bluuebunny/crossref_metadata_2025 huggingface dataset:
Home initiation of chronic non-invasive ventilation in COPD patients with chronic hypercapnic respiratory failure: a randomised controlled trial
Authors: Duiverman Marieke L , Vonk Judith M , Bladder Gerrie , van Melle Joost P , Nieuwenhuis Jellie , Hazenberg Anda , Kerstjens Huib A M , van Boven Job F M , Wijkstra Peter J
Published: September 2019

Introduction

Chronic non-invasive ventilation (NIV) has become evidence-based care for stable hypercapnic COPD patients. While the number of patients increases, home initiation of NIV would greatly alleviate the healthcare burden. We hypothesise that home initiation of NIV with the use of telemedicine in stable hypercapnic COPD is non-inferior to in-hospital NIV initiation.

Methods

Sixty-seven stable hypercapnic COPD patients were randomised to initiation of NIV in the hospital or at home using telemedicine. Primary outcome was daytime arterial carbon dioxide pressure (PaCO2) reduction after 6 months NIV, with a non-inferiority margin of 0.4 kPa. Secondary outcomes were health-related quality of life (HRQoL) and costs.

Results

Home NIV initiation was non-inferior to in-hospital initiation (adjusted mean difference in PaCO2change home vs in-hospital: 0.04 kPa (95% CI −0.31 to 0.38 kPa), with both groups showing a PaCO2reduction at 6 months compared with baseline (home: from 7.3±0.9 to 6.4±0.8 kPa (p<0.001) and in-hospital: from 7.4±1.0 to 6.4±0.6 kPa (p<0.001)). In both groups, HRQoL improved without a difference in change between groups (Clinical COPD Questionnaire total score-adjusted mean difference 0.0 (95% CI −0.4 to 0.5)). Furthermore, home NIV initiation was significantly cheaper (home: median €3768 (IQR €3546–€4163) vs in-hospital: median €8537 (IQR €7540–€9175); p<0.001).

Discussion

This is the first study showing that home initiation of chronic NIV in stable hypercapnic COPD patients, with the use of telemedicine, is non-inferior to in-hospital initiation, safe and reduces costs by over 50%.

Trial registration number

NCT02652559.
Evaluating smoking control policies in the e-cigarette era: a modelling study
Authors: Doan Thi Thanh Tra , Tan Ken Wei , Dickens Borame Sue Lee , Lean Yin Ai , Yang Qianyu , Cook Alex R
Published: September 2019

Background

In jurisdictions in which electronic cigarettes are currently prohibited, policy makers must weigh the potentially lower risk compared with conventional cigarettes against the risk of initiation of e-cigarettes among non-smokers.

Methods

We simulated a synthetic population over a 50-year time horizon with an open cohort model using data from Singapore, a country where e-cigarettes are currently prohibited, and data from the USA, the UK and Japan. Using the smoking prevalence and the quality-adjusted life year gained calculated, we compared tobacco control policies without e-cigarettes—namely, raising the minimum legal age (MLA), introducing a smoke-free generation (SFG) and tax rises on tobacco consumption—with policies legalising e-cigarettes, either taking a laissez-faire approach or under some form of restriction. We also evaluated combinations of these policies.

Results

Regardless of the country informing the transition probabilities to and from e-cigarette use in Singapore, a laissez-faire e-cigarette policy could reduce the smoking prevalence in the short term, but it is not as effective as other policies in the long term. The most effective single policies evaluated were SFG and aggressive tax rises; the most effective combination of policies considered was MLA plus moderate tax rises and e-cigarettes on prescription.

Conclusion

Policy makers in jurisdictions in which e-cigarettes are not yet established may be advised not to prioritise e-cigarettes in their tobacco end-game strategy, unless their use can be restricted to current smokers seeking to quit.
Identifying hidden biocomplexity and genomic diversity in Chinook salmon, an imperiled species with a history of anthropogenic influence
Authors: Meek Mariah H. , Stephens Molly R. , Goodbla Alisha , May Bernie , Baerwald Melinda R.
Published: September 2019

Biocomplexity is an important mechanism for population resilience in changing environments. However, we are just beginning to understand how to identify biocomplexity so that species management efforts promote resilience and stability. Genomic techniques are emerging as an important method for identifying biocomplexity. Central Valley (CV) Chinook salmon are an example of a species at risk of extinction if better methods for identifying and protecting biocomplexity are not employed. To address this knowledge gap, we employed restriction site associated DNA sequencing to conduct the first genomic study of all major populations of CV Chinook salmon. We found greater population structure across the Central Valley than previously documented. Additionally, we show evidence for differentiation and adaptation within migratory phenotypes despite high levels of gene flow. We also determined that genomic data can vastly improve our ability to assign individuals to their natal populations, even as they mix during migration, a finding that will assist management practices. These results demonstrate how genomic study can greatly improve our ability to identify and conserve biocomplexity.
Rapid adoption of nest boxes by Prothonotary Warblers (Protonotaria citrea) in mesic deciduous forest
Authors: Mueller A.J. , Twedt D.J. , Bowers E.K.
Published: September 2019

