89Zr]DFO-CR011 tumor uptake in gpNMB-expressing MDA-MB-468 xenografts had a mean SUV of 2.9, while significantly lower in gpNMB-negative MDA-MB-231 tumors with a mean SUV of 1.9. [89Zr]DFO-CR011 was also evaluated in patient-derived xenograft models of TNBC, where tumor uptake in vivo had a positive correlation with total gpNMB protein expression via ELISA (r = 0.79), despite the heterogeneity of gpNMB expression within the same group of PDX mice. Lastly, the radiation dosimetry calculated from biodistribution studies in MDA-MB-468 xenografts determined the effective dose for human use would be 0.54 mSv/MBq. Overall, these studies demonstrate that [89Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC.

Two approaches for the synthesis of rodlike polymers having metal bis(dicarbollide) anions connected by organic linkers, such as acetylene and 1,4-dibutyl-2,5-diethynylbenzene, in the backbone are reported. Route 1 involved connecting nido-bis(carborane) compounds, containing the linkers, via π coordination with Co or Ni metals. This reaction yielded small oligomers having one to six repeating units. Route 2 utilized a palladium-catalyzed cross-coupling copolymerization of diiodo-substituted cobaltocarboranes and a zinc-derivatized aromatic linker. This approach gave a mixture of oligomers and polymers. The polymers were separated from the smaller oligomers by dialysis and were characterized by 1H NMR, 11B NMR, 11B{1H} NMR, IR, UV–vis, TEM, and AFM techniques. End-group analysis and dynamic-light scattering experiments (DLS) determined that the average number of repeating units in the polymers ranged between 35 and 44. GPC analyses failed to aid the molecular weight determination due to the adsorption of ...

Empirical electronic polarizabilities allow the prediction of total mineral polarizabilities and mean refractive indices of the vast majority of minerals and synthetic oxides. However, deviations from the valence-sum rule at cations in some minerals are associated with large deviations of observed from calculated total polarizabilities. We have identified several groups of minerals and compounds where deviations from the valence-sum rule at cations lead to polarizability deviations of 2–5%: M(SO4)·nH2O, n = 1–6, blodite-group minerals [Na2M2+(SO4)2·4H2O], and the kieserite-related minerals: isokite, panasqueiraite and tilasite. In these minerals, the environment of the M ions contains both O and H2O: Mg[O4(H2O)2] in kieserite, szmikite, and szomolnokite; Mg[O2(H2O)4] in starkeyite, ilesite, and rozenite, and Mg[(H2O)6] in hexahydrite. In compounds where the ligands are only H2O, deviations from the valence-sum rule at the M(H2O)6 groups are not accompanied by significant polarizability deviations. This is the case for epsomite, MgSO4·7H2O; bieberite, CoSO4·7H2O; goslarite, ZnSO4·7H2O, six silicofluorides, MSiF6·6H2O; eighteen Tutton’s salts, M2M′(SO4)2·6H2O, where M = K, Rb, Cs and M′ = Mg, Mn, Fe, Co, Ni, Cu, and Zn; and eleven MM′(SO4)2·12H2O alums, where M = Na, K, Rb and Cs, and M′ = Al, Cr, Ga and In. This is also the case for the sulfates alunogen, Al2(SO4)3·17H2O and halotrichite, FeAl2(SO4)4·22H2O; three hydrated nitrates; one phosphate; three antimonates and two hydrated perchlorates. A possible explanation for this different behavior is that the bond-valence model treats O and H separately, whereas polarizability calculations treat the polarizability of the entire H2O molecule.

A novel, hydrogel-supported photocatalyst activity indicator, Hpaii , is presented, based on an agar gel containing the pH indicator dye propyl red (PR), and the photoacid generator, diphenyliodonium nitrate (DPIN). The latter is broken down when the film is on an active photocatalytic film, and the acid released protonates the PR, turning the gel from a yellow colour to a red. Initially tested on a TiO 2 sol-gel film, the Hpaii is also shown to be effective in indicating the activity of several different commercially available photocatalytic surfaces, including: glass, tiles and paint. This is the first example of a water-based photocatalyst activity indicator ink based on monitoring a photocatalytic process via the change in pH induced in the indicator films, as revealed by the pH-indicator, propyl red.

