bluuebunny/crossref_metadata_2025 huggingface dataset:
Nutrition support and clinical outcome in advanced cancer patients
Authors: Laviano Alessandro , Di Lazzaro Luca , Koverech Angela
Published: July 2018

Newly diagnosed cancer patients are frequently found suffering from a metastatic disease, which poses additional challenges to the delivery of effective therapies. Chemotherapy and radiotherapy are associated with side effects which reduce tolerance to treatment and likelihood of tumour response. Identifying preventable factors of reduced response to therapy would translate into better care of cancer patients. Among other factors, malnutrition, as diagnosed by non-volitional weight loss, and cachexia, as revealed by sarcopenia, are universally recognised negative prognostic factors. Less certainty exists on the role of nutrition therapy in improving cancer patients’ body composition and clinical outcome. The reasons for the lack of convincing evidence are manifold, mostly related to the poor design of nutritional trials. Metastatic cancer patients should receive a quantitatively and qualitatively adequate diet, and in case of reduced tolerance of food, artificial nutrition is indicated. Most importantly, nutritional care should target the underlying mechanisms of reduced food intake/impaired anabolic response, and aim at minimising the impact of catabolic crisis, to maximise the recovery phase. The combined and early use of supplemental energies and proteins, as well as modulators of inflammatory response has been shown to improve nutritional status and may also benefit clinical outcome. When part of early palliative care, nutrition therapy improves cancer patients’ quality of life and may prolong survival at a fraction of the costs of developing new drugs.
Leisure Activities and Motivational Profiles in Adaptation to Nursing Homes
Authors: Altintas Emin , Guerrien Alain , Vivicorsi Bruno , Clément Evelyne , Vallerand Robert J.
Published: July 2018

Cette recherche étudie les liens entre motivation, participation aux activités de loisirs et adaptation de personnes âgées au centre d’hébergement dans lequel elles vivent. En accord avec lathéorie de l’autodétermination, nous avons testé l’hypothèse que les profils les plus autodéterminés présenteront la meilleure adaptation, la plus grande participation aux activités de loisirs at la meilleure satisfaction de vie. Les participants ont rempli des questionnaires évaluant la motivation, la participation aux activités de loisirs ainsi que l’adaptation au centre d’hébergement. Une analyse des profils latents révèle que lesprofils hautement autodéterminés(score élevé de motivation autodéterminée et faible score de motivation non-autodéterminée) etles profils additifs(motivation autodéterminée et non autodéterminée élevées) ne diffèrent pas significativement alors que les participants auxprofils modéréset auxprofils faiblement autodéterminésprésentent les scores les plus bas d’adaptation au centre d’hébergement, de participation aux activités de loisirs et de satisfaction de vie.
First assessment of all-cause acute diarrhoea and rotavirus-confirmed cases following massive vaccination in Argentina
Authors: Degiuseppe J. I. , Stupka J. A.
Published: July 2018

Argentina incorporated rotavirus massive vaccination in 2015. No specific strategy has been designed to accurately measure the impact of this recent introduction on the diarrhoeal disease burden in our country. We assessed post-vaccine introduction data (all-cause acute diarrhoea and rotavirus laboratory-confirmed cases, and genotype distribution), compared with pre-vaccination period in children under 5 years of age in Argentina. Cross-sectional ecologic analysis was conducted with data from the Argentine Surveillance Health System. Endemic channel and global and seasonal incidence rates of pre- and post-vaccination periods were calculated and further compared. Conventional binary genotypification on rotavirus-positive samples was also performed. In post-vaccination period, a global decrease of 20.8% in the rate of all-cause acute diarrhoea cases was found. The endemic channel showed that declination was more significant in the autumn/winter season. Rotavirus laboratory-confirmed cases showed 61.7% of reduction and the weekly distribution analyses indicated a significant flattening of the expected seasonal peak. G2P[4] was the most prevalent circulating genotype (57.2%). This study represents the first assessment of diarrhoeal disease burden since rotavirus massive vaccination strategy was implemented in Argentina. This introduction represented a successful intervention due to the significant decrease in all-cause acute diarrhoea cases and rotavirus laboratory-confirmed cases.
THE MIDDLE PRECLASSIC FIGURINES FROM CAHAL PECH, BELIZE VALLEY
Authors: Peniche May Nancy , DeLance Lisa , Awe Jaime J.
Published: July 2018