Breeding territory selection in Prothonotary Warblers (Protonotaria citrea (Boddaert, 1783)) is thought to hinge on standing water, with a strong preference for low-lying areas prone to seasonal flooding. However, we have observed this species nesting in much drier areas than previously reported. We recently initiated a study of the Carolina Wren (Thryothorus ludovicianus (Latham, 1790)) using wooden nest boxes, and nearly 60% of all nests produced in these boxes during the initial study year were produced by Prothonotary Warblers, despite this species being absent from our field site during the year preceding nest-box availability. Most nests were produced in dense, closed-canopy forest with a thick shrub layer >100 m from any water body. There was no difference in the mean distance from water between nests of the Prothonotary Warbler and those of the Carolina Wren, a habitat generalist that does not nest over water. We then observed a 60% increase in the number of Prothonotary Warbler nests the following year, along with significant increases in breeding productivity. Although they nested on sites that they are not thought to prefer, our observations suggest that Prothonotary Warblers may nest in drier areas than usual if appropriate nest cavities are provided.
Newstead’s Mayer–Vietoris argument in characteristic 2
Authors: Scaduto Christopher , Stoffregen Matthew
Published: September 2019

Consider the moduli space of framed flat [Formula: see text] connections with fixed odd determinant over a surface. Newstead combined some fundamental facts about this moduli space with the Mayer–Vietoris sequence to compute its betti numbers over any field not of characteristic 2. We adapt his method in characteristic 2 to produce conjectural recursive formulae for the mod two betti numbers of the framed moduli space which we partially verify. We also discuss the interplay with the mod two cohomology ring structure of the unframed moduli space.
The KLOE-2 experiment: Overview of recent results
Authors: Krzemien Wojciech , del Río Elena Pérez
Published: September 2019

The KLOE detector at the DA[Formula: see text]NE [Formula: see text]-factory has been operating in two periods from 2001–2006 and from 2014–2018 collecting a large sample of [Formula: see text]-meson decays. This allowed to perform precision measurements and studies of fundamental symmetries, and searches of New Physics phenomena. In this overview, the results of KLOE and KLOE-2 Collaborations are presented. The most recent results from the KLOE experiment are discussed, covering: the measurement of the running fine-structure constant [Formula: see text], the Dalitz plot measurement of [Formula: see text], the search of a [Formula: see text] boson, tests of discrete symmetries and quantum decoherence.
ROBUST DISCRIMINATION OF LEUKOCYTES PROTUBERANT TYPES FOR EARLY DIAGNOSIS OF LEUKEMIA
Authors: NAZ ISRA , MUHAMMAD NAZEER , YASMIN MUSSARAT , SHARIF MUHAMMAD , SHAH JAMAL HUSSAIN , FERNANDES STEVEN LAWRENCE
Published: September 2019

Advanced laboratory technology has made blood testing more automated, robust and tests are being implemented comprehensively. Leukocytes type differentiation is a critical hematological images analysis step of blood film as it delivers valuable information in diagnosis of several diseases. At present, the morphological examination of leukocytes is done manually and this process is very tedious, inefficient and slow. Although many white blood cells detection or classification techniques are presented by different researchers, there is still a need of fully automated and an efficient detection system of blood cells with its particular types for an early diagnosis of leukemia. This paper presents a technique for the classification of protuberant types of leukocytes and early diagnosis of leukemia. The work is divided into the following main stages: (a) image augmentation, (b) wavelet composition and decomposition for attaining high and low frequency bands of the cell image, (c) convolutional neural network (CNN) training model for the classification of leukocytes categories and (d) prediction of leukemia. The main intention behind this study is to develop an automated, robust and efficient classification and detection system of leukocytes for microscopic blood images.
EXPERIMENTAL COMPARISON OF MCF7 AND MCF10A RESPONSE TO LOW INTENSITY ULTRASOUND
Authors: IVONE MARIANTONIETTA , LAMBERTI LUCIANO , PAPPALETTERE CARMINE , CARATOZZOLO MARIANO FRANCESCO , TULLO APOLLONIA
Published: September 2019

The low-intensity ultrasound effects on MCF7 (human breast adenocarcinoma) and MCF10A (healthy breast cells) have been investigated at different sonication protocol to probe the effectiveness and the selectivity of the ultrasound (US) treatment and to understand the implications between cell mortality, biomechanical interactions and cell elastic modulus. Experiments performed at fixed and variable frequency demonstrated the effectiveness of some protocols in killing carcinogenic cells and the healthy cells insensitivity. Variation of elastic properties of MCF7 cells exposed to US under varying sonication conditions was examined. Sonication was carried out at fixed frequency (as it is usually done in therapy protocols), between 400[Formula: see text]kHz and 620[Formula: see text]kHz, following two protocols: (i) at fixed power output; (ii) at fixed voltage of the US generator. Evolution of cell stiffness during the US treatment was monitored via atomic force spectroscopy (AFS). It was found that cell mortality has a similar trend of variation with respect to sonication frequency regardless of the way specimens are exposed to US. Mechanical properties do not show a uniform trend with respect to frequency, but variations of Young’s modulus are more marked near the very low (400–480) kHz or very high frequencies (580–620) kHz. The observed variations may be related to mechanical interactions occurring in the cell culture, suggesting a primacy of the environment on other factors.
BORDER ADJUSTMENTS SUPPLEMENTING A CAP AND TRADE SYSTEM TO COMBAT CLIMATE CHANGE
Authors: HECHT MELANIE , PETERS WOLFGANG
Published: September 2019

