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The one-dimensional (1-D) coordination polymer [Ni(bdc)(pico)2(H2O)2] (where bdc = terephthalate, pico = 4-picoline) is hosted within a two-dimensional (2-D) hydrogen-bonded grid [Ni(bdc)(pico)2(H2...

The formation of a self-interpenetrated honeycomb molecular network based upon 4,6-dichlororesorcinol (4,6-diCl res), a water molecule, and the photoproduct rtct-tetrakis(pyridin-4-yl)cyclobutane ( rtct -TPCB) is reported. Interestingly, only three of the four pyridine rings on the central cyclobutane ring are found to engage in O—H...N hydrogen bonds with either the 4,6-diCl res or an included water molecule, resulting in a three-connected net. Notably, the solid (4,6-diCl res)·( rtct -TPCB)·(H2O), C6H4Cl2O2·C24H20N4·H2O, contains channels that run along the crystallographic b axis, which are found to be interpenetrated. Although rtct -TPCB has been employed as a bridging ligand in the formation of numerous metal–organic materials, surprisingly neither the single-component X-ray structure nor any multi-component molecular solids based upon this stereoisomer have been reported previously. Lastly, the single-crystal X-ray structure of the photoproduct rtct -TPCB is also reported.

The formation of three isostructural co-crystals that utilize iodoperchlorobenzene as a dual halogen-bond donor is reported. These molecular solids are held together by the combination of I⋯N and Cl⋯N halogen bonds to form one-dimensional polymeric chains. Curiously, these co-crystals are isostructural to a series of related solids based upon the isosteric halogen-bond donor 1,4-diiodoperchlorobenzene. It is noteworthy that the co-crystal containing trans-1,2-bis(4-pyridyl)ethylene undergoes a near quantitative [2 + 2] cycloaddition reaction.

We report the synthesis of a Na-ion-conducting ionogel (IG) electrolyte using a one-pot, siloxane-modified sol–gel approach. The resulting pseudosolid electrolyte provides a nonflammable alternativ...

The 12(th) International Society for the Study of Xenobiotics (ISSX) meeting, held in Portland, OR, USA from July 28–31, 2019, was attended by diverse members of the pharmaceutical sciences community. The ISSX New Investigators Group provides learning and professional growth opportunities for student and early career members of ISSX. To share meeting content with those who were unable to attend, the ISSX New Investigators herein elected to highlight the “Advances in the Study of Drug Metabolism” symposium, as it engaged attendees with diverse backgrounds. This session covered a wide range of current topics in drug metabolism research including predicting sites and routes of metabolism, metabolite identification, ligand docking, and medicinal and natural products chemistry, and highlighted approaches complemented by computational modeling. In silico tools have been increasingly applied in both academic and industrial settings, alongside traditional and evolving in vitro techniques, to strengthen and streamline pharmaceutical research. Approaches such as quantum mechanics simulations facilitate understanding of reaction energetics towards prediction of routes and sites of drug metabolism. Furthermore, in tandem with crystallographic and orthogonal wet lab techniques for structural validation of drug metabolizing enzymes, in silico models can aid understanding of substrate recognition by particular enzymes, identify metabolic soft spots and predict toxic metabolites for improved molecular design. Of note, integration of chemical synthesis and biosynthesis using natural products remains an important approach for identifying new chemical scaffolds in drug discovery. These subjects, compiled by the symposium organizers, presenters, and the ISSX New Investigators Group, are discussed in this review.

The formation of cocrystals based upon 1,4-diiodoperchlorobenzene (C6I2Cl4) as a halogen bond donor along with a series of isomeric pyridine vinyl esters, namely, (E)-methyl-3-(pyridine-X-yl)prop-2...

A halogen-bonded eight-fold interpenetrated diamondoid net was constructed employing a node generated in the solid state. Specifically, co-crystallization of a tetrahedral-like tecton, rctt-tetrakis(4-pyridyl)cyclobutane (4,4′-TPCB), combined with a rigid halogen-bond donor, 1,4-diiodoperchlorobenzene, achieved a diamondoid architecture. In the co-crystal, 4,4′-TPCB is found to form three types of linkages based on one cis- and two trans-orientations enabled by the intrinsic rctt-stereochemisty of the central cyclobutane ring. Thus, 4,4′-TPCB is able to adapt to the constraints of the diamondoid net owing to the flexibility of the pendant 4-pyridyl groups.

The formation and photoreactivity of a series of mixed co-crystals containing 4-stilbazole along with both 4,6-dichlororesorcinol and 4,6-dibromoresorcinol at various ratios is reported. In all cases, the quantitative [2 + 2] cycloaddition reaction yields an identical head-to-tail photoproduct, namely rctt-1,3-bis(4-pyridyl)-2,4-bis(phenyl)cyclobutane. The selectivity in the cycloaddition reaction occurred due to a shorter distance observed between two carbon-carbon double bonds that were found between and not within the hydrogen-bonded assemblies.

Ionogels, pseudo-solid-state electrolytes consisting of an ionic liquid electrolyte confined in a mesoporous inorganic matrix, have attracted interest recently due to their high ionic conductivity and physicochemical stability. These traits, coupled with their inherent solution processability, make them a viable solid electrolyte for solid-state battery systems. Despite the promising properties of ionogels, there have been very few investigations of the electrode–ionogel interface. In the present study, X-ray photoelectron spectroscopy, Raman spectroscopy, and electrochemical measurements were utilized to probe the surface reactions occurring at the electrode–ionogel interface for several electrode materials. Our results indicate that the sol acidity initiates breakdown of the organic constituents of the sol and reduction of the transition metals present in the electrode materials. This chemical attack forms an organic surface layer and affects the electrode composition, both of which can impede Li+ acces...

