bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic parameter estimates for gastrointestinal nematode parasite resistance and maternal efficiency indicator traits in Santa Inês breed
Authors: Berton Mariana P. , Silva Rosiane P. , Carvalho Felipe E. , Chiaia Hermenegildo Lucas Justino , Oliveira Priscila S. , Eler Joanir P. , Banchero Georgget , Ferraz José B. S. , Baldi Fernando
Published: July 2019

Infection with Haemonchus contortus is the most economically important gastrointestinal nematode parasitosis and the most important cause of mortality in sheep production. The aim of this study was to estimate variance components of gastrointestinal parasite resistance traits, maternal efficiency (ME) and ewe adult weight (AW) in Santa Inês breed in tropical conditions. The phenotypic records were collected from 700 animals, belonging to four flocks located south‐east and north‐east in Brazil. The evaluated traits were as follows: degree of anaemia assessed using the FAMACHA chart (FMC), haematocrit (HCT), white blood cell (WBC), red blood cell (RBC), haemoglobin (HGB), platelets (PLT), faecal egg count (EPGlog), ME, metabolic maternal efficiency (MME), AW and metabolic ewe adult weight (MAW). From the 700 animals, 576 (82% of the evaluated population) were genotyped with the Ovine SNP12k BeadChip (Illumina, Inc.). Markers with unknown genomic position, located on sex chromosomes, monomorphic, with minor allele frequency <0.05, call rate <90% and with excess heterozygosity were excluded. The variance components were estimated using a single‐trait animal model with ssGBLUP procedure. The correlation between the parasite's resistance indicators and the ME suggested that selecting animals with both higher adult weight and ME will also favour the selection of animals with better resistance to gastrointestinal nematodes parasites, specially H. contortus. Therefore, since there are few or no studies with Santa Inês breed in this area, it is important to study those traits to better manage selection programs.
An Empirical Assessment of the Influence of March and Simon’s Organizations: The Realized Contribution and Unfulfilled Promise of a Masterpiece
Authors: Anderson Marc H. , Lemken Russell K.
Published: July 2019

March and Simon’s Organizations is a seminal work in management studies. We assess the contribution Organizations has made to management studies through a citation context analysis of 1,400 articles from top management journals. By categorizing the content from Organizations cited in subsequent works, we find that two related categories associated with cognitive limits and routines or programs account for half (50.5%) of all citation contexts since 1990. We also investigate whether citations to Organizations have been peripheral or substantial to the citing authors’ claims, how cited content has changed over time, and the extent to which citing works have provided empirical evidence to test March and Simon’s propositions or have been critical of their assertions. Our investigation reveals disturbingly few attempts to empirically validate the assertions made in Organizations. Overall, we provide a critical reflection on how well subsequent scholarship fulfils the aims and promise heralded by this masterpiece.
A MYST family histone acetyltransferase, MoSAS3, is required for development and pathogenicity in the rice blast fungus
Authors: Dubey Akanksha , Lee Jongjune , Kwon Seomun , Lee Yong‐Hwan , Jeon Junhyun
Published: July 2019

Histone acetylation has been established as a principal epigenetic regulatory mechanism in eukaryotes. Sas3, a histone acetyltransferase belonging to the largest family of acetyltransferase, MYST, is the catalytic subunit of a conserved histone acetyltransferase complex. To date, the functions of Sas3 and its orthologues have been extensively studied in yeast, humans and flies in relation to global acetylation and transcriptional regulation. However, its precise impact on development and pathogenicity in fungal plant pathogens has yet to be elucidated. Considering the importance of Sas3 in H3K14 acetylation, here we investigate the roles of its orthologue in the rice blast fungus, Magnaporthe oryzae (Pyricularia oryzae). Unlike a previously reported Sas3 deletion in yeast, which led to no remarkable phenotypic changes, we found that MoSAS3 deletion alone had a profound effect on fungal growth and development, including asexual reproduction, germination and appressorium formation in M. oryzae. Such defects in pre‐penetration development resulted in complete loss of pathogenicity in the deletion mutant. Furthermore, genetic analysis of MoSAS3 and MoGCN5 encoding a Gcn5‐related N‐acetyltransferase family histone acetyltransferase suggested that two conserved components of histone acetylation are integrated differently into epigenetic regulatory mechanisms in the yeast and a filamentous fungus. RNA‐seq analysis of ΔMosas3 showed two general trends: many DNA repair and DNA damage response genes are up‐regulated, while carbon and nitrogen metabolism genes are down‐regulated in ΔMosas3. Our work demonstrates the importance of MYST family histone acetyltransferase as a developmental regulator and illuminates a degree of functional variation in conserved catalytic subunits among different fungal species.
Revisiting the classification of adhesion GPCRs
Authors: Scholz Nicole , Langenhan Tobias , Schöneberg Torsten
Published: July 2019

