bluuebunny/crossref_metadata_2025 huggingface dataset:
Thyrotropin‐releasing hormone (TRH) in the brain and pituitary of the teleost, Clarias batrachus and its role in regulation of hypophysiotropic dopamine neurons
Authors: Singh Omprakash , Pradhan Dipti R. , Nagalakashmi B. , Kumar Santosh , Mitra Saptarsi , Sagarkar Sneha , Sakharkar Amul J. , Lechan Ronald M. , Singru Praful S.
Published: October 2018

Thyrotropin‐releasing hormone (TRH) regulates the hypothalamic–pituitary–thyroid axis in mammals and also regulates prolactin secretion, directly or indirectly via tuberoinfundibular dopamine neurons. Although TRH is abundantly expressed in teleost brain and believed to mediate neuronal communication, empirical evidence is lacking. We analyzed pro‐TRH‐mRNA expression, mapped TRH‐immunoreactive elements in the brain and pituitary, and explored its role in regulation of hypophysiotropic dopamine (DA) neurons in the catfish, Clarias batrachus. Partial pro‐TRH transcript from C. batrachus transcriptome showed six TRH progenitors repeats. Quantitative real‐time polymerase chain reaction (qRT‐PCR) identified pro‐TRH transcript in a number of different brain regions and immunofluorescence showed TRH‐immunoreactive cells/fibers in the olfactory bulb, telencephalon, preoptic area (POA), hypothalamus, midbrain, hindbrain, and spinal cord. In the pituitary, TRH‐immunoreactive fibers were seen in the neurohypophysis, proximal pars distalis, and pars intermedia but not rostral pars distalis. In POA, distinct TRH‐immunoreactive cells/fibers were seen in nucleus preopticus periventricularis anterior (NPPa) that demonstrated a significant increase in TRH‐immunoreactivity when collected during preparatory and prespawning phases, reaching a peak in the spawning phase. Although tyrosine hydroxylase (TH)‐immunoreactive neurons in NPPa are hypophysiotropic, none of the TRH‐immunoreactive neurons in NPPa accumulated neuronal tracer DiI following implants into the pituitary. However, 87 ± 1.6% NPPa TH‐immunoreactive neurons were surrounded by TRH‐immunoreactive axons that were seen in close proximity to the somata. Superfused POA slices treated with TRH (0.5–2 μM) significantly reduced TH concentration in tissue homogenates and the percent TH‐immunoreactive area in the NPPa. We suggest that TRH in the brain of C. batrachus regulates a range of physiological functions but in particular, serves as a potential regulator of hypophysiotropic DA neurons and reproduction.
Terabit encryption in a second: Performance evaluation of block ciphers in GPU with Kepler, Maxwell, and Pascal architectures
Authors: Lee Wai‐Kong , Goi Bok‐Min , Phan Raphael C.‐W.
Published: October 2018

With the emergence of IoT and cloud computing technologies, massive data are generated from various applications everyday and communicated through the Internet. Secure communication is essential to protect these data from malicious attacks. Block ciphers are one mechanism to offer such protection but unfortunately involve intensive computations that can be performance bottlenecks to the servers, especially when the data center needs to handle thousands of concurrent transactions. In this paper, we investigate the feasibility of the GPU as an accelerator to perform high‐speed encryption in server environments. We present optimized implementations of a conventional block cipher (AES) and new lightweight block ciphers (LEA, Chaskey, SIMON, SPECK, and SIMECK) across three new GPU architectures (Kepler, Maxwell, and Pascal). For AES, we improve the fine‐grain implementation by utilizing the warp shuffle instruction available in these three new GPU architectures, which yield a 6%‐16% improvement over the previous implementations. For LEA, Chaskey, SIMON, SPECK, and SIMECK, we first analyze why they cannot have efficient fine‐grain implementations in the GPU and then present our optimization techniques, which are able to achieve impressive encryption speeds of 1.912, 637, 1.485, 2.291, and 1.478 Tb/s, respectively, in GTX1080.
Hydroxyl Groups of Exceptionally High Acidity in Desilicated Zeolites Y
Authors: Gackowski Mariusz , Kuterasiński Łukasz , Podobiński Jerzy , Datka Jerzy
Published: October 2018

The desilication of dealuminated zeolite Y in NaOH/tetrabutylammonium hydroxide mixtures produces hierarchical zeolite Y containing a micropore system as well as mesopores of significant volume and surface. IR studies evidenced that a new kind of hydroxyls was formed if desilication was realized above 318 K. This new kind of acidic hydroxyls is characterized by IR band at 3600 cm−1. IR studies showed, that these new hydroxyls showed extremely high acidity. This was evidenced by very high frequency shifts of IR bands of OH interacting with probe molecules: CO and N2:
=411 cm−1 and
=164 cm−1, resp. These frequency shift are the highest in all the chemistry of zeolites including very strongly acidic dealuminated mazzite and steamed zeolite USY (
=ca. 380 cm−1) indicating that 3600 cm−1 hydroxyls are the most acidic in all the zeolites.
Antibiotics as both friends and foes of the human gut microbiome: The microbial community approach
Authors: Nogueira Teresa , David Pedro H. C. , Pothier Joël
Published: October 2018