The formation and crystal structure of a hydrated molecular salt that results in a square network is reported. The crystalline solid is based upon the tetraprotonated photoproduct rtct-tetrakis(pyridin-4-yl)cyclobutane (4H- rtct -TPCB)4+ along with two sulfate anions (SO4 2−) and eight waters of hydration, namely, 4,4′,4′′,4′′′-(cyclobutane-1,2,3,4-tetrayl)tetrapyridinium bis(sulfate) octahydrate, C24H24N4 4+·2SO4 2−·8H2O. The fully protonated photoproduct acts as a four-connecting node within the square network by engaging in four charge-assisted N+—H...O hydrogen bonds to the sulfate anion. The observed hydrogen-bonding pattern in this square network is akin to T-silica, which is a metastable form of SiO2. The included water molecules and sulfate anions engage in numerous O—H...O hydrogen bonds to form various hydrogen-bonded ring structures.

Methods to form cyclobutane rings by an intermolecular [2 + 2] cross-photoreaction (CPR) with four different substituents are rare. These reactions are typically performed in the liquid phase, involve multiple steps, and generate product mixtures. Here, we report a CPR that generates a cyclobutane ring with four different aryl substituents. The CPR occurs quantitatively, without side products, and without a need for product purification. Generally, we demonstrate how face-to-face stacking interactions of aromatic rings can be exploited in the process of cocrystallization and the field of crystal engineering to stack and align unsymmetrical alkenes in CPRs to afford chiral cyclobutanes with up to four different aryl groups via binary cocrystals. Overall, we expect the process herein to be useful to generate chiral carbon scaffolds, which is important given the presence of four-membered carbocyclic rings as structural units in biological compounds and materials science. Preparation of cyclobutanes with four different substituents is rare and often arduous. Here a cocrystallisation strategy enables the intermolecular [2+2] cross-photoreaction of non-symmetrical stilbene derivatives to obtain chiral tetrasubstituted cyclobutanes with up to four different substituents in quantitative yield.

Elevated citrulline and C5-OH levels are reported as part of the newborn screening of core and secondary disorders on the Recommended Uniform Screening Panel (RUSP). Additionally, some state laboratory newborn screening programs report low citrulline levels, which may be observed in proximal urea cycle disorders. We report six patients who were found on newborn screening to have low citrulline and/or elevated C5-OH levels in whom confirmatory testing showed the combination of these two abnormal analytes. Mitochondrial sequencing revealed known pathogenic variants in MT-ATP6 at high heteroplasmy levels in all cases. MT-ATP6 at these heteroplasmy levels is associated with Leigh syndrome, a progressive neurodegenerative disease. Patients were treated with supplemental citrulline and, in some cases, mitochondrial cofactor therapy. These six patients have not experienced metabolic crises or developmental regression, and early diagnosis and management may help prevent the neurological sequelae of Leigh syndrome. The affected mothers and siblings are asymptomatic or paucisymptomatic (e.g. intellectual disability, depression, migraines, obsessive-compulsive disorder, and poor balance) despite high heteroplasmy or apparent homoplasmy of the familial variant, thus expanding the clinical spectrum seen in pathogenic variants of MT-ATP6. Confirmatory plasma amino acid analysis and acylcarnitine profiling should be ordered in a patient with either low citrulline and/or elevated C5-OH, as this combination appears specific for pathogenic variants in MT-ATP6.

The formation of a pair of extended networks sustained by halogen bonds based upon two regioisomers of a photoproduct, namely rctt-1,3-bis(4-pyridyl)-2,4-bis(phenyl)cyclobutane (ht-PP) and rctt-1,2-bis(4-pyridyl)-3,4-bis(phenyl)cyclobutane (hh-PP), that have varied topology is reported. These networks are held together via I⋯N halogen bonds between the photoproduct and the halogen-bond donor 1,4-diiodoperchlorobenzene (C6I2Cl4). The observed topology in each solid is controlled by the regiochemical position of the halogen-bond accepting 4-pyridyl group. This paper demonstrates the ability to vary the topology of molecular networks by altering the position of the halogen bond acceptor within the cyclobutane-based node.

The ability to form both infinite and discrete co-crystals based upon 1,2-bis(iodoethynyl)benzene as a halogen bond donor has been realized. The various co-crystals are held together by I⋯N halogen bonds from the donor to either a symmetrical bipyridine or an unsymmetrical monopyridine-based acceptor producing a one-dimensional wave-like polymer or discrete assembly, respectively.

A halogen-bonded supramolecular ladder comprised of a novel pyrimidine-based cyclobutane photoproduct synthesized in the organic solid state via a [2 + 2] photoreaction is reported. The photoproduct rctt-tetrakis(5′-pyrimidyl)cyclobutane functions as rungs while the linear divergent halogen-bond donor 1,4-diiodoperchlorobenzene acts as the rails. Our report also confirms the structure and stereochemistry of the tetrapyrimidyl cyclobutane ring system.

