bluuebunny/crossref_metadata_2025 huggingface dataset:
An ionic–chemical–mechanical model for muscle contraction
Authors: Manning Gerald S.
Published: September 2016

The dynamic process underlying muscle contraction is the parallel sliding of thin actin filaments along an immobile thick myosin fiber powered by oar‐like movements of protruding myosin cross bridges (myosin heads). The free energy for functioning of the myosin nanomotor comes from the hydrolysis of ATP bound to the myosin heads. The unit step of translational movement is based on a mechanical‐chemical cycle involving ATP binding to myosin, hydrolysis of the bound ATP with ultimate release of the hydrolysis products, stress‐generating conformational changes in the myosin cross bridge, and relief of built‐up stress in the myosin power stroke. The cycle is regulated by a transition between weak and strong actin–myosin binding affinities. The dissociation of the weakly bound complex by addition of salt indicates the electrostatic basis for the weak affinity, while structural studies demonstrate that electrostatic interactions among negatively charged amino acid residues of actin and positively charged residues of myosin are involved in the strong binding interface. We therefore conjecture that intermediate states of increasing actin–myosin engagement during the weak‐to‐strong binding transition also involve electrostatic interactions. Methods of polymer solution physics have shown that the thin actin filament can be regarded in some of its aspects as a net negatively charged polyelectrolyte. Here we employ polyelectrolyte theory to suggest how actin–myosin electrostatic interactions might be of significance in the intermediate stages of binding, ensuring an engaged power stroke of the myosin motor that transmits force to the actin filament, and preventing the motor from getting stuck in a metastable pre‐power stroke state. We provide electrostatic force estimates that are in the pN range known to operate in the cycle.
Metabolic flux analysis of carbon balance in Lactobacillus strains
Authors: Zhang Yixing , Zeng Fan , Hohn Keith , Vadlani Praveen V.
Published: September 2016

Metabolic flux analyses were performed based on the carbon balance of six different Lactobacillus strains used in this study. Results confirmed that L. delbrueckii, L. plantarum ATCC 21028, L. plantarum NCIMB 8826 ΔldhL1, L. plantarum NCIMB 8826 ΔldhL1‐pCU‐PxylAB, and L. plantarum NCIMB 8826 ΔldhL1‐pLEM415‐xylAB metabolized glucose via EMP: whereas, L. brevis metabolized glucose via PK pathway. Xylose was metabolized through the PK pathway in L. brevis, L. plantarum NCIMB 8826 ΔldhL1‐pCU‐PxylAB and L. plantarum NCIMB 8826 ΔldhL1‐pLEM415‐xylAB. Operation of both EMP and PK pathways was found in L. brevis, L. plantarum NCIMB 8826 ΔldhL1‐pCU‐PxylAB, and L. plantarum NCIMB 8826 ΔldhL1‐pLEM415‐xylAB when glucose plus xylose were used as carbon source. The information of detailed carbon flow may help the strain and biomass selection in a designed process of lactic acid biosynthesis. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1397–1403, 2016
Gels prepared from egg yolk and its fractions for tissue engineering
Authors: Rodil Andrea , Laca Amanda , Paredes Benjamín , Rendueles Manuel , Meana Álvaro , Díaz Mario
Published: September 2016

New biomaterials prepared from egg yolk and its main fractions (plasma and granules) have been developed for use in tissue engineering. Protein gels obtained via transglutaminase cross‐linking were characterized by rheometry, texturometry and scanning electron microscopy. All the gels exhibited suitable physical and mechanical characteristics for use as potential biomaterials in skin regeneration. Specifically, results showed that these materials presented a compact, uniform structure, with granular gel being found to be the most resistant as well as the most elastic material. Accordingly, these gels were subsequently evaluated as scaffolds for murine fibroblast growth. The best results were obtained with granule gels. Not only adhesion and cell growth were detected when using these gels, but also continuous coatings of cells growing on their surface. These findings can be attributed to the higher protein content of this fraction and to the particular structure of its proteins. Thus, granules have proved to be an interesting potential raw material for scaffold development. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1577–1583, 2016
Understanding and modeling retention of mammalian cells in fluidized bed centrifuges
Authors: Kelly William , Rubin Jonathan , Scully Jennifer , Kamaraju Hari , Wnukowski Piotr , Bhatia Ravinder
Published: September 2016

Within the last decade, fully disposable centrifuge technologies, fluidized‐bed centrifuges (FBC), have been introduced to the biologics industry. The FBC has found a niche in cell therapy where it is used to collect, concentrate, and then wash mammalian cell product while continuously discarding centrate. The goal of this research was to determine optimum FBC conditions for recovery of live cells, and to develop a mathematical model that can assist with process scaleup. Cell losses can occur during bed formation via flow channels within the bed. Experimental results with the kSep400 centrifuge indicate that, for a given volume processed: the bed height (a bed compactness indicator) is affected by RPM and flowrate, and dead cells are selectively removed during operation. To explain these results, two modeling approaches were used: (i) equating the centrifugal and inertial forces on the cells (i.e., a force balance model or FBM) and (ii) a two‐phase computational fluid dynamics (CFD) model to predict liquid flow patterns and cell retention in the bowl. Both models predicted bed height vs. time reasonably well, though the CFD model proved more accurate. The flow patterns predicted by CFD indicate a Coriolis‐driven flow that enhances uniformity of cells in the bed and may lead to cell losses in the outflow over time. The CFD‐predicted loss of viable cells and selective removal of the dead cells generally agreed with experimental trends, but did over‐predict dead cell loss by up to 3‐fold for some of the conditions. © 2016 American Institute of Chemical EngineersBiotechnol. Prog., 32:1520–1530, 2016
Dabigatran antagonizes growth, cell‐cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines
Authors: Vianello Fabrizio , Sambado Luisa , Goss Ashley , Fabris Fabrizio , Prandoni Paolo
Published: September 2016