The exposure of the human gut to antibiotics can have a great impact on human health. Antibiotics pertain to the preservation of human health and are useful tools for fighting bacterial infections. They can be used for curing infections and can play a critical role in immunocompromised or chronic patients, or in fighting childhood severe malnutrition. Yet, the genomic and phylogenetic diversity of the human gut changes under antibiotic exposure. Antibiotics can also have severe side effects on human gut health, due to the spreading of potential antibiotic resistance genetic traits and to their correlation with virulence of some bacterial pathogens. They can shape, and even disrupt, the composition and functioning diversity of the human gut microbiome. Traditionally bacterial antibiotic resistances have been evaluated at clone or population level. However, the understanding of these two apparently disparate perspectives as both friends and foes may come from the study of microbiomes as a whole and from the evaluation of both positive and negative effects of antibiotics on microbial community dynamics and diversity. In this review we present some metagenomic tools and databases that enable the studying of antibiotic resistance in human gut metagenomes, promoting the development of personalized medicine strategies, new antimicrobial therapy protocols and patient follow‐up.
Marine bacteria and fungi as promising source for new antibiotics
Authors: Wiese Jutta , Imhoff Johannes F.
Published: October 2018

Natural products and derivatives thereof are of considerable importance in the discovery of new pharmaceuticals, for example, for the treatment of cancer, diabetes, inflammation diseases, and infection diseases caused by bacteria, fungi, viruses, or parasites. The great biodiversity of marine microorganisms is reflected in their huge chemical diversity, which provides a rich source of biologically active compounds. An increasing interest in marine microorganisms as promising producers of new compounds with potential medical applications has raised increasing interest in the sustainable exploration of marine microbial resources for the discovery of new antibiotics, which is highlighted. The bottlenecks in the development of drugs using the large marine natural product pipeline are also discussed.
Association with outcomes and response to treatment of trimethylamine N‐oxide in heart failure: results from BIOSTAT‐CHF
Authors: Suzuki Toru , Yazaki Yoshiyuki , Voors Adriaan A. , Jones Donald J.L. , Chan Daniel C.S. , Anker Stefan D. , Cleland John G. , Dickstein Kenneth , Filippatos Gerasimos , Hillege Hans L. , Lang Chim C. , Ponikowski Piotr , Samani Nilesh J. , van Veldhuisen Dirk J. , Zannad Faiez , Zwinderman Aeilko H. , Metra Marco , Ng Leong L.
Published: October 2018

Aims

Association of elevated circulating levels of trimethylamine N‐oxide (TMAO) with adverse outcomes in patients with heart failure (HF) has been described. However, response of TMAO levels to treatment and medications has not been investigated. Therefore, we investigated whether TMAO levels are responsive to guideline‐recommended treatment and medications, and further reflect changes in outcomes.

Methods and results

TMAO levels were investigated in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF), which addressed response to guideline‐recommended pharmacological treatment. TMAO levels in 2234 patients with new‐onset or progressively worsening HF showed strong associations with adverse events (mortality and/or rehospitalisation) at 1, 2 and 3 years [hazard ratio (HR) 1.37–1.51, P ≤ 0.019). Analysis of 972 patients with plasma available at both enrolment and follow‐up visit showed reductions of B‐type natriuretic peptide (BNP) levels with guideline‐based treatment (P < 0.001), but not for TMAO levels. Moreover, patients with higher TMAO levels than median before and after treatment showed increased association with adverse outcomes [HR 2.21, 95% confidence interval (CI) 1.43–3.43, P < 0.001] compared to patients with lower than median levels either before or after treatment (HR 1.13, 95% CI 0.63–2.04, P = 0.684 and HR 1.14, 95% CI 0.64–2.03, P = 0.662, respectively).

Conclusion

TMAO levels were associated with adverse outcomes (mortality and/or rehospitalisation) in BIOSTAT‐CHF, and did not respond to guideline‐based pharmacological treatment in contrast to BNP levels which did as expected. Lower TMAO levels were associated with favourable outcome regardless of treatment.
Gold(I) Complexes of Fulvenyl‐Functionalized Arylisocyanides
Authors: Schraff Sandra , Sun Yu , Orthaber Andreas , Pammer Frank
Published: October 2018

Gold(I) chloride complexes of arylisocyanides derived from 9‐benzylidene‐9H‐fluorene (Flu), 5‐benzylidene‐1,2,3,4‐tetraphenylcyclopentadiene (TPCp), and 5‐benzylidene‐5H‐dibenzo[a,d]cycloheptene (Dbs) have been prepared. The crystal structures and electronic properties of the three complexes are discussed. UV/Vis data complemented by DFT calculations indicate that the gold(I) centers act as Lewis acids and increase the acceptor strength of the isocyano group. The metal center therefore indirectly affects the optical properties of the π‐conjugated ligands, but is not directly involved in electronic transitions.
Noncovalent Complexes Formed between Metal‐Substituted Polyoxometalates and Hen Egg White Lysozyme
Authors: Vandebroek Laurens , Mampaey Yentl , Antonyuk Svetlana , Van Meervelt Luc , Parac‐Vogt Tatjana N.
Published: October 2018

Four Wells–Dawson type metal‐substituted polyoxometalates (MSPs), 1:2 ZrIV‐Wells–Dawson [ZrIV(α2‐P2W17O61)]8– (1), 1:1 CoII‐Wells–Dawson [CoII(α2‐P2W17O61)]10– (2), 1:1 NiII‐Wells–Dawson [NiII(α2‐P2W17O61)]10– (3) and 1:1 CuII‐Wells–Dawson [CuII(α2‐P2W17O61)]10– (4), which differ in the nature of the imbedded metal ion, were examined in co‐crystallization experiments with a protein Hen Egg White Lysozyme (HEWL). Single crystal X‐ray structures of four noncovalent complexes between POMs and HEWL have been determined, and the influence of the type of substituted metal on the mode of POM binding to a protein was investigated. All crystal structures exhibited a high degree of similarity, suggesting that the interaction is largely independent on the nature of substituted metal within the same polyoxometalate (POM) archetype. The main driving force for the formation of the noncovalent complex is electrostatic attraction between POM and HEWL surface regions. Stabilization is further provided by direct and water mediated hydrogen bonding between terminal oxygen atoms of the POM framework and flexible HEWL residues.
Molybdenum Complexes Supported by PN3P Pincer Ligands: Synthesis, Characterization, and Application to Synthetic Nitrogen Fixation
Authors: Stucke Nadja , Krahmer Jan , Näther Christian , Tuczek Felix
Published: October 2018