In the post-Paris Agreement era, the number of carbon pricing initiatives in order to combat climate change grows continuously. However, carbon prices vary substantially among countries which yields negative drawbacks in terms of carbon leakage and loss of competitiveness for firms producing in countries with more stringent regulations. Border adjustments (BAs) could help tackle these negative drawbacks through harmonizing carbon prices across countries. We model a two-stage game where Country A can choose whether to implement BAs in the first stage. In the second stage, producers from both countries compete over prices in Bertrand competition or over quantities in Cournot competition. Most analyses on BAs so far focus on carbon pricing in the form of carbon taxes. However, we observe that many governments achieve their mitigation targets by implementing a cap and trade system with some kind of free allocation of emission allowances. From the current global carbon pricing situation, we identify two conditions for the compliance with the WTO’s national treatment principle that have not been dealt with in detail in previous models: (i) the application of BAs in the form of a cap and trade system and (ii) accounting for free allocation of emission allowances. Our results show that irrespective of the competition type, BAs supplementing a cap and trade system with free allocation improve welfare if the competitive pressure is high.
Cambro-Ordovician anatexis and magmatic recycling at the thinned Gondwana margin: new constraints from the Kouřim Unit, Bohemian Massif
Authors: Soejono Igor , Machek Matěj , Sláma Jiří , Janoušek Vojtěch , Kohút Milan
Published: September 2019

The Kouřim Unit represents one of the largest pre-Variscan meta-igneous complexes in the Bohemian Massif and a geochronological, whole-rock geochemical and Sr–Nd isotopic study was conducted to better understand the magmatic evolution of the Early Paleozoic Gondwana margin. Five orthogneisses yield U–Pb zircon ages ranging from 492 ± 4 to 484 ± 2 Ma. Two leucogranites give U–Pb zircon ages of 500 ± 4 and 485 ± 2 Ma, interpreted to be inherited from their orthogneiss host rock. Two samples from the metasedimentary host rock are dominated by Neoproterozoic–Cambrian detrital zircons. The abundance of zircon inheritance in the orthogneisses and whole-rock Sr–Nd isotopic composition imply an origin from relatively mature continental crustal material. The subalkaline, subaluminous–slightly peraluminous and high-K calc-alkaline arc-like geochemical signature of the orthogneisses is interpreted as inherited from the recycled Cadomian metasedimentary source and both the magmatic and metasedimentary rocks are correlated with similar occurrences in the adjacent Moldanubicum and Teplá–Barrandian Unit. The Late Cambrian–Early Ordovician magmatic activity is linked to crustal anatexis, which was probably initiated by thermal and gravitational relaxation of the thickened Cadomian arc-type crust, followed by lithospheric thinning assisted by far-field forces. The extensional event led to the formation of a passive margin associated with the opening of the Rheic Ocean.

Supplementary material:
Analytical methods, petrographic descriptions with photographs of studied samples, collections of CL images of representative zircon grains, results of LA-ICP-MS U–Pb analyses of zircons and an additional geochemical diagram are available at
https://doi.org/10.6084/m9.figshare.c.4649255
Tethyan ophiolites and Tethyan seaways
Authors: Dilek Yildirim , Furnes Harald
Published: September 2019

Tethyan ophiolites have played a major role in the development of the ophiolite concept during the past 200 years, and contributed significantly to the formulations of the suprasubduction-zone (SSZ) ophiolite paradigm and the plate-tectonics theory. Their melt evolution and magmatic construction witnessed the dispersal of the supercontinent Pangaea via continental rifting and seafloor spreading, opening and closure of multiple seaways in an eastward widening, latitudinal ocean basin (Neotethys), and deep mantle recycling processes through subduction-zone tectonics and plume activities. Neotethyan ophiolites are highly diverse in their crustal–mantle structures and compositions, pointing to major differences in their melt sources and tectonic settings of magmatic construction. The papers in this thematic set demonstrate these differences in the Neotethyan ophiolite record through new structural, geochemical, isotopic and geochronological data and interpretations. The Jurassic Western Alpine Ophiolites formed in a narrow basin (Alpine Tethys) that developed between Europe and North Africa–Adria–Iberia. Their peridotites represent exhumed, continental lithospheric mantle. The Triassic, Jurassic and Cretaceous ophiolites east of Adria formed in different Neotethyan seaways, and their SSZ magmatic construction involved multiple episodes of melting, depletion and refertilization of subduction-modified oceanic mantle. The Late Cretaceous peri-Arabian and peri-Indian ophiolites, which are discontinuously exposed along a
c.
9000 km long belt from SW Anatolia to SE Tibet, formed above a Trans-Tethyan subduction–accretion system within Southern Neotethys. Diachronous collisions of Arabia and India with this intraoceanic subduction–accretion system in the latest Mesozoic and the Paleogene (respectively) resulted in diachronous ophiolite emplacement in the Mediterranean and Tibetan–Himalayan orogenic belts.