Thrombin activates its G‐coupled seven transmembrane protease‐activated receptor (PAR‐1) by cleaving the receptor's N‐terminal end. In several human cancers, PAR1 expression and activation correlates with tumor progression and metastatization. This provides compelling evidence for the effectiveness of an appropriate antithrombin agent for the adjuvant treatment of patients with cancer. Dabigatran is a selective direct thrombin inhibitor that reversibly binds to thrombin. In this study, we aimed to explore if dabigatran may affect mechanisms favoring tumor growth by interfering with thrombin‐induced PAR‐1 activation.

We confirmed that exposure of tumor cells to thrombin significantly increased cell proliferation and this was coupled with downregulation of p27 and concomitant induction of cyclin D1. Dabigatran was consistently effective in antagonizing thrombin‐induced proliferation as well as it restored the baseline pattern of cell cycle protein expression. Thrombin significantly upregulated the expression of proangiogenetic proteins like Twist and GRO‐α in human umbilical vascular endothelial cells (HUVEC) cells and their expression was significantly brought down to control levels when dabigatran was added to culture. We also found that the chemoattractant effect of thrombin on tumor cells was lost in the presence of dabigatran, and that the thrombin antagonist was effective in dampening vascular tube formation induced by thrombin. Our data support a role of thrombin in inducing the proliferation, migration, and proangiogenetic effects of tumor cells in vitro. Dabigatran has activity in antagonizing all these effects, thereby impairing tumor growth and progression. In vivo models may help to understand the relevance of this pathway.
Chemodiversity Associated with Cytotoxicity and Antimicrobial Activity ofPiper aduncumvar.ossanum
Authors: Gutiérrez Yamilet , Montes Rodny , Scull Ramón , Sánchez Arturo , Cos Paul , Monzote Lianet , Setzer William N.
Published: September 2016

Chemical analysis, antimicrobial activity and cytotoxic effects of essential oils (EOs) from leaves ofPiper aduncumvar.ossanumfrom two localities Bauta (EO‐B) and Ceiba (EO‐C), Artemisa Province, Cuba, were determined.EOs were obtained by hydrodistillation and analyzed by gas chromatography/mass spectrometry.EO‐B demonstrated higher activity againstS. aureusandL. amazonensis; while a lower cytotoxicity on mammalian cells was observed. BothEOs displayed the same activity againstPlasmodium falciparum,Trypanosoma cruzi,Trypanosoma brucei, andLeishmania infantum. BothEOs were inactive againstEscherichia coliandCandida albicans.
Importance of a Conserved Lys/Arg Residue for Ligand/PDZ Domain Interactions as Examined by Protein Semisynthesis
Authors: Pedersen Søren W. , Moran Griffin E. , Sereikaitė Vita , Haugaard‐Kedström Linda M. , Strømgaard Kristian
Published: September 2016

PDZ domains are ubiquitous small protein domains that are mediators of numerous protein–protein interactions, and play a pivotal role in protein trafficking, synaptic transmission, and the assembly of signaling‐transduction complexes. In recent years, PDZ domains have emerged as novel and exciting drug targets for diseases (in the brain in particular), so understanding the molecular details of PDZ domain interactions is of fundamental importance. PDZ domains bind to a protein partner at either a C‐terminal peptide or internal peptide motifs. Here, we examined the importance of a conserved Lys/Arg residue in the ligand‐binding site of the second PDZ domain of PSD‐95, by employing a semisynthetic approach. We generated six semisynthetic PDZ domains comprising different proteogenic and nonproteogenic amino acids representing subtle changes of the conserved Lys/Arg residue. These were tested with four peptide interaction partners, representing the two different binding modes. The results highlight the role of a positively charged amino acid in the β1–β2 loop of PDZ domains, and show subtle differences for canonical and noncanonical interaction partners, thus providing additional insight into the mechanism of PDZ/ligand interaction.
MiR‐21 inhibitor suppressed the progression of retinoblastoma via the modulation of PTEN/PI3K/AKT pathway
Authors: Gui Fu , Hong Zhengdong , You Zhipeng , Wu Hongxi , Zhang Yulan
Published: September 2016

MicroRNA‐21 (miR‐21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR‐21 in retinoblastoma (RB). In this study, we examined the expression of miR‐21 in RB tissues and explored the relationship between miR‐21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol‐3‐OH kinase (PI3K)/AKT signal. Quantitative real‐time PCR (qRT‐PCR) results showed that the level of miR‐21 in RB tissues was higher than that in retinal normal tissues. In Weri‐Rb‐1 cells, miR‐21 inhibitor suppressed the expression of miR‐21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl‐2. Meanwhile, miR‐21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p‐AKT. Taken together, miR‐21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR‐21 functioning in the progression of RB and provided a new means for cell therapy in RB.
Zeolite Beta Formation from Clear Sols: Silicate Speciation, Particle Formation and Crystallization Monitored by Complementary Analysis Methods
Authors: Castro Maria , Haouas Mohamed , Lim Ivy , Bongard Hans J. , Schüth Ferdi , Taulelle Francis , Karlsson Gunnel , Alfredsson Viveka , Breyneart Eric , Kirschhock Christine E. A. , Schmidt Wolfgang
Published: September 2016