We demonstrate the synthesis of the first anionic aluminum metal-organic framework (MOFs) constructed from tetrahedral AlO4 sites. Al-Td-MOF-1 was obtained in a simple two-step synthesis by condensation of 1,4-dihydroxybenzene and lithium aluminum hydride into an amorphous aluminate framework before applying a solvothermal treatment under basic conditions to obtain the crystalline Al-Td-MOF-1 with a chemical composition of Li[Al(C6 H4 O2 )2 ]. The overall Al-Td-MOF-1 structure consists of one-dimensional chains of alternating edge-sharing AlO4 and LiO4 tetrahedral sites describing unidirectional pore channels with a square window aperture of ≈5×5 A2 , best described topologically as a uninodal 6-coordinated snp rod net. Al-Td-MOF-1 features the highest Li+ loading reported to date for a MOF (2.50 wt %) and proved to be an effective single-ion solid electrolyte. An ionic conductivity of 5.7×10-5 S cm-1 was measured for Al-Td-MOF-1 and the beneficial contribution of crystallinity was evidenced by an 8-fold increase in conductivity between the disordered and crystalline material.

Co-crystallization of 3-phenylazopyridine (3PAzP) with dihalogenated resorcinols (res) 4,6-diX res (where: X = Cl, Br, and I) yields co-crystals that support molecular pedal motion in the crystalli...

The influence of molecular pedal motion on the thermal expansion properties of three isostructural hydrogen-bonded co-crystals based upon resorcinol is reported. The resulting co-crystals all exhibit discrete four-component assemblies held together by O–H···N hydrogen bonds and comprise resorcinol (res) with a series of isosteric bipyridines, namely, 4,4′-azopyridine (4,4′-AP), trans-1,2-bis(4-pyridyl)ethylene (4,4′-BPE), and 1,2-bis(4-pyridyl)acetylene (4,4′-BPA). The ability to change the core of the hydrogen bond acceptor molecules from an azo (N═N) to an ethylene (C═C) and finally an acetylene (C≡C) group affords co-crystals that differ in their tendency to undergo dynamic pedal motion in the organic solid state. All three co-crystals, 2(res)•2(4,4′-AP), 2(res)•2(4,4′-BPE), and 2(res)•2(4,4′-BPA), exhibit thermal expansions that correlate with the strength of the noncovalent interactions, as well as the propensity of the core to undergo pedal motion.

The thermal expansion properties of a co-crystal containing the photodimerization product rctt-tetrakis(4-pyridyl)cyclobutane and resorcinol is reported. The photocycloaddition reaction generates new carbon–carbon bonds in the solid, resulting in a significant decrease in the ability of the co-crystal to expand along the direction of the newly formed bonds.

The ability to vary the thermal expansion parameters within halogen- or hydrogen-bonded co-crystals is reported. An acceptor molecule, 1,2-bis(4-pyridyl)acetylene, was selected due to its ability to form supramolecular one-dimensional chains, regardless of the ditopic donor type. We demonstrate that the smallest expansion occurs along the chain, and greater expansion occurs within the two-dimensional sheet, which is based on weaker halogen interactions.

Soils export large amounts of organic matter to rivers, and there are still major uncertainties concerning the composition and reactivity of this material, and its fate within the fluvial network. Here we reconstructed the pattern of movement and processing of dissolved organic matter (DOM) along a soil-stream-river continuum under summer base-flow conditions in a boreal region of Quebec (Canada), using a combination of fluorescence spectra, size-exclusion chromatography and ultrahigh-resolution mass spectrometry. Our results show that there is a clear sequence of selective DOM degradation along the soil-stream-river continuum, which results in pronounced compositional shifts downstream. The soil-stream interface was a hotspot of DOM degradation, where biopolymers and low molecular weight (LMW) compounds were selectively removed. In contrast, processing in the stream channel was dominated by the degradation of humic-like aromatic DOM, likely driven by photolysis, with little further degradation of either biopolymers or LMW compounds. Overall, there was a high degree of coherence between the patterns observed in DOM chemical composition, optical properties, and molecular profiles, and none of these approaches pointed to measurable production of new DOM components, suggesting that the DOM pools removed during transit were likely mineralized to CO2. Our first order estimates suggest that rates of soil-derived DOM mineralization could potentially sustain over half of the measured CO2 emissions from this stream network, with mineralization of biopolymers and humic hubstances contributing roughly equally to these fluvial emissions.

Metal-oxide thin films find many uses in (opto)electronic and renewable energy technologies. Their deposition by solution methods aims to reduce manufacturing costs relative to vacuum deposition while achieving comparable electronic properties. Solution deposition on temperature-sensitive substrates (e.g., plastics), however, remains difficult due to the need to produce dense films with minimal thermal input. Here, we investigate combustion thin-film deposition, which has been proposed to produce high-quality metal-oxide films with little externally applied heat, thereby enabling low-temperature fabrication. We compare chemical composition, chemical structure, and evolved species from reactions of several metal nitrate [In(NO3)3, Y(NO3)3, and Mg(NO3)2] and fuel additive (acetylacetone and glycine) mixtures in bulk and thin-film forms. We observe combustion in bulk materials but not in films. It appears acetylacetone is removed from the films before the nitrates, whereas glycine persists in the film beyond...