G protein–coupled receptors (GPCRs) are encoded by over 800 genes in the human genome. Motivated by different scientific rationales, the two classification systems that are mainly in use, the ABC and GRAFS systems, organize GPCRs according to their pharmacological features and phylogenetic relations, respectively. Within those systems, adhesion GPCRs (aGPCRs) constitute a group of over 30 mammalian homologs, most of which are still orphans with undefined activating signals and signal transduction properties. Previous efforts have further subdivided mammalian aGPCRs into nine subfamilies to indicate phylogenetic relationships. However, this subclassification scheme has shortcomings and inconsistencies that require attention. Here, we have reassessed the phylogenetic relationships of aGPCRs from vertebrate and invertebrate species. Our findings confirm that secretin receptor–like GPCRs most probably emerged from ancestral aGPCRs. We show that reassignment of several aGPCRs to families essentially requires input from functional data. Our analyses establish the need for introducing novel aGPCR subfamilies due to aGPCR sequences from invertebrate species that are not readily assignable to any existing subfamily. We conclude that the current classification systems ought to be updated to consider an unambiguous taxonomy of a hierarchically organized classification and pharmacological properties, and to accommodate phylogenetic affiliations between aGPCR genes within mammals and across the animal kingdom.
Base editing in crops: current advances, limitations and future implications
Authors: Mishra Rukmini , Joshi Raj Kumar , Zhao Kaijun
Published: July 2019

Targeted mutagenesis via genome‐editing technologies holds great promise in developing improved crop varieties to meet future demands. Point mutations or single nucleotide polymorphisms often determine important agronomic traits of crops. Genome‐editing‐based single‐base changes could generate elite trait variants in crop plants which help in accelerating crop improvement. Among the genome‐editing technologies, base editing has emerged as a novel and efficient genome‐editing approach which enables direct and irreversible conversion of one target base into another in a programmable manner. A base editor is a fusion of catalytically inactive CRISPR–Cas9 domain (Cas9 variants) and cytosine or adenosine deaminase domain that introduces desired point mutations in the target region enabling precise editing of genomes. In the present review, we have summarized the development of different base‐editing platforms. Then, we have focussed on the current advances and the potential applications of this precise technology in crop improvement. The review also sheds light on the limitations associated with this technology. Finally, the future perspectives of this emerging technology towards crop improvement have been highlighted.
Metabolic diversification of nitrogen‐containing metabolites by the expression of a heterologous lysine decarboxylase gene in Arabidopsis
Authors: Shimizu Yohei , Rai Amit , Okawa Yuko , Tomatsu Hajime , Sato Masaru , Kera Kota , Suzuki Hideyuki , Saito Kazuki , Yamazaki Mami
Published: July 2019

Lysine decarboxylase converts l‐lysine to cadaverine as a branching point for the biosynthesis of plant Lys‐derived alkaloids. Although cadaverine contributes towards the biosynthesis of Lys‐derived alkaloids, its catabolism, including metabolic intermediates and the enzymes involved, is not known. Here, we generated transgenic Arabidopsis lines by expressing an exogenous lysine/ornithine decarboxylase gene from Lupinus angustifolius (La‐L/ODC) and identified cadaverine‐derived metabolites as the products of the emerged biosynthetic pathway. Through untargeted metabolic profiling, we observed the upregulation of polyamine metabolism, phenylpropanoid biosynthesis and the biosynthesis of several Lys‐derived alkaloids in the transgenic lines. Moreover, we found several cadaverine‐derived metabolites specifically detected in the transgenic lines compared with the non‐transformed control. Among these, three specific metabolites were identified and confirmed as 5‐aminopentanal, 5‐aminopentanoate and δ‐valerolactam. Cadaverine catabolism in a representative transgenic line (DC29) was traced by feeding stable isotope‐labeled [α‐15N]‐ or [ε‐15N]‐l‐lysine. Our results show similar 15N incorporation ratios from both isotopomers for the specific metabolite features identified, indicating that these metabolites were synthesized via the symmetric structure of cadaverine. We propose biosynthetic pathways for the metabolites on the basis of metabolite chemistry and enzymes known or identified through catalyzing specific biochemical reactions in this study. Our study shows that this pool of enzymes with promiscuous activities is the driving force for metabolite diversification in plants. Thus, this study not only provides valuable information for understanding the catabolic mechanism of cadaverine but also demonstrates that cadaverine accumulation is one of the factors to expand plant chemodiversity, which may lead to the emergence of Lys‐derived alkaloid biosynthesis.
Reviewer Acknowledgements
Authors: Smith Robert
Published: July 2019

Journal of Education and Training Studies (JETS) would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether JETS publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue.Reviewers for Volume 7, Number 8 Gianpiero Greco, University of Study of Bari, ItalyGuilherme Tucher, Universidade Federal do Rio de Janeiro (UFRJ), BrazilIntakhab Khan, King Abdulaziz University, Saudi ArabiaJohn Cowan, Edinburgh Napier University, UKMatt Varacallo, University of Kentucky, USAMehmet Galip Zorba, Akdeniz University, TurkeyMichail Kalogiannakis, University of Crete, GreeceOzgur Demirtas, Inonu University, TurkeySelloane Pitikoe, University of Kwazulu-Natal, South AfricaShu-wen Lin, Sojo University, JapanVjacheslav Ivanovich Babich, Luhansk Taras Shevchenko National University, Ukraine Robert SmithEditorial AssistantOn behalf of,The Editorial Board of Journal of Education and Training StudiesRedfame Publishing9450 SW Gemini Dr. #99416Beaverton, OR 97008, USAURL: http://jets.redfame.com
Reviewer Acknowledgements
Authors: Walter Andrew
Published: July 2019