Thematic collection:
This article is part of the ‘Tethyan ophiolites and Tethyan seaways collection’ available at:
https://www.lyellcollection.org/cc/tethyan-ophiolites-and-tethyan-seaways
Decreased SLC26A3 expression and function in intestinal epithelial cells in response to Cryptosporidium parvum infection
Authors: Kumar Anoop , Jayawardena Dulari , Anbazhagan Arivarasu N. , Chatterjee Ishita , Priyamvada Shubha , Alrefai Waddah A. , Borthakur Alip , Dudeja Pradeep K.
Published: September 2019

The protozoan parasite Cryptosporidium parvum (CP) causes cryptosporidiosis, a diarrheal disease worldwide. Infection in immunocompetent hosts typically results in acute, self-limiting, or recurrent diarrhea. However, in immunocompromised individuals infection can cause fulminant diarrhea, extraintestinal manifestations, and death. To date, the mechanisms underlying CP-induced diarrheal pathogenesis are poorly understood. Diarrheal diseases most commonly involve increased secretion and/or decreased absorption of fluid and electrolytes. We and others have previously shown impaired chloride absorption in infectious diarrhea due to dysregulation of SLC26A3 [downregulated in adenoma (DRA)], the human intestinal apical membrane Cl−/[Formula: see text] exchanger protein. However, there are no studies on the effects of CP infection on DRA activity. Therefore, we examined the expression and function of DRA in intestinal epithelial cells in response to CP infection in vitro and in vivo. CP infection (0.5 × 106 oocysts/well in 24-well plates, 24 h) of Caco-2 cell monolayers significantly decreased Cl−/[Formula: see text] exchange activity (measured as DIDS-sensitive 125I uptake) as well as DRA mRNA and protein levels. Substantial downregulation of DRA mRNA and protein was also observed following CP infection ex vivo in mouse enteroid-derived monolayers and in vivo in the ileal and jejunal mucosa of C57BL/6 mice for 24 h. However, at 48 h after infection in vivo, the effects on DRA mRNA and protein were attenuated and at 5 days after infection DRA returned to normal levels. Our results suggest that impaired chloride absorption due to downregulation of DRA could be one of the contributing factors to CP-induced acute, self-limiting diarrhea in immunocompetent hosts.
Contribution of transcription factor EB to adipoRon-induced inhibition of arterial smooth muscle cell proliferation and migration
Authors: Wang Yun-Ting , Chen Jiajie , Li Xiang , Umetani Michihisa , Chen Yang , Li Pin-Lan , Zhang Yang
Published: September 2019

Abnormal vascular smooth muscle cell (SMC) dedifferentiation with increased proliferation and migration during pathological vascular remodeling is associated with vascular disorders, such as atherosclerosis and in-stent restenosis. AdipoRon, a selective agonist of adiponectin receptor, has been shown to protect against vascular remodeling by preventing SMC dedifferentiation. However, the molecular mechanisms that mediate adipoRon-induced SMC differentiation are not well understood. The present study aimed to elucidate the role of transcription factor EB (TFEB), a master regulator of autophagy, in mediating adipoRon’s effect on SMCs. In cultured arterial SMCs, adipoRon dose-dependently increased TFEB activation, which is accompanied by upregulated transcription of genes involved in autophagy pathway and enhanced autophagic flux. In parallel, adipoRon suppressed serum-induced cell proliferation and caused cell cycle arrest. Moreover, adipoRon inhibited SMC migration as characterized by wound-healing retardation, F-actin reorganization, and matrix metalloproteinase-9 downregulation. These inhibitory effects of adipoRon on proliferation and migration were attenuated by TFEB gene silencing. Mechanistically, activation of TFEB by adipoRon is dependent on intracellular calcium, but it is not associated with changes in AMPK, ERK1/2, Akt, or molecular target of rapamycin complex 1 activation. Using ex vivo aortic explants, we demonstrated that adipoRon inhibited sprouts that had outgrown from aortic rings, whereas lentiviral TFEB shRNA transduction significantly reversed this effect of adipoRon on aortic rings. Taken together, our results indicate that adipoRon activates TFEB signaling that helps maintain the quiescent and differentiated status of arterial SMCs, preventing abnormal SMC dedifferentiation. This study provides novel mechanistic insights into understanding the therapeutic effects of adipoRon on TFEB signaling and pathological vascular remodeling.
Lactobacillus reuteriDSM 17938 feeding of healthy newborn mice regulates immune responses while modulating gut microbiota and boosting beneficial metabolites
Authors: Liu Yuying , Tian Xiangjun , He Baokun , Hoang Thomas K. , Taylor Christopher M. , Blanchard Eugene , Freeborn Jasmin , Park Sinyoung , Luo Meng , Couturier Jacob , Tran Dat Q. , Roos Stefan , Wu Guoyao , Rhoads J. Marc
Published: September 2019

Early administration of Lactobacillus reuteri DSM 17938 (LR) prevents necrotizing enterocolitis and inhibits regulatory T-cell (Treg)-deficiency-associated autoimmunity in mice. In humans, LR reduces crying time in breastfed infants with colic, modifies severity in infants with acute diarrheal illnesses, and improves pain in children with functional bowel disorders. In healthy breastfed newborns with evolving microbial colonization, it is unclear if early administration of LR can modulate gut microbiota and their metabolites in such a way as to promote homeostasis. We gavaged LR (107colony-forming units/day, daily) to C57BL/6J mice at age of day 8 for 2 wk. Both male and female mice were investigated in these experiments. We found that feeding LR did not affect clinical phenotype or inflammatory biomarkers in plasma and stool, but LR increased the proportion of Foxp3+regulatory T cells (Tregs) in the intestine. LR also increased bacterial diversity and the relative abundance of p_Firmicutes, f_Lachnospiraceae, f_Ruminococcaceae, and genera Clostridium and Candidatus arthromitus, while decreasing the relative abundance of p_Bacteriodetes, f_Bacteroidaceae, f_Verrucomicrobiaceae, and genera Bacteroides, Ruminococcus, Akkermansia, and Sutterella. Finally, LR exerted a major impact on the plasma metabolome, upregulating amino acid metabolites formed via the urea, tricarboxylic acid, and methionine cycles and increasing tryptophan metabolism. In conclusion, early oral administration of LR to healthy breastfed mice led to microbial and metabolic changes which could be beneficial to general health.