The thermal decompositions of metallaisoxazolin-5-ones containing Ir, Rh, or Co are investigated using density functional theory. The experimentally observed decarboxylations of these molecules are found to proceed through retro-(3+2)-cycloaddition reactions, generating the experimentally reported η2 side-bonded nitrile complexes. These intermediates can isomerize in situ to yield a η1 nitrile complex. A competitive alternative pathway is also found where the decarboxylation happens concertedly with an aryl migration process, producing a η1 isonitrile complex. Despite their comparable stability, these η1 bonded species were not detected experimentally. The experimentally detected η2 side bound species are likely involved in the subsequent C–H activation reactions with hydrocarbon solvents reported for some of these metallaisoxazolin-5-ones.

Boron neutron capture therapy (BNCT) was performed at the University of Missouri Research Reactor in mice bearing CT26 colon carcinoma flank tumors and the results were compared with previously performed studies with mice bearing EMT6 breast cancer flank tumors. Mice were implanted with CT26 tumors subcutaneously in the caudal flank and were given two separate tail vein injections of unilamellar liposomes composed of cholesterol, 1,2-distearoyl-sn-glycer-3-phosphocholine, and K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the lipid bilayer and encapsulated Na3[1-(2`-B10H9)-2-NH3B10H8] within the liposomal core. Mice were irradiated 30 hours after the second injection in a thermal neutron beam for various lengths of time. The tumor size was monitored daily for 72 days. Despite relatively lower tumor boron concentrations, as compared to EMT6 tumors, a 45 minute neutron irradiation BNCT resulted in complete resolution of the tumors in 50% of treated mice, 50% of which never recurred. Median time to tumor volume tripling was 38 days in BNCT treated mice, 17 days in neutron-irradiated mice given no boron compounds, and 4 days in untreated controls. Tumor response in mice with CT26 colon carcinoma was markedly more pronounced than in previous reports of mice with EMT6 tumors, a difference which increased with dose. The slope of the dose response curve of CT26 colon carcinoma tumors is 1.05 times tumor growth delay per Gy compared to 0.09 times tumor growth delay per Gy for EMT6 tumors, indicating that inherent radiosensitivity of tumors plays a role in boron neutron capture therapy and should be considered in the development of clinical applications of BNCT in animals and man.

The effects of reservoir temperature and percent levels of methane and ethane in CO 2 on the minimum miscibility pressures (MMPs) of crude oils were measured using a vanishing interfacial tension (VIT) method. MMPs increased linearly with methane concentrations but decreased when ethane was added to CO 2 . Higher reservoir temperatures yielded much higher MMPs for the same oil, apparently because of the reduction in CO 2 densities that occur with increasing temperature. Oil samples collected from the CO 2 -dominated mobile “miscible” phase demonstrated that higher pressures mobilized more oil regardless of MMP, and that CO 2 preferentially mobilizes lighter hydrocarbons, especially at lower pressures.

