bluuebunny/crossref_metadata_2025 huggingface dataset:
Muscarinic M5 receptors trigger acetylcholine‐induced Ca2+ signals and nitric oxide release in human brain microvascular endothelial cells
Authors: Zuccolo Estella , Laforenza Umberto , Negri Sharon , Botta Laura , Berra‐Romani Roberto , Faris Pawan , Scarpellino Giorgia , Forcaia Greta , Pellavio Giorgia , Sancini Giulio , Moccia Francesco
Published: September 2018

Basal forebrain neurons control cerebral blood flow (CBF) by releasing acetylcholine (Ach), which binds to endothelial muscarinic receptors to induce nitric (NO) release and vasodilation in intraparenchymal arterioles. Nevertheless, the mechanism whereby Ach stimulates human brain microvascular endothelial cells to produce NO is still unknown. Herein, we sought to assess whether Ach stimulates NO production in a Ca2+‐dependent manner in hCMEC/D3 cells, a widespread model of human brain microvascular endothelial cells. Ach induced a dose‐dependent increase in intracellular Ca2+ concentration ([Ca2+]i) that was prevented by the genetic blockade of M5 muscarinic receptors (M5‐mAchRs), which was the only mAchR isoform coupled to phospholipase Cβ (PLCβ) present in hCMEC/D3 cells. A comprehensive real‐time polymerase chain reaction analysis revealed the expression of the transcripts encoding for type 3 inositol‐1,4,5‐trisphosphate receptors (InsP3R3), two‐pore channels 1 and 2 (TPC1–2), Stim2, Orai1–3. Pharmacological manipulation showed that the Ca2+ response to Ach was mediated by InsP3R3, TPC1–2, and store‐operated Ca2+ entry (SOCE). Ach‐induced NO release, in turn, was inhibited in cells deficient of M5‐mAchRs. Likewise, Ach failed to increase NO levels in the presence of l‐NAME, a selective NOS inhibitor, or BAPTA, a membrane‐permeant intracellular Ca2+ buffer. Moreover, the pharmacological blockade of the Ca2+ response to Ach also inhibited the accompanying NO production. These data demonstrate for the first time that synaptically released Ach may trigger NO release in human brain microvascular endothelial cells by stimulating a Ca2+ signal via M5‐mAchRs.
Stat3 activation is critical for pluripotency maintenance
Authors: Zhang Yan , Wang Dan , Xu Jia , Wang Yuebing , Ma Fengxia , Li Zongjin , Liu Na
Published: September 2018

Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription with many important functions, including regulation of cell proliferation, differentiation, survival, angiogenesis, and immune response. Besides, it plays critical roles in regulating the pluripotency. With the ability of self‐renewal and differentiation, embryonic stem (ES) cells provide an unlimited source for cell transplantation. ES cells can maintain its undifferentiated state with leukemia inhibitory factor, the role which is achieved by the activation of the Stat3 pathway. Moreover, Stat3 activation is necessary for the naïve state maintenance of the ES cells and somatic stem cells reprogramming. This study presents an overview of the critical roles of Stat3 activation in the pluripotency maintenance of ES cells, somatic cell reprogramming, and naïve‐primed pluripotent states conversion of ES cells.
Nanostructured lipid carriers containing rapamycin for prevention of corneal fibroblasts proliferation and haze propagation after burn injuries: In vitro and in vivo
Authors: Zahir‐Jouzdani Forouhe , Khonsari Fatemeh , Soleimani Masoud , Mahbod Mirgholamreza , Arefian Ehsan , Heydari Mostafa , Shahhosseini Saeed , Dinarvand Rassoul , Atyabi Fatemeh
Published: September 2018

Chemical burns are a major cause of corneal haze and blindness. Corticosteroids are commonly used after corneal burns to attenuate the severity of the inflammation‐related fibrosis. While research efforts have been aimed toward application of novel therapeutics. In the current study, a novel drug delivery system based nanostructured lipid carriers (NLCs) were designed to treat corneal alkaline burn injury. Rapamycin, a potent inhibitor of mammalian target of rapamycin pathway, was loaded in NLCs (rapa‐NLCs), and the NLCs were characterized. Cell viability assay, cellular uptake of NLCs, and in vitro evaluation of the fibrotic/angiogenic genes suppression by rapa‐NLCs were carried out on human isolated corneal fibroblasts. Immunohistochemistry (IHC) assays were also performed after treatment of murine model of corneal alkaline burn with rapa‐NLCs. According to the results, rapamycin was efficiently loaded in NLCs. NLCs could enhance coumarin‐6 fibroblast uptake by 1.5 times. Rapa‐NLCs efficiently downregulated platelet‐derived growth factor and transforming growth factor beta genes in vitro. Furthermore, proliferation of fibroblasts, a major cause of corneal haze after injury, reduced. IHC staining of treated cornea with alpha‐smooth muscle actin and CD34
+ antibodies showed efficient prevention of myofibroblasts differentiation and angiogenesis, respectively. In conclusion, ocular delivery of rapamycin using NLCs after corneal injury may be considered as a promising antifibrotic/angiogenic treatment approach to preserve patient eyesight.
Nerve growth factor prevents arsenic‐induced toxicity in PC12 cells through the AKT/GSK‐3β/NFAT pathway
Authors: Tan Zhen , Kang Ting , Zhang Xiuli , Tong Yingying , Chen Siyu
Published: September 2018