Ceramic figurines are ubiquitous throughout the archaeological record of Mesoamerica. These small, handheld objects continue to fascinate archaeologists, and their role in the daily lives of the people who created and used them remains a point of debate in some academic circles. The figurines have been interpreted variously as children's toys, fertility fetish tools, and ritual objects. At the site of Cahal Pech, located in the Belize Valley of west-central Belize, a large assemblage of figurines has been recovered from construction fill dating to the Cunil (1200–900b.c.) and Kanluk ceramic phases (900–350b.c.) of the Preclassic period. In this article, we analyzed the temporal and spatial distribution of these objects in the settlement and conclude that these objects were used in a variety of ritual events. Although they mainly served as venues for invoking ancestors in domestic rituals, their discovery in public spaces suggests diverse social uses. Most importantly, their limited presence in residential and public spaces outside the Plaza B section of the site core during the late facet of the Kanluk phase may indicate that certain rituals were not performed by the entire community.
Portable Health Care Facilities in Disaster and Rescue Zones: Characteristics and Future Suggestions
Authors: Bitterman Noemi , Zimmer Yoni
Published: July 2018

Introduction

Natural and man-made disasters are becoming global concerns. Natural disasters appear to be growing in number and intensity due to global warming, population explosion, increased travel, and overcrowding of cities. In addition, man-made disasters do not seem to be diminishing.

At disaster sites, an immediate response is needed. National and international organizations; nongovernmental, military, and commercial organizations; and even private donors enlist to provide humanitarian and medical support and to send supplies, shelters, and temporary health care facilities to disaster zones.

Problem

The literature is sparse regarding the design of portable health care facilities intended for disaster zones and their adaptability to the tasks required and site areas.

Methods

Data were collected from peer-reviewed literature, scientific reports, magazines, and websites regarding health care facilities at rescue and salvage situations. Information was grouped according to categories of structure and properties, and relative strengths and weaknesses. Next, suggestions were made for future directions.

Results

Permanent structures and temporary constructed facilities were the two primary categories of health care facilities functioning at disaster zones. Permanent hospitals were independent functioning medical units that were moved or transported to and from disaster zones as complete units, as needed. These facilities included floating hospitals, flying (airborne) hospitals, or terrestrial mobile facilities. Thus, these hospitals self-powered and contained mobility aids within their structure using water, air, or land as transporting media.

Temporary health care facilities were transported to disaster zones as separate, nonfunctioning elements that were constructed or assembled on site and were subsequently taken apart. These facilities included the classical soft-type tents and solid containers that were organized later as hospitals in camp configurations. The strengths and weaknesses of the diverse hospital options are discussed.

Conclusions

Future directions include the use of innovative materials, advanced working methods, and integrated transportation systems. In addition, a holistic approach should be developed to improve the performance, accessibility, time required to function, sustainability, flexibility, and modularity of portable health care facilities.

Bitterman N, Zimmer Y. Portable health care facilities in disaster and rescue zones: characteristics and future suggestions. Prehosp Disaster Med. 2018;33(4):411–417
Diverse and durophagous: Early Carboniferous chondrichthyans from the Scottish Borders
Authors: Richards Kelly R. , Sherwin Janet E. , Smithson Timothy R. , Bennion Rebecca F. , Davies Sarah J. , Marshall John E. A. , Clack Jennifer A.
Published: July 2018

Chondrichthyan teeth from a new locality in the Scottish Borders supply additional evidence of Early Carboniferous chondrichthyans in the UK. The interbedded dolostones and siltstones of the Ballagan Formation exposed along Whitrope Burn are interpreted as representing a restricted lagoonal environment that received significant amounts of land-derived sediment. This site is palynologically dated to the latest Tournaisian–early Viséan. The diverse dental fauna documented here is dominated by large crushing holocephalan toothplates, with very few, small non-crushing chondrichthyan teeth. Two new taxa are named and described. Our samples are consistent with worldwide evidence that chondrichthyan crushing faunas are common following the Hangenberg extinction event. The lagoonal habitat represented by Whitrope Burn may represent a temporary refugium that was host to a near-relict fauna dominated by large holocephalan chondrichthyans with crushing dentitions. Many of these had already become scarce in other localities by the Viséan and become extinct later in the Carboniferous. This fauna provides evidence of early endemism or niche separation within European chondrichthyan faunas at this time. This evidence points to a complex picture in which the diversity of durophagous chondrichthyans is controlled by narrow spatial shifts in niche availability over time.
The Effects of Climate Change on GDP by Country and the Global Economic Gains From Complying With the Paris Climate Accord
Authors: Kompas Tom , Pham Van Ha , Che Tuong Nhu
Published: July 2018