Studies in Engineering and Technology (SET) would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether SET publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue.Reviewers for Volume 6, Number 1 Hassan Shaaban, Atomic energy Authority, EgyptKrzysztof Wolk, Polish-Japanese Academy of Information Technology, PolandArnaud Duchosal, University of Montpellier, FranceHossam Zaqoot, Ministry of Environmental Affairs, GazaAlexander Pisarevskiy, Bauman Moscow State Tecnnical University, RussiaGirish Upreti, University of Tennessee, USAMartin Jaeger, Australian College of Kuwait, KuwaitHala Abd El Megeed, National Institute for Standards, EgyptMarco A Ruano, Economics Department Universidad Carlos III de Madrid, SpainSimona Rainis, International Research Center for Mountain, ItalyMahdieh Zabihimayvan, Wright State University, USAYi Zheng, National Institute for Occupational Safety and Health (NIOSH), USALoc Nguyen, Sunflower Soft Company, VietnamMohammad Reza Barati, Flinders University, Australia Andrew WalterEditorial AssistantStudies in Engineering and Technology-------------------------------------------Redfame Publishing9450 SW Gemini Dr. #99416Beaverton, OR 97008, USATel: 1-503-828-0536 ext. 504Fax: 1-503-828-0537E-mail: set@redfame.comURL: http://set.redfame.com
Reconfigurable topological insulator for elastic waves
Authors: Darabi Amir , Leamy Michael J.
Published: July 2019

Inspired by the quantum valley Hall effect, a mechanical topological insulator (TI) purposely built for reconfigurability is proposed and experimentally demonstrated. An aluminum plate serves as the host medium with periodically arranged voids and fixed inclusions used to break mirror symmetry. Reconfigurability is derived from the ability to easily alter the imperfection type (void or fixed inclusion) in any unit cell. The corresponding band structure of the proposed hexagonal unit cell is obtained using numerical means, which documents double-folded Dirac cones at the K-points. The breaking of mirror symmetry results in a topologically protected bandgap. Furthermore, topologically protected edge states (TPES) at the interface of two structures with opposite Chern numbers have been demonstrated numerically, and verified experimentally, for different desired trajectories. These TPES are robust against backscattering at defect locations and sharp bends. The proposed reconfigurable TI can be a stepping-stone platform toward building mechanical logic and circuits, which have advantages over electronic equivalents in harsh operating conditions, or to replace wireless systems near dead-zones of metallic and carbon fiber structures.
Non-reciprocal wave propagation in mechanically-modulated continuous elastic metamaterials
Authors: Goldsberry Benjamin M. , Wallen Samuel P. , Haberman Michael R.
Published: July 2019

Acoustic and elastic metamaterials with time- and space-dependent effective material properties have recently received significant attention as a means to induce non-reciprocal wave propagation. Recent analytical models of spring-mass chains have shown that external application of a nonlinear mechanical deformation, when applied on time scales that are slow compared to the characteristic times of propagating linear elastic waves, may induce non-reciprocity via changes in the apparent elastic modulus for perturbations around that deformation. Unfortunately, it is rarely possible to derive analogous analytical models for continuous elastic metamaterials due to complex unit cell geometry. The present work derives and implements a finite element approach to simulate elastic wave propagation in a mechanically-modulated metamaterial. This approach is implemented on a metamaterial supercell to account for the modulation wavelength. The small-on-large approximation is utilized to separate the nonlinear mechanical deformation (the “large” wave) from superimposed linear elastic waves (the “small” waves), which are then analyzed via Bloch wave analysis with a Fourier expansion in the harmonics of the modulation frequency. Results on non-reciprocal wave propagation in a negative stiffness chain, a structure exhibiting large stiffness modulations due to the presence of mechanical instabilities, are then shown as a case example.
A new approach to local drug delivery bubbling under the surface
Authors: O’Cearbhaill Eoin
Published: July 2019

Ultrasound is coupled with a needle-based minimally invasive electrode to enhance targeted drug delivery to superficial tumors.
Whole-Genome Sequences of Two Multidrug-Resistant Acinetobacter baumannii Strains Isolated from Patients with Urinary Tract Infection in Ghana
Authors: Agyepong Nicholas , Govinden Usha , Owusu-Ofori Alex , Allam Mushal , Ismail Arshad , Pedersen Torunn , Sundsfjord Arnfinn , Essack Sabiha
Published: July 2019

Multidrug-resistant
Acinetobacter baumannii
is a major nosocomial pathogen. We describe the whole-genome sequences of two multidrug-resistant
Acinetobacter baumannii
strains isolated from hospitalized patients in the intensive care unit at Komfo Anokye Teaching Hospital in Ghana. The isolates carry multiple resistance genes, including those for β-lactams, sulfonamides, aminoglycosides, and tetracycline.
Metagenome-Assembled Genome Sequence of
Sulfuricurvum
sp. Strain IAE1, Isolated from a 4-Chlorophenol-Degrading Consortium
Authors: Li Xiuying , Yang Yi , Zeng Xiangfeng , Wang Jingjing , Jin Huijuan , Sheng Zhi , Yan Jun
Published: July 2019

The draft genome sequence of
Sulfuricurvum
sp. strain IAE1 was assembled and annotated from the metagenome of an anaerobically grown 4-chlorophenol-degrading consortium. The draft genome size is 2,338,235 bp with a G+C content of 52.6%.
De Novo
Genome Sequence of a
Fusarium xylarioides
Race Pathogenic to Robusta Coffee (
Coffea canephora
) in Uganda
Authors: Olal Sammy , Bitalo Daphne N. , Olango Nicholas D. , Mulindwa Julius , Ochwo Silver , Opiyo Stephen Obol , Arinaitwe Geoffrey , Ogwok Emmanuel
Published: July 2019