The potential risk of arsenic‐related neurodegeneration has been a growing concern. Arsenic exposure has been reported to disrupt neurite growth and neuron body integrity in vitro; however, its underlying mechanism remains unclear. Previously, we showed that arsenic sulfide (AS) exerted cytotoxicity in gastric and colon cancer cells through regulating nuclear factor of the activated T cells (NFAT) pathway. The NFAT pathway regulates axon path finding and neural development. Using neural crest cell line PC12 cells as a model, here we show that AS caused mitochondrial membrane potential collapse, reactive oxygen species production, and cytochrome c release, leading to mitochondria‐mediated apoptosis via the AKT/GSK‐3β/NFAT pathway. Increased glycogen synthase kinase‐3 beta (GSK‐3β) activation leads to the inactivation of NFAT and its antiapoptotic effects. Through inhibiting GSK‐3β activity, both nerve growth factor (NGF) and Tideglusib, a GSK‐3β inhibitor partially rescued the PC12 cells from the AS‐induced cytotoxicity and restored the expression of NFATc3. In addition, overexpression of NFATc3 stimulated neurite outgrowth and potentiated the effect of NGF on promoting the neurite outgrowth. Collectively, our results show that NFATc3 serves as the downstream target of NGF and plays a key role in preventing AS‐induced neurotoxicity through regulating the AKT/GSK‐3β/NFAT pathway in PC12 cells.
Recovery from hypoxia‐induced internalization of cardiac Na+/H+ exchanger 1 requires an adequate intracellular store of antioxidants
Authors: Şimşek Gül , Vaughan‐Jones Richard D. , Swietach Pawel , Kandilci H. Burak
Published: September 2018

The heart is highly active metabolically but relatively underperfused and, therefore, vulnerable to ischemia. In addition to acidosis, a key component of ischemia is hypoxia that can modulate gene expression and protein function as part of an adaptive or even maladaptive response. Here, using cardiac‐derived HL‐1 cells, we investigate the effect of various hypoxic stimuli on the expression and activity of Na+/H
+ exchanger 1 (NHE1), a principal regulator of intracellular pH. Acute (10 min) anoxia produced a reversible decrease in the sarcolemmal NHE1 activity attributable to NHE1 internalization. Treatment with either 1% O
2 or dimethyloxaloylglycine (DMOG; 1 mM) for 48‐hr stabilized hypoxia‐inducible factor 1 and reduced the sarcolemmal NHE1 activity by internalization, but without a change in total NHE1 immunoreactivity or message levels of the coding gene (
SLC9A1) determined in whole‐cell lysates. Unlike the effect of DMOG, which was rapidly reversed on washout, reoxygenation after a prolonged period of hypoxia did not reverse the effects on NHE1, unless media were also supplemented with a membrane‐permeant derivative of glutathione (GSH). Without a prior hypoxic episode, GSH supplementation had no effect on the NHE1 activity. Thus, posthypoxic NHE1 reinsertion can only take place if cells have a sufficient reservoir of a reducing agent. We propose that oxidative stress under prolonged hypoxia depletes intracellular GSH to an extent that curtails NHE1 reinsertion once the hypoxic stimulus is withdrawn. This effect may be cardioprotective, as rapid postischaemic restoration of the NHE1 activity is known to trigger reperfusion injury by producing an intracellular Na
+‐overload, which is proarrhythmogenic.
Long noncoding RNA H19 participates in metformin‐mediated inhibition of gastric cancer cell invasion
Authors: Li Peiwen , Tong Linhao , Song Yongxi , Sun Jingxu , Shi Jinxin , Wu Zhonghua , Diao Yao , Li Yaming , Wang Zhenning
Published: September 2018

Recent research suggests that the first‐line oral antidiabetes drug metformin may prevent gastric cancer progression and improve prognosis. Many studies have also shown that long noncoding RNAs (lncRNAs) play important roles in many biological processes. Therefore, we aimed to explore whether lncRNAs participate in the mechanisms by which metformin affects gastric cancer cells. In the current study, we found that metformin significantly inhibited the cellular functions of gastric cancer cells through Cell Counting Kit‐8 and invasion assays. We found that lncRNA H19 was greatly downregulated in gastric cancer cells treated with metformin using lncRNA microassays. Based on bioinformatics analyses of the Oncomine and The Cancer Genome Atlas databases, H19 is shown to be overexpressed in gastric cancer tissues, with increased expression of H19 relating to advanced pathological tumor stage and pathological tumor node metastasis stage, indicating that H19 may be associated with the invasive ability of gastric cancer. We knocked down H19 in AGS and SGC7901 cell lines and found that knocked‐down H19 could decrease gastric cancer cell invasion and that metformin could not further decrease invasion after the knock down. Moreover, H19 depletion increased AMPK activation and decreased MMP9 expression, and metformin could not further activate AMPK or decrease MMP9 in H19 knocked‐down gastric cancer cells. In summary, metformin has a profound antitumor effect on gastric cancer cells, and H19 is a key component in the process of metformin suppressing gastric cancer cell invasion.
Heme oxygenase‐1 reduces the sensitivity to imatinib through nonselective activation of histone deacetylases in chronic myeloid leukemia
Authors: Wei Danna , Lu Tingting , Ma Dan , YU Kunlin , Li Xinyao , Chen Bingqing , Xiong Ji , Zhang Tianzhuo , Wang Jishi
Published: September 2018