The formation of silicate nanoaggregates (NAs) at the very early stages of precursor sols and zeolite beta crystallization from silicate nanoparticles (NPs) are investigated in detail using a combination of different analysis methods, including liquid‐state 29Si, 27Al, 14N, and 1H NMR spectroscopy, mass spectrometry (MS), small‐angle X‐ray scattering (SAXS), X‐ray diffraction (XRD), and transmission electron microscopy at cryogenic temperatures (cryo‐TEM). Prior to hydrothermal treatment, silicate NAs are observed if the Si/OH ratio in the reaction mixture is greater than 1. Condensation of oligomers within the NAs then generates NPs. Aluminum doped into the synthesis mixtures is located exclusively in the NPs, and is found exclusively in a state that is fourfold connected to silicate, favoring their condensation and aggregation. These results are in agreement with general trends observed for other systems. Silicate NAs are essential intermediates for zeolite formation and are generated by the aggregation of hydrated oligomers, aluminate, and templating cations. Subsequent further intra‐nanoaggregate silicate condensation results in the formation of NPs. 1H and 14N liquid NMR as well as diffusion ordered spectroscopy (DOSY) experiments provide evidence for weakly restricted rotational and translational mobility of the organic template within NAs as a consequence of specific silicate–template interactions. NAs thus appear as key species in clear sols, and their presence in the precursor sol favors silicate condensation and further crystallization, promoted either by increasing the Si/OH ratio or by heating.
Asymmetric Diels–Alder Reaction of α‐Substituted and β,β‐Disubstituted α,β‐Enals via Diarylprolinol Silyl Ether for the Construction of All‐Carbon Quaternary Stereocenters
Authors: Hayashi Yujiro , Bondzic Bojan P. , Yamazaki Tatsuya , Gupta Yogesh , Ogasawara Shin , Taniguchi Tohru , Monde Kenji
Published: September 2016

The asymmetric Diels–Alder reaction of α‐substituted acrolein proceeds in the presence of the trifluoroacetic acid salt of trifluoromethyl‐substituted diarylprolinol silyl ether to afford the exo‐isomer with both excellent diastereoselectivity and high enantioselectivity. In the Diels–Alder reaction of a β,β‐disubstituted α,β‐unsaturated aldehyde, good exo‐selectivity and excellent enantioselectivity was obtained when the perchloric acid salt of the bulky triisopropyl silyl ether of trifluoromethyl substituted diarylprolinol was employed as an organocatalyst in the presence of water. In both cases, all‐carbon quaternary stereocenters are constructed enantioselectively.
Characterization of G‐Quadruplex/Hairpin Transitions of RNAs by 19F NMR Spectroscopy
Authors: Granqvist Lotta , Virta Pasi
Published: September 2016

2′‐O‐[(4‐Trifluoromethyl‐triazol‐1‐yl)methyl] reporter groups have been incorporated into guanosine‐rich RNA models (including a known bistable Qd/Hp RNA and two G‐rich regions of mRNA of human prion protein, PrP) and applied for the 19F NMR spectroscopic characterization of plausible G‐quadruplex/hairpin (Qd/Hp) transitions in these RNA structures. For the synthesis of the CF3‐labeled RNAs, phosphoramidite building blocks of 2′‐O‐[(4‐CF3‐triazol‐1‐yl)methyl] nucleosides (cytidine, adenosine, and guanosine) were prepared and used as an integral part of the standard solid‐phase RNA synthesis. The obtained 19F NMR spectra supported the usual characterization data (obtained by UV‐ and CD‐melting profiles and by 1H NMR spectra of the imino regions) and additionally gave more detailed information on the Qd/Hp transitions. The molar fractions of the secondary structural species (Qd, Hp) upon thermal denaturation and under varying ionic conditions could be determined from the intensities and shifts of the 19F NMR signals. For a well‐behaved Qd/Hp transition, thermodynamic parameters could be extracted.
Differential impact of minimal residual disease negativity according to the salvage status in patients with relapsed/refractory B‐cell acute lymphoblastic leukemia
Authors: Jabbour Elias , Short Nicholas J. , Jorgensen Jeffrey L. , Yilmaz Musa , Ravandi Farhad , Wang Sa A. , Thomas Deborah A. , Khoury Joseph , Champlin Richard E. , Khouri Issa , Kebriaei Partow , O'Brien Susan M. , Garcia‐Manero Guillermo , Cortes Jorge E. , Sasaki Koji , Dinardo Courtney D. , Kadia Tapan M. , Jain Nitin , Konopleva Marina , Garris Rebecca , Kantarjian Hagop M.
Published: September 2016

BACKGROUND

Minimal residual disease (MRD) assessment predicts survival for patients with newly diagnosed acute lymphoblastic leukemia (ALL). Its significance in relapsed/refractory ALL is less clear.

METHODS

This study identified 78 patients with relapsed/refractory B‐cell ALL who achieved a morphologic response with inotuzumab ozogamicin (n = 41), blinatumomab (n = 11), or mini‐hyperfractionated cyclophosphamide, vincristine, and doxorubicin plus inotuzumab (n = 26) during either salvage 1 (S1; n = 46) or salvage 2 (S2; n = 32) and had undergone an MRD assessment by multiparameter flow cytometry at the time of remission.