Here, we report the first whole-genome assembly of a
Fusarium xylarioides
race pathogenic to robusta coffee in Uganda. It comprises 55,122,624 bases and 14,552 genes. Gene ontology analysis assigned 5,720 genes to biological processes, 4,545 genes to cellular components, and 6,021 genes to molecular function.
Draft Genome Sequence of the Necrotrophic Plant-Pathogenic Bacterium Pectobacterium carotovorum subsp. carotovorum Strain LMG 2410
Authors: Rooney William M. , Wojnowska Marta , Walker Daniel
Published: July 2019

Here, we report the draft genome sequence of
Pectobacterium carotovorum
subsp.
carotovorum
strain LMG 2410, isolated from cucumber in the United Kingdom. The draft genome is 4,773,000 bp, with a G+C content of 51.9%, and carries a total of 4,536 coding sequences.
Metagenomic Analysis Reveals a Nearly Complete Genome Sequence of
Alfalfa Mosaic Virus
from a Field Pea in Australia
Authors: Maina S. , Zheng L. , Kinoti W. M. , Aftab M. , Nancarrow N. , Trębicki P. , King S. , Constable F. , Rodoni B.
Published: July 2019

Here, we report the first nearly complete genome sequence of
Alfalfa mosaic virus
(AMV) obtained from a symptomatic field pea sample (Aus295) in Australia. Its genome RNA1 and RNA2 segments resembled those of the Argentinian isolate Manfredi, with 99.4% and 96.7% nucleotide (nt) identity, respectively; its RNA3 segment resembled that of Chinese isolate AMV-Gyn, with 99.6% nt identity.
Health at the writing desk of John Ruskin: a study of handwriting and illness
Authors: Thorpe Deborah E , Alty Jane E , Kempster Peter A
Published: July 2019

Though John Ruskin (1819–1900) is remembered principally for his work as a theorist, art critic and historian of visual culture, he wrote exhaustively about his health in his correspondence and diaries. Ruskin was prone to recurring depressive and hypochondriacal feelings in his youth and adulthood. In 1871, at the age of 52 years, he developed an illness with relapsing psychiatric and neurological features. He had a series of attacks of brain disturbance, and a deterioration of his mental faculties affected his writing for years before curtailing his career a decade before he died. Previous writers have suggested he had a psychiatric malady, perhaps schizophrenia or schizoaffective disorder. But the more obvious conclusion from a close medical reading of Ruskin’s descriptions of his illness is he had some sort of ‘organic’ brain illness. This paper aims to give insight into the relationship between Ruskin’s state of well-being and the features of his writing through a palaeographical study of his letters and diary entries. We examine the handwriting for physical traces of Ruskin’s major brain illness, guided by the historical narrative of the illness. We also examine Ruskin’s recording of his experiences for what they reveal about the failure of his health and its impact on his work. Ruskin’s handwriting does not have clear-cut pathological features before around 1885, though suggestions of subtle writing deficits were present as early as 1876. After 1887, Ruskin’s handwriting shows fixed pathological signs—tremor, disturbed letter formation and features that reflect a slow and laborious process of writing. These observations are more than could be explained by normal ageing, and suggest the presence of a neurological deficit affecting writing control. Our findings are consistent with conclusions that we drew from the historical record—that John Ruskin had an organic neurological disorder with cognitive, behavioural, psychiatric and motor effects.
Combined consumption of a single high-dose vitamin A supplement with provision of vitamin A fortified oil to households maintains adequate milk retinol concentrations for 6 months in lactating Moroccan women
Authors: Atalhi Naima , El Hamdouchi Asmaa , Barkat Amina , Elkari Khalid , Hamrani Abdeslam , El Mzibri Mohammed , Haskell Marjorie J. , Mokhtar Najat , Aguenaou Hassan
Published: July 2019

In Morocco, postpartum women systematically receive a single, high dose of vitamin A (VA; 200 000 IU) within the first month of giving birth and vegetable oil is fortified to increase the VA intake. The efficacy of this combined approach of supplementation and fortification for increasing maternal VA status during lactation is not known. The purpose of the study is to evaluate the effect of postpartum high dose VA supplementation and provision of VA fortified oil for household consumption on plasma and milk retinol concentrations of lactating Moroccan women during the first 6 months after giving birth. Postpartum women aged 19–40 years received a VA supplement and thereafter were randomly assigned to one of two groups to receive weekly vitamin A fortified oil (FO) or non-fortified oil (NFO) for 6 months. Serum retinol concentration was higher in the FO group than in the NFO group at 6 months after giving birth (p < 0.0001). Milk retinol per gram fat at baseline did not differ by group; by 3 months after giving birth, milk retinol per gram fat was higher in the FO group than in the NFO group (p = 0.02) and remained higher throughout the 6 months (p < 0.0001). The combination of supplementation and fortification has a more sustained impact on milk retinol concentrations than supplementation alone, which did not have a sustained impact on milk VA concentrations. The fortification approach seems to be more effective for maintaining adequate milk VA concentrations among lactating Moroccan women. Fortification seems to be a long-term solution for the problem of VA deficiency, especially among women in low-income communities.
Channel geomorphology differences between stream reaches with grass- or tree-dominated riparian vegetation in southern Manitoba
Authors: Satchithanantham Sanjayan , Wilson Henry F. , Michiels Patsy , Dubois Melanie , Li Sheng , Koiter Alexander J.
Published: July 2019