Computable general equilibrium (CGE) models are a standard tool for policy analysis and forecasts of economic growth. Unfortunately, due to computational constraints, many CGE models are dimensionally small, aggregating countries into an often limited set of regions or using assumptions such as static price‐level expectations, where next period's price is conditional only on current or past prices. This is a concern for climate change modeling, since the effects of global warming by country, in a fully disaggregated and global trade model, are needed, and the known future effects of global warming should be included in forward‐looking forecasts for prices and profitability. This work extends a large dimensional intertemporal CGE trade model to account for the various effects of global warming (e.g., loss in agricultural productivity, sea level rise, and health effects) on Gross Domestic Product (GDP) growth and levels for 139 countries, by decade and over the long term, where producers look forward and adjust price expectations and capital stocks to account for future climate effects. The potential economic gains from complying with the Paris Accord are also estimated, showing that even with a limited set of possible damages from global warming, these gains are substantial. For example, with the comparative case of Representative Concentration Pathway 8.5 (4°C), the global gains from complying with the 2°C target (Representative Concentration Pathway 4.5) are approximately US$17,489 billion per year in the long run (year 2100). The relative damages from not complying to Sub‐Sahara Africa, India, and Southeast Asia, across all temperature ranges, are especially severe.
Silica Dissolution and Precipitation in Glaciated Volcanic Environments and Implications for Mars
Authors: Rutledge A. M. , Horgan B. H. N. , Havig J. R. , Rampe E. B. , Scudder N. A. , Hamilton T. L.
Published: July 2018

The surface of Mars exhibits strong evidence for a widespread and long‐lived cryosphere. Observations of the surface have identified phases produced by water‐rock interactions, but the contribution of glaciers to the observed alteration mineralogy is unclear. To characterize the chemical alteration expected on an icy early Mars, we collected water and rock samples from terrestrial glaciated volcanics. We related geochemical measurements of meltwater to the mineralogy and chemistry of proglacial rock coatings. In these terrains, water is dominated by dissolved silica relative to other dissolved cations, particularly at mafic sites. Rock coatings associated with glacial striations on mafic boulders include a silica‐rich component, indicating that silica precipitation is occurring in the subglacial environment. We propose that glacial alteration of volcanic bedrock is dominated by a combination of high rates of silica dissolution and precipitation of opaline silica. On Mars, cryosphere‐driven chemical weathering could be the origin of observed silica‐enriched phases.
Temperature and Composition Dependence of Sea Spray Aerosol Production
Authors: Forestieri S. D. , Moore K. A. , Martinez Borrero R. , Wang A. , Stokes M. D. , Cappa C. D.
Published: July 2018

A discrepancy between laboratory and field‐derived parameterizations for the dependence of sea spray aerosol (SSA) particle number concentrations (Np) and size distributions on water temperature (Tw) exists. Here we address this discrepancy by quantifying the Tw dependence of SSA production over the range −2–25 °C for laboratory‐generated particles using a marine aerosol reference tank (MART), a miniature MART (miniMART), and a plunging jet. Four water types were considered: NaCl water, reef salt (RS) water, filtered and autoclaved reef salt (FARS), and filtered but not autoclaved seawater (NASW). For NaCl, RS, and FARS water the Np exhibited a moderate, monotonic increase with Tw for all generation methods (sensitivity of 2.1–4.1%/°C). This contrasts with some previous laboratory studies but is consistent with parameterizations derived from ambient observations. The reconciliation of laboratory results with these parameterizations supports their use in global models. The Tw sensitivity also increased with particle size in the submicron size range. This indicates the fraction of primary SSA that can act as cloud condensation nuclei has a different sensitivity to Tw than the total particle number. The particle production for actual seawater (NASW) differed from the other water types, exhibiting complex, irreproducible behavior with no clear Tw dependence due most likely to biologically or physically driven temporal evolution of seawater composition. This suggests that variability in seawater composition may have as large an impact as temperature on actual SSA production. These observations provide new constraints and context for understanding the dependence of SSA production on water temperature and composition.
Iodine Catalyzed Ozone Destruction at the Texas Coast and Gulf of Mexico
Authors: Tuite K. , Brockway N. , Colosimo S. F. , Grossmann K. , Tsai C. , Flynn J. , Alvarez S. , Erickson M. , Yarwood G. , Nopmongcol U. , Stutz J.
Published: July 2018

Iodine monoxide and ozone measurements were taken using long‐path differential optical absorption spectroscopy along the Gulf of Mexico coast near Galveston, Texas, in spring/summer of 2016. During the eight‐week campaign, half of the days were characterized by O3 between 12 and 25 ppb. These air masses coincided with onshore flow and had measurable levels of IO, with an average daily maximum around 0.8 ppt and values as high as 2 ppt. The presence of IO indicates the influence of iodine chemistry which catalytically destroys O3. Using observed IO and NO2 levels, along with model HO2 data, an O3 destruction rate between 1.5 and 2 ppb/day was calculated. Assuming a background O3 level of 30 ppb, it is very likely that iodine chemistry is responsible for destroying enough O3 along a 10‐day back trajectory through the Gulf of Mexico to explain the low mixing ratios frequently experienced along the Texas coast.
Impact of Ningaloo Niño on Tropical Pacific and an Interbasin Coupling Mechanism
Authors: Zhang Lei , Han Weiqing
Published: July 2018