Three PN3P pincer ligands with a central pyridine ring, amine groups in the ligand backbone and different substituents at the terminal phosphine donors are synthesized and coordinated to molybdenum(III) precursors. Conversion of the resulting MoIII compounds to dinitrogen complexes is investigated and compared to the literature‐known complex trans‐[Mo(N2)2(PMe2Ph)(PNPtBu)] supported by a classic PNP pincer ligand. The difference between PN3P ligands terminated by di‐tert‐butyl and diphenyl substituents regarding the synthesis and the properties of corresponding Mo0 dinitrogen complexes is elucidated. Application of the synthesized Mo0‐ and MoIII‐PN3P complexes in the conversion of dinitrogen to ammonia reveals a strong influence of the terminal substituents and the atoms in the backbone of the pincer ligand on the catalytic activity.
Hetero Diels–Alder Reaction and Ene Reaction of Acylnitroso Species in situ Generated by Hypoiodite Catalysis
Authors: Uraoka Saki , Shinohara Ikumi , Shimizu Hisato , Noguchi Keiichi , Yoshimura Akira , Zhdankin Viktor V. , Saito Akio
Published: October 2018

As a first non‐metal‐catalyzed oxidation for the in situ generation of acylnitroso species, we describe the hypoiodite catalysis using tetra‐n‐butylammonium iodide as precatalyst with tert‐butyl hydroperoxide or hydrogen peroxide as a terminal oxidant. This method can be applied to hetero Diels–Alder (HDA) reactions with dienes and ene reactions with alkenes. Furthermore, the conversions of the representative HDA adduct to nitrone and 2‐amino alcohols were demonstrated. Compared with previous metal‐catalyzed oxidation methods, this work provides a more efficient and environmentally friendly procedure.
Treatment of early life status epilepticus: What can we learn from animal models?
Authors: Thompson Kerry W. , Suchomelova Lucie , Wasterlain Claude G.
Published: October 2018

Treatment of status epilepticus (SE) in infants and children is challenging. There is a recognition that a broad set of developmental processes need to be considered to fully appreciate the physiologic complexity of severe seizures, and seizure outcomes, in infants and children. The development and use of basic models to elucidate important mechanisms will help further our understanding of these processes. Here we review some of the key experimental models and consider several areas relevant to treatment that could lead to productive translational research. Terminating seizures quickly is essential. Understanding pharmacoresistance of SE as it relates to receptor trafficking will be critical to seizure termination. Once a severe seizure is terminated, how will the developing brain respond? Basic studies suggest that there are important acute and long‐term histopathologic, and pathophysiologic, consequences that, if left unaddressed, will produce long‐lasting deficits on the form and function of the central nervous system. To fully utilize the evidence that basic models produce, age‐ and development‐ and model‐specific frameworks have to be considered carefully. Studies have demonstrated that severe seizures can cause perturbations to developmental processes during critical periods of development that lead to life‐long deficits. Unfortunately, some of the drugs that are commonly used to treat seizures may also produce negative outcomes by enhancing Cl‐‐mediated depolarization, or by accelerating programmed cell death. More research is needed to understand these phenomena and their relevance to the human condition, and to develop rational drugs that protect the developing brain from severe seizures to the fullest extent possible.
Autism spectrum disorder and cognitive profile in children with Dravet syndrome: Delineation of a specific phenotype
Authors: Ouss Lisa , Leunen Dorothee , Laschet Jacques , Chemaly Nicole , Barcia Giulia , Losito Emma M. , Aouidad Aveline , Barrault Zoe , Desguerre Isabelle , Breuillard Delphine , Nabbout Rima
Published: October 2018

Objective

We aimed to assess a cohort of young patients with Dravet syndrome (DS) for intellectual disability (ID) and autism spectrum disorder (ASD) using standardized tools and parental questionnaires to delineate their specific profiles.

Methods

We included 35 patients with DS aged 24 months to 7 years, excluding patients with a developmental age (DA) <18 months (n = 5). We performed specific tests adapted for ID (Psychoeducational Profile, Third Edition [PEP‐3]), in addition to the Child Development Inventory (CDI) and Vineland Adaptive Behavior Scales, Second Edition (VABS‐II) questionnaires. We used 2 standardized tools for ASD: the Autism Diagnostic Observation Schedule, Second Edition (ADOS‐2) and the Autism Diagnostic Interview‐Revised (ADI‐R). We compared the with parental questionnaires and the VABS‐II, and with ASD characteristics.

Results

PEP‐3 subscales showed pathologic development in all but one patient (97%): ID in 23 of 30 (77%), and borderline cognitive functioning in 6 of 30 (22%). Eleven patients (39%) had ASD and 2 (7%) had a Social Communication Disorder (SCD) diagnosis. We found no difference between PEP‐3 and CDI categorization except for fine motor skills. We found significant negative correlations between ADOS‐2 and PEP‐3 for the majority of scores. For patients aged older than 50 months, 2 groups emerged (ASD/no ASD) with significant difference in DA. The logistic regression for ASD diagnosis explained by VABS‐II showed a significant effect for Socialization, Motor Skills, and Adaptive Behavior.