Summary Ionogels have recently attracted attention as pseudo-solid-state electrolytes based on their ability to confine an ionic liquid electrolyte within the mesoporous network of a sol-gel-derived inorganic matrix. Herein we report on the development of two important capabilities for ionogels. In one case, we incorporated spin-coated, 600-nm Li + -conducting ionogel films in electrochemical cells of LiFePO 4 /ionogel/Li. A key feature in this work is the ability to have the sol thoroughly penetrate the LiFePO 4 electrode prior to gelation. Devices operating at C/2 achieved capacities of 125 mAh/g for some 150 cycles with minimal capacity loss. In the second case, we developed a UV crosslinking synthesis method and demonstrated photo-patterning of the ionogel. The realization of a photo-patterned pseudo-solid-state electrolyte increases the versatility of ionogels and potentially enables new fabrication routes for electrochemical device architectures.

C–H···N hydrogen bonds support an intermolecular [2 + 2] photodimerization in the solid state. The photocycloaddition occurs in a co-crystal of composition (tbrb)·(4,4′-bpe) (where tbrb = 1,2,4,5-tetrabromobenzene; 4,4′-bpe = trans-1,2-bis(4-pyridyl)ethylene) that consists of one-dimensional (1D) chains that self-assemble to form corrugated sheets. Stacking of 4,4′-bpe between sheets conforms to the topochemical postulate of Schmidt. The alkene reacts to form rctt-tetrakis(4-pyridyl)cyclobutane (4,4′-tpcb) stereoselectively and in quantitative yield. C–H···N hydrogen bonds also support the assembly of the components in (tbrb)·(4,4′-azo) (where: 4,4′-azo = 4,4′-azopyridine) into planar sheets. Density-functional theory calculations reveal identical face-to-face stacks of tbrb to aide in the stabilization of the structures of the co-crystals.

Routine monitoring stations on the west coast of North America serve to monitor baseline levels of criteria pollutants such as ozone (O3) arriving from the Pacific Ocean. In Canada, the Amphitrite Point Observatory (APO) on Vancouver Island has been added to this network to provide regional baseline measurements. In 2014, McKendry, I. G., Christensen, E., Schiller, C., Vingarzan, R., Macdonald, A. M., & Li, Y. (2014) reported frequent nocturnal O3 depletion events (ODEs) at APO that generally correlated with alongshore winds, elevated concentrations of carbon dioxide (CO2), and stable boundary layer conditions but the cause (causes) for this remains (remain) unclear.This manuscript presents results from the Ozone-depleting Reactions in a Coastal Atmosphere (ORCA) campaign, which took place in July 2015 to further investigate ODEs at APO. In addition to the long-term measurements at the site (e.g., CO2 and O3 mixing ratios), abundances of biogenic volatile organic compounds (BVOC) and aerosol size ...

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Lymphocyte trafficking via chemokine receptors such as CCR5 plays a critical role in alloreactive responses, and previous data suggest that CCR5 blockade with maraviroc results in a low incidence of visceral GVHD. However, the full scope of clinical and immunologic effects of CCR5 blockade in HSCT has not been described. We compared a cohort of patients enrolled on a trial of reduced-intensity allo-HSCT with standard GVHD prophylaxis plus maraviroc to a contemporary control cohort receiving standard GVHD prophylaxis alone. Maraviroc treatment was associated with a lower incidence of acute GVHD without increased risk of disease relapse, as well as reduced levels of gut-specific markers. At day 30, maraviroc treatment increased CCR5 expression on T cells and dampened T-cell activation in peripheral blood without impairing early immune reconstitution or increasing risk for infections. Patients who developed acute GVHD despite maraviroc prophylaxis showed increased T-cell activation, naive T-cell skewing, and elevated serum CXCL9 and CXCL10 levels. Collectively, these data suggest that maraviroc effectively protects against GVHD by modulating alloreactive donor T-cell responses, and that CXCR3 signaling may be an important resistance mechanism to CCR5 blockade in GVHD.

GDC-0425 [5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c9]dipyridine-6-carbonitrile] is an orally bioavailable small-molecule inhibitor of checkpoint kinase 1 that was investigated as a novel cotherapy to potentiate chemotherapeutic drugs, such as gemcitabine. In a radiolabeled absorption, distribution, metabolism, and excretion study in Sprague-Dawley rats, trace-level but long-lived 14C-labeled thiocyanate was observed in circulation. This thiocyanate originated from metabolic decyanation of GDC-0425 and rapid conversion of cyanide to thiocyanate. Excretion studies indicated decyanation was a minor metabolic pathway, but placing 14C at nitrile magnified its observation. Cytochrome P450s catalyzed the oxidative decyanation reaction in vitro when tested with liver microsomes, and in the presence of 18O2, one atom of 18O was incorporated into the decyanated product. To translate this finding to a clinical risk assessment, the total circulating levels of thiocyanate (endogenous plus drug-derived) were measured following repeated administration of GDC-0425 to rats and cynomolgus monkeys. No overt increases were observed with thiocyanate concentrations of 121–154 µM in rats and 71–110 µM in monkeys receiving vehicle and all tested doses of GDC-0425. These findings were consistent with results from the radiolabel rat study where decyanation accounted for conversion of