The Ningaloo Niño refers to the evident interannual variability of sea surface temperature anomalies in the southeast Indian Ocean (SEIO), which can be caused by the Pacific La Niña. Through performing atmospheric general circulation model experiments, this study shows that the Ningaloo Niño can also actively impact on the tropical Pacific. The sea surface temperature anomalies associated with the Ningaloo Niño induces negative sea level pressure anomalies extending from the SEIO to the Maritime Continent, strengthens western Pacific trade winds, and thus cools the central tropical Pacific. In turn, the central Pacific cooling anomalies generate cyclonic wind anomalies over the SEIO, and the strengthened trades enhance the Indonesian throughflow, with both enhancing the Ningaloo Niño. As such, a positive feedback loop associated with an interbasin coupling mechanism is proposed, which acts to amplify the Ningaloo Niño and its subsequent impact on the tropical Pacific.
Jupiter Lightning‐Induced Whistler and Sferic Events With Waves and MWR During Juno Perijoves
Authors: Imai Masafumi , Santolík Ondřej , Brown Shannon T. , Kolmašová Ivana , Kurth William S. , Janssen Michael A. , Hospodarsky George B. , Gurnett Donald A. , Bolton Scott J. , Levin Steven M.
Published: July 2018

During the Juno perijove explorations from 27 August 2016 through 1 September 2017, strong electromagnetic impulses induced by Jupiter lightning were detected by the Microwave Radiometer (MWR) instrument in the form of 600‐MHz sferics and recorded by the Waves instrument in the form of Jovian low‐dispersion whistlers discovered in waveform snapshots below 20 kHz. We found 71 overlapping events including sferics, while Waves waveforms were available. Eleven of these also included whistler detections by Waves. By measuring the separation distances between the MWR boresight and the whistler exit point, we estimated the distance whistlers propagate below the ionosphere before exiting to the magnetosphere, called the coupling distance, to be typically one to several thousand of kilometers with a possibility of no subionospheric propagation, which gives a new constraint on the atmospheric whistler propagation.
Melting in High‐Pressure Ice Layers of Large Ocean Worlds—Implications for Volatiles Transport
Authors: Kalousová Klára , Sotin Christophe
Published: July 2018

A high‐pressure ice layer controls the exchange of heat and material between the silicate core and the ocean of Ganymede and Titan. We have shown (Kalousová et al., 2018, http://doi.org/10.1016/j.icarus.2017.07.018) that a temperate (partially molten) layer is always present at the ocean interface. Another temperate layer with a few percent of water may be present at the silicates interface for low values of Rayleigh number. We derive scaling laws to predict the critical value under which this temperate layer exists and the amount of generated melt. The presence of liquid water in contact with silicates was probably limited to the early history, providing a pathway for the transfer of salts and volatiles like 40Ar to the ocean. We also derive scaling laws for the water outflow velocity and for the top temperate layer thickness. These laws can be used to model the global thermal and compositional evolution of large ocean worlds.
Detectable Impacts of the Past Half‐Degree Global Warming on Summertime Hot Extremes in China
Authors: Chen Yang , Zhai Panmao , Zhou Baiquan
Published: July 2018

Avoided risks in a 1.5°C warmer world as opposed to a 2°C one become urgent to be assessed after the Paris Agreement, especially at regional scales. To provide an observable analog, this study quantified detectable impacts of the past 0.5°C global warming on summertime hot extremes in China. The half‐degree global warming has preferentially facilitated the emergence and prevalence of complex hot extremes (sequential hot day‐night), which experienced a twofold‐fourfold increase in their frequency in Southeast China, lower reaches of the Yangtze River, and northern China, along with a doubling to tripling of duration and intensity. The past global warming of 0.5°C further exacerbated the vulnerability of above hot spots by exposing them to drastically augmented (over 300%) excess heat accumulated during the severest complex events. These observation‐based solid evidences imply that a 0.5°C reduction in future global warming does matter for China to avoid excessively escalated risks of complex hot extremes.
Saturn's Northern Auroras and Their Modulation by Rotating Current Systems During Late Northern Spring in Early 2014
Authors: Kinrade J. , Badman S. V. , Provan G. , Cowley S. W. H. , Lamy L. , Bader A.
Published: July 2018