NEW & NOTEWORTHY Oral administration of Lactobacillus reuteri DSM 17938 (LR) to healthy breastfed mice promotes intestinal immune tolerance and is linked to proliferation of beneficial gut microbiota. LR upregulates plasma metabolites that are involved in the urea cycle, the TCA cycle, methionine methylation, and the polyamine pathway. Herein, we show that LR given to newborn mice specifically increases levels of tryptophan metabolites and the purine nucleoside adenosine that are known to enhance tolerance to inflammatory stimuli.
Skeletal muscle amino acid uptake is lower and alanine production is greater in late gestation intrauterine growth-restricted fetal sheep hindlimb
Authors: Chang Eileen I. , Wesolowski Stephanie R. , Gilje Elizabeth A. , Baker Peter R. , Reisz Julie A. , D’Alessandro Angelo , Hay, William W. , Rozance Paul J. , Brown Laura D.
Published: September 2019

In a sheep model of intrauterine growth restriction (IUGR) produced from placental insufficiency, late gestation fetuses had smaller skeletal muscle mass, myofiber area, and slower muscle protein accretion rates compared with normally growing fetuses. We hypothesized that IUGR fetal muscle develops adaptations that divert amino acids (AAs) from protein accretion and activate pathways that conserve substrates for other organs. We placed hindlimb arterial and venous catheters into late gestation IUGR ( n = 10) and control (CON, n = 8) fetal sheep and included an external iliac artery flow probe to measure hindlimb AA uptake rates. Arterial and venous plasma samples and biceps femoris muscle were analyzed by mass spectrometry-based metabolomics. IUGR fetuses had greater abundance of metabolites enriched within the alanine, aspartate, and glutamate metabolism pathway compared with CON. Net uptake rates of branched-chain AA (BCAA) were lower by 42%–73%, and muscle ammoniagenic AAs (alanine, glycine, and glutamine) were lower by 107%–158% in IUGR hindlimbs versus CON. AA uptake rates correlated with hindlimb weight; the smallest hindlimbs showed net release of ammoniagenic AAs. Gene expression levels indicated a decrease in BCAA catabolism in IUGR muscle. Plasma purines were lower and plasma uric acid was higher in IUGR versus CON, possibly a reflection of ATP conservation. We conclude that IUGR skeletal muscle has lower BCAA uptake and develops adaptations that divert AAs away from protein accretion into alternative pathways that sustain global energy production and nitrogen disposal in the form of ammoniagenic AAs for metabolism in other organs.
Telemetric monitoring of penile pressure during mating in rats after chronic spinal cord injury
Authors: Steadman Casey J. , Vangoor Sai S. , Hubscher Charles H.
Published: September 2019

In men with a spinal cord injury (SCI), erectile function, ejaculation, and fertility are severely impaired. The present study utilized a telemetric pressure transducer implanted into the corpus cavernosum of the penis to examine sexual function during awake mating behavior in a rat contusion model with a range of Infinite Horizon Impactor forces distributed between 150 and 215 kdyn. The mating behavior paradigm included examination of the counts, average pressure, and average duration for mounts, intromissions, and ejaculations. Male Wistar rats were mated with receptive females in 30-min sessions preinjury (sexual acclimation) and once per week for 6 wk beginning after a 2-wk recovery period post-SCI. All SCI animals had significant deficits in sexual function in the parameters measured. These deficiencies were more prevalent in a subset having less than 20% white matter sparing, likely a reflection of the extent of bilateral spino-bulbo-spinal sexual circuitry disruption at the lesion epicenter. The resulting discoordination of the autonomic and somatic reflex control of erection and ejaculation recorded using telemetry devices in an awake, behaving animal model provides an effective means of gauging sexual function deficits after SCI and could have utility for quantifying recovery after a therapeutic intervention.
Impact of acute antioxidant administration on inflammation and vascular function in heart failure with preserved ejection fraction
Authors: Ratchford Stephen M. , Clifton Heather L. , Gifford Jayson R. , LaSalle D. Taylor , Thurston Taylor S. , Bunsawat Kanokwan , Alpenglow Jeremy K. , Richardson Russell S. , Wright Josephine B. , Ryan John J. , Wray D. Walter
Published: September 2019