RESULTS

MRD negativity was achieved in 41 patients overall (53%). The MRD negativity rate was 57% in S1 and 47% in S2. Among patients in S1, achieving MRD negativity was associated with longer event‐free survival (EFS; median, 18 vs 7 months; 2‐year EFS rate, 46% vs 17%; P = .06) and overall survival (OS; median, 27 vs 9 months; 2‐year OS, 52% vs 36%; P = .15). EFS and OS were similar in S2, regardless of the MRD response. Among MRD‐negative patients who underwent allogeneic stem cell transplantation (SCT), EFS and OS were superior for those who underwent SCT in S1 rather than S2 (P = .003 and P = .04, respectively). Patients in S1 who achieved MRD negativity and subsequently underwent SCT had the best outcomes with a 2‐year OS rate of 65%.

CONCLUSIONS

Patients with relapsed/refractory ALL who achieve MRD negativity in S1 can have long‐term survival. Patients in S2 generally have poor outcomes, regardless of their MRD status. Cancer 2017;123:294–302. © 2016 American Cancer Society.
Targeted therapy in endometrial cancer: Making progress
Authors: Mutch David G.
Published: September 2016

The most promising avenue for treating cancers that progress after standard chemotherapy regimens is targeted therapy, in which drugs are chosen to disrupt specific pathways known to be important in disease progression. Significant progress is being made in targeted therapies as we gain understanding of the molecular basis of the cancers we treat. See also pages 3519–28.
A multicenter, single‐arm, open‐label, phase 2 study of apitolisib (GDC‐0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study)
Authors: Makker Vicky , Recio Fernando O. , Ma Ling , Matulonis Ursula A. , Lauchle Jennifer O. , Parmar Hema , Gilbert Houston N. , Ware Joseph A. , Zhu Rui , Lu Shan , Huw Ling‐Yuh , Wang Yulei , Koeppen Hartmut , Spoerke Jill M. , Lackner Mark R. , Aghajanian Carol A.
Published: September 2016

BACKGROUND

The current single‐arm, open‐label trial was designed to evaluate the activity of apitolisib (GDC‐0980), a dual phosphoinositide 3‐kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, in patients with advanced endometrial cancer (EC).

METHODS

Patients with recurrent or persistent EC who were treated with 1 to 2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral apitolisib at a dose of 40 mg daily during 28‐day cycles until disease progression or intolerable toxicity occurred. Patients with type I/II diabetes who required insulin were excluded. The primary endpoints were progression‐free survival (PFS) at 6 months and objective response rate.

RESULTS

A total of 56 women were enrolled, including 13 (23%) with well‐controlled diabetes. Reasons for discontinuation were disease progression (24 patients; 43%), adverse events (13 patients; 23%), and withdrawal by subject (12 patients; 21%). Grade 3/4 apitolisib‐related adverse events were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The PFS rate at 6 months was 20% (Kaplan‐Meier estimate; 95% confidence interval [95% CI], 7%‐33%). The objective response rate was 6% (confirmed). The median PFS was 3.5 months (95% CI, 2.7‐3.7 months) and the median overall survival was 15.7 months (95% CI, 9.2‐17.0 months). Nineteen patients discontinued the study before the first tumor assessment. Dose reductions were required for 4 diabetic (31%) and 18 nondiabetic (42%) patients. Comprehensive molecular profiling of 46 evaluable archival tumor samples demonstrated that 57% of patients had at least 1 alteration in phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), or AKT1. All 3 patients with a confirmed response had at least 1 alteration in a PI3K pathway gene.

CONCLUSIONS

The antitumor activity noted with the use of a dose of 40 mg of apitolisib daily was limited by tolerability, especially in diabetic patients. Patients with PI3K pathway mutations may have derived enhanced benefit from apitolisib. Cancer 2016;122:3519–28. © 2016 American Cancer Society.
Patterns and predictors of colorectal cancer care coordination: A population‐based survey of Australian patients
Authors: Durcinoska Ivana , Young Jane M. , Solomon Michael J.
Published: September 2016

BACKGROUND

Improving care coordination is a key priority for health services. The aims of this study were to identify patient‐ and health service–related predictors of poorly coordinated care and to explore patient preferences to assist care coordination.

METHODS

Patients with incident colorectal cancer, identified from a state‐wide cancer registry, completed a self‐report questionnaire 6 to 8 months after their diagnosis. Care coordination was assessed with the Cancer Care Coordination Questionnaire for Patients. Multiple linear regression models were used to predict factors associated with a poor experience with cancer care coordination.

RESULTS

Among 560 patients (56% response rate), care coordination experiences were normally distributed (mean score, 76.1; standard deviation, 10.9). Patients who had 3 or more comorbid conditions (β, –4.56; standard error [SE], 1.46; P = .006), little or no understanding of the health system (β, –4.34; SE, 0.94; P < .001), and no regular general practitioner (GP; β, –4.09; SE, 2.07; P = .049) experienced poorer care coordination. At the health service level, patients who did not receive a written pretreatment plan (β, –4.15; SE, 0.95; P < .001) or did not see a cancer care coordinator (β, –3.29; SE, 1.03; P = .001) had lower scores. The most preferred resources included information packs (92%), written care plans (88%), and improved access to their own personal medical records (electronic, 86; paper, 84%), with most patients preferring a shared GP and surgeon care model.