11 pages, 5 figures, 1 appendix, Streams are typically supersaturated in carbon dioxide (CO) and methane (CH), and are recognized as important components of regional carbon (C) emissions in northern landscapes. Whereas there is consensus that in most of the systems the CO emitted by streams represents C fixed in the terrestrial ecosystem, the pathways delivering this C to streams are still not well understood. We assessed the contribution of direct soil CO injection versus the oxidation of soil-derived dissolved organic C (DOC) and CH in supporting CO supersaturation in boreal streams in Québec. We measured the concentrations of CO, CH and DOC in 43 streams and adjacent soil waters during summer base-flow period. A mass balance approach revealed that all three pathways are significant, and that the mineralization of soil-derived DOC and CH accounted for most of the estimated stream CO emissions (average 75% and 10%, respectively), and that these estimated contributions did not change significantly between the studied low order (≤ 3) streams. Whereas some of these transformations take place in the channel proper, our results suggest that they mainly occur in the hyporheic zones of the streams. Our results further show that stream CH emissions can be fully explained by soil CH inputs. This study confirms that these boreal streams, and in particular their hyporheic zones, are extremely active processors of soil derived DOC and CH, not just vents for soil produced CO, This study was co-funded by the Natural Sciences and Engineering Research Council of Canada and Hydro-Québec Industrial Research Chair in Carbon Biogeochemistry in Boreal Aquatic Systems (NSERC Grant #592000)

This study aims to investigate the effect of the potential window on heat generation in carbon-based electrical double layer capacitors (EDLCs) with ionic-liquid (IL)-based electrolytes using in operando calorimetry. The EDLCs consisted of two identical activated-carbon electrodes with either neat 1-butyl-1-methylpyrrolidinium bis(trifluoromethane-sulfonyl)imide ([Pyr14 ][TFSI]) electrolyte or 1.0 m [Pyr14 ][TFSI] in propylene carbonate (PC) as electrolyte. The instantaneous heat generation rate at each electrode was measured under galvanostatic cycling for different potential windows ranging from 1 to 4 V. First, the heat generation rates at the positive and negative electrodes differed significantly in neat IL owing to the differences in the ion sizes and diffusion coefficients. However, these differences were minimized when the IL was diluted in PC. Second, for EDLC in neat [Pyr14 ][TFSI] at high potential window (4 V), a pronounced endothermic peak was observed at the beginning of the charging step at the positive electrode owing to TFSI- intercalation in the activated carbon. On the other hand, for EDLC in 1.0 m [Pyr14 ][TFSI] in PC at potential window above 3 V, an endothermic peak was observed only at the negative electrode owing to the decomposition of PC. Third, for both neat and diluted [Pyr14 ][TFSI] electrolytes, the irreversible heat generation rate increased with increasing potential window and exceeded Joule heating. This was attributed to the effect of potential-dependent charge redistribution resistance. A further increase in the irreversible heat generation rate was observed for the largest potential windows owing to the degradation of the PC solvent. Finally, for both types of electrolyte, the reversible heat generation rate increased with increasing potential window because of the increase in the amount of ion adsorbed/desorbed at the electrode/electrolyte interface.

Uridine diphosphate glucuronosyltransferases (UGTs) catalyze glucuronidation to facilitate systemic and local clearance of numerous chemicals and drugs. To investigate whether UGT expression is coregulated in human liver, we analyzed the protein expression of UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 3A1, and 3A2 using western blots from 164 healthy human liver samples, comparing expression with age and sex. UGT1A6 levels were significantly higher in children than adults, and UGT3A1 and 3A2 expression significantly increased with age from childhood to age65 yearas. In children aged18 years, UGT1A4/1A9 protein expression was significantly correlated, but not for adults aged18 years. UGT1A3 expression was always significantly correlated with other UGT1A isoforms in all adults aged18 years. In individuals aged ≥12 years, expression of UGT1A1/1A4, UGT1A1/1A6, UGT1A1/1A9, and UGT1A4/1A6 significantly correlated, which was not observed in children aged12 years. In contrast, UGT1A4/2B7 showed significant correlation in children aged12 years, but not in individuals aged ≥12 years, and this was observed in female but not male individuals. Expression of UGT1A6/1A9 and UGT3A1/3A2 correlated in the entire sample population, but UGT3As did not correlate with other UGTs. These correlations were sex dependent, as UGT1A3/1A1, UGT1A4/2B7 and UGT3A1/3A2 correlated more highly in male than female individuals, while UGT1A4/1A6 protein correlated more significantly in female than male individuals. This is the first report on the ontogeny of UGT3A isoforms, showing maximal expression in the elderly, and is the first demonstration that UGT isoforms commonly coexpress in vivo, in both age-dependent and sex-dependent manners.

Background Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer. Materials and methods Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS. Results Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy. Conclusion Regorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control. Implications for practice Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.

We investigate a previously unobserved phase transition in an organic co-crystal containing the olefin trans-1,2-bis(4-pyridyl)ethylene. The olefin undergoes molecular motion in the crystalline state, and converts from a disordered to ordered phase upon cooling. Ordering causes a unit cell change to occur via a reversible single-crystal-to-single-crystal (SCSC) transformation. The ordered phase is only accessed via slow cooling; flash cooling locks the crystal in a kinetically trapped, disordered state, and SCSC reversibility is lost. The common practice of flash cooling may inhibit access to thermodynamic products and unique phases.