Although it is now well established that heart failure with preserved ejection fraction (HFpEF) is associated with marked inflammation and a prooxidant state that is accompanied by vascular dysfunction, whether acute antioxidant (AO) administration can effectively target these disease-related decrements has not been evaluated. Thus, the present study sought to evaluate the efficacy of an acute over-the-counter AO cocktail (600 mg α-lipoic acid, 1,000 mg vitamin C, and 600 IU vitamin E) to mitigate inflammation and oxidative stress, and subsequently improve nitric oxide (NO) bioavailability and vascular function, in patients with HFpEF. Flow-mediated dilation (FMD) and reactive hyperemia (RH) were evaluated to assess conduit vessel and microvascular function, respectively, 90 min after administration of either placebo (PL) or AO in 16 patients with HFpEF (73 ± 10 yr, EF 54–70%) using a double-blind, crossover design. Circulating biomarkers of inflammation (C-reactive protein, CRP), oxidative stress (malondialdehyde and protein carbonyl), free radical concentration (EPR spectroscopy), antioxidant capacity, ascorbate and NO bioavailability (plasma nitrate, [Formula: see text], and nitrite, [Formula: see text]) were also assessed. FMD improved following AO administration (PL: 3.49 ± 0.7%, AO: 5.83 ± 1.0%), whereas RH responses were similar between conditions (PL: 428 ± 51 mL, AO: 425 ± 51 mL). AO administration decreased CRP (PL: 4,429 ± 705 ng/mL, AO: 3,664 ± 520 ng/mL) and increased ascorbate (PL: 30.0 ± 2.9 µg/mL, AO: 45.1 ± 3.7 µg/mL) and [Formula: see text] (PL: 182 ± 21 nM, AO: 213 ± 24 nM) but did not affect other biomarkers. Together, these data suggest that acute AO administration can exert anti-inflammatory effects and improve conduit artery vasodilation, but not microvascular function, in patients with HFpEF.
Differential contribution of pyramidal cells and interneurons to activity-dependent gene transcription changes
Authors: Salar Seda , Guhathakurta Debarpan , Marx Hofmann Lena
Published: September 2019

The type of neuronal activity determines the outcome of gene expression. Hence, the characterization of underlying mechanisms in transcriptome alterations may serve as a biomarker and provide new intervention methods for the treatment of pathologic conditions. Parrish et al. (Parrish RR, Codadu NK, Racca C, Trevelyan AJ. J Neurophysiol 120: 2358–2367, 2018) show that the changes in interneuronal gene transcription are correlated with the type of the activated neuronal population and that the initiation route of Ras/ERK MAPK pathway determines the polarity of the gene expression.
Electrical microstimulation evokes saccades in posterior parietal cortex of common marmosets
Authors: Ghahremani Maryam , Johnston Kevin D. , Ma Liya , Hayrynen Lauren K. , Everling Stefan
Published: September 2019

The common marmoset ( Callithrix jacchus) is a small-bodied New World primate increasing in prominence as a model animal for neuroscience research. The lissencephalic cortex of this primate species provides substantial advantages for the application of electrophysiological techniques such as high-density and laminar recordings, which have the capacity to advance our understanding of local and laminar cortical circuits and their roles in cognitive and motor functions. This is particularly the case with respect to the oculomotor system, as critical cortical areas of this network such as the frontal eye fields (FEF) and lateral intraparietal area (LIP) lie deep within sulci in macaques. Studies of cytoarchitecture and connectivity have established putative homologies between cortical oculomotor fields in marmoset and macaque, but physiological investigations of these areas, particularly in awake marmosets, have yet to be carried out. Here we addressed this gap by probing the function of posterior parietal cortex of the common marmoset with electrical microstimulation. We implanted two animals with 32-channel Utah arrays at the location of the putative area LIP and applied microstimulation while they viewed a video display and made untrained eye movements. Similar to previous studies in macaques, stimulation evoked fixed-vector and goal-directed saccades, staircase saccades, and eyeblinks. These data demonstrate that area LIP of the marmoset plays a role in the regulation of eye movements, provide additional evidence that this area is homologous with that of the macaque, and further establish the marmoset as a valuable model for neurophysiological investigations of oculomotor and cognitive control.

NEW & NOTEWORTHY The macaque monkey has been the preeminent model for investigations of oculomotor control, but studies of cortical areas are limited, as many of these areas are buried within sulci in this species. Here we applied electrical microstimulation to the putative area LIP of the lissencephalic cortex of awake marmosets. Similar to the macaque, microstimulation evoked contralateral saccades from this area, supporting the marmoset as a valuable model for studies of oculomotor control.
Breakdown of multiple sclerosis genetics to identify an integrated disease network and potential variant mechanisms
Authors: Shepard C. Joy , Cline Sara G. , Hinds David , Jahanbakhsh Seyedehameneh , Prokop Jeremy W.
Published: September 2019

Genetics of multiple sclerosis (MS) are highly polygenic with few insights into mechanistic associations with pathology. In this study, we assessed MS genetics through linkage disequilibrium and missense variant interpretation to yield a MS gene network. This network of 96 genes was taken through pathway analysis, tissue expression profiles, single cell expression segregation, expression quantitative trait loci (eQTLs), genome annotations, transcription factor (TF) binding profiles, structural genome looping, and overlap with additional associated genetic traits. This work revealed immune system dysfunction, nerve cell myelination, energetic control, transcriptional regulation, and variants that overlap multiple autoimmune disorders. Tissue-specific expression and eQTLs of MS genes implicate multiple immune cell types including macrophages, neutrophils, and T cells, while the genes in neural cell types enrich for oligodendrocyte and myelin sheath biology. There are eQTLs in linkage with lead MS variants in 25 genes including the multitissue eQTL, rs9271640, for HLA-DRB1/ DRB5. Using multiple functional genomic databases, we identified noncoding variants that disrupt TF binding for GABPA, CTCF, EGR1, YY1, SPI1, CLOCK, ARNTL, BACH1, and GFI1. Overall, this paper suggests multiple genetic mechanisms for MS associated variants while highlighting the importance of a systems biology and network approach when elucidating intersections of the immune and nervous system.
Synthesis and Study of an Efficient Metal-Organic Framework Adsorbent (MIL-96(Al)) for Fluoride Removal from Water
Authors: Wang Xingang , Zhu Hui , Sun Tongshuai , Liu Yinbo , Han Ting , Lu Jingxian , Dai Hongliang , Zhai Linzhi
Published: September 2019