Significance

We found a high prevalence of ID in patients with DS. ID is characterized by expressive and comprehensive communication deficits in addition to visuospatial difficulties. ASD showed a specific profile with a relative preservation of social skills, emphasizing a possible underdiagnosis. Parental questionnaires can provide a good assessment of cognitive profile and might allow the difficulty of addressing cognitive scales in DS to be overcome. The profile of ID and ASD should help to establish early adapted rehabilitation programs and emphasizes the global need for care beyond seizures in DS and other developmental epileptic encephalopathies.
Synthesis and odour evaluation of novel sulfur‐containing cyclic acetals
Authors: Miyazawa Yamato , Masuda Yui , Ohmori Yuichiro , Katsuta Ryo , Nukada Tomoo , Ishigami Ken
Published: October 2018

Some sulfur‐containing compounds are known as useful flavours, but they have the drawback of instability in flavour composition. Therefore, we decided to develop stable sulfur‐containing compounds. We focused on 3‐mercapto‐2‐butanone (1), which is known for a meat‐like flavour. The carbonyl group of 1 was acetalized to improve the stability and to develop new flavouring compounds. We expected the resulting steric hindrance to also improve the stability of mercapto group. We synthesized 11 novel acetals based on these hypotheses. As a result, we were successful in the development of stable sulfur‐containing cyclic acetals with attractive odours.
A roadmap to climate data rescue services
Authors: Brönnimann Stefan , Brugnara Yuri , Allan Rob J. , Brunet Manola , Compo Gilbert P. , Crouthamel Richard I. , Jones Philip D. , Jourdain Sylvie , Luterbacher Jürg , Siegmund Peter , Valente Maria Antónia , Wilkinson Clive W.
Published: October 2018

Quantitative approaches to climate risk management such as mapping or impact modelling rely on past meteorological data with daily or sub‐daily resolution, a large fraction of which have not yet been digitized. Over the last decade or so, a number of projects have contributed to the rescue of some of these data. Here we provide a summary of a survey we have undertaken of several meteorological and climate data rescue projects, in order to identify the needs of climate data rescue services. To make these efforts more sustainable, additional integrated activities are needed. We argue that meteorological and climate data rescue must be seen as a continuous, coordinated long‐term effort. Technical developments (e.g. data assimilation), new scientific questions (e.g. process understanding of extreme events) and new social (e.g. risk assessment, health) or economic (e.g. new renewable energy sources, agriculture and forestry, tourism, infrastructure, etc.) services are highlighting the immense value of data previously neglected or never considered. This continuous effort is currently undertaken by projects of various sizes, structure, funding and staffing, as well as by dedicated programmes, ranging from those within many national weather services down to “grassroots” initiatives. These activities are often not sufficiently coordinated, staffed, or funded at an international level and will benefit considerably from climate data rescue services being established within the Copernicus Climate Change Service (C3S) (https://climate.copernicus.eu/).

Open Practices

This article has earned an Open Data badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki.
Socioeconomic factors and the risk of cognitive decline among the elderly population in Japan
Authors: Okamoto Shohei
Published: October 2018

Aim

In Japan, with the largest percentage of population aged 65 years or over, a dementia strategy is needed not only from a medical perspective, but also from a social policy viewpoint. This study aimed to verify the association between socioeconomic factors and cognitive decline among Japanese elderly people.

Methods

Cognitive decline was assessed over a 15‐year follow‐up period using memory tests or through identifying missing/proxy responses to survey questions due to cognitive dysfunction. I analysed 1886 men and 2102 women in Japan, using competing risk models for cognitive decline, to consider survival effects. Survival effects have not been considered so far although those who live longer may be more likely to experience cognitive decline.

Results

Men with higher income had a lower risk of cognitive decline (sub‐hazard ratio [SHR]: 0.997, 95% confidence interval (CI): 0.995‐0.999). Women with higher education had a lower risk of cognitive decline: 8 to 9 years (SHR: 0.646, 95% CI: 0.457‐0.914) and ≥12 years (SHR: 0.360, 95% CI: 0.164‐0.794) than women with 0 to 7 years of education.

Conclusion

This study suggests that cognitive decline among the elderly Japanese population is associated with socioeconomic factors, such as income and education, even after taking survival effects into account.
Concomitant use of benzodiazepines and opioids in community‐dwelling older people with or without Alzheimer's disease—A nationwide register‐based study in Finland
Authors: Karttunen Niina , Taipale Heidi , Hamina Aleksi , Tanskanen Antti , Tiihonen Jari , Tolppanen Anna‐Maija , Hartikainen Sirpa
Published: October 2018

Objective

The study aims to determine the prevalence of concomitant use of benzodiazepines and opioids among community‐dwelling older people with or without Alzheimer's disease (AD). An additional aim was to describe the factors associated with prolonged concomitant use, and the most commonly used combinations of these drugs.

Methods

This study utilized data from the register‐based Medication Use and Alzheimer's disease (MEDALZ) study, including all community‐dwelling residents of Finland who received a clinically verified AD diagnosis between 2005 and 2011 (n = 70 718) and their matched comparison persons without AD. After exclusion of individuals who were hospitalized throughout the follow‐up, 69 353 persons with and 69 353 without AD were included in this study.