This study investigates the effect of temperature on the heat generation and the associated electrochemical phenomena occurring in IL-based EDLCs. The EDLCs consisted of two identical activated carbon electrodes with neat Pyr14TFSI or Pyr14TFSI diluted in propylene carbonate (PC) as electrolytes. The instantaneous heat generation rate at each electrode was measured by isothermal calorimetry between 5 and 80 °C under constant current cycling and potential window of 2.5 V.First, the instantaneous heat generation rate was similar at each electrode in neat IL. However, it was smaller at the negative electrode in diluted IL and featured endothermic dips growing with increasing temperature > 40 °C due to overscreening effects, ion desolvation, and/or decomposition of PC. The irreversible heat generation was similar in each half-cell and decreased with increasing temperature due to the reduction in internal resistance, particularly with neat IL. The irreversible heat generation exceeded Joule heating in all cases, especially at high temperature and low current. This was attributed to ion desorption and charge redistribution in the porous electrodes. Finally, the reversible heat generation for both electrolytes was larger at the positive than at the negative electrode due to the difference in anion and cation sizes.

Metal phosphate compounds are considered promising candidates as positive electrode materials for Na-ion batteries because they offer higher cation-insertion potentials than analogous metal oxides. One such example is sodium iron fluorophosphate (Na2FePO4F), a compound that is typically synthesized by high-temperature solid-state routes. In this study, we prepare phase-pure Na2FePO4F using the polyol route, a low-temperature process that allows for the synthesis of nanoparticles (15–25 nm), a form that enhances Na-ion insertion kinetics and cycling stability. We then apply two methods to enhance the electronic conductivity of Na2FePO4F: (i) converting residual organic byproducts of the polyol synthesis to conductive carbon coatings; and (ii) preparing a nanocomposite with reduced graphene oxide. The resulting electrode materials are characterized in nonaqueous Na-ion electrolytes, assessing such metrics as specific capacity, rate capability, and cycling stability. A thorough electrochemical kinetics analysis is performed to deconvolve surface-vs.-bulk Na-ion insertion as a function of composite structure. Specific capacities between 60–110 mA h g−1 were achieved in galvanostatic charge–discharge tests when cycling in the range from 10C to C/10, respectively.

The solvent-free formation and purification of the photoproduct rctt-tetrakis(4-pyridyl)cyclobutane has been achieved using 1,2-dibromo-4,5-difluorobenzene as the template. Dry vortex grinding yielded the photoreactive co-crystal. During the [2 + 2] cycloaddition reaction, the template readily sublimes resulting in virtually pure photoproduct in a completely solvent-free approach.

Aqueous-processed aluminum oxide phosphate (AlPO) dielectric films were studied to determine how water desorbs and absorbs on heating and cooling, respectively. In-situ Fourier transform infrared spectroscopy showed a distinct, reversible mono- to bidentate phosphate structural change associated with water loss and uptake. Temperature programmed desorption measurements on a 1-μm thick AlPO film revealed water sorption was inhibited by an aqueous-processed HfO2 capping film only 11-nm thick. The HfO2 capping film prevents water resorption, thereby preserving the exceptional performance of AlPO as a thin-film dielectric.

Prisoners bear much of the burden of the hepatitis C epidemic in the United States. Yet little is known about the scope and cost of treating hepatitis C in state prisons-particularly since the release of direct-acting antiviral medications. In the forty-one states whose departments of corrections reported data, 106,266 inmates (10 percent of their prisoners) were known to have hepatitis C on or about January 1, 2015. Only 949 (0.89 percent) of those inmates were being treated. Prices for a twelve-week course of direct-acting antivirals such as sofosbuvir and the combination drug ledipasvir/sofosbuvir varied widely as of September 30, 2015 ($43,418-$84,000 and $44,421-$94,500, respectively). Numerous corrections departments received smaller discounts than other government agencies did. To reduce the hepatitis C epidemic, state governments should increase funding for treating infected inmates. State departments of corrections should consider collaborating with other government agencies to negotiate discounts with pharmaceutical companies and with qualified health care facilities to provide medications through the federal 340B Drug Discount Program. Helping inmates transition to providers in the community upon release can enhance the gains achieved by treating hepatitis C in prison.

A new lab-based aerosol jet fog (ajFOG) deposition system with an atomizer consisting of two opposing jets located within the deposition chamber is introduced and its capabilities are examined. The unique opposing configuration of the atomizer enables the formation of a highly uniform fog even from low volatility precursors. Aluminum oxide phosphate (AlPO) thin films were deposited onto Si wafers at room temperature and sub-atmospheric pressure by using an aqueous precursor. Films were characterized by spectroscopic ellipsometry, x-ray diffraction and reflectivity, scanning electron microscopy, and metal/oxide/semiconductor (MOS) capacitor electrical measurements. Film thickness uniformity, density, surface roughness, and charge transport mechanisms were found to be comparable to spin-coated thin films deposited using the same precursor, demonstrating the effectiveness of this aerosol technique. A process model was developed to predict film thickness as a function of precursor concentration, exposure time, fog settling time, and number of exposures.

Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule-targeting drug eribulin on different stages of metastasis in triple-negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells, providing foundation for the combination therapy. Mechanistically, AURKA inhibition induces cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. These preclinical data provide a new understanding of the mechanisms by which MLN8237 mediates its antimetastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early-stage solid tumors. Mol Cancer Ther; 15(8); 1809–22. ©2016 AACR.