Resistance towards imatinib (IM) remains troublesome in treating many chronic myeloid leukemia (CML) patients. Heme oxygenase‐1 (HO‐1) is a key enzyme of antioxidative metabolism in association with cell resistance to apoptosis. Our previous studies have shown that overexpression of HO‐1 resulted in resistance development to IM in CML cells, while the mechanism remains unclear. In the current study, the IM‐resistant CML cells K562R indicated upregulation of some of the histone deacetylases (HDACs) compared with K562 cells. Therefore, we herein postulated HO‐1 was associated with HDACs. Silencing HO‐1 expression in K562R cells inhibited the expression of some HDACs, and the sensitivity to IM was increased. K562 cells transfected with HO‐1 resisted IM and underwent obvious some HDACs. These findings related to the inhibitory effects of high HO‐1 expression on the reactive oxygen species (ROS) signaling pathway that negatively regulated HDACs. Increased expression of HO‐1 activated HDACs by inhibiting ROS production. In summary, HO‐1, which is involved in the development of drug resistance in CML cells by regulating the expression of HDACs, is probably a novel target for improving CML therapy.
Mll‐COMPASS complexes mediate H3K4me3 enrichment and transcription of the osteoblast master gene Runx2/p57 in osteoblasts
Authors: Rojas Adriana , Sepulveda Hugo , Henriquez Berta , Aguilar Rodrigo , Opazo Tatiana , Nardocci Gino , Bustos Fernando , Lian Jane B. , Stein Janet L. , Stein Gary S. , van Zundert Brigitte , van Wijnen Andre J. , Allende Miguel L. , Montecino Martin
Published: September 2018

Expression of Runx2/p57 is a hallmark of the osteoblast‐lineage identity. Although several regulators that control the expression of Runx2/p57 during osteoblast‐lineage commitment have been identified, the epigenetic mechanisms that sustain this expression in differentiated osteoblasts remain to be completely determined. Here, we assess epigenetic mechanisms associated with Runx2/p57 gene transcription in differentiating MC3T3 mouse osteoblasts. Our results show that an enrichment of activating histone marks at the Runx2/p57 P1 promoter is accompanied by the simultaneous interaction of Wdr5 and Utx proteins, both are components of COMPASS complexes. Knockdown of Wdr5 and Utx expression confirms the activating role of both proteins at the Runx2‐P1 promoter. Other chromatin modifiers that were previously described to regulate Runx2/p57 transcription in mesenchymal precursor cells (Ezh2, Prmt5, and Jarid1b proteins) were not found to contribute to Runx2/p57 transcription in full‐committed osteoblasts. We also determined the presence of additional components of COMPASS complexes at the Runx2/p57 promoter, evidencing that the Mll2/COMPASS‐ and Mll3/COMPASS‐like complexes bind to the P1 promoter in osteoblastic cells expressing Runx2/p57 to modulate the H3K4me1 to H3K4me3 transition.
Efficient processing of bioglycerol to a novel biobased polyunsaturated monomer
Authors: Gómez Claudia L , Echeverri David A , Inciarte Helen C , Rios Luis A
Published: September 2018

BACKGROUND

Commercial synthesis of polyunsaturated monomers, like polyester resins, involves an energy‐demanding esterification process, which is usually carried out at 150–220 °C and long reaction times (>12 h). In addition, most of these monomers come from petrochemical sources and, therefore, are not renewable. In this research, a new polyunsaturated monomer was synthesized using crude glycerol from biodiesel production (bioglycerol), through an alternative and efficient process.

RESULTS

Bioglycerol was transformed to a polyunsaturated resin through maleinization and methacrylation reactions, under mild conditions (<100 °C and 2 h). The effects of temperature and molar ratio of reactants on these reactions were evaluated through a factorial design. The so‐obtained monomer was highly functionalized (5.05 double bonds per molecule) and negligible acid value (<2 mg KOH g−1). To assess its reactivity, the monomer was copolymerized with methyl methacrylate (MMA), affording a rigid material with excellent mechanical properties. In general, the properties were better than those obtained for commercial unsaturated polyester thermosets (flexural modulus, 3783.4 MPa; flexural strength, 161.5 MPa; surface hardness, 76 (Shore D) and Tg, 100.9 °C). This new monomer could also be suitable for the production of other polymers such as alkyd resins.

CONCLUSION

A new route to polyunsaturated monomers was developed from bioglycerol at relatively low temperatures, without solvents and with minimum intermediate purification stages. The monomer was suitable for reacting with MMA, affording a material with mechanical properties resembling those of a commercial unsaturated polyester thermoset. © 2018 Society of Chemical Industry
Potential of sugar beet vinasse as a feedstock for biocatalyst production within an integrated biorefinery context
Authors: Suhaili Nurashikin , Cárdenas‐Fernández Max , Ward John M , Lye Gary J
Published: September 2018

BACKGROUND

This work explores the feasibility of vinasse as an inexpensive feedstock for industrial biocatalyst production within the context of an integrated sugar beet biorefinery. As an exemplar, production of CV2025 ω‐Transaminase (ω‐TAm) in Escherichia coli BL21 was studied.