CONCLUSIONS

There was wide variation in experiences across the state. The factors associated with lower scores provide a focus for targeted strategies for improving patients' experience with colorectal cancer care coordination. Cancer 2017;123:319–326. © 2016 American Cancer Society.
DIANA‐TarBase and DIANA Suite Tools: Studying Experimentally Supported microRNA Targets
Authors: Paraskevopoulou Maria D. , Vlachos Ioannis S. , Hatzigeorgiou Artemis G.
Published: September 2016

microRNAs (miRNAs) are short non‐coding RNAs (∼22 nts) present in animals, plants, and viruses. They are considered central post‐transcriptional regulators of gene expression and are key components in a great number of physiological and pathological conditions. The accurate characterization of their targets is considered essential to a series of applications and basic or applied research settings. DIANA‐TarBase (http://www.microrna.gr/tarbase) was initially launched in 2006. It is a reference repository indexing experimentally derived miRNA‐gene interactions in different cell types, tissues, and conditions across numerous species. This unit focuses on the study of experimentally supported miRNA‐gene interactions, as well as their functional interpretation through the use of available tools in the DIANA suite (http://www.microrna.gr). The proposed use‐case scenarios are presented in protocols, describing how to utilize the DIANA‐TarBase database and DIANA‐microT‐CDS server and perform miRNA‐targeted pathway analysis with DIANA‐miRPath‐v3. All analyses are directly invoked or initiated from DIANA‐TarBase. © 2016 by John Wiley & Sons, Inc.
Tempest: Accelerated MS/MS Database Search Software for Heterogeneous Computing Platforms
Authors: Adamo Mark E. , Gerber Scott A.
Published: September 2016

MS/MS database search algorithms derive a set of candidate peptide sequences from in silico digest of a protein sequence database, and compute theoretical fragmentation patterns to match these candidates against observed MS/MS spectra. The original Tempest publication described these operations mapped to a CPU‐GPU model, in which the CPU (central processing unit) generates peptide candidates that are asynchronously sent to a discrete GPU (graphics processing unit) to be scored against experimental spectra in parallel. The current version of Tempest expands this model, incorporating OpenCL to offer seamless parallelization across multicore CPUs, GPUs, integrated graphics chips, and general‐purpose coprocessors. Three protocols describe how to configure and run a Tempest search, including discussion of how to leverage Tempest's unique feature set to produce optimal results. © 2016 by John Wiley & Sons, Inc.
Film Grain‐Size Related Long‐Term Stability of Inverted Perovskite Solar Cells
Authors: Chiang Chien‐Hung , Wu Chun‐Guey
Published: September 2016

The power conversion efficiency (PCE) of the perovskite solar cell is high enough to be commercially viable. The next important issue is the stability of the device. This article discusses the effect of the perovskite grain‐size on the long‐term stability of inverted perovskite solar cells. Perovskite films composed of various sizes of grains were prepared by controlling the solvent annealing time. The grain‐size related stability of the inverted cells was investigated both in ambient atmosphere at relative humidity of approximately 30–40 % and in a nitrogen filled glove box (H2O<0.1 ppm, O2<10 ppm). The PCE of the solar cell based on a perovskite film having the grain size larger than 1 μm (D‐10) decreases less than 10 % with storage in a glove box and less than 15 % when it was stored under an ambient atmosphere for 30 days. However, the cell using the perovskite film composed of small (∼100 nm) perovskite grains (D‐0) exhibits complete loss of PCE after storage under the ambient atmosphere for only 15 days and a PCE loss of up to 70 % with storage in the glove box for 30 days. These results suggest that, even under H2O‐free conditions, the chemical‐ and thermal‐induced production of pin holes at the grain boundaries of the perovskite film could be the reason for long‐term instability of inverted perovskite solar cells.
Application of fluorescent dye substrates for functional characterization of ABC multidrug transporters at a single cell level
Authors: Nerada Zsuzsanna , Hegyi Zoltán , Szepesi Áron , Tóth Szilárd , Hegedüs Csilla , Várady György , Matula Zsolt , Homolya László , Sarkadi Balázs , Telbisz Ágnes
Published: September 2016

ABC multidrug transporters are key players in cancer multidrug resistance and in determining the ADME‐Tox properties of drugs and xenobiotics. The most sensitive and specific detection of these transporters is based on functional assays. Assessment of the transporter‐dependent reduction of cellular uptake of the fluorescent dyes, such as Hoechst 33342 (Ho) and more recently DyeCycle Violet (DCV), have been widely advocated for the characterization of both ABCB1 and ABCG2 multidrug transporters. Detailed comparison of these supravital DNA‐binding dyes revealed that DCV is less toxic to ABCG2‐ and ABCB1‐expressing cells than Ho. ATPase measurements imply that DCV and Ho are similarly handled by ABCB1, whereas ABCG2 seems to transport DVC more effectively. In addition, we have developed an image‐based high content microscopy screening method for simultaneous in situ measurement of the cellular activity and expression of the ABCG2 multidrug transporter. We demonstrated the applicability of this method for identifying ABCG2‐positive cells in heterogeneous cell population by a single dye uptake measurement. These results may promote multidrug transporter studies at a single cell level and allow the quantitative detection of clinically important drug‐resistant sub‐populations. © 2016 International Society for Advancement of Cytometry
Lifespan oxytocin signaling: Maturation, flexibility, and stability in newborn, adolescent, and aged brain
Authors: Sannino Sara , Chini Bice , Grinevich Valery
Published: September 2016