The Hubble Space Telescope imaged Saturn's northern ultraviolet auroras during February–June 2014, when Saturn's northern and southern magnetic perturbation fields were locked in antiphase and matched in rotation period (~10.69 hr). During this coalescence period, we test for evidence of rotational modulation of the auroras using the latest rotating current system model and kilometric radio phases derived from Cassini measurements. While we see modulation of auroral intensity in the rotating frames of the planetary period current systems, the pattern is opposite to that expected and is dominated by an asymmetric local time profile that peaks at dawn. Enhancement of the north emission by rotating upward field aligned currents (FACs) is expected to peak at magnetic longitudes of ~90°, whereas here the intensity increased at ~270°. This unexpected finding is attributed to the presence of nonplanetary period oscillation dynamics having affected the auroral morphology, together with insufficient sampling of the rotational system orientations provided during such Hubble Space Telescope campaigns. Rotational modulation is clearest at dawn regardless of the pattern's orientation, suggesting that the physical relationship between rotating FACs and auroral intensity is not direct, having a local time dependence that is not generally observed in the rotating FAC magnitudes. We also find no statistically significant planetary period oscillation of the auroral circle position, but the mean center was offset from the spin pole by ~3° latitude toward early morning local times. Mean auroral boundaries were located at equatorward and poleward colatitudes of 15.0 ± 2.8° and 12.4 ± 3.0°, respectively.
MENTAT: A New Wind Model for Earth's Thermosphere
Authors: Dandenault P. B.
Published: July 2018

A global database of ionosonde hmF2 observations was used to develop a global database of equivalent neutral winds, which was then used to develop a new empirical horizontal neutral wind model called the Magnetic mEridional NeuTrAl Thermospheric model. In this paper, we (1) developed and optimized a technique for deriving magnetic meridional thermospheric neutral winds using the altitude of the peak ionosphere (hmF2) observations from bottomside ionospheric sounders, (2) validated these neutral winds with observations from Fabry‐Pérot interferometers (FPIs), (3) developed a new model of horizontal, magnetic meridional, equivalent neutral winds in the midlatitude regions from a global database of ionosonde observations spanning the years 1961 to 1990. Our new method for generating the winds compares well with FPI wind observations and illuminates nonphysical behavior in the horizontal thermospheric neutral wind model. Magnetic mEridional NeuTrAl Thermospheric neutral winds compare well with FPI wind observations over both short‐ and long‐time periods, and the model produces winds as a function of the year, day of year, universal time, solar flux, geographic latitude, and geographic longitude. Two major findings are (1) a distinct solar cycle wind variation that was not captured in other empirical models using other data sets and (2) global measurements of ionospheric hmF2, which provide constraints on the global wind field that is particularly valuable considering the persistent lack of space‐based F region winds and the inability of FPIs to operate during the day, when cloudy, or under moon‐up conditions.
The 6 September 2017 X‐Class Solar Flares and Their Impacts on the Ionosphere, GNSS, and HF Radio Wave Propagation
Authors: Yasyukevich Y. , Astafyeva E. , Padokhin A. , Ivanova V. , Syrovatskii S. , Podlesnyi A.
Published: July 2018

On 6 September 2017, the Sun emitted two significant solar flares (SFs). The first SF, classified X2.2, peaked at 09:10 UT. The second one, X9.3, which is the most intensive SF in the current solar cycle, peaked at 12:02 UT and was accompanied by solar radio emission. In this work, we study ionospheric response to the two X‐class SFs and their impact on the Global Navigation Satellite Systems and high‐frequency (HF) propagation. In the ionospheric absolute vertical total electron content (TEC), the X2.2 SF caused an overall increase of 2–4 TECU on the dayside. The X9.3 SF produced a sudden increase of ~8–10 TECU at midlatitudes and of ~15–16 TECU enhancement at low latitudes. These vertical TEC enhancements lasted longer than the duration of the EUV emission. In TEC variations within 2–20 min range, the two SFs provoked sudden increases of ~0.2 TECU and 1.3 TECU. Variations in TEC from geostationary and GPS/GLONASS satellites show similar results with TEC derivative of ~1.3–1.7 TECU/min for X9.3 and 0.18–0.24 TECU/min for X2.2 in the subsolar region. Further, analysis of the impact of the two SFs on the Global Navigation Satellite Systems‐based navigation showed that the SF did not cause losses‐of‐lock in the GPS, GLONASS, or Galileo systems, while the positioning error increased by ~3 times in GPS precise point positioning solution. The two X‐class SFs had an impact on HF radio wave propagation causing blackouts at <30 MHz in the subsolar region and <15 MHz in the postmidday sector.
Correction: Author Correction: Metabolic engineering of Saccharomyces cerevisiae for production of very long chain fatty acid-derived chemicals
Authors: Yu Tao , Zhou Yongjin J. , Wenning Leonie , Liu Quanli , Krivoruchko Anastasia , Siewers Verena , Nielsen Jens , David Florian
Published: July 2018