Pink-orange crystals of a composition within the ferri-obertiite compositional space were found in vesicles in a pale beige silicate vein found from a basalt quarry at Mount Rothenberg, Eifel district, Germany. Associated minerals are potassic feldspar, alpha quartz paramorphic afterbeta quartz, eifelite (the second occurrence after the Caspar quarry at Bellerberg volcano, Eifel region), tridymite, rutile, roedderite and other amphiboles. The ideal formula of ferri-obertiite is ANaBNa2C(Mg3Fe3+Ti)TSi8O22WO2; the empirical formula derived for the holotype specimen from Mount Rothenberg from the results of electron-microprobe analysis and single-crystal structure refinement is A(Na0.76K0.22)∑0.98B(Na1.61Ca0.35Mn0.042+)∑2.00C(Mg3.58Mn0.112+Fe0.623+Ti0.664+Cr0.013+Zn0.01Ni0.01)∑5.00T(Si7.82Ti0.124+Al0.06)∑8.00O22W[O1.26F0.55(OH)0.19]∑2.00. The unit-cell dimensions are a = 9.7901(7), b = 17.9354(13), c = 5.2892(4)Å, β= 104.142(2)°, V = 900.58 (11) Å3. The space group is C2/m, Z = 2. Ferri-obertiite is biaxial (+), with α = 1.664, β = 1.680, γ = 1.722, all ±0.002 and 2V (meas.) = 66.4(3)o, 2V (calc.) = 64.7o.The strongest eight reflections in the powder X-ray pattern [d values (in Å), I, (hkl)] are: 2.704, 100, (151); 3.116, 76, (310); 3.388, 72, (131); 8.931, 72, (110); 2.529, 67, (202); 2.583, 39, (061); 2.160, 38, (261); 3.260, 37, (240). Both the mineral and thename have been approved by the Commission on New Minerals, Nomenclature and Classification of the International Mineralogical Association (IMA 2015-079); the rock specimen has been deposited at the Museo di Mineralogia, Dipartimento di Scienze della Terra e dell'Ambiente, Universitàdegli Studi di Pavia, under the code 2015-02.

Agricultural insect pests frequently exhibit geographic variation in levels of insecticide resistance, which are often presumed to be due to the intensity of insecticide use for pest management. However, regional differences in the evolution of resistance to novel insecticides suggests that other factors are influencing rates of adaptation. We examined LC50 bioassay data spanning 15 years and six insecticides (abamectin, imidacloprid, spinosad, cyantraniliprole, chlorantraniliprole, and metaflumizone) for evidence of regional differences in Colorado potato beetle (CPB) baseline sensitivity to insecticides as they became commercially available. We consistently found that CPB populations from the Western USA had the highest baseline sensitivity to novel insecticides, while populations from the Eastern USA had the lowest. Comparisons of gene expression between populations from these regions revealed constitutively elevated expression of an array of detoxification genes in the East, but no evidence of additional induction when exposed to imidacloprid. Our results suggest a mechanism for geographic variation in rates of adaptation to insecticides whereby baseline levels of gene expression determine a population’s response to novel insecticides. These findings have implications for the regional development of insecticide resistance management strategies and for the fundamental question of what determines the rate of adaptation to insecticides.

UV wavelength laser sources are an important area of research due to their use in atmospheric and atomic sensing; however, diode lasers at these wavelengths often have low power, poor spatial mode quality, and broad optical spectra. An alternative approach to a UV laser source is an IR diode laser with frequency conversion. In this work, a dual element ridge waveguide device is presented for third harmonic generation of UV wavelengths. This design has been successfully implemented to generate and sustain 3mW of UV from 200mW of IR pump in the waveguide.

Ulcerative colitis and Crohn’s disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, that display heterogeneity in inflammatory and symptomatic burden between patients, and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients.This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn’s and Colitis UK).A systematic review of 88,247 publications, and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence and expert opinion based-recommendations for pharmacological, nonpharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn’s disease. Comprehensive, up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and post-operative management, as well as structure and function of the multidisciplinary team, and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2,379 electronic survey responses from individuals living with ulcerative colitis and Crohn’s disease, including patients, their families and friends.