The hypothalamic neuropeptide oxytocin (OT) is a forefront molecule among neuropeptides due to its pronounced prosocial effects and its potential use in socioemotional deficits that characterize the most prevalent neurodevelopmental and psychiatric disorders (autism spectrum disorders and schizophrenia). The effects of OT have been studied in young and adult subjects (either animals or humans), while the complete lifespan trajectories of OT system development and activity have been far less investigated. In this (mini) review, we will primarily focus on three temporal distinct periods of life—early postnatal period, puberty/adolescence, and elderly. We selected the neonatal period to discuss the role of OT in the switch of GABA action from excitation to inhibition in the first days after birth (in rodents), with potential implications in neurodevelopmental disorders. In the puberty/adolescence period, we consider of particular relevance the OT impact on drug consumption, stress and aggression. Finally, OT could potentially contribute to maintain social capacities of aged people and to ameliorate socially emotional deficits and symptoms of neurodegenerative diseases. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 158–168, 2017
iRhom2 regulates CSF1R cell surface expression and non‐steady state myelopoiesis in mice
Authors: Qing Xiaoping , D. Rogers Lindsay , Mortha Arthur , Lavin Yonit , Redecha Patricia , Issuree Priya D. , Maretzky Thorsten , Merad Miriam , R. McIlwain David , Mak Tak W. , Overall Christopher M. , Blobel Carl P. , Salmon Jane E.
Published: September 2016

CSF1R (colony stimulating factor 1 receptor) is the main receptor for CSF1 and has crucial roles in regulating myelopoeisis. CSF1R can be proteolytically released from the cell surface by ADAM17 (A disintegrin and metalloprotease 17). Here, we identified CSF1R as a major substrate of ADAM17 in an unbiased degradomics screen. We explored the impact of CSF1R shedding by ADAM17 and its upstream regulator, inactive rhomboid protein 2 (iRhom2, gene name Rhbdf2), on homeostatic development of mouse myeloid cells. In iRhom2‐/‐ mice, we found constitutive accumulation of membrane‐bound CSF1R on myeloid cells at steady state, although cell numbers of these populations were not altered. However, in the context of mixed bone marrow (BM) chimera, under competitive pressure, iRhom2‐/‐ BM progenitor‐derived monocytes, tissue macrophages and lung DCs showed a repopulation advantage over those derived from wild‐type (WT) BM progenitors, suggesting enhanced CSF1R signaling in the absence of iRhom2. In vitro experiments indicate that iRhom2‐/‐ Lin−SCA‐1+c‐Kit+ (LSKs) cells, but not granulocyte‐macrophage progenitors (GMPs), had faster growth rates than WT cells in response to CSF1. Our results shed light on an important role of iRhom2/ADAM17 pathway in regulation of CSF1R shedding and repopulation of monocytes, macrophages and DCs.
Back to the drawing board: Understanding the complexity of hepatic innate lymphoid cells
Authors: Marotel Marie , Hasan Uzma , Viel Sébastien , Marçais Antoine , Walzer Thierry
Published: September 2016

Recent studies of immune populations in nonlymphoid organs have highlighted the great diversity of the innate lymphoid system. It has also become apparent that mouse and human innate lymphoid cells (ILCs) have distinct phenotypes and properties. In this issue of the European Journal of Immunology, Harmon et al. [Eur. J. Immunol. 2016. 46: 2111–2120] characterized human hepatic NK‐cell subsets. The authors report that hepatic CD56bright NK cells resemble mouse liver ILC1s in that they express CXCR6 and have an immature phenotype. However, unlike mouse ILC1s, they express high levels of Eomes and low levels of T‐bet, and upon stimulation with tumor cells, secrete low amounts of cytokines. These unexpected findings further support the differences between human and mouse immune populations and prompt the study of the role of hepatic ILC subsets in immune responses.
Silver‐Promoted Cascade Reaction of 4‐Hydroxycoumarins with α‐Keto Acids under Microwave Irradiation: One‐Step Construction of Quaternary Stereocenters
Authors: Zha Dandan , Li Hongji , Wang Lei
Published: September 2016

A new Ag2O‐promoted cascade reaction of 4‐hydroxycoumarins with α‐keto acids under mircowave irradiation has been developed. The reaction provides an efficient approach to fused chromenes with quaternary stereocenters in 10 min, and gives good yields. Chromene derivatives can be prepared on a gram scale using this method.
Modulation of immune and antioxidant responses by azinphos-methyl in the freshwater mussel Diplodon chilensis challenged with Escherichia coli
Authors: Castro Juan Manuel , Bianchi Virginia Angélica , Pascual Mariano , Venturino Andrés , Luquet Carlos Marcelo
Published: September 2016