Removal of trees for pasture or crop production is common along the stream reaches in the Canadian Prairies, resulting in a patchwork of forested and nonforest riparian vegetation along most streams. The effect of vegetation type on channel geomorphology and potential to influence sediment dynamics was studied using eight paired reaches (forested and nonforest) within agricultural watersheds in southern Manitoba, Canada. High potential for bank erosion was observed at all sites (bank erosion hazard index scores), but Pfankuch channel stability scores were significantly higher for forested reaches compared with nonforested reaches. Furthermore, forested reaches had higher width to depth ratios, but flood-prone widths did not differ significantly, resulting in lower entrenchment ratios. Reduced channel width and cross-sectional area in nonforested reaches created an overall reduction of in-stream habitat, increased velocity, and increased potential for exceedance of channel capacity and floodplain access during high-flow events. Channel widening in response to riparian afforestation efforts has been observed in a variety of other locations globally and the results of this study suggest that widening with afforestation can still be anticipated in this region where stream gradients are low, hydrology is dominated by snowmelt, and forest cover is minimal.
Chaotic image encryption algorithm based on pseudo-random bit sequence and DNA plane
Authors: Wang Xingyuan , Zhao Hongyu , Hou Yutao , Luo Chao , Zhang Yingqian , Wang Chunpeng
Published: July 2019

In this paper, a new chaotic image encryption algorithm based on pseudo-random bit sequence and DNA plane is proposed. The coupled map lattice (CML) is applied to design a pseudo-random bit sequence generation (PBSG) system and use the system to generate the random sequence needed in the encryption process. The initial values and parameters of the system are generated by the SHA-256 hash algorithm combined with given keys. Firstly, the plane image is decomposed into four DNA planes in combination with the DNA encoding rules, and then the four DNA planes are subjected to row circular permutation and column circular permutation. After that, the diffusion operation on each DNA plane is performed. Finally, the four DNA planes are decoded and then combined into a pixel matrix, that is, the final cipher image is obtained. Throughout the encryption process, the choice of DNA encoding and decoding rules is determined by the PBSG system. Simulation results and security analysis show that the algorithm not only has good encryption effect, but also can resist various classic attacks, and has excellent security performance.
Orexins alleviate motor deficits via increasing firing activity of pallidal neurons in a mouse model of Parkinson’s disease
Authors: Wang Ying , Chen An-Qi , Xue Yan , Liu Mei-Fang , Liu Cui , Liu Yun-Hai , Pan Yi-Peng , Diao Hui-Ling , Chen Lei
Published: July 2019

Orexin is a peptide neurotransmitter released in the globus pallidus. Morphological evidence reveals that both orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) exist in the globus pallidus. Here we showed that bilateral microinjection of both orexin-A and orexin-B into the globus pallidus alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Further in vivo extracellular single-unit recording revealed that the basal spontaneous firing rate of the globus pallidus neurons in MPTP parkinsonian mice was slower than that of normal mice. Application of orexin-A or orexin-B significantly increased the spontaneous firing rate of pallidal neurons. The influx of Ca2+ through the L-type Ca2+ channel is the major mechanism involved in orexin-induced excitation in the globus pallidus. Orexin-A-induced increase in firing rate of pallidal neurons in MPTP parkinsonian mice was stronger than that of normal mice. Orexin-A exerted both electrophysiological and behavioral effects mainly via OX1R, and orexin-B exerted the effects via OX2R. Endogenous orexins modulated the excitability of globus pallidus neurons mainly through OX1R. The present behavioral and electrophysiological results suggest that orexins ameliorate parkinsonian motor deficits through increasing the spontaneous firing of globus pallidus neurons.
The lipidated connexin mimetic peptide SRPTEKT-Hdc is a potent inhibitor of Cx43 channels with specificity for the pS368 phospho-isoform
Authors: Cotter Maura L. , Boitano Scott , Lampe Paul D. , Solan Joell L. , Vagner Josef , Ek-Vitorin Jose F. , Burt Janis M.
Published: July 2019

Connexin (Cx) mimetic peptides derived from extracellular loop II sequences (e.g., Gap27: SRPTEKTIFII; Peptide5: VDCFLSRPTEKT) have been used as reversible, Cx-specific blockers of hemichannel (HCh) and gap junction channel (GJCh) function. These blockers typically require high concentrations (~5 µM, <1 h for HCh; ~100 µM, >1 h for GJCh) to achieve inhibition. We have shown that addition of a hexadecyl ( Hdc) lipid tail to the conserved SRPTEKT peptide sequence (SRPTEKT- Hdc) results in a novel, highly efficacious, and potent inhibitor of mechanically induced Ca2+-wave propagation (IC50 64.8 pM) and HCh-mediated dye uptake (IC50 45.0 pM) in Madin-Darby canine kidney cells expressing rat Cx43 (MDCK43). The lack of similar effect on dye coupling (NBD-MTMA) suggested channel conformation-specific inhibition. Here we report that SRPTEKT- Hdc inhibition of Ca2+-wave propagation, dye coupling, and dye uptake depended on the functional configuration of Cx43 as determined by phosphorylation at serine 368 (S368). Ca2+-wave propagation was enhanced in MDCK cells expressing single-site mutants of Cx43 that mimicked (MDCK43-S368D) or favored (MDCK43-S365A) phosphorylation at S368. Furthermore, SRPTEKT- Hdc potently inhibited GJCh-mediated Ca2+-wave propagation (IC50 230.4 pM), dye coupling, and HCh-mediated dye uptake in MDCK43-S368D and -S365A cells. In contrast, Ca2+-wave propagation, dye coupling, and dye uptake were largely unaffected (IC50 12.3 μM) by SRPTEKT- Hdc in MDCK43-S368A and -S365D cells, mutations that mimic or favor dephosphorylation at S368. Together, these data indicate that SRPTEKT- Hdc is a potent inhibitor of physiological Ca2+-wave signaling mediated specifically by the pS368 phosphorylated form of Cx43.
The N6-methyladenosine (m6A)-forming enzyme METTL3 facilitates M1 macrophage polarization through the methylation of STAT1 mRNA
Authors: Liu Yihan , Liu Zhujiang , Tang Hao , Shen Yicong , Gong Ze , Xie Nan , Zhang Xu , Wang Wengong , Kong Wei , Zhou Yuan , Fu Yi
Published: July 2019