Long-term consumption of drinking water that contains excessive amounts of fluoride can endanger human health; therefore, the preparation and application of a high-efficiency defluorination adsorbent for advanced purification of drinking water are of significant interest. This study presents a metal-organic framework adsorbent (MIL-96(Al)) with the granular structure of rice, which was generated by hydrothermal reaction. The specific surface area of MIL-96(Al) was ~220 m2 g-1, and it showed a good thermal stability. Several experiments were conducted wherein conditions, including adsorbent dosage, initial concentration, pH, and coexisting anions, were varied to understand the defluorination performance of the material. Results showed that pH (6–9) and coexisting anions had little effect on the removal efficiency of fluoride. The adsorption isotherm can be described by the Langmuir model, and the theoretical fluoride adsorption capacity of MIL-96(Al) was up to 42.19 mg Fg-1 at 298 K, which is much higher than that of the commonly used activated alumina. The adsorption process of fluoride is endothermic and follows pseudo second-order kinetics. In addition, MIL-96(Al) was shown to still achieve ~61.8% of the adsorption capacity after seven regenerations. This study shows that MIL-96(Al) is a good application prospect and could be widely used to remove fluoride from water.
Hoveniae Semen Seu Fructus Ethanol Extract Exhibits Anti-Inflammatory Activity via MAPK, AP-1, and STAT Signaling Pathways in LPS-Stimulated RAW 264.7 and Mouse Peritoneal Macrophages
Authors: Jeong Yun Hee , Oh You-Chang , Cho Won-Kyung , Yim Nam-Hui , Ma Jin Yeul
Published: September 2019

Hoveniae semen seu fructus (HSF, fruit and seed of Hovenia dulcis Thunb) is an important traditional herbal medicine and food supplement in East Asia for the treatment of liver diseases, alcohol poisoning, obesity, allergy, and cancer. HSF has also been reported to have anti-inflammatory activity, but the cellular mechanism of action is not fully understood. We assessed the anti-inflammatory properties of an HSF ethanol (HSFE) extract and explored its precise mechanism. The ability of HSFE to suppress inflammatory responses was investigated in a murine macrophage cell line, RAW 264.7, and mouse primary macrophages. Secretions of NO, proinflammatory cytokines, inflammatory factors, and related proteins were measured using the Griess assay, ELISA, Western blot analysis, and real-time PCR, respectively. In addition, the main components of HSFE were analyzed by HPLC, and their anti-inflammatory activity was confirmed. Our results showed that pretreatment of HSFE markedly reduced the expression of NO and iNOS without causing cytotoxicity and significantly attenuated secretion of proinflammatory cytokines, including TNF-α, IL-6, and IL-1β. In addition, HSFE strongly suppressed phosphorylation of MAPK and decreased the activation of AP-1, JAK2/STAT, and NF-κB in LPS-stimulated RAW 264.7 cells in a concentration-dependent manner. Furthermore, HSFE strongly suppressed the inflammatory cytokine levels in mouse peritoneal macrophages. Also, as a result of HPLC analysis, three main components, ampelopsin, taxifolin, and myricetin, were identified in the HSFE extract, and each compound effectively inhibited the secretion of inflammatory mediators induced by LPS. These findings show that HSFE exerts anti-inflammatory effects by suppressing the activation of MAPK, AP-1, JAK2/STAT, and NF-κB signaling pathways in LPS-stimulated macrophages. In addition, the anti-inflammatory efficacy of HSFE appears to be closely related to the action of the three main components. Therefore, HSFE appears to be a promising candidate for the treatment of inflammatory diseases.
Clonal Mutations Activate the NF-κB Pathway to Promote Recurrence of Nasopharyngeal Carcinoma
Authors: You Rui , Liu You-Ping , Lin De-Chen , Li Qing , Yu Tao , Zou Xiong , Lin Mei , Zhang Xiao-Long , He Gui-Ping , Yang Qi , Zhang Yi-Nuan , Xie Yu-Long , Jiang Rou , Wu Chen-Yan , Zhang Chao , Cui Cheng , Wang Jing-Qi , Wang Yue , Zhuang Ai-Hua , Guo Gui-Fang , Hua Yi-Jun , Sun Rui , Yun Jing-Ping , Zuo Zhi-Xiang , Liu Ze-Xian , Zhu Xiao-Feng , Kang Tie-Bang , Qian Chao-Nan , Mai Hai-Qiang , Sun Ying , Zeng Mu-Sheng , Feng Lin , Zeng Yi-Xin , Chen Ming-Yuan
Published: September 2019

The genetic events occurring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 patients with rNPC and 44 primarily diagnosed NPC (pNPC), with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (TRAF3, CYLD, and NFKBIA) were significantly mutated in both pNPC and rNPC. Notably, mutations in TRAF3, CYLD, and NFKBIA were all clonal in rNPC, however, 55.6% to 57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway–associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with locoregional relapse than in those without relapse. Furthermore, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Finally, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity in vitro and in vivo. In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival.

Significance:

This study uncovers genetic events that promote the progression and recurrence of nasopharyngeal carcinoma and has potential prognostic and therapeutic implications.