Results

Benzodiazepines and related drugs (BZDRs) were used by 28 475 (41.1%) of those with and 24 506 (35.3%) of those without AD. Prolonged (greater than or equal to 90 days) concomitant use of BZDRs and opioids was more common among BZDR users without AD (N = 3936; 16.1%) than among those with AD (N = 2963; 10.4%). A shorter duration of concomitant use (1‐89 days) revealed similar results, N = 3821; 15.6% and N = 3008; 10.6%, respectively. Prolonged concomitant use of BZDRs and opioids was associated with female sex, low socioeconomic position, most of the common comorbidities and history of substance abuse or long‐term benzodiazepine use. The most commonly used combinations were Z‐drug (31.7%) or benzodiazepine (29.9%) with a weak opioid.

Conclusions

Despite the recommendations and risks, the prevalence of concomitant BZDR and opioid use was common in older persons with or without AD. It is important to develop strategies to reduce unnecessary concomitant use of these drugs.
DNAX Activating Protein of 12 kDa/Triggering Receptor Expressed on Myeloid Cells 2 Expression by Mouse and Human Liver Dendritic Cells: Functional Implications and Regulation of Liver Ischemia–Reperfusion Injury
Authors: Nakao Toshimasa , Ono Yoshihiro , Dai Helong , Nakano Ryosuke , Perez‐Gutierrez Angelica , Camirand Geoffrey , Huang Hai , Geller David A. , Thomson Angus W.
Published: October 2018

Liver interstitial dendritic cells (DCs) have been implicated in the control of ischemia–reperfusion injury (IRI) and host immune responses following liver transplantation. Mechanisms underlying these regulatory functions of hepatic DCs remain unclear. We have shown recently that the transmembrane immunoadaptor DNAX‐activating protein of 12 kDa (DAP12) negatively regulates mouse liver DC maturation and proinflammatory and immune stimulatory functions. Here, we used PCR analysis and flow cytometry to characterize expression of DAP12 and its associated triggering receptor, triggering receptor expressed on myeloid cells 2 (TREM2), by mouse and human liver DCs and other immune cells compared with DCs in other tissues. We also examined the roles of DAP12 and TREM2 and their expression by liver DCs in the regulation of liver IRI. Injury was induced in DAP12–/–, TREM2–/–, or wild‐type (WT) mice by 1 hour of 70% clamping and quantified following 6 hours of reperfusion. Both DAP12 and TREM2 were coexpressed at comparatively high levels by liver DCs. Mouse liver DCs lacking DAP12 or TREM2 displayed enhanced levels of nuclear factor κB and costimulatory molecule expression. Unlike normal WT liver DCs, DAP12–/– liver DC failed to inhibit proliferative responses of activated T cells. In vivo, DAP12–/– and TREM2–/– mice exhibited enhanced IRI accompanied by augmented liver DC activation. Elevated alanine aminotransferase levels and tissue injury were markedly reduced by infusion of WT but not DAP12–/– DC. Conclusion: Our data reveal a close association between DAP12 and TREM2 expression by liver DC and suggest that, by negatively regulating liver DC stimulatory function, DAP12 promotes their control of hepatic inflammatory responses; the DAP12/TREM2 signaling complex may represent a therapeutic target for control of acute liver injury/liver inflammatory disorders.
Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease in Mice
Authors: Tornai David , Furi Istvan , Shen Zu T. , Sigalov Alexander B. , Coban Sahin , Szabo Gyongyi
Published: October 2018

Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil leukocyte recruitment and activation in the liver. Damage‐ and pathogen‐associated molecular patterns contribute to a self‐perpetuating proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 (TREM‐1) is a surface receptor that amplifies inflammation induced by toll‐like receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We hypothesized that TREM‐1 signaling contributes to proinflammatory pathway activation in ALD. Using an in vivo ALD model in mice, we tested the effects of ligand‐independent TREM‐1 inhibitory peptides that were formulated into human high‐density lipoprotein (HDL)‐mimicking complexes GF9‐HDL and GA/E31‐HDL. As revealed in vitro, macrophages endocytosed these rationally designed complexes through scavenger receptors. A 5‐week alcohol feeding with the Lieber‐DeCarli diet in mice resulted in increased serum alanine aminotransferase (ALT), liver steatosis, and increased proinflammatory cytokines in the liver. TREM‐1 messenger RNA (mRNA) expression was significantly increased in alcohol‐fed mice, and TREM‐1 inhibitors significantly reduced this increase. TREM‐1 inhibition significantly attenuated alcohol‐induced spleen tyrosine kinase (SYK) activation, an early event in both TLR4 and TREM‐1 signaling. The TREM‐1 inhibitors significantly inhibited macrophage (epidermal growth factor‐like module‐containing mucin‐like hormone receptor‐like 1 [F4/80], clusters of differentiation [CD]68) and neutrophil (lymphocyte antigen 6 complex, locus G [Ly6G] and myeloperoxidase [MPO]) markers and proinflammatory cytokines (monocyte chemoattractant protein 1 [MCP‐1], tumor necrosis factor α [TNF‐α], interleukin‐1β [IL‐1β], macrophage inflammatory protein 1α [MIP‐1α]) at the mRNA level compared to the HDL vehicle. Administration of TREM‐1 inhibitors ameliorated liver steatosis and early fibrosis markers (α‐smooth muscle actin [αSMA] and procollagen1α [Pro‐Col1α]) at the mRNA level in alcohol‐fed mice. However, the HDL vehicle also reduced serum ALT and some cytokine protein levels in alcohol‐fed mice, indicating HDL‐related effects. Conclusion: HDL‐delivered novel TREM‐1 peptide inhibitors ameliorate early phases of inflammation and neutrophil and macrophage recruitment and activation in the liver and attenuate hepatocyte damage and liver steatosis. TREM‐1 inhibition represents a promising therapeutic approach for further investigations in ALD.
Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice
Authors: Morrison Martine C. , Verschuren Lars , Salic Kanita , Verheij Joanne , Menke Aswin , Wielinga Peter Y. , Iruarrizaga‐Lejarreta Marta , Gole Laurent , Yu Wei‐Miao , Turner Scott , Caspers Martien P.M. , Martínez‐Arranz Ibon , Pieterman Elsbet , Stoop Reinout , van Koppen Arianne , van den Hoek Anita M. , Mato José M. , Hanemaaijer Roeland , Alonso Cristina , Kleemann Robert
Published: October 2018