Nature Communications 8: Article number: 15587 (2017); Published: 26 May 2017, Updated: 13 July 2018 In the originally published version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include support from the European Union’s Horizon 2020 Framework Programme for Research and Innovation—Grant Agreement No.
Correction: Author Correction: Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
Authors: Machutta Carl A. , Kollmann Christopher S. , Lind Kenneth E. , Bai Xiaopeng , Chan Pan F. , Huang Jianzhong , Ballell Lluis , Belyanskaya Svetlana , Besra Gurdyal S. , Barros-Aguirre David , Bates Robert H. , Centrella Paolo A. , Chang Sandy S. , Chai Jing , Choudhry Anthony E. , Coffin Aaron , Davie Christopher P. , Deng Hongfeng , Deng Jianghe , Ding Yun , Dodson Jason W. , Fosbenner David T. , Gao Enoch N. , Graham Taylor L. , Graybill Todd L. , Ingraham Karen , Johnson Walter P. , King Bryan W. , Kwiatkowski Christopher R. , Lelièvre Joël , Li Yue , Liu Xiaorong , Lu Quinn , Lehr Ruth , Mendoza-Losana Alfonso , Martin John , McCloskey Lynn , McCormick Patti , O’Keefe Heather P. , O’Keeffe Thomas , Pao Christina , Phelps Christopher B. , Qi Hongwei , Rafferty Keith , Scavello Genaro S. , Steiginga Matt S. , Sundersingh Flora S. , Sweitzer Sharon M. , Szewczuk Lawrence M. , Taylor Amy , Fern Toh May , Wang Juan , Wang Minghui , Wilkins Devan J. , Xia Bing , Yao Gang , Zhang Jean , Zhou Jingye , Donahue Christine P. , Messer Jeffrey A. , Holmes David , Arico-Muendel Christopher C. , Pope Andrew J. , Gross Jeffrey W. , Evindar Ghotas
Published: July 2018

Nature Communications 8: Article number: 16081 (2017); Published: 17 July 2017, Updated: 13 July 2018 The original version of this Article omitted the following from the Acknowledgements: ‘We thank Robert Kirkpatrick for implementing the high throughput protein design strategy that enabled screeningand triage of essential A.
The major depressive disorder GWAS-supported variant rs10514299 in TMEM161B-MEF2C predicts putamen activation during reward processing in alcohol dependence
Authors: Muench Christine , Schwandt Melanie , Jung Jeesun , Cortes Carlos R. , Momenan Reza , Lohoff Falk W.
Published: July 2018

Alcohol dependence (AD) frequently co-occurs with major depressive disorder (MDD). While this comorbidity is associated with an increase in disease burden, worse treatment outcomes, and greater economic costs, the underlying neurobiology remains poorly understood. A recent large-scale GWAS of MDD has identified a locus in theTMEM161B-MEF2Cregion (rs10514299) as a novel risk variant; however, the biological relevance of this variant has not yet been studied. Given previous reports of disrupted reward processing in both AD and MDD, we hypothesized that rs10514299 would be associated with differences in striatal BOLD responses during reward/loss anticipation in AD. DNA samples from 45 recently detoxified patients with AD and 45 healthy controls (HC) were genotyped for rs10514299. Participants performed the Monetary Incentive Delay task in a 3-Tesla MRI scanner. Effects of rs10514299 on striatal activation during anticipation of high/low reward/loss were investigated. Furthermore, we examined associations between rs10514299 and lifetime AD diagnosis in two independent clinical samples [NIAAA:n = 1858 (1123 cases, 735 controls); SAGE:n = 3838 (1848 cases, 1990 controls)], as well as its association with depression severity in a subsample of individuals with a lifetime AD diagnosis(n = 953). Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward (p = 0.014), low reward (at trend-level;p = 0.081), high loss (p = 0.024), and low loss (p = 0.046) compared to HCs. Association analyses in the NIAAA sample showed a trend-level relationship between rs10514299 and a lifetime AD diagnosis in the European American subgroup (odds ratio = 0.82,p = 0.09). This finding was not replicated in the SAGE sample. In the NIAAA sample, the T allele was significantly associated with greater depression symptom severity in individuals with a lifetime AD diagnosis (β = 1.25,p = 0.02); this association was driven by the African American ancestry subgroup (β = 2.11,p = 0.008). We show for the first time that the previously identified MDD risk variant rs10514299 inTMEM161B-MEF2Cpredicts neuronal correlates of reward processing in an AD phenotype, possibly explaining part of the shared pathophysiology and comorbidity between the disorders.
A broad-spectrum antibiotic, DCAP, reduces uropathogenic Escherichia coli infection and enhances vorinostat anticancer activity by modulating autophagy
Authors: Allavena Giulia , Debellis Doriana , Marotta Roberto , Joshi Chetanchandra S. , Mysorekar Indira U. , Grimaldi Benedetto
Published: July 2018