RESULTS

Characterisation of vinasse showed that it comprised mainly of glycerol along with several reducing sugars, sugar alcohols, acetate, polyphenols and protein. Preliminary results showed E. coli BL21 cell growth and CV2025 ω‐TAm production were feasible in cultures using 17% to 25% (v/v) vinasse with higher concentrations demonstrating inhibitory effects. The d‐galactose present in vinasse facilitated auto‐induction of the pQR801 plasmid enabling CV2025 ω‐TAm expression without addition of expensive Isopropyl‐β‐d‐thiogalactopyranoside (IPTG). Assessment of different vinasse pre‐processing options confirmed simple dilution of the vinasse was sufficient to reduce the concentration of polyphenols to below inhibitory levels. Optimisation experiments, carried out using a controlled, 24‐well microbioreactor platform, showed supplementation of diluted vinasse medium with 10 g L−1 yeast extract enabled enhancements of 2.8, 2.5, 5.4 and 3‐fold in specific growth rate, maximum biomass concentration, CV2025 ω‐TAm volumetric and specific activity, respectively. Investigation into the metabolic preferences of E. coli BL21 when grown in vinasse showed a preference for D‐mannitol utilisation before simultaneous metabolism of glycerol, d‐xylitol, d‐dulcitol and acetate. Scale‐up of optimised conditions for batch CV2025 ω‐TAm production to a 7.5 L stirred tank reactor (STR) was demonstrated based on matched volumetric mass transfer coefficient (kLa). The results showed good comparability with respect to cell growth, substrate consumption and CV2025 ω‐TAm production representing over a 700‐fold volumetric scale translation. Further enhancements in CV2025 ω‐TAm production were possible in the STR when operated at higher kLa values.

CONCLUSION

This work describes the promising application of vinasse for production of microbial enzymes and insights into carbon source utilisation in complex feedstocks. Exploitation of vinasse as a fermentation feedstock could be further extended to other processes involving different microorganisms and target enzymes. © 2018 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Dynamic Linkage Between Economic Growth and Human Development: Time Series Evidence from Nigeria
Authors: Chikalipah Sydney , Okafor Godwin
Published: September 2018

A consensus among academics and policymakers holds that investing in human development not only improves lives, but also by itself promotes stellar economic growth. We investigate these claims by estimating the two‐way causality between economic growth and human development in Nigeria over the period from 1961 to 2015. By employing three statistical frameworks (Gregory–Hansen Cointegration, Stock–Watson Dynamic Ordinary Least Square and Vector Error Correction Model), our estimates suggest the following. First, economic growth and human development share a long run relationship, that is, they are cointegrated. Second, despite the two variables sharing a long run relationship, only economic growth can exercise a positive effect on human development, and no evidence of reverse causality was observable. Far importantly, we prescribe a policy recommendations from these findings. © 2018 John Wiley & Sons, Ltd.
Radioiodination and biological distribution of a new s‐triazine derivative for tumor uptake evaluation
Authors: Motaleb Mohamed A. , Ibrahim Ismail T. , Sarhan Mona O. , Zaghary Wafaa A.
Published: September 2018

A newly synthesized s‐triazine derivative 1,1′,1″‐(((1,3,5‐triazine‐2,4,6‐triyl) tris (azanediyl)) tris (benzene‐4,1‐diyl))tris (ethan‐1‐one), (1), was synthesized as a part of an ongoing research for development of novel s‐triazine‐based radiopharmaceuticals. In‐vitro cell viability assay against different human cancer cell lines showed very promising inhibitory activity of the synthesized compound. This finding encouraged the radioiodination of 1 to study the degree of its localization in tumor site for evaluating the possibility of its use as a tumor imaging agent. The biodistribution study showed good localization of the radioiodinated derivative 2 at tumor site following i.v. administration in solid tumor‐bearing mice. Finally, in a trial to understand the mechanism of the anticancer effect exerted by 1, a target prediction study and a docking study were performed. The results of the first study showed that focal adhesion kinase is a possible target for compound 1 and the docking study confirmed successful binding of both compound 1 and its radioiodinated derivative 2 to the binding site of focal adhesion kinase. As a conclusion, the results of this study suggest that, compound 2 could be used as a potential agent for tumor imaging after preclinical trials.
Exploration and validation of diphosphate‐based Plasmodium LytB inhibitors using computational approaches
Authors: Bhuyan Rajabrata , Seal Alpana
Published: September 2018

LytB or IspH is an indispensable enzyme and a suitable drug target of Plasmodium falciparum that participate in isoprenoid biosynthesis of nonmevalonate pathway (MEP). Recently, we have investigated the structural dynamics of Plasmodium LytB and proposed some novel diphosphate‐based inhibitors using molecular modeling and docking studies. Here, we have tried to characterize those previously screened molecules by quantitative structure activity relationships and pharmacophore‐based analyses, as well as validated the dynamics of their interactions with LytB protein. Five total compounds having PubChem CID 516, 125696, 165275, 448012, and 9921431 were predicted with significant inhibitory activity by quantitative structure activity relationships and pharmacophore models. Again, the molecular dynamics simulation results showed that these five compounds are able to form stable complexes with the receptor through many direct and water mediated interactions. The binding free energies calculated by Poisson‐Boltzmann surface area method resulted within the range between −99.77 and − 43.74 kcal/mol, which favoured their profound inhibitory affinity. Residues of LytB like His41, His74, Ser222, Ser223, and Asn224 in LytB were the main protagonists in contributing the majority of interaction energies to the ligands. Finally, the ADMET, toxicity, and drug‐likeness scores also affirm these compounds to be considered for further development of new antimalarial inhibitor in the future.
Rapid hepatitis C virus clearance by antivirals correlates with immune status of infected patients
Authors: Sasaki Reina , Meyer Keith , Moriyama Mitsuhiko , Kato Naoya , Yokosuka Osamu , Ray Ratna B. , Aurora Rajeev , Ray Ranjit , Kanda Tatsuo
Published: September 2018