Current clinical poly (ADP-ribose) polymerase (PARP) inhibitors target both PARP1 and PARP2 and they all cause clinical cytopenias with varying severity. Understanding the mechanism underlying the hematological toxicity of these agents is key for the rational design of a best-in-class molecule with greater therapeutic potential, both as monotherapy and in combination with chemotherapy. We validated the rat as a physiologically competent translational model to investigate PARP inhibitor-driven hematological toxicity. Here we demonstrate that in comparison with a representative PARP1/2 inhibitor, olaparib, the novel highly potent PARP1-selective inhibitor and trapper, AZD5305, does not cause hematological toxicity as a monotherapy in pre-clinical rat models at predicted clinically efficacious exposures. Thus, monotherapy toxicity of PARP1/2 inhibitors likely depends on PARP2 inhibition. Next, we proceeded to investigate whether PARP1-selective inhibition would be better tolerated in chemotherapy combinations than PARP1/2 inhibition. We performed a rat in vivo study comparing daily olaparib or daily AZD5305 at matched exposures in combination with one cycle of intravenous carboplatin for 14 days. We show that olaparib and PARP1-selective AZD5305 cause comparable exacerbation of carboplatin-induced peripheral blood effects implicating PARP1 inhibition in combination-driven hematological toxicity. Importantly however, AZD5305+carboplatin showed improved hematological tolerability over olaparib+carboplatin because peripheral reticulocytes and bone marrow erythroid precursor cells recover in the presence of continuous AZD5305 but not in the presence of continuous olaparib. Importantly, this differentiation was maintained in a subsequent rat in vivo study, where daily olaparib or daily AZD5305 were combined with two three-weekly cycles of a higher dose of carboplatin to more closely mimic clinical protocol. AZD5305+carboplatin was associated with a more rapid recovery of reticulocytes, red blood cells and hemoglobin following both cycles of carboplatin. In contrast, olaparib+carboplatin was associated with a slower recovery resulting in a more sustained reduction in red cells and hemoglobin during both the first and second cycle of carboplatin. Thus, in rodents the novel potent PARP1-selective inhibitor AZD5305 has improved hematological tolerability over dual PARP1/2 inhibitors, both as a monotherapy and in carboplatin combinations. Citation Format: Sonja J. Gill, Ruth Macdonald, Carmen Pin, Rob Collins, Emilyanne Leonard, Gareth Maglennon, Andy Pike, Peter Cotton, Glen Hawthorne, Jordan Pugh, Rebecca Sargeant, Daniel Sutton, James Atkinson, Stewart Jones, Sarah Chinery, Mark Anderton. The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1374.

Although the use of engineered nanomaterials continues to increase, how these materials interact with coexisting contaminants in the environment is largely unknown. The effect of silver (Ag) in bulk, ionic, and nanoparticle (NP; bare and polyvinyl pyrrolidone-coated) forms at 3 concentrations (0 mg/kg, 500 mg/kg, 1000 mg/kg, 2000 mg/kg; ion at 69 mg/kg, 138 mg/kg, 276 mg/kg) on the accumulation of field-weathered chlordane and dichlorodiphenyldichloroethylene + metabolites (DDX) by Eisenia fetida (earthworm) was investigated. Earthworm biomass and survival were unaffected by treatment. At the 500 mg/kg and 1000 mg/kg exposure levels, NP-exposed earthworms contained significantly greater Ag (194-245%) than did the bulk exposed organisms; NP size or coating had no impact on element content. Generally, exposure to Ag of any type or at any concentration significantly reduced pesticide accumulation, although reductions for DDX (35.1%; 8.9-47.0%) were more modest than those for chlordane (79.0%; 17.4-92.9%). For DDX, the reduction in pesticide accumulation was not significantly affected by Ag type or concentration. For chlordane, the 3 NP exposures suppressed chlordane accumulation significantly more than did bulk exposure; earthworms exposed to bulk Ag contained 1170 ng/g chlordane, but levels in the NP-exposed earthworms were 279 ng/g. At the 500 mg/kg exposure, the smallest coated NPs exerted the greatest suppression in chlordane accumulation; at the 2 higher concentrations, chlordane uptake was unaffected by NP size or coating. The findings show that in exposed earthworms Ag particle size does significantly impact accumulation of the element itself, as well as that of coexisting weathered pesticides. The implications of these findings with regard to NP exposure and risk are unknown but are the topic of current investigation. Environ Toxicol Chem 2017;36:1864-1871. © 2016 SETAC.