Concerns have been raised about whether preclinical models sufficiently mimic molecular disease processes observed in nonalcoholic steatohepatitis (NASH) patients, bringing into question their translational value in studies of therapeutic interventions in the process of NASH/fibrosis. We investigated the representation of molecular disease patterns characteristic for human NASH in high‐fat diet (HFD)‐fed Ldlr‐/‐.Leiden mice and studied the effects of obeticholic acid (OCA) on these disease profiles. Multiplatform serum metabolomic profiles and genome‐wide liver transcriptome from HFD‐fed Ldlr‐/‐.Leiden mice were compared with those of NASH patients. Mice were profiled at the stage of mild (24 weeks HFD) and severe (34 weeks HFD) fibrosis, and after OCA intervention (24‐34 weeks; 10 mg/kg/day). Effects of OCA were analyzed histologically, biochemically, by immunohistochemistry, using deuterated water technology (de novo collagen formation), and by its effect on the human‐based transcriptomics and metabolomics signatures. The transcriptomics and metabolomics profile of Ldlr‐/‐.Leiden mice largely reflected the molecular signature of NASH patients. OCA modulated the expression of these molecular profiles and quenched specific proinflammatory‐profibrotic pathways. OCA attenuated specific facets of cellular inflammation in liver (F4/80‐positive cells) and reduced crown‐like structures in adipose tissue. OCA reduced de novo collagen formation and attenuated further progression of liver fibrosis, but did not reduce fibrosis below the level before intervention. Conclusion: HFD‐fed Ldlr‐/‐.Leiden mice recapitulate molecular transcriptomic and metabolomic profiles of NASH patients, and these signatures are modulated by OCA. Intervention with OCA in developing fibrosis reduces collagen deposition and de novo synthesis but does not resolve already manifest fibrosis in the period studied. These data show that human molecular signatures can be used to evaluate the translational character of preclinical models for NASH.
Sharp‐wave ripple features in macaques depend on behavioral state and cell‐type specific firing
Authors: Hussin Ahmed T. , Leonard Timothy K. , Hoffman Kari L.
Published: October 2018

Sharp‐wave ripples (SWRs) are spontaneous, synchronized neural population events in the hippocampus widely thought to play a role in memory consolidation and retrieval. They occur predominantly in sleep and quiet immobility, and in primates, they also appear during active visual exploration. Typical measures of SWRs in behaving rats include changes in the rate of occurrence, or in the incidence of specific neural ensemble activity contained within the categorical SWR event. Much less is known about the relevance of spatiotemporal SWR features, though they may index underlying activity of specific cell types including ensemble‐specific internally generated sequences. Furthermore, changes in SWR features during active exploratory states are unknown. In this study, we recorded hippocampal local‐field potentials and single‐units during periods of quiescence and as macaques performed a memory‐guided visual search task. We observed that (a) ripples during quiescence have greater amplitudes and larger postripple waves (PRW) compared to those in task epochs, and (b) during “remembered” trials, ripples have larger amplitudes than during “forgotten” trials, with no change in duration or PRWs. We further found that spiking activity influences SWR features as a function of cell type and ripple timing. As expected, larger ripple amplitudes were associated with putative pyramidal or putative basket interneuron (IN) activity, even when the spikes in question exceed the duration of the ripple. In contrast, the PRW was attenuated with activity from low firing rate cells and enhanced with activity from high firing rate cells, with putative IN spikes during ripples leading to the most prominent PRW peaks. The selective changes in SWR features as a function of time window, cell type, and cognitive/vigilance states suggest that this mesoscopic field event can offer additional information about the local network and animal's state than would be appreciated from SWR event rates alone.
Induction chemotherapy followed by allogeneic HCT versus upfront allogeneic HCT for advanced myelodysplastic syndrome: A propensity score matched analysis
Authors: Konuma Takaaki , Shimomura Yoshimitsu , Ozawa Yukiyasu , Ueda Yasunori , Uchida Naoyuki , Onizuka Makoto , Akiyama Megumi , Mori Takehiko , Nakamae Hirohisa , Ohno Yuju , Shiratori Souichi , Onishi Yasushi , Kanda Yoshinobu , Fukuda Takahiro , Atsuta Yoshiko , Ishiyama Ken ,   Adult Myelodysplastic Syndrome Working Group of the Japan Society for Hematopoietic Cell Transplantation
Published: October 2018