Altered immune parameters associated with hepatitis C virus (HCV) genotype 1b infection and their correlation with virus eradication in direct‐acting antivirals (DAA)‐treated patients were examined. Thirty‐one HCV‐infected patients were treated with DAAs for 12 weeks. Pre‐DAA‐treatment and post‐DAA‐treatment sera were analyzed for cytokines/chemokines using MILLIPLEX MAP. Serum complement level and antibody neutralization activity were measured separately. Sera from 11 spontaneously cleared HCV subjects were included for comparison. Rapid virological responders (RVR) or end‐of‐treatment responders (EOTR) were defined as patients with HCV RNA negative at week 4 or positive at week 4 and negative at week 12, respectively. HCV RNA eradication and a decrease in liver fibrosis‐related cytokines after treatment were observed when compared with pretreatment sera from RVR and EOTR. In pretreatment sera, interferons and T‐helper 1 or 2 cell‐associated cytokines/chemokines were significantly higher among RVR as compared with EOTR. Furthermore, serum complement and virus neutralizing antibody levels were higher in pretreatment RVR sera. Eradication of HCV RNA by DAA decreased liver fibrosis‐related cytokines. Pretreatment sera from RVR displayed an enhanced cytokine/chemokine, complement and virus neutralizing antibody response as compared with EOTR sera. Our results suggested that enhanced host immune status may play an additive role on HCV RNA clearance by DAA.
Priorities for science to overcome hurdles thwarting the full promise of the ‘digital agriculture’ revolution
Authors: Shepherd Mark , Turner James A , Small Bruce , Wheeler David
Published: September 2018

Abstract

The world needs to produce more food, more sustainably, on a planet with scarce resources and under changing climate. The advancement of technologies, computing power and analytics offers the possibility that ‘digitalisation of agriculture’ can provide new solutions to these complex challenges. The role of science is to evidence and support the design and use of digital technologies to realise these beneficial outcomes and avoid unintended consequences. This requires consideration of data governance design to enable the benefits of digital agriculture to be shared equitably and how digital agriculture could change agricultural business models; that is, farm structures, the value chain and stakeholder roles, networks and power relations, and governance. We argue that this requires transdisciplinary research (at pace), including explicit consideration of the aforementioned socio‐ethical issues, data governance and business models, alongside addressing technical issues, as we now have to simultaneously deal with multiple interacting outcomes in complex technical, social, economic and governance systems. The exciting prospect is that digitalisation of science can enable this new, and more effective, way of working. The question then becomes: how can we effectively accelerate this shift to a new way of working in agricultural science? As well as identifying key research areas, we suggest organisational changes will be required: new research business models, agile project management; new skills and capabilities; and collaborations with new partners to develop ‘technology ecosystems’. © 2018 The Authors. © 2018 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Embracing change: The MIT Press and the future of university‐based publishing
Authors: Brand Amy
Published: September 2018

As a relatively new university press director intent on future‐proofing the MIT Press during a time of rapid change, a crucial question for me is how to honor a legacy of excellence in content, design, and production as we move into the future as part of an educational institution committed to experimentation, invention, and open information access. For us, the answer is that we not only embrace it but actively participate in creating and defining that future. This article provides a high‐level overview of current strategic priorities and objectives at the MIT Press, focused mainly on the book side of the house.
Edinburgh University Press: From a department to a subsidiary business
Authors: Wright Timothy E.
Published: September 2018

Key points

Edinburgh University Press (EUP) moved from subsidized to sustainable in the past 20 years.

Managing publishing focus, stock levels, and salaries allowed EUP to become financially secure.

All university presses share the same goal: to publish the best academic books and journals.
Decoupling the academic book
Authors: Hill Steven A.
Published: September 2018

Key points

Technological and policy developments are changing the context for long‐form scholarly writing.

In the face of a changing context, the structures supporting the publication of academic books have been stable.

There may be potential benefits in separating the functions of the journal in a decoupled model.

Separating functions could also be applied to long‐form scholarly works, with potential benefits that are worth exploring.
Examining the Influence of Organophosphorus Flame Retardants on the Thermal Behavior of Aromatic Polybenzoxazines
Authors: Taylor Martin , Cavalli Gabriel , Hamerton Ian
Published: September 2018

2,2‐bis(3,4‐Dihydro‐3‐phenyl‐2H‐1,3‐benzoxazine)propane (BA‐a) is blended with three commercial organophosphorus compounds, bis(4‐ hydroxyphenyl)phenylphosphine oxide (BHPPO), diphenyl phosphorami‐date (DPPA), and 9,10‐dihydro‐9‐oxa‐10‐phosphaphenanthrene‐10‐oxide (DOPO), at different loadings (1–10 wt%). Incorporation of all dopants results in a reduction in the initiation temperature for the curing mechanism (by some 30–60 K), but only the DOPO truly moves the curing into a lower temperature regime by decreasing the end temperature by 25 K (DPPA lowered this by 5 K). DPPA and DOPO are also shown to have a significant effect on the enthalpy of polymerization each decreasing the value by 50 J g−1. Differential scanning calorimetry rescan indicates all three additives have a positive impact on the glass transition temperature of poly(BA‐a) with increases of 9 K (BHPPO) and 14 K (DPPA, DOPO). Thermogravimetric analysis indicates that all additives have little effect on the magnitude of char formed (BHPPO and DPPA both increased the char yield by 3%, whereas DOPO reduces the nal char yield by 3%). However, importantly, the mechanism of thermal degradation for poly(BA‐a) differs for all three additives and is shown to change with increasing concentra‐ tion. DOPO has the greatest effect on promoting the formation of char at elevated temperatures.
Blood lysosphingolipids accumulation in patients with parkinson's disease with glucocerebrosidase 1 mutations
Authors: Pchelina Sofya , Baydakova Galina , Nikolaev Mikhael , Senkevich Konstantin , Emelyanov Anton , Kopytova Alena , Miliukhina Irina , Yakimovskii Andrey , Timofeeva Alla , Berkovich Olga , Fedotova Ekatrina , Illarioshkin Sergey , Zakharova Ekaterina
Published: September 2018

Introduction: Glucocerebrosidase 1 mutations, the most common genetic contributor to Parkinson's disease (PD), have been associated with decreased glucocerebrosidase enzymatic activity in PD patients with glucocerebrosidase 1 mutations (glucocerebrosidase 1–PD). However, it is unknown whether this decrease in enzymatic activity leads to lysosphingolipid accumulations.