Biochar is seeing increased usage as an amendment in agricultural soils but the significance of nanoscale interactions between this additive and engineered nanoparticles (ENP) remains unknown. Corn, lettuce, soybean and zucchini were grown for 28 d in two different soils (agricultural, residential) amended with 0–2000 mg engineered nanoparticle (ENP) CeO2 kg−1 and biochar (350 °C or 600 °C) at application rates of 0–5% (w/w). At harvest, plants were analyzed for biomass, Ce content, chlorophyll and lipid peroxidation. Biomass from the four species grown in residential soil varied with species and biochar type. However, biomass in the agricultural soil amended with biochar 600 °C was largely unaffected. Biochar co-exposure had minimal impact on Ce accumulation, with reduced or increased Ce content occurring at the highest (5%) biochar level. Soil-specific and biochar-specific effects on Ce accumulation were observed in the four species. For example, zucchini grown in agricultural soil with 2000 mg CeO2 kg−1 and 350 °C biochar (0.5–5%) accumulated greater Ce than the control. However, for the 600 °C biochar, the opposite effect was evident, with decreased Ce content as biochar increased. A principal component analysis showed that biochar type accounted for 56–99% of the variance in chlorophyll and lipid peroxidation across the plants. SEM and μ-XRF showed Ce association with specific biochar and soil components, while μ-XANES analysis confirmed that after 28 d in soil, the Ce remained largely as CeO2. The current study demonstrates that biochar synthesis conditions significantly impact interactions with ENP, with subsequent effects on particle fate and effects.

Summary Compared with a conventional reservoir, the ultralow permeability in the Bakken Formation makes it very challenging to perform normal waterflooding or gasflooding operations. “Permeability-jail” effects cause low injectivity and prevent injected fluids from sweeping oil out of the matrix efficiently. Two distinguishable flow regimes have been identified in fractured, hydrocarbon-rich shale formations: viscous flow in high-permeability fracture networks and diffusion-dominated flow in the low-permeability matrix with high oil saturation. Improving hydrocarbon transport (and technically recoverable resources) in unconventional reservoirs relies on our ability to enhance diffusion-dominated flow from the oil-saturated matrix to the natural- or induced-fracture network, which is the focus of this study. To unlock the unproduced Bakken and Three Forks oil, high-pressure carbon dioxide (CO2) may be used to enhance the diffusion-dominated flow in the matrix and keep the viscous flow in the fractures under reservoir temperature and pressure conditions (e.g., 230°F and 5,000 psi). Core samples were collected from two Bakken wells, including all oil-bearing intervals: Upper Bakken (UB), Middle Bakken (MB), and Lower Bakken (LB) Members and the Three Forks (TF) Formation. Detailed core analyses were performed to measure petrophysical properties and characterize these units. Ten samples were selected for pore-size-distribution measurement and 21 samples (11-mm-diameter rods) were used for 24-hour CO2 exposures and hydrocarbon-recovery experiments. These experiments were conducted as CO2 “bathing” at reservoir conditions (rather than “flow through” tests) and were aimed at increasing our understanding of the microstructure and diffusion-dominated-flow ability within these tight geologic formations. CO2-exposure and hydrocarbon-extraction experimental results clearly showed the improvement of diffusion-dominated flow in all the Bakken members. The UB and LB samples, characterized by generally high total-organic-carbon (TOC) content (10–15 wt%) and small pore size (approximately 3–7 nm), yielded approximately 60% of the present mature hydrocarbon at the end of the 24-hour exposure. The MB and TF samples, characterized by lower TOC content ( CO2 greatly enhances the diffusion process to improve hydrocarbon transport in the tight matrix. This observation is especially useful for densely fractured shale-oil formations (high surface-area/volume ratio) where CO2 has greater areal contact with the reservoir, enabling CO2 diffusion into the matrix and hydrocarbon diffusion out of the matrix to occur more efficiently (increasing recoverable reserves), and where the fracture networks assist in alleviating potential injectivity challenges.

Objective Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1 / 2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo . Methods Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naive PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting. Results Five PDX models were evaluated in vivo . Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2 -deficient PDX. Conclusions Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition.

We report here a simplification of the capillary-rise/vanishing interfacial tension (IFT) method to measure minimum miscibility pressure (MMP) based on only requiring knowledge of when the interfacial tension approaches zero. Simply measuring the height of the crude oil in a capillary at several pressures from ambient to near the MMP pressure and extrapolating the oil height versus pressure plot to zero oil height yields the MMP without the need of the additional instrumentation and labor required to perform actual IFT measurements. A total of 2–4 MMP values can be determined per day with only one experimental apparatus, and the method greatly reduces the initial cost and complexity of the required instrumentation. The use of three capillaries having different inner diameters allows for triplicate determinations of MMP from each experiment. Because the actual MMP pressure need not be reached during the experiment, MMP values that exceed the pressure ratings of the equipment can be reasonably estimated (e....