To reduce post‐transplant relapse, acute myeloid leukemia (AML) type remission induction chemotherapy has been attempted to reduce disease burden before allogeneic hematopoietic cell transplantation (HCT) in patients with advanced myelodysplastic syndrome (MDS). However, the efficacy of induction chemotherapy before HCT is unclear. We retrospectively analyzed the Japanese registration data of 605 adult patients, who had received allogeneic HCT for advanced MDS between 2001 and 2016, to compare the post‐transplant relapse between patients who received induction chemotherapy followed by allogeneic HCT and those who received upfront HCT. Propensity score matching identified 230 patients from each cohort. There were no significant differences in overall survival and non‐relapse mortality between the two groups. The cumulative incidence of relapse was significantly higher in patients who received induction chemotherapy than those who received upfront HCT. In the subgroup analyses, upfront HCT had a significantly reduced relapse incidence among patients with poor cytogenetics, those with higher international prognostic scoring system at diagnosis, and those who received reduced‐intensity conditioning. Our results suggested that AML type remission induction chemotherapy before HCT did not improve post‐transplant relapse and survival for adult patients with advanced MDS. Upfront HCT is preferable for patients with a poor karyotype.
Conditional cash transfer policies in maternal health service utilization in Nepal: Analysis of safe delivery incentive program (Aama Surakshya Karyakram) using Kingdon's multiple streams framework
Authors: Khanal Geha Nath
Published: October 2018

Various factors limit access to and utilization of health services even when provided at subsidized cost. This results in poor utilization of services that contributes to further economic impoverishment and health care disparity. Many countries are experimenting with various approaches to tackle the poor utilization of health care services including demand‐side financing policy. This paper explains the policymaking process during the formulation of safe delivery incentive program, a conditional cash transfer program in Nepal using Kindgon's multiple streams framework. Analysis of earlier policies and programs around safe motherhood concludes that high transportation cost was a major cause for poor utilization of institutional obstetric care, despite being provided at free of cost. Health was recognized as fundamental constitutional right in 2007. This assured societal support and political commitments for protecting health constitutionally. Furthermore, there was commitment from external development partners (EDPs) for investment in maternal health. Together, these problem, policy, and politics opened Kingdon's “windows of opportunity” for formulation of conditional cash transfer policy. This paper presents evolution of Aama Surakshya Karyakram and uses Kingdon's multiple streams framework to explain how problem, policy, and politics streams converged together to allow this program to be introduced in Nepal.
Reforms in the Portuguese health care sector: Challenges and proposals
Authors: Nunes Alexandre Morais , Ferreira Diogo Cunha
Published: October 2018

Portugal has one of the most complete public systems worldwide. Since 1979, the Portuguese National Health Service (NHS) was developed based on the integration and complementarity between different levels of care (primary, secondary, continued, and palliative care). However, in 2009, the absence of economic growth and the increased foreign debt led the country to a severe economic slowdown, reducing the public funding and weakening the decentralized model of health care administration. During the austerity period, political attention has focused primarily on reducing health care costs and consolidating the efficiency and sustainability with no structural reform. After the postcrisis period (since 2016), the recovery of the public health system begun. Since then, some proposals have required a reform of the health sector's governance structure based on the promotion of access, quality, and efficiency. This study presents several key issues involved in the current postcrisis reform of the Portuguese NHS response structure to citizens' needs. The article also discusses the implications of this Portuguese experience based on current reforms with impact on the future of citizens' health.
Prediction of river temperature surges is dependent on precipitation method
Authors: Croghan Danny , Van Loon Anne F. , Sadler Jon P. , Bradley Chris , Hannah David M.
Published: October 2018

Urban river systems are particularly sensitive to precipitation‐driven water temperature surges and fluctuations. These result from rapid heat transfer from low‐specific heat capacity surfaces to precipitation, which can cause thermally polluted surface run‐off to enter urban streams. This can lead to additional ecological stress on these already precarious ecosystems. Although precipitation is a first‐order driver of hydrological response, water temperature studies rarely characterize rain event dynamics and typically rely on single gauge data that yield only partial estimates of catchment precipitation. This paper examines three precipitation measuring methods (a statutory automatic weather station, citizen science gauges, and radar estimates) and investigates relationships between estimated rainfall inputs and subhourly surges and diurnal fluctuations in urban river water temperature. Water temperatures were monitored at 12 sites in summer 2016 in the River Rea, in Birmingham, UK. Generalized additive models were used to model the relationship between subhourly water temperature surges and precipitation intensity and subsequently the relationship between daily precipitation totals and standardized mean water temperature. The different precipitation measurement sources give highly variable precipitation estimates that relate differently to water temperature fluctuations. The radar catchment‐averaged method produced the best model fit (generalized cross‐validation score [GCV] = 0.30) and was the only model to show a significant relationship between water temperature surges and precipitation intensity (P < 0.001, R2 = 0.69). With respect to daily metrics, catchment‐averaged precipitation estimates from citizen science data yielded the best model fit (GCV score = 0.20). All precipitation measurement and calculation methods successfully modelled the relationship between standardized mean water temperature and daily precipitation (P < 0.001). This research highlights the potential for the use of alternative precipitation datasets to enhance understanding of event‐based variability in water quality studies. We conclude by recommending the use of spatially distributed precipitation data operating at high spatial (<1 km2) and temporal (<15 min) resolutions to improve the analysis of event‐based water temperature and water quality studies.
Effect of Direct Electrical Current on Bones Infected with Staphylococcus epidermidis
Authors: Schmidt‐Malan Suzannah M , Brinkman Cassandra L , Karau Melissa J , Brown Robert A , Waletzki Brian E , Berglund Lawrence J , Schuetz Audrey N , Greenwood‐Quaintance Kerryl E , Mandrekar Jayawant N , Patel Robin
Published: October 2018