Methods: The levels of hexosylsphingosines, globotriaosylsphingosine, sphingomyelin, and sphingomyelin‐509 were measured in dried blood spots from glucocerebrosidase 1–PD patients (n = 23), sporadic PD patients (n = 105), Gaucher disease patients (n = 32), and controls (n = 88) by liquid chromatography‐tandem mass spectrometry.

Results: Glucocerebrosidase 1–PD patients had increased hexosylsphingosine levels when compared with sporadic PD patients (P < .001) and controls (P < .0001). Hexosylsphingosine levels were increased in glucocerebrosidase 1 mutation carriers of glucocerebrosidase 1 (L444P; N370S; n = 11, P = .001) and glucocerebrosidase 1 polymorphic variants (E326K, T369M) associated with PD (n = 12, P = .04) when compared with controls.

Conclusions: Lysosphingolipid accumulations in PD patients who bear glucocerebrosidase 1 mutations suggest that substrate reduction therapy might be viewed as a possible strategy for glucocerebrosidase 1–PD treatment. © 2018 International Parkinson and Movement Disorder Society
Maternal Red Blood Cell Folate and Infant Vitamin B12 Status Influence Methylation of Genes Associated with Childhood Acute Lymphoblastic Leukemia
Authors: Potter Catherine , Moorman Anthony Vincent , Relton Caroline Laura , Ford Dianne , Mathers John Cummings , Strathdee Gordon , MKay Jill Ann
Published: September 2018

Scope

Inadequate maternal folate intake is associated with increased childhood acute lymphoblastic leukemia (ALL) risk. Folate provides methyl groups for DNA methylation, which is dramatically disrupted in ALL. Whether or not maternal folate (and related B‐vitamin) intake during pregnancy may affect ALL risk via influencing DNA methylation is investigated.

Methods and Results

Genes in which methylation changes are reported both in response to folate status and in ALL are investigated. Folate‐responsive genes (n = 526) are identified from mouse models of maternal folate depletion during pregnancy. Using published data, 2621 genes with persistently altered methylation in ALL are identified. Overall 25 overlapping genes are found, with the same directional methylation change in response to folate depletion and in ALL. Hypermethylation of a subset of genes (ASCL2, KCNA1, SH3GL3, SRD5A2) in ALL is confirmed by measuring 20 patient samples using pyrosequencing. In a nested cohort of cord blood samples (n = 148), SH3GL3 methylation is inversely related to maternal RBC folate concentrations (p = 0.008). Furthermore, ASCL2 methylation is inversely related to infant vitamin B12 levels. (p = 0.016).

Conclusion

Findings demonstrate proof of concept for a plausible mechanism, i.e., variation in DNA methylation, by which low intake of folate, and related B‐vitamins during pregnancy may influence ALL risk.
Phytoene and Phytofluene Isolated from a Tomato Extract are Readily Incorporated in Mixed Micelles and Absorbed by Caco‐2 Cells, as Compared to Lycopene, and SR‐BI is Involved in their Cellular Uptake
Authors: Mapelli‐Brahm Paula , Desmarchelier Charles , Margier Marielle , Reboul Emmanuelle , Meléndez Martínez Antonio J. , Borel Patrick
Published: September 2018

Scope

Absorption mechanisms of phytoene (PT) and phytofluene (PTF) are poorly known. The main objectives of the study are to measure their micellization and intestinal cell uptake efficiencies and to compare them to those of commonly consumed carotenoids. Other objectives are to assess the involvement of protein(s) in their cellular uptake and whether they compete with other carotenoids for micellization and cellular uptake.

Methods and results

Tomato‐extract‐purified PT and PTF, mainly present as cis‐isomers, are much better incorporated in synthetic mixed micelles than pure all‐trans lycopene. PT impairs lycopene micellization (−56%, P < 0.05) while PT and PTF do not significantly affect the micellization of other carotenoids, and vice versa. At low concentration, Caco‐2 PTF uptake is higher (P < 0.05) than that of PT and lycopene (29%, 21%, and not detectable). SR‐BI, but not CD36 neither NPC1L1, is involved in PT and PTF uptake. PT and PTF impair (p < 0.05) β‐carotene uptake (−13 and −22%, respectively).

Conclusions

The high bioaccessibility of PT and PTF can be partly explained by their high micellization efficiency, which is likely due to their natural cis isomerization and/or to their high molecular flexibility. SR‐BI is involved in their cellular uptake, which can explain competitions with other carotenoids.
Volume dependence in hypoxia‐targeted dose escalation
Authors: Chvetsov Alexei V. , Zeng Jing , Rajendran Joseph G.
Published: September 2018

Purpose

Dose painting techniques based on dose escalation to hypoxic regions are usually governed by the spatial distribution of Oxygen Enhancement Ratio (OER) derived from PET or MRI images. The goal of this article is to show that the volume of the hypoxic region is also a parameter which may affect the radiobiological effectiveness of hypoxia‐targeted dose escalation.