See related commentary by Sehgal and Barbie, p. 5915
Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance
Authors: Dalin Simona , Sullivan Mark R. , Lau Allison N. , Grauman-Boss Beatrice , Mueller Helen S. , Kreidl Emanuel , Fenoglio Silvia , Luengo Alba , Lees Jacqueline A. , Vander Heiden Matthew G. , Lauffenburger Douglas A. , Hemann Michael T.
Published: September 2019

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the United States. The deoxynucleoside analogue gemcitabine is among the most effective therapies to treat PDAC, however, nearly all patients treated with gemcitabine either fail to respond or rapidly develop resistance. One hallmark of PDAC is a striking accumulation of stromal tissue surrounding the tumor, and this accumulation of stroma can contribute to therapy resistance. To better understand how stroma limits response to therapy, we investigated cell-extrinsic mechanisms of resistance to gemcitabine. Conditioned media from pancreatic stellate cells (PSC), as well as from other fibroblasts, protected PDAC cells from gemcitabine toxicity. The protective effect of PSC-conditioned media was mediated by secretion of deoxycytidine, but not other deoxynucleosides, through equilibrative nucleoside transporters. Deoxycytidine inhibited the processing of gemcitabine in PDAC cells, thus reducing the effect of gemcitabine and other nucleoside analogues on cancer cells. These results suggest that reducing deoxycytidine production in PSCs may increase the efficacy of nucleoside analog therapies.

Significance:

This study provides important new insight into mechanisms that contribute to gemcitabine resistance in PDAC and suggests new avenues for improving gemcitabine efficacy.
Mitohormesis, UPRmt, and the Complexity of Mitochondrial DNA Landscapes in Cancer
Authors: Kenny Timothy C. , Gomez Maria L. , Germain Doris
Published: September 2019

The discovery of the Warburg effect, the preference of cancer cells to generate ATP via glycolysis rather than oxidative phosphorylation, has fostered the misconception that cancer cells become independent of the electron transport chain (ETC) for survival. This is inconsistent with the need of ETC function for the generation of pyrimidines. Along with this misconception, a large body of literature has reported numerous mutations in mitochondrial DNA (mtDNA), further fueling the notion of nonfunctional ETC in cancer cells. More recent findings, however, suggest that cancers maintain oxidative phosphorylation capacity and that the role of mtDNA mutations in cancer is likely far more nuanced in light of the remarkable complexity of mitochondrial genetics. This review aims at describing the various model systems that were developed to dissect the role of mtDNA in cancer, including cybrids, and more recently mitochondrial–nuclear exchange and conplastic mice. Furthermore, we put forward the notion of mtDNA landscapes, where the surrounding nonsynonymous mutations and variants can enhance or repress the biological effect of specific mtDNA mutations. Notably, we review recent studies describing the ability of some mtDNA landscapes to activate the mitochondrial unfolded protein response (UPRmt) but not others. Furthermore, the role of the UPRmt in maintaining cancer cells in the mitohormetic zone to provide selective adaptation to stress is discussed. Among the genes activated by the UPRmt, we suggest that the dismutases SOD2 and SOD1 may play key roles in the establishment of the mitohormetic zone. Finally, we propose that using a UPRmt nuclear gene expression signature may be a more reliable readout than mtDNA landscapes, given their diversity and complexity.
NKT Cells Coexpressing a GD2-Specific Chimeric Antigen Receptor and IL15 Show Enhanced In Vivo Persistence and Antitumor Activity against Neuroblastoma
Authors: Xu Xin , Huang Wei , Heczey Andras , Liu Daofeng , Guo Linjie , Wood Michael , Jin Jingling , Courtney Amy N. , Liu Bin , Di Pierro Erica J. , Hicks John , Barragan Gabriel A. , Ngai Ho , Chen Yuhui , Savoldo Barbara , Dotti Gianpietro , Metelitsa Leonid S.
Published: September 2019

Purpose:

Vα24-invariant natural killer T cells (NKT) are attractive carriers for chimeric antigen receptors (CAR) due to their inherent antitumor properties and preferential localization to tumor sites. However, limited persistence of CAR-NKTs in tumor-bearing mice is associated with tumor recurrence. Here, we evaluated whether coexpression of the NKT homeostatic cytokine IL15 with a CAR enhances the in vivo persistence and therapeutic efficacy of CAR-NKTs.

Experimental Design:

Human primary NKTs were ex vivo expanded and transduced with CAR constructs containing an optimized GD2-specific single-chain variable fragment and either the CD28 or 4-1BB costimulatory endodomain, each with or without IL15 (GD2.CAR or GD2.CAR.15). Constructs that mediated robust CAR-NKT cell expansion were selected for further functional evaluation in vitro and in xenogeneic mouse models of neuroblastoma.

Results:

Coexpression of IL15 with either costimulatory domain increased CAR-NKT absolute numbers. However, constructs containing 4-1BB induced excessive activation-induced cell death and reduced numeric expansion of NKTs compared with respective CD28-based constructs. Further evaluation of CD28-based GD2.CAR and GD2.CAR.15 showed that coexpression of IL15 led to reduced expression levels of exhaustion markers in NKTs and increased multiround in vitro tumor cell killing. Following transfer into mice bearing neuroblastoma xenografts, GD2.CAR.15 NKTs demonstrated enhanced in vivo persistence, increased localization to tumor sites, and improved tumor control compared with GD2.CAR NKTs. Importantly, GD2.CAR.15 NKTs did not produce significant toxicity as determined by histopathologic analysis.

Conclusions:

Our results informed selection of the CD28-based GD2.CAR.15 construct for clinical testing and led to initiation of a first-in-human CAR-NKT cell clinical trial (NCT03294954).