The construction and application of a unique monodisperse closomer drug-delivery system (CDDS) integrating three different functionalities onto an icosahedral closo-dodecaborane [B12 ](2-) scaffold is described. Eleven B-OH vertices of [closo-B12 (OH)12 ](2-) were used to attach eleven copies of the anticancer drug chlorambucil and the targeting vector glucosamine through a bifurcating lysine linker. The remaining twelfth vertex was used to attach a fluorescent imaging probe. The presence of multiple glucosamine units offered a monodisperse and highly water-soluble CDDS with a high payload of therapeutic cargo. This array enhanced the penetration of the drug into cancer cells by exploiting the overexpression of GLUT-1 receptors present on cancer cells. About 15-fold enhancement in cytotoxicity was observed for CDDS-1 against Jurkat cells, compared to CDDS-2, which lacks the GLUT-1 targeting glucosamine. A cytotoxicity comparison of CDDS-1 against colorectal RKO cells and its GLUT-1 knock-out version confirmed that GLUT-1 mediates endocytosis. Using fluorescent markers both CDDS-1 and -2 were traced to the mitochondria, a novel target for alkylating agents.

Wernerbaurite (IMA 2012–064) and schindlerite (IMA 2012–063) from the St. Jude mine, Slick Rock district, San Miguel County, Colorado, USA, were described as hydronium-bearing decavanadate minerals with the formulae {[Ca(H 2 O) 7 ] 2 (H 2 O) 2 (H 3 O) 2 }{V 10 O 28 } and {[Na 2 (H 2 O) 10 ](H 3 O) 4 }{V 10 O 28 }, respectively. Because these phases correspond to known synthetic phases with these formulae, the presence of NH 4 in these minerals was not considered. Recent investigations of a similar phase discovered at a vanadium locality in the Fergana Valley of Kyrgyzstan showed it to contain NH 4 , leading us to reanalyze the original electron-microprobe mounts of wernerbaurite and schindlerite, specifically seeking N; those analyses confirmed the presence of sufficient NH 4 to replace the originally assigned H 3 O. With the additional H sites included and O replaced by N at the NH 4 sites, the structure refinement residual improved for wernerbaurite from R 1 = 3.41% to R 1 = 3.26% and for schindlerite from R 1 = 3.99% to R 1 = 3.70%. The newly assigned NH 4 sites exhibited normal NH 4 –O bond distances and coordination and reasonable bond-valence sums. The H 3 O synthetic equivalents of both phases had been reported, as well as the NH 4 synthetic equivalent of schindlerite. Subsequent to the publication of the original description of the minerals, the NH 4 equivalent of wernerbaurite has also been reported.

Four mixed-ligand bis(dicarbollyl)nickel(IV) complexes 4b-e were prepared in good yields via a two-step procedure including (1) ligand exchange reactions between the nickelacarborane complex 3,3-(PPh3)2-closo-3,1,2-NiC2B9H11 (1) and the appropriate substituted dicarbollide-dianions generated from the TBA-salts of nido-carborane anions [7,8-C2B9H11(R)]− {R = 3-[(CH2)5C16H9] (2b); 5-[m-CF3C6H4] (2c); 5-[p-CH3OC6H4] (2d); and 1-[C≡CTIPS] (2e)} in THF and (2) subsequent oxidation of the prepared paramagnetic intermediate Ni(III) complexes 3b-e by FeCl3 in acetonitrile. Target compounds were characterized using a combination of spectroscopic techniques. The structure of 4e was determined using X-ray diffraction.