Methods

Our analysis is performed using the equation for Tumor Control Probability (TCP) derived from Poisson statistics. A tumor response model based on two levels of oxygenated and hypoxic cells with the survival curves described by the Linear Quadratic (LQ) model was used in the calculations. The model allows for analytical solutions which can be used for additional validation of our numerical simulations. The model was used to compute the average tumor cell survival that defines TCP. Dependence of average tumor cell survival on the relative hypoxic volume and dose escalation was computed for the conventional 30 × 2 Gy and hypofractionated 4 × 12 Gy dose regimens in a model problem with radiobiological parameters for nonsmall cell lung cancer.

Results

We show that equal average tumor cell survival and TCP can be achieved with smaller hypoxia‐targeted dose escalation for smaller relative hypoxic volumes if the dose escalation does not exceed 50% of dose in the oxygenated region. This effect is explained by the dependence of average tumor cell survival and TCP mostly on the hypoxic tumor volume in this dose escalation range. Assuming a linear relationship between the number of clonogens and the hypoxic volume, smaller hypoxic volumes have smaller number of clonogens, therefore, smaller doses are needed to eradicate them.

Conclusions

The theoretical analysis performed in this article predicts that tumors with smaller relative hypoxic volumes may require smaller hypoxia‐targeted dose escalation to maintain equal TCP. The results of this research can be used for dose de‐escalation strategies in dose painting techniques which may reduce dose to normal tissue and normal tissue complications without deterioration of TCP.
An apparatus and method for directly measuring the depth‐dependent gain and spatial resolution of turbid scintillators
Authors: Howansky Adrian , Lubinsky A.R. , Suzuki Katsuhiko , Ghose S. , Zhao Wei
Published: September 2018

Purpose

Turbid (powder or columnar‐structured) scintillators are widely used in indirect flat panel detectors (I‐FPDs) for scientific, industrial, and medical radiography. Light diffusion and absorption within these scintillators is expected to cause depth‐dependent variations in their x ray conversion gain and spatial blur. These variations degrade the detective quantum efficiency of I‐FPDs at all spatial frequencies. Despite their importance, there are currently no established methods for directly measuring scintillator depth effects. This work develops the instrumentation and methods to achieve this capability.

Methods

An ultra‐high‐sensitivity camera was assembled for imaging single x ray interactions in two commercial Gd2O2S:Tb (GOS) screens (Lanex Regular and Fast Back, Eastman Kodak Company). X ray interactions were localized to known depths in the screens using a slit beam of parallel synchrotron radiation (32 keV), with beam width (~20 μm) much narrower than the screen thickness. Depth‐localized x ray interaction images were acquired in 30 μm depth‐intervals, and analyzed to measure each scintillator's depth‐dependent average gain and modulation transfer function MTF(z,f). These measurements were used to calculate each screen's expected MTF(f) in an energy‐integrating detector (e.g., I‐FPD). Calculations were compared to presampling MTF measurements made by coupling each screen to a high‐resolution CMOS image sensor (48 μm pixel) and using the slanted‐edge method.

Results

Both and MTF(z,f) continuously increased as interactions occurred closer to each screen's sensor‐coupled surface. The Regular yielded 1351 ± 66 and 2117 ± 54 photons per absorbed x ray (42–66 keV−1) in interactions occurring furthest from and nearest to the image sensor, while the Fast Back yielded 833 ± 22 and 1910 ± 39 photons (26–60 keV−1). At f = 1 mm−1, MTF(z,f) varied between 0.63 and 0.78 in the Regular and 0.30–0.76 in the Fast Back. Calculations of presampling MTF(f) using and MTF(z,f) showed excellent agreement with slanted‐edge measurements.

Conclusions

The developed instrument and method enable direct measurements of the depth‐dependent gain and spatial resolution of turbid scintillators. This knowledge can be used to predict, understand, and potentially improve I‐FPD imaging performance.
Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial
Authors: Statland Jeffrey M. , Moore Dan , Wang Yunxia , Walsh Maureen , Mozaffar Tahseen , Elman Lauren , Nations Sharon P. , Mitsumoto Hiroshi , Fernandes J. Americo , Saperstein David , Hayat Ghazala , Herbelin Laura , Karam Chafic , Katz Jonathan , Wilkins Heather M. , Agbas Abdulbaki , Swerdlow Russell H. , Santella Regina M. , Dimachkie Mazen M. , Barohn Richard J. ,   The Rasagiline Investigators of the Muscle Study Group and Western ALS Consortium
Published: September 2018

Introduction: Rasagiline is a monoamine oxidase B (MAO‐B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). Methods: We performed a randomized, double‐blind, placebo‐controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale—Revised (ALSFRS‐R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse‐event reporting. Results: There was no difference in the average 12‐month ALSFRS‐R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug‐target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. Discussion: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201–207, 2019
Effects of Mechanical Stretching on the Properties of Conjugated Polymers: Case Study for MEH‐PPV and P3HT Oligomers
Authors: Roldao Juan Carlos , Batagin‐Neto Augusto , Lavarda Francisco Carlos , Sato Fernando
Published: September 2018