We are developing electrical approaches to treat biofilm‐associated orthopedic foreign‐body infection. Although we have previously shown that such approaches have antibiofilm activity, the effects on bone have not been assessed. Herein, low‐amperage 200 μA fixed direct current (DC) was compared with no current, in a rat femoral foreign‐body infection model. In the infected group, a platinum implant seeded with S. epidermidis biofilm (105 CFU/cm2), plus 50 μL of a 109 CFU suspension of bacteria, were placed in the femoral medullary cavity of 71 rats. One week later, rats were assigned to one of four groups: infected with no current or DC, or uninfected with no current or DC. After 2 weeks, bones were removed and subjected to histopathology, micro‐computed tomography (μCT), and strength testing. Histopathology showed no inflammation or bony changes/remodeling in the uninfected no current group, and some osteoid formation in the DC group; bones from the infected no current group had evidence of inflammation without bony changes/remodeling; along with inflammation, there was moderate osteoid present in the DC group. μCT showed more cortical bone volume and density, trabecular thickness, and cancellous bone volume in the DC group compared with the no current group, for both uninfected and infected bones (p < 0.05). There was no difference in torsional strength or stiffness between the no current versus DC groups, for both infected and uninfected bones (p > 0.05). © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
Mechanistic insight into the attenuation of gouty inflammation by Taiwanese green propolis via inhibition of the NLRP3 inflammasome
Authors: Hsieh Chih‐Yu , Li Lan‐Hui , Rao Yerra Koteswara , Ju Tz‐Chuen , Nai Yu‐Shin , Chen Yue‐Wen , Hua Kuo‐Feng
Published: October 2018

Dysregulation of NACHT, LRR, and PYD domains‐containing protein 3 (NLRP3) inflammasome is involved in many chronic inflammatory diseases, including gouty arthritis. Activation of the NLRP3 inflammasome requires priming and activation signals: the priming signal controls the expression of NLRP3 and interleukin (IL)‐1β precursor (proIL‐1β), while the activation signal leads to the assembly of the NLRP3 inflammasome and to caspase‐1 activation. Here, we reported the effects of the alcoholic extract of Taiwanese green propolis (TGP) on the NLRP3 inflammasome in vitro and in vivo. TGP inhibited proIL‐1β expression by reducing nuclear factor kappa B activation and reactive oxygen species (ROS) production in lipopolysaccharide‐activated macrophages. Additionally, TGP also suppressed the activation signal by reducing mitochondrial damage, ROS production, lysosomal rupture, c‐Jun N‐terminal kinases 1/2 phosphorylation and apoptosis‐associated speck‐like protein oligomerization. Furthermore, we found that TGP inhibited the NLRP3 inflammasome partially via autophagy induction. In the in vivo mouse model of uric acid crystal‐induced peritonitis, TGP attenuated the peritoneal recruitment of neutrophils, and the levels of IL‐1β, active caspase‐1, IL‐6 and monocyte chemoattractant protein‐1 in lavage ﬂuids. As a proof of principle, in this study, we purified a known compound, propolin G, from TGP and identified this compound as a potential inhibitor of the NLRP3 inflammasome. Our results indicated that TGP might be useful for ameliorating gouty inflammation via inhibition of the NLRP3 inflammasome.
Intratumoral infiltrating lymphocytes correlate with improved survival in colorectal cancer patients: Independent of oncogenetic features
Authors: Nazemalhosseini‐Mojarad Ehsan , Mohammadpour Somayeh , Torshizi Esafahani Amir , Gharib Ehsan , Larki Pegah , Moradi Afshin , Amin Porhoseingholi Mohammad , Asadzade Aghdaei Hamid , Kuppen Peter J. K. , Zali Mohammad Reza
Published: October 2018

Background

The clinical relevance and prognostic value of tumor‐infiltrating lymphocytes (TILs) as an interplay between malignant cells and immune function has been known for decades. On contrary, this potential may be different by T lymphocytes subsets endowed with a different function. Colorectal cancer (CRC) is a heterogeneous disease with different suggested prognostic biomarkers. So, this study was conducted to examine the prognostic value of CD8+ TILs on the survival rate of CRC as an independent factor of oncogenetic tumor features.

Methods

With respect to this, 281 formalin‐fixed, paraffin‐embedded tissue samples of Iranian CRC patients were evaluated for clinical features including tumor location, tumor stage, differentiation grade, and mucinous characteristics. Then, using the standard immunohistochemical technique, tumor sections were examined, and CD8+ TILs were counted and identified in two regions of the tumor, including intratumoral (ITCIL TILs) and stromal (S TILs). The prognostic value of CD8+ TILs was determined by comparing with parameters, such as diagnostic age, tumor stage, adjuvant therapy, microsatellite instability (MSI) status, KRAS and BRAF mutations, family history, and survival.

Results

The presence of intratumoral tumor cell‐infiltrating lymphocytes (ITCIL) CD8+ lymphocytes are significantly associated with differentiation (p = 0.004), tumor, node, and metastases (TNM) stage (p = 0.001), and MSI (p = 0.001). Meanwhile, based on the level of stromal infiltrating lymphocytes (SIL) infiltration, analysis of CRC patients was statistically associated with a location (p = 0.002), TNM stage (p < 0.001), metastasis (p < 0.001), and KRAS mutation (p = 0.031). Also, tumors with severe ITCIL CD8+ lymphocytes have a good prognosis compared with tumors with poor or moderate ITCIL CD8+ lymphocytes.

Conclusions

These results suggest that intratumor cell‐infiltrating CD8− T lymphocytes as an independent prognostic factor that have an antitumor activity as judged by their favorable effect on patients’ survival and could potentially be exploited in the treatment of CRC.