The symmetrical octafluoro stilbene trans -1,2-bis(2,3,5,6-tetrafluorophenyl)ethylene ( 1 ) undergoes a stereoselective and quantitative [2 + 2] photodimerization in the solid state. The olefin self-assembles via C-H⋯F and face-to-face interactions of the fluorinated phenyl rings into a geometry for a topochemical photodimerization. The crystal structure and stereochemistry of the photoproduct rctt -1,2,3,4-tetrakis(2,3,5,6-tetrafluorophenyl)cyclobutane ( 2 ) has been determined.

1. The absorption, metabolism and excretion of cobimetinib, an allosteric inhibitor of MEK1/2, was characterized in mass balance studies following single oral administration of radiolabeled (14C) cobimetinib to Sprague–Dawley rats (30 mg/kg) and Beagle dogs (5 mg/kg).2. The oral dose of cobimetinib was well absorbed (81% and 71% in rats and dogs, respectively). The maximal plasma concentrations for cobimetinib and total radioactivity were reached at 2–3 h post-dose. Drug-derived radioactivity was fully recovered (∼90% of the administered dose) with the majority eliminated in feces via biliary excretion (78% of the dose for rats and 65% for dogs). The recoveries were nearly complete after the first 48 h following dosing.3. The metabolic profiles indicated extensive metabolism of cobimetinib prior to its elimination. For rats, the predominant metabolic pathway was hydroxylation at the aromatic core. Lower exposures for cobimetinib and total radioactivity were observed in male rats compared with fema...

The reaction path from aqueous oxohydroxometalate [(CH3)4N]6[H2Ta6O19]·xH2O to Ta2O5 thin film explains observed thin-film morphological characteristics–high density, uniform, pore free, and smooth. Film dehydration and tetramethylammonium thermal decomposition were observed via temperature-programmed desorption. The morphological, structural, and optical properties of the films were examined by X-ray diffraction, X-ray reflectivity, scanning electron microscopy, transmission electron microscopy, atomic force microscopy, and spectroscopic ellipsometry. Evolution of (CH3)4N+ reaction products in concert with condensation of the polyoxometalate clusters and structural relaxation led to film densities as high as 95% of single-crystal β-Ta2O5. The process enabled film deposition with single-digit-nanometer thickness.

During viral RNA synthesis by the viral RNA-dependent RNA polymerase (vRdRp) of vesicular stomatitis virus, the sequestered RNA genome must be released from the nucleocapsid in order to serve as the template. Unveiling the sequestered RNA by interactions of vRdRp proteins, the large subunit (L) and the phosphoprotein (P), with the nucleocapsid protein (N) must not disrupt the nucleocapsid assembly. We noticed that a flexible structural motif composed of an α-helix and a loop in the N protein may act as the access gate to the sequestered RNA. This suggests that local conformational changes in this structural motif may be induced by interactions with the polymerase to unveil the sequestered RNA, without disrupting the nucleocapsid assembly. Mutations of several residues in this structural motif—Glu169, Phe171, and Leu174—to Ala resulted in loss of viral RNA synthesis in a minigenome assay. After implementing these mutations in the viral genome, mutant viruses were recovered by reverse genetics and serial passages. Sequencing the genomes of the mutant viruses revealed that compensatory mutations in L, P, and N were required to restore the viral viability. Corresponding mutations were introduced in L, P, and N, and their complementarity to the N mutations was confirmed by the minigenome assay. Introduction of the corresponding mutations is also sufficient to rescue the mutant viruses. These results suggested that the interplay of the N structural motif with the L protein may play a role in accessing the nucleotide template without disrupting the overall structure of the nucleocapsid. IMPORTANCE During viral RNA synthesis of a negative-strand RNA virus, the viral RNA-dependent RNA polymerase (vRdRp) must gain access to the sequestered RNA in the nucleocapsid to use it as the template, but at the same time may not disrupt the nucleocapsid assembly. Our structural and mutagenesis studies showed that a flexible structural motif acts as a potential access gate to the sequestered RNA and plays an essential role in viral RNA synthesis. Interactions of this structural motif within the vRdRp may be required for unveiling the sequestered RNA. This mechanism of action allows the sequestered RNA to be released locally without disrupting the overall structure of the nucleocapsid. Since this flexible structural motif is present in the N proteins of many NSVs, release of the sequestered RNA genome by local conformational changes in the N protein may be a general mechanism in NSV viral RNA synthesis.

Negative-strand RNA viruses (NSVs) include some of the most pathogenic human viruses known. NSVs completely rely on the host cell for protein translation, but their codon usage bias is often different from that of the host. This discrepancy may have originated from the unique mechanism of NSV RNA synthesis in that the genomic RNA sequestered in the nucleocapsid serves as the template. The stability of the genomic RNA in the nucleocapsid appears to regulate its accessibility to the viral RNA polymerase, thus placing constraints on codon usage to balance viral RNA synthesis. By in situ analyses of vesicular stomatitis virus RNA synthesis, specific activities of viral RNA synthesis were correlated with the genomic RNA sequence. It was found that by simply altering the sequence and not the amino acid that it encoded, a significant reduction, up to an ∼750-fold reduction, in viral RNA transcripts occurred. Through subsequent sequence analysis and thermal shift assays, it was found that the purine/pyrimidine content modulates the overall stability of the polymerase complex, resulting in alteration of the activity of viral RNA synthesis. The codon usage is therefore constrained by the obligation of the NSV genome for viral RNA synthesis. IMPORTANCE Negative-strand RNA viruses (NSVs) include the most pathogenic viruses known. New methods to monitor their evolutionary trends are urgently needed for the development of antivirals and vaccines. The protein translation machinery of the host cell is currently recognized as a main genomic regulator of RNA virus evolution, which works especially well for positive-strand RNA viruses. However, this approach fails for NSVs because it does not consider the unique mechanism of their viral RNA synthesis. For NSVs, the viral RNA-dependent RNA polymerase (vRdRp) must gain access to the genome sequestered in the nucleocapsid. Our work suggests a paradigm shift that the interactions between the RNA genome and the nucleocapsid protein regulate the activity of vRdRp, which selects codon usage.