Nowadays, the development of new materials for applications in flexible optoelectronic devices is one of the main frontiers of science. However, in order to improve the applicability and durability of such devices, a deeper understanding of the effects induced by mechanical deformations on the properties of their components is still necessary. In this sense, in the present study, it is evaluated the effect of mechanical stretching in the structural, electronic, and optical responses of two widely investigated organic polymers with great technological interest: poly(2‐methoxy,5‐(2′‐ethylhexyloxy)‐1,4‐phenylene vinylene) and poly(3‐hexylthiophene‐2,5‐diyl). Hartree–Fock and density functional theory electronic structure calculation methods were employed for the study of oligomeric structures subjected to increasing stretch levels along the polymerization axis. The results show a dependence of the polymer properties with the mechanical deformation, allowing to identify distinct response regimes according to the main chain stretching. In particular, it is noticed that large stretches lead to nonfunctional devices, mainly due to the localization of the frontier orbitals and degradation of optoelectronic properties. In addition, it was also identified that very small deformations can lead to some interesting optoelectronic responses, which could indicate an alternative route for the design of organic devices via mechanical processes. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018, 56, 1413–1426
Novel film‐forming formulations of the biocontrol agent Candida sake CPA‐1: biocontrol efficacy and performance at field conditions in organic wine grapes
Authors: Carbó Anna , Torres Rosario , Usall Josep , Marín Anna , Chiralt Amparo , Teixidó Neus
Published: September 2018

BACKGROUND

The biocontrol agent (BCA) Candida sake CPA‐1 has previously effectively reduced Botrytis bunch rot (BBR) and it was also suggested as a promising strategy to control sour rot in grapes under field conditions. However, biocontrol efficacy of solid formulations of CPA‐1 has never been tested in field trials. The present study aims to confirm the efficacy against BBR and sour rot in grapes under field conditions of two novel formulations recently developed by the addition of biodegradable coatings using a fluidized‐bed spray‐drying system.

RESULTS

Novel film‐forming formulations of the BCA C. sake CPA‐1 controlled B. cinerea as well as liquid formulation. Sour rot control resulted better in the second season and severity reductions were more satisfactory than incidence control. Visual and cryoSEM observations revealed that film‐forming treatments were uniformly distributed on plant surfaces. CPA‐1 coating could be observed on grapes at harvest time.

CONCLUSION

The results of this work suggest that solid formulations would be a competitive alternative to conventional fungicides because they were easy to package and transport, and cell viability could be maintained for a long period of time. © 2018 Society of Chemical Industry
A comparison of hybrid variational data assimilation methods for global NWP
Authors: Lorenc Andrew C. , Jardak Mohamed
Published: September 2018

Variational data assimilation methods are reviewed and compared in the Met Office global numerical weather prediction system. This supports hybrid background‐error covariances which are a weighted combination of modelled static “climatological” covariances with covariances calculated from a current ensemble of forecasts, in both three‐ and four‐dimensional methods. For the latter, we compare the use of linear and adjoint models (hybrid‐4DVar) with the direct use of ensemble forecast trajectories (hybrid‐4DEnVar). Earlier studies had shown that hybrid‐4DVar outperforms hybrid‐4DEnVar, and 4DVar outperforms 3DVar. Improvements in the processing of ensemble covariances and computer enhancements mean we are now able to explore these comparisons for the full range of hybrid weights. We find that, using our operational 44‐member ensemble, the static covariance is still beneficial in hybrid‐4DVar, so that it significantly outperforms hybrid‐4DEnVar. In schemes not using linear and adjoint models, the static covariance is less beneficial. It is shown that the time‐propagated static covariance is the main cause of the better performance of 4DVar; when using pure ensemble covariances, 4DVar and 4DEnVar show similar skill. These results are consistent with nonlinear dynamics theory about assimilation in the unstable subspace.
A novel method to measure steroid hormone concentrations in walrus bone from archaeological, historical, and modern time periods using liquid chromatography/tandem mass spectrometry
Authors: Charapata Patrick , Horstmann Lara , Jannasch Amber , Misarti Nicole
Published: September 2018

Rationale

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was validated and utilized to measure and analyze four steroid hormones related to stress and reproduction in individual samples from a novel tissue, Pacific walrus (Odobenus rosmarus divergens, herein walrus) bone. This method determines steroid hormone concentrations in the remote walrus population over millennia from archaeological (>200 bp), historical (200–20 bp), and modern (2014–2016) time periods.

Methods

Lipids were extracted from walrus bone collected from these periods using methanol before LC/MS/MS analysis. Isotopically labeled internal standards for each target hormone were added to every sample. Analytical and physiological validations were performed. Additionally, a tissue comparison was done among paired walrus bone, serum, and blubber samples. A rapid resolution liquid chromatography system coupled to a QqQ mass spectrometer was used to analyze all samples after derivatization for progesterone, testosterone, cortisol, and estradiol concentrations. Multiple reaction monitoring was used for MS analysis and data were acquired in positive electrospray ionization mode.

Results

Progesterone, testosterone, cortisol, and estradiol were linear along their respective standard calibration curves based on their R2 values (all > 0.99). Accuracy ranged from 93–111% for all hormones. The recovery of extraction, recovery of hormones without matrix effect, was 92–101%. The overall process efficiency of our method for measuring hormones in walrus bone was 93–112%. Progesterone and testosterone concentrations were not affected by reproductive status among adult females and males, respectively. However, estradiol was different among pregnant and non‐pregnant adult females. Overall, steroid hormones reflect a long‐term reservoir in cortical bone. This method was also successfully applied to walrus bone as old as 3585 bp.

Conclusions

LC/MS/MS analysis of bone tissue (0.2–0.3 g) provides stress and reproductive data from elusive walruses that were alive thousands of years ago. Based on physiological validations, tissue comparison, and published literature, steroid hormone concentrations measured in walrus cortical bone could represent an accumulated average around a 10–20‐year time span. By investigating how stress and reproductive physiology may have changed over the past ~3000 years based on bone steroid hormone concentrations, this method will help answer how physiologically resilient walruses are to climate change in the Arctic.