Compelling evidence indicates that epigenetic regulations orchestrate dynamic macrophage polarization. N6-methyladenosine (m6A) methylation is the most abundant epigenetic modification of mammalian mRNA, but its role in macrophage polarization is still completely unknown. Here, we show that the m6A-catalytic enzyme methyltransferase like 3 (METTL3) is specifically upregulated following the M1 polarization of mouse macrophages. Furthermore, METTL3 knockdown through siRNA transfection markedly inhibited M1, but enhanced M2, macrophage polarization. Conversely, its overexpression via plasmid transfection greatly facilitated M1, but attenuated M2, macrophage polarization. Further methylated RNA immunoprecipitation and in vitro m6A methylation assays suggested that METTL3 directly methylates mRNA encoding signal transducer and activator of transcription 1 (STAT1), a master transcription factor controlling M1 macrophage polarization, at its coding sequence and 3′-untranslated regions. In addition, METTL3-mediated STAT1 mRNA methylation significantly increased mRNA stability and subsequently upregulated STAT1 expression. In conclusion, METTL3 drives M1 macrophage polarization by directly methylating STAT1 mRNA, potentially serving as an anti-inflammatory target.
Influences of hypobaric hypoxia on skin blood flow and sweating responses during exercise in neutral and hot environments
Authors: Charkoudian Nisha , Mitchell Katherine M. , Yurkevicius Beau R. , Luippold Adam J. , Bradbury Karleigh E. , Kenefick Robert W.
Published: July 2019

Exposure to hot environments augments cutaneous vasodilation and sweating during exercise compared with these responses in cooler environments. The effects of hypobaric hypoxia on these responses are less clear, as are the effects of heat and simulated altitude combined. We evaluated the individual and potential additive effects of environmental heat and hypobaric hypoxia on skin blood flow and sweating responses during exercise. Thirteen volunteers (11 M, 2 F; age 25.3 ± 6.1 yr; height 177 ± 9 cm; weight 81.2 ± 16.8 kg) completed 30 min of steady-state (SS) exercise on a cycle ergometer at 50% V̇o2peak during four separate conditions: 1) sea level thermoneutral (SLTN; 250 m, 20°C, 30–50% RH), 2) sea level hot (SLH; 250 m, 35°C, 30% RH), 3) simulated altitude thermoneutral (ATN; 3,000 m, 20°C, 30–50% RH), and 4) simulated altitude hot (AH; 3,000 m, 35°C, 30% RH). Skin blood flow and local sweating rate (LSR) were recorded on the ventral forearm. During exercise, SS cutaneous vascular conductance in AH (63 ± 31% peak) and SLH (52 ± 19% peak) were significantly higher than both SLTN (20 ± 9% peak, P < 0.001) and ATN (25 ± 12% peak, P < 0.05) but were not different from each other ( P > 0.05). SS LSR was similarly increased in the hot environments but unaffected by simulated altitude. We propose that multiple antagonistic mechanisms during exposure to 3,000-m simulated altitude result in no net effect on skin blood flow or sweating responses during exercise in thermoneutral or hot environments.
Mg2+restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia
Authors: Ferdaus Mohammed Z. , Mukherjee Anindit , Nelson Jonathan W. , Blatt Philip J. , Miller Lauren N. , Terker Andrew S. , Staub Olivier , Lin Dao-Hong , McCormick James A.
Published: July 2019

Hypomagnesemia is associated with reduced kidney function and life-threatening complications and sustains hypokalemia. The distal convoluted tubule (DCT) determines final urinary Mg2+excretion and, via activity of the Na+-Cl−cotransporter (NCC), also plays a key role in K+homeostasis by metering Na+delivery to distal segments. Little is known about the mechanisms by which plasma Mg2+concentration regulates NCC activity and how low-plasma Mg2+concentration and K+concentration interact to modulate NCC activity. To address this, we performed dietary manipulation studies in mice. Compared with normal diet, abundances of total NCC and phosphorylated NCC (pNCC) were lower after short-term (3 days) or long-term (14 days) dietary Mg2+restriction. Altered NCC activation is unlikely to play a role, since we also observed lower total NCC abundance in mice lacking the two NCC-activating kinases, STE20/SPS-1-related proline/alanine-rich kinase and oxidative stress response kinase-1, after Mg2+restriction. The E3 ubiquitin-protein ligase NEDD4-2 regulates NCC abundance during dietary NaCl loading or K+restriction. Mg2+restriction did not lower total NCC abundance in inducible nephron-specific neuronal precursor cell developmentally downregulated 4-2 (NEDD4-2) knockout mice. Total NCC and pNCC abundances were similar after short-term Mg2+or combined Mg2+-K+restriction but were dramatically lower compared with a low-K+diet. Therefore, sustained NCC downregulation may serve a mechanism that enhances distal Na+delivery during states of hypomagnesemia, maintaining hypokalemia. Similar results were obtained with long-term Mg2+-K+restriction, but, surprisingly, NCC was not activated after long-term K+restriction despite lower plasma K+concentration, suggesting significant differences in distal tubule adaptation to acute or chronic K+restriction.
Cell-free hemoglobin augments acute kidney injury during experimental sepsis
Authors: Shaver Ciara M. , Paul Melinda G. , Putz Nathan D. , Landstreet Stuart R. , Kuck Jamie L. , Scarfe Lauren , Skrypnyk Nataliya , Yang Haichun , Harrison Fiona E. , de Caestecker Mark P. , Bastarache Julie A. , Ware Lorraine B.
Published: July 2019