Polyamides have been shown to bind double-stranded DNA by complementing the curvature of the minor groove and forming various hydrogen bonds with DNA. Several polyamide molecules have been found to have potent antiviral activities against papillomavirus, a double-stranded DNA virus. By analogy, we reason that polyamides may also interact with the structured RNA bound in the nucleocapsid of a negative-strand RNA virus. Vesicular stomatitis virus (VSV) was selected as a prototype virus to test this possibility since its genomic RNA encapsidated in the nucleocapsid forms a structure resembling one strand of an A-form RNA duplex. One polyamide molecule, UMSL1011, was found to inhibit infection of VSV. To confirm that the polyamide targeted the nucleocapsid, a nucleocapsid-like particle (NLP) was incubated with UMSL1011. The encapsidated RNA in the polyamide-treated NLP was protected from thermo-release and digestion by RNase A. UMSL1011 also inhibits viral RNA synthesis in the intracellular activity assay for the viral RNA-dependent RNA polymerase. The crystal structure revealed that UMSL1011 binds the structured RNA in the nucleocapsid. The conclusion of our studies is that the RNA in the nucleocapsid is a viable antiviral target of polyamides. Since the RNA structure in the nucleocapsid is similar in all negative-strand RNA viruses, polyamides may be optimized to target the specific RNA genome of a negative-strand RNA virus, such as respiratory syncytial virus and Ebola virus. IMPORTANCE Negative-strand RNA viruses (NSVs) include several life-threatening pathogens, such as rabies virus, respiratory syncytial virus, and Ebola virus. There are no effective antiviral drugs against these viruses. Polyamides offer an exceptional opportunity because they may be optimized to target each NSV. Our studies on vesicular stomatitis virus, an NSV, demonstrated that a polyamide molecule could specifically target the viral RNA in the nucleocapsid and inhibit viral growth. The target specificity of the polyamide molecule was proved by its inhibition of thermo-release and RNA nuclease digestion of the RNA bound in a model nucleocapsid, and a crystal structure of the polyamide inside the nucleocapsid. This encouraging observation provided the proof-of-concept rationale for designing polyamides as antiviral drugs against NSVs.

In the face of increasing drug resistance and the rapidly increasing necessity for practicality in clinical settings, drugs targeting different viral proteins are needed in order to control influenza A and B. A small molecule that tenaciously adheres to the PB2cap binding domain, part of the heterotrimeric RNA polymerase machinery of influenza A virus and influenza B virus, is a promising drug candidate. Understanding the anatomic behavior of PB2cap upon ligand binding will aid in the development of a more robust inhibitor. In this report, the anatomic behavior of the influenza A virus PB2cap domain is established by solving the crystal structure of native influenza A virus PB2cap at 1.52 Å resolution. By comparing it with the ligand-bound structure, the dissociation and rotation of the ligand-binding domain in PB2cap from the C-terminal domain is identified. This domain movement is present in many PB2cap structures, suggesting its functional relevance for polymerase activity.

Co-crystallization of a symmetrical azo bipyridine with isosteric resorcinols affords isostructural co-crystals that exhibit linear thermal expansion along each axis. The thermal expansions involve interplay between intra-layer halogen and hydrogen bonds.

Information on what aerosol particle types are the major sources of ice nucleating particles (INPs) in the atmosphere is needed for climate predictions. To determine which aerosol particles are the major sources of immersion-mode INPs at a coastal site in Western Canada, we investigated correlations between INP number concentrations and both concentrations of different atmospheric particles and meteorological conditions. We show that INP number concentrations are strongly correlated with the number concentrations of fluorescent bioparticles between −15 and −25 °C, and that the size distribution of INPs is most consistent with the size distribution of fluorescent bioparticles. We conclude that biological particles were likely the major source of ice nuclei at freezing temperatures between −15 and −25 °C at this site for the time period studied. At −30 °C, INP number concentrations are also well correlated with number concentrations of the total aerosol particles ≥ 0.5 μm, suggesting that non-biological particles may have an important contribution to the population of INPs active at this temperature. As we found that black carbon particles were unlikely to be a major source of ice nuclei during this study, these non-biological INPs may include mineral dust. Furthermore, correlations involving chemical tracers of marine aerosols and marine biological activity, sodium and methanesulfonic acid, indicate that the majority of INPs measured at the coastal site likely originated from terrestrial rather than marine sources. Finally, six existing empirical parameterizations of ice nucleation were tested to determine if they accurately predict the measured INP number concentrations. We found that none of the parameterizations selected are capable of predicting INP number concentrations with high accuracy over the entire temperature range investigated. This finding illustrates that additional measurements are needed to improve parameterizations of INPs and their subsequent climatic impacts.