Arterial stiffening is a consequence of aging and a cholesterol-independent risk factor for cardiovascular disease (CVD). Arterial stiffening and CVD show a sex bias, with men more susceptible than premenopausal women. How arterial stiffness and sex interact at a molecular level to confer risk of CVD is not well understood. Here, we used the sexual dimorphism in LDLR-null mice to show that the protective effect of female sex on atherosclerosis is linked to reduced aortic stiffness and reduced expression of matrix metalloproteinase-12 (MMP12) by lesional macrophages. Deletion of MMP12 in LDLR-null mice attenuated the male sex bias for both arterial stiffness and atherosclerosis, and these effects occurred despite high serum cholesterol. Mechanistically, we found that oxidized LDL stimulates secretion of MMP12 in human as well as mouse macrophages. Estrogen antagonizes this effect by downregulating MMP12 expression. Our data support cholesterol-independent causal relationships between estrogen, oxidized LDL–induced secretion of macrophage MMP12, and arterial stiffness that protect against atherosclerosis in females and emphasize that reduced MMP12 functionality can confer atheroprotection to males.

Background Overexpression of the RAN GTP (RAN) gene has been shown to be linked to metastatic activity of MDA-MB231 human breast cancer cells by increasing Ras/MEK/ERK and PI3K/Akt/mTORC1 signalling. The aim of this study was to investigate the potential of polymeric nanoparticles to deliver two novel shRNA sequences, targeted against the RAN gene, to MDA-MB231 cells grown in culture and to assess their effects in a range of biological assays. Methods Biodegradable PLGA nanoparticles, loaded with shRNA-1 and shRNA-4, were fabricated using a double emulsion solvent evaporation technique and characterised for size, zeta potential and polydispersity index before testing on the MDA-MB231 cell line in a range of assays including cell viability, migration, invasion and gene knock down. Results shRNA-loaded nanoparticles were successfully fabricated and delivered to MDA-MB231 cells in culture, where they effectively released their payload, causing a decrease in both cell invasion and cell migration by knocking down RAN gene expression. Conclusion Results indicate the anti-RAN shRNA-loaded nanoparticles deliver and release biological payload to MDA-MB231 cells in culture. This works paves the way for further investigations into the possible use of anti-RAN shRNA-loaded NP formulations for the treatment of breast cancer in vivo.

Background & AimsFibroblast activation protein-a (FAP) is a post-proline peptidase closely related to dipeptidyl peptidase-4. FAP degrades bioactive peptides including fibroblast growth factor-21 (FGF-21) and neuropeptide Y. We examined metabolic outcomes of specific genetic ablation of FAP and its enzyme activity in a mouse model of diet-induced obesity (DIO) causing fatty liver.MethodsWildtype (WT) and genetically modified FAP deficient mice that specifically lacked either the FAP protein or FAP enzyme activity received chow, or an atherogenic diet for 8 to 20 weeks of DIO.ResultsFAP deficient male and female mice in the DIO model were more metabolically healthy than controls. The FAP deficient mice had less glucose intolerance, liver lipid, adiposity, insulin resistance, pancreatic and plasma insulin, pancreatic β-cell hyperplasia, serum alanine transaminase and circulating cholesterol compared to wild type controls. Furthermore, FAP deficiency lowered respiratory exchange ratio and greatly increased intrahepatic non-esterified free fatty acids, indicative of increased lipolysis and β-oxidation. Concordantly, lipogenic genes (Pparg, Gck, Acc, Fasn) and hepatic triglyceride and fatty acid uptake genes (Cd36, Apoc3, Ldlr) and plasma low-density lipoprotein cholesterol were downregulated. Glucagon like peptide-1 levels were unaltered. FAP was localized to human pancreatic β-cells and pancreas from diabetes mellitus patients contained elevated FAP activity. Comparable data from a FAP gene knockout mouse and a novel mouse lacking FAP enzyme activity indicated that these metabolic changes depended upon the enzymatic activity of FAP. These changes may be driven by FGF-21, which was upregulated in livers of FAP deficient DIO mice.ConclusionThis is the first study to show that specific genetic ablation of FAP activity or protein protects against DIO-driven glucose intolerance, hyperinsulinaemia, insulin resistance, hypercholesterolaemia and liver steatosis in mice and provide mechanistic insights.