Acute kidney injury is a common complication of severe sepsis and contributes to high mortality. The molecular mechanisms of acute kidney injury during sepsis are not fully understood. Because hemoproteins, including myoglobin and hemoglobin, are known to mediate kidney injury during rhabdomyolysis, we hypothesized that cell-free hemoglobin (CFH) would exacerbate acute kidney injury during sepsis. Sepsis was induced in mice by intraperitoneal injection of cecal slurry (CS). To mimic elevated levels of CFH observed during human sepsis, mice also received a retroorbital injection of CFH or dextrose control. Four groups of mice were analyzed: sham treated (sham), CFH alone, CS alone, and CS + CFH. The addition of CFH to CS reduced 48-h survival compared with CS alone (67% vs. 97%, P = 0.001) and increased the severity of illness. After 24 and 48 h, CS + CFH mice had a reduced glomerular filtration rate from baseline, whereas sham, CFH, and CS mice maintained baseline glomerular filtration rate. Biomarkers of acute kidney injury, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), were markedly elevated in CS+CFH compared with CS (8-fold for NGAL and 2.4-fold for KIM-1, P < 0.002 for each) after 48 h. Histological examination showed a trend toward increased tubular injury in CS + CFH-exposed kidneys compared with CS-exposed kidneys. However, there were similar levels of renal oxidative injury and apoptosis in the CS + CFH group compared with the CS group. Kidney levels of multiple proinflammatory cytokines were similar between CS and CS + CFH groups. Human renal tubule cells (HK-2) exposed to CFH demonstrated increased cytotoxicity. Together, these results show that CFH exacerbates acute kidney injury in a mouse model of experimental sepsis, potentially through increased renal tubular injury.
Metabolic constraints on synaptic learning and memory
Authors: Karbowski Jan
Published: July 2019

Dendritic spines, the carriers of long-term memory, occupy a small fraction of cortical space, and yet they are the major consumers of brain metabolic energy. What fraction of this energy goes for synaptic plasticity, correlated with learning and memory? It is estimated here based on neurophysiological and proteomic data for rat brain that, depending on the level of protein phosphorylation, the energy cost of synaptic plasticity constitutes a small fraction of the energy used for fast excitatory synaptic transmission, typically 4.0–11.2%. Next, this study analyzes a metabolic cost of new learning and its memory trace in relation to the cost of prior memories, using a class of cascade models of synaptic plasticity. It is argued that these models must contain bidirectional cyclic motifs, related to protein phosphorylation, to be compatible with basic thermodynamic principles. For most investigated parameters longer memories generally require proportionally more energy to store. The exceptions are the parameters controlling the speed of molecular transitions (e.g., ATP-driven phosphorylation rate), for which memory lifetime per invested energy can increase progressively for longer memories. Furthermore, in general, a memory trace decouples dynamically from a corresponding synaptic metabolic rate such that the energy expended on new learning and its memory trace constitutes in most cases only a small fraction of the baseline energy associated with prior memories. Taken together, these empirical and theoretical results suggest a metabolic efficiency of synaptically stored information.

NEW & NOTEWORTHY Learning and memory involve a sequence of molecular events in dendritic spines called synaptic plasticity. These events are physical in nature and require energy, which has to be supplied by ATP molecules. However, our knowledge of the energetics of these processes is very poor. This study estimates the empirical energy cost of synaptic plasticity and considers theoretically a metabolic rate of learning and its memory trace in a class of cascade models of synaptic plasticity.
Simultaneous Determination of Over-the-Counter Pain Relievers in Commercial Pharmaceutical Products Utilizing Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) Multivariate Calibration Model
Authors: Shaaban Heba , Mostafa Ahmed , Almatar Zahra , Alsheef Reem , Alrubh Safia
Published: July 2019

The quality of over-the-counter (OTC) pain relievers is important to ensure the safety of the marketed products in order to maintain the overall health care of patients. In this study, the multivariate curve resolution-alternating least squares (MCR-ALS) chemometric method was developed and validated for the resolution and quantification of the most commonly consumed OTC pain relievers (acetaminophen, acetylsalicylic acid, ibuprofen, naproxen, and caffeine) in commercial drug formulations. The analytical performance of the developed chemometric methods such as root mean square error of prediction, bias, standard error of prediction, relative error of prediction, and coefficients of determination was calculated for the developed model. The obtained results are linear with concentration in the range of 0.5–7 μg/mL for acetaminophen and 0.5–3.5 and 0.5–3 μg/mL for naproxen and caffeine, respectively, while the linearity ranges for acetyl salicylic acid and ibuprofen were 1–15 μg/mL. High values of coefficients of determination ≥0.9995 reflected high predictive ability of the developed model. Good recoveries ranging from 98.0% to 99.7% were obtained for all analytes with relative standard deviations (RSDs) not higher than 1.62%. The optimized method was successfully applied for the analysis of the studied drugs either in their single or coformulated pharmaceutical products without any separation step. The optimized method was also compared with a reported HPLC method using paired t-test and F-ratio at 95% confidence level, and the results showed no significant difference regarding accuracy and precision. The developed method is eco-friendly, simple, fast, and amenable for routine analysis. It could be used as a cost-effective alternative to chromatographic techniques for the analysis of the studied drugs in commercial formulations.
Antibacterial Activity of BSA-Capped Gold Nanoclusters against Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Intermediate Staphylococcus aureus (VISA)
Authors: Kuo Shu-Hua , Chien Chi-Sheng , Wang Chun-Chi , Shih Chi-Jen
Published: July 2019