The aim of the present study was to characterize the immune response—total hemocyte number, cell type proportion, hemocyte viability, lysosomal membrane stability, phagocytic activity, cellular acid and alkaline phosphatase activity, and humoral bacteriolytic and phenoloxidase activity—­in Diplodon chilensis exposed to 0.2 mg/L of azinphos-methyl (AZM), using Escherichia coli as immunological and pro-oxidant challenges. In addition, glutathione-S-transferase and lipid peroxidation thiobarbituric acid reactive substances were analyzed in gill tissue. Mussels from an unpolluted site were treated for 3 d as follows: 1) experimental control; 2) solvent effects control (acetone 0.01%); 3) bacterial challenge effects control (E. coli, 5 cells/mL × 104 cells/mL); 4) pesticide effects control (AZM in acetone); 5) control for combined effects of solvent and bacterial challenge; and 6) exposed to AZM, then challenged with E. coli. The results showed increased granulocyte proportion and phagocytic activity. Partial reversion of deleterious effects of E. coli on lysosomal membranes was observed in mussels exposed to AZM and then challenged with E. coli. Total hemocyte number and humoral bacteriolytic activity were increased only by E. coli challenge. Acid phosphatase activity was increased by both E. coli and AZM, whereas the stimulating effect of E. coli on alkaline phosphatase activity was negatively modulated by AZM. Azinphos-methyl inhibited phenoloxidase activity regardless of the E. coli challenge. Gill glutathione-S-transferase activity was increased by E. coli treatment either alone or pretreated with acetone or AZM and by AZM alone. Thiobarbituric acid reactive substance levels were reduced by AZM alone or combined with the E. coli challenge and by acetone followed by the E. coli challenge. Both acetone and AZM seem to be important modulators of immune and antioxidant responses in D. chilensis. Environ Toxicol Chem 2017;36:1785–1794. © 2016 SETAC
Sensitivity of lake sturgeon (Acipenser fulvescens) early life stages to 2,3,7,8-tetrachlorodibenzo-P-dioxin and 3,3′,4,4′,5-pentachlorobiphenyl
Authors: Tillitt Donald E. , Buckler Justin A. , Nicks Diane K. , Candrl James S. , Claunch Rachel A. , Gale Robert W. , Puglis Holly J. , Little Edward E. , Linbo Tiffany L. , Baker Mary
Published: September 2016

The aquatic food web of the Great Lakes has been contaminated with polychlorinated biphenyls (PCBs) since the mid-20th century. Threats of PCB exposures to long-lived species of fish, such as lake sturgeon (Acipenser fulvescens), have been uncertain because of a lack of information on the relative sensitivity of the species. The objective of the present study was to evaluate the sensitivity of early–life stage lake sturgeon to 3,3′,4,4′,5-pentachlorobiphenyl (PCB-126) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Mortality, growth, morphological and tissue pathologies, swimming performance, and activity levels were used as assessment endpoints. Pericardial and yolk sac edema, tubular heart, yolk sac hemorrhaging, and small size were the most commonly observed pathologies in both TCDD and PCB-126 exposures, beginning as early as 4 d postfertilization, with many of these pathologies occurring in a dose-dependent manner. Median lethal doses for PCB-126 and TCDD in lake sturgeon were 5.4 ng/g egg (95% confidence interval, 3.9–7.4 ng/g egg) and 0.61 ng/g egg (0.47–0.82 ng/g egg), respectively. The resulting relative potency factor for PCB-126 (0.11) was greater than the World Health Organization estimate for fish (toxic equivalency factor = 0.005), suggesting that current risk assessments may underestimate PCB toxicity toward lake sturgeon. Swimming activity and endurance were reduced in lake sturgeon survivors from the median lethal doses at 60 d postfertilization. Threshold and median toxicity values indicate that lake sturgeon, like other Acipenser species, are more sensitive to PCB and TCDD than the other genus of sturgeon, Scaphirhynchus, found in North America. Indeed, lake sturgeon populations in the Great Lakes and elsewhere are susceptible to PCB/TCDD-induced developmental toxicity in embryos and reductions in swimming performance. Environ Toxicol Chem 2017;36:988–998. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
The Effect of Team Affective Tone on Team Performance: The Roles of Team Identification and Team Cooperation
Authors: Lin Chieh‐Peng , He Hongwei , Baruch Yehuda , Ashforth Blake E.
Published: September 2016

Affective tones abound in work teams. Drawing on the affect infusion model and social identity theory, this study proposes that team affective tone is related to team performance indirectly through team identification and team cooperation. Data from 141 hybrid‐virtual teams drawn from high‐tech companies in Taiwan generally supported our model. Specifically, positive affective tone is positively associated—while negative affective tone is negatively associated—with both team identification and team cooperation; team identification is positively associated with team cooperation; and team cooperation is positively associated with team performance. Managerial implications and limitations are discussed. © 2016 Wiley Periodicals, Inc.
Groundwater—Surface waters interactions at slope and catchment scales: implications for landsliding in clay‐rich slopes
Authors: Marc Vincent , Bertrand Catherine , Malet Jean‐Philippe , Carry Nicolas , Simler Roland , Cervi Federico
Published: September 2016

Understanding water infiltration and transfer in soft‐clay shales slopes is an important scientific issue, especially for landsliding. Geochemical investigations are carried out at the Super‐Sauze and Draix‐Laval landslides, both developed in the Callovo‐Oxfordian black marls, with the objective to define the origin of the groundwater. In situ investigations, soil leaching experiments and geochemical modeling are combined to identify the boundaries of the hydrological systems. At Super‐Sauze, the observations indicate that an external water flow occurs in the upper part of the landslide at the contact between the weathered black marls and the overlying formations, or at the landslide basement through a fault network. Such external origin of water is not observed at the local scale of the Draix‐Laval landslide but is detected at the catchment scale with the influence of deep waters in the streamwater quality of low river flows. Hydrogeological conceptual models are proposed emphasizing the role of the interactions between local (slope) and regional (catchment) flow systems. The observations suggest that this situation is a common case in the Alpine area. Expected consequences of the regional flows on slope stability are discussed in term of rise of pore water pressures and physicochemical weathering of the clay shales.
Assessing the relevance of ecotoxicological studies for regulatory decision making
Authors: Rudén Christina , Adams Julie , Ågerstrand Marlene , Brock Theo CM , Poulsen Veronique , Schlekat Christian E , Wheeler James R , Henry Tala R
Published: September 2016