The emergence of drug-resistant pathogens and the abuse of antibiotics have posed dominant threats to society. In this study, we propose an antibacterial use of bovine serum albumin-capped gold nanoclusters (BSA-AuNCs) to address the issue. BSA-AuNCs have a great antibacterial activity against MRSA and VISA which is proved by time-killing curves (TKC). The possible antibacterial mechanisms of BSA-AuNCs against MRSA and VISA are confirmed by fluorescence image observation.
Disturbance Rejection in a One‐Half Semiactive Vehicle Suspension by means of a Fuzzy-H∞ Controller
Authors: Félix-Herrán L. C. , Mehdi Driss , Rodríguez-Ortiz José de Jesús , Benitez Victor H. , Ramirez‐Mendoza Ricardo A. , Soto Rogelio
Published: July 2019

A fuzzy-H∞ control, improved with weighting functions, has been designed and applied to a novel model of a one‐half semiactive lateral vehicle (OHSLV) suspension. The herein contribution resides in the development and computation of an H∞ controller with parallel distributed compensation (PDC) designed from a highly nonlinear system modelled via the Takagi–Sugeno (T‐S) fuzzy approach. A fuzzy-H∞ controller is synthesized for an OHSLV T‐S fuzzy model of a suspension with two magnetorheological (MR) dampers including actuators’ nonlinear dynamics. The realism of results has been improved by considering the MR damper’s behaviours (viscoplasticity, hysteresis, and saturation) and the handling of the phase angle of the sinusoidal disturbance, not included in other reported work. Time‐domain tests remark transient time achievements, whereas precise performance criterion indices in the frequency domain are employed to assess the generated outcomes. The proposed solution complies with all performance criteria compared with a benchmark passive average suspension that fails in satisfying most of the performance criteria.
IGF-1R Inhibition Suppresses Cell Proliferation and Increases Radiosensitivity in Nasopharyngeal Carcinoma Cells
Authors: Wang Zhe , Liu Guangyan , Mao Jiwei , Xie Min , Zhao Ming , Guo Xuefen , Liang Shanshan , Li Heming , Li Xuefeng , Wang Ruoyu
Published: July 2019

Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC) treatment, radioresistance is still a major threat for some subsets of patients. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is tightly regulated and plays critical roles in mediating cell proliferation, growth, and survival. Thus, IGF-1R may be a potential therapeutic target for patients with different malignancies. However, its mechanism in NPC is not fully investigated. Linsitinib is an oral small molecule and is a tyrosine kinase inhibitor (TKI) of IGF-1R, which has been known for antitumor effects used widely. Here, we evaluated the proliferation and radiosensitivity of NPC cell lines (CNE-2 and SUNE-1) after linsitinib treatment. We found that linsitinib suppresses IGF-1-induced cell proliferation through inhibiting Akt and ERK phosphorylation. Moreover, linsitinib further boosted IR-induced DNA damage, G2-M cell cycle delay, and apoptosis in NPC cells. Finally, linsitinib reversed radioresistant NPC cells by decreasing the phosphorylation of IGF-1R. Our data indicated that the combination of linsitinib and IR and targeting IGF-1R by linsitinib could be a promising therapeutic strategy for NPC.
Isorhamnetin Inhibits Liver Fibrosis by Reducing Autophagy and Inhibiting Extracellular Matrix Formation via the TGF-β1/Smad3 and TGF-β1/p38 MAPK Pathways
Authors: Liu Ning , Feng Jiao , Lu Xiya , Yao Zhilu , Liu Qing , Lv Yang , Han Yuru , Deng Jingfan , Zhou Yingqun
Published: July 2019

Objective. Liver fibrosis is a consequence of wound-healing responses to chronic liver insult and may progress to liver cirrhosis if not controlled. This study investigated the protection against liver fibrosis by isorhamnetin. Methods. Mouse models of hepatic fibrosis were established by intraperitoneal injection of carbon tetrachloride (CCl4) or bile duct ligation (BDL). Isorhamnetin 10 or 30 mg/kg was administered by gavage 5 days per week for 8 weeks in the CCl4 model and for 2 weeks in the BDL model. Protein and mRNA expressions were assayed by western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. Results. Isorhamnetin significantly inhibited liver fibrosis in both models, inhibiting hepatic stellate cell (HSC) activation, extracellular matrix (ECM) deposition, and autophagy. The effects were associated with downregulation of transforming growth factor β1 (TGF-β1) mediation of Smad3 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Conclusion. Isorhamnetin protected against liver fibrosis by reducing ECM formation and autophagy via inhibition of TGF-β1-mediated Smad3 and p38 MAPK signaling pathways.