Regulatory policies in many parts of the world recognize either the utility of or the mandate that all available studies be considered in environmental or ecological hazard and risk assessment (ERA) of chemicals, including studies from the peer-reviewed literature. Consequently, a vast array of different studies and data types need to be considered. The first steps in the evaluation process involve determining whether the study is relevant to the ERA and sufficiently reliable. Relevance evaluation is typically performed using existing guidance but involves application of “expert judgment” by risk assessors. In the present paper, we review published guidance for relevance evaluation and, on the basis of the practical experience within the group of authors, we identify additional aspects and further develop already proposed aspects that should be considered when conducting a relevance assessment for ecotoxicological studies. From a regulatory point of view, the overarching key aspect of relevance concerns the ability to directly or indirectly use the study in ERA with the purpose of addressing specific protection goals and ultimately regulatory decision making. Because ERA schemes are based on the appropriate linking of exposure and effect estimates, important features of ecotoxicological studies relate to exposure relevance and biological relevance. Exposure relevance addresses the representativeness of the test substance, environmental exposure media, and exposure regime. Biological relevance deals with the environmental significance of the test organism and the endpoints selected, the ecological realism of the test conditions simulated in the study, as well as a mechanistic link of treatment-related effects for endpoints to the protection goal identified in the ERA. In addition, uncertainties associated with relevance should be considered in the assessment. A systematic and transparent assessment of relevance is needed for regulatory decision making. The relevance aspects also need to be considered by scientists when designing, performing, and reporting ecotoxicological studies to facilitate their use in ERA. Integr Environ Assess Manag 2017;13:652–663. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

Key Points

Relevance assessment of ecotoxicological studies is required to ensure appropriate use in hazard and risk assessment of chemicals. Structured and systematic evaluation processes are preferred to promote reproducibility and transparency. Relevance assessment consists of overarching regulatory relevance and associated aspects concerning exposure and biological components. The examples provided may inform and improve guidance for relevance assessment of ecotoxicological studies for use in regulatory decision making.
Epstein‐Barr virus mRNA profiles and viral DNA methylation status in nasopharyngeal brushings from nasopharyngeal carcinoma patients reflect tumor origin
Authors: Ramayanti Octavia , Juwana Hedy , Verkuijlen Sandra A.M.W. , Adham Marlinda , Pegtel Michiel D. , Greijer Astrid E. , Middeldorp Jaap M.
Published: September 2016

Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein‐Barr virus (EBV) as oncogenic driver. NPC is often diagnosed late due to initial vague complaints and obscured location. Prior studies suggest that measurement of EBV DNA load and RNA transcripts in nasopharyngeal (NP) brushings is useful for minimally invasive NPC diagnosis. However, whether these EBV markers relate to local virus replication or reflect tumor origin remains to be demonstrated. To resolve this, we analysed EBV‐DNA characteristics and quantified latent and lytic viral RNA transcripts in NP brushings and matching frozen NP‐biopsy specimens from patients suspected of having NPC.

We observed non‐fragmented and Cp‐promotor methylated EBV‐DNA in both NP brushings and biopsies suggestive of tumor origin. Using quantitative RT‐PCR we determined expression levels of 7 critical latent (EBER1, Qp‐EBNA1, EBNA2, BART, LMP1, LMP2, BARF1) and 5 lytic (Zta, Rta, TK, PK and VCA‐p18) RNA transcripts. Although latent and early lytic RNA transcripts were frequently detected in conjunction with high EBV viral load, in both brushings and biopsies the latent transcripts prevailed and reflected a typical NPC‐associated latency‐II transcription profile without EBNA2. Late lytic RNA transcripts were rare and detected at low levels mainly in NP brushings, suggestive of abortive viral reactivation rather than complete virus replication. EBV‐IgA serology (EBNA1, VCA, Zta) did not correlate to the level of viral reactivation in situ.

Overall, viral RNA profiling, DNA fragmentation and methylation analysis in NP brushings and parallel biopsies indicate that NP brush sampling provides a true and robust indicator of NPC tumor presence.
Chemical exposures and risk of acute myeloid leukemia and myelodysplastic syndromes in a population‐based study
Authors: Poynter Jenny N. , Richardson Michaela , Roesler Michelle , Blair Cindy K. , Hirsch Betsy , Nguyen Phuong , Cioc Adina , Cerhan James R. , Warlick Erica
Published: September 2016

Benzene exposure is one of the few well‐established risk factors for myeloid malignancy. Exposure to other chemicals has been inconsistently associated with hematologic malignancies. We evaluated occupational and residential chemical exposures as risk factors for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) using population‐based data. AML and MDS cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota driver's license/identification card list. Chemical exposures were measured by self‐report. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI). We included 265 MDS cases, 420 AML cases and 1388 controls. We observed significant associations between both MDS and AML and benzene (OR = 1.77, 95% CI 1.19, 2.63 and OR = 2.10, 95% CI 1.35, 3.28, respectively) and vinyl chlorides (OR = 2.05, 95% CI 1.15, 3.63 and OR = 2.81, 95% CI 1.14, 6.92). Exposure to soot, creosote, inks, dyes and tanning solutions and coal dust were associated with AML (range ORs = 2.68–4.03), while no association was seen between these exposures and MDS (range ORs = 0.57–1.68). Pesticides and agricultural chemicals were not significantly associated with AML or MDS. Similar results were observed in analyses stratified by sex. In addition to providing risk estimates for benzene from a population‐based sample, we also identified a number of other occupational and residential chemicals that were significantly associated with AML; however, all exposures were reported by only a small percentage of cases (≤10%). While chemical exposures play a clear role in the etiology of myeloid malignancy, these exposures do not account for the majority of cases.