The cellular recycling pathway of autophagy plays a fundamental role in adaptive responses to nutrient deprivation and other forms of stress under physiological and pathological conditions. However, autophagy can also be a double-edge sword during certain bacterial infections (such as urinary tract infections) and in cancer, where it can be hijacked by the pathogens and cancer cells, respectively, to promote their own survival. Thus, autophagy modulation can potentially have multiple effects in multiple contexts and this property can be leveraged to improve outcomes. In this report, we identify that a broad-spectrum antibiotic, 2-((3-(3, 6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl) amino)-2-(hydroxymethyl) propane-1, 3-diol (DCAP) modulates autophagy. We employed combined biochemical, fluorescence microscopy and correlative light electron microscopy approaches to demonstrate that DCAP treatment blocks autophagy at the late stages by preventing autophagolysosome maturation and interrupting the autophagic flux. We further show that, DCAP significantly reduces UPEC infection in urinary tract epithelial cells via inhibition of autophagy. Finally, we reveal that DCAP enhances the anticancer activity of the histone acetyltransferase (HDAC) inhibitor, vorinostat, which has been reported to increase susceptibility to bacterial infections as a common adverse effect. Collectively, our data support the concept that DCAP represents a valuable chemical scaffold for the development of an innovative class of bactericidal autophagy inhibitors for treatment of urinary tract infections and/or for adjuvant therapy in cancer treatment.
PRMT5-mediated regulation of developmental myelination
Authors: Scaglione Antonella , Patzig Julia , Liang Jialiang , Frawley Rebecca , Bok Jabez , Mela Angeliki , Yattah Camila , Zhang Jingxian , Teo Shun Xie , Zhou Ting , Chen Shuibing , Bernstein Emily , Canoll Peter , Guccione Ernesto , Casaccia Patrizia
Published: July 2018

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system. They are derived from differentiation of oligodendrocyte progenitors through a process requiring cell cycle exit and histone modifications. Here we identify the histone arginine methyl-transferase PRMT5, a molecule catalyzing symmetric methylation of histone H4R3, as critical for developmental myelination. PRMT5 pharmacological inhibition, CRISPR/cas9 targeting, or genetic ablation decrease p53-dependent survival and impair differentiation without affecting proliferation. Conditional ablation of Prmt5 in progenitors results in hypomyelination, reduced survival and differentiation. Decreased histone H4R3 symmetric methylation is followed by increased nuclear acetylation of H4K5, and is rescued by pharmacological inhibition of histone acetyltransferases. Data obtained using purified histones further validate the results obtained in mice and in cultured oligodendrocyte progenitors. Together, these results identify PRMT5 as critical for oligodendrocyte differentiation and developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation.
Abrupt events and population synchrony in the dynamics of Bovine Tuberculosis
Authors: Moustakas Aristides , Evans Matthew R. , Daliakopoulos Ioannis N. , Markonis Yannis
Published: July 2018

Disease control strategies can have both intended and unintended effects on the dynamics of infectious diseases. Routine testing for the harmful pathogen Bovine Tuberculosis (bTB) was suspended briefly during the foot and mouth disease epidemic of 2001 in Great Britain. Here we utilize bTB incidence data and mathematical models to demonstrate how a lapse in management can alter epidemiological parameters, including the rate of new infections and duration of infection cycles. Testing interruption shifted the dynamics from annual to 4-year cycles, and created long-lasting shifts in the spatial synchrony of new infections among regions of Great Britain. After annual testing was introduced in some GB regions, new infections have become more de-synchronised, a result also confirmed by a stochastic model. These results demonstrate that abrupt events can synchronise disease dynamics and that changes in the epidemiological parameters can lead to chaotic patterns, which are hard to be quantified, predicted, and controlled.
The potassium channel KCNJ13 is essential for smooth muscle cytoskeletal organization during mouse tracheal tubulogenesis
Authors: Yin Wenguang , Kim Hyun-Taek , Wang ShengPeng , Gunawan Felix , Wang Lei , Kishimoto Keishi , Zhong Hua , Roman Dany , Preussner Jens , Guenther Stefan , Graef Viola , Buettner Carmen , Grohmann Beate , Looso Mario , Morimoto Mitsuru , Mardon Graeme , Offermanns Stefan , Stainier Didier Y. R.
Published: July 2018

Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13-mutant trachea phenotypes. These results provide insight into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.
Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo
Authors: Dunn Matthew , Henke Adam , Clark Samuel , Kovalyova Yekaterina , Kempadoo Kimberly A. , Karpowicz Richard J. , Kandel Eric R. , Sulzer David , Sames Dalibor
Published: July 2018

Norepinephrine is a monoamine neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent false neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug’s effect.
Microglia permit climbing fiber elimination by promoting GABAergic inhibition in the developing cerebellum
Authors: Nakayama Hisako , Abe Manabu , Morimoto Chie , Iida Tadatsune , Okabe Shigeo , Sakimura Kenji , Hashimoto Kouichi
Published: July 2018

Circuit refinement during postnatal development is finely regulated by neuron–neuron interactions. Recent studies suggest participation of microglia in this process but it is unclear how microglia cooperatively act with neuronal mechanisms. To examine roles of microglia, we ablate microglia by microglia-selective deletion of colony-stimulating factor 1 receptor (Csf1r) by crossing floxed-Csf1r and Iba1-iCre mice (Csf1r-cKO). In Csf1r-cKO mice, refinement of climbing fiber (CF) to Purkinje cell (PC) innervation after postnatal day 10 (P10)–P12 is severely impaired. However, there is no clear morphological evidence suggesting massive engulfment of CFs by microglia. In Csf1r-cKO mice, inhibitory synaptic transmission is impaired and CF elimination is restored by diazepam, which suggests that impairment of CF elimination is caused by a defect of GABAergic inhibition on PCs, a prerequisite for CF elimination. These results indicate that microglia primarily promote GABAergic inhibition and secondarily facilitate the mechanism for CF elimination inherent in PCs.
CTC1-STN1 terminates telomerase while STN1-TEN1 enables C-strand synthesis during telomere replication in colon cancer cells
Authors: Feng Xuyang , Hsu Shih-Jui , Bhattacharjee Anukana , Wang Yongyao , Diao Jiajie , Price Carolyn M.
Published: July 2018

Telomerase elongates the telomeric G-strand to prevent telomere shortening through conventional DNA replication. However, synthesis of the complementary C-strand by DNA polymerase α is also required to maintain telomere length. Polymerase α cannot perform this role without the ssDNA binding complex CST (CTC1-STN1-TEN1). Here we describe the roles of individual CST subunits in telomerase regulation and G-overhang maturation in human colon cancer cells. We show that CTC1-STN1 limits telomerase action to prevent G-overhang overextension. CTC1−/− cells exhibit telomeric DNA damage and growth arrest due to overhang elongation whereas TEN1−/− cells do not. However, TEN1 is essential for C-strand synthesis and TEN1−/− cells exhibit progressive telomere shortening. DNA binding analysis indicates that CTC1-STN1 retains affinity for ssDNA but TEN1 stabilizes binding. We propose CTC1-STN1 binding is sufficient to terminate telomerase action but altered DNA binding dynamics renders CTC1-STN1 unable to properly engage polymerase α on the overhang for C-strand synthesis.
Non-covalent control of spin-state in metal-organic complex by positioning on N-doped graphene
Authors: de la Torre Bruno , Švec Martin , Hapala Prokop , Redondo Jesus , Krejčí Ondřej , Lo Rabindranath , Manna Debashree , Sarmah Amrit , Nachtigallová Dana , Tuček Jiří , Błoński Piotr , Otyepka Michal , Zbořil Radek , Hobza Pavel , Jelínek Pavel
Published: July 2018

Nitrogen doping of graphene significantly affects its chemical properties, which is particularly important in molecular sensing and electrocatalysis applications. However, detailed insight into interaction between N-dopant and molecules at the atomic scale is currently lacking. Here we demonstrate control over the spin state of a single iron(II) phthalocyanine molecule by its positioning on N-doped graphene. The spin transition was driven by weak intermixing between orbitals with z-component of N-dopant (pz of N-dopant) and molecule (dxz, dyz, dz2) with subsequent reordering of the Fe d-orbitals. The transition was accompanied by an electron density redistribution within the molecule, sensed by atomic force microscopy with CO-functionalized tip. This demonstrates the unique capability of the high-resolution imaging technique to discriminate between different spin states of single molecules. Moreover, we present a method for triggering spin state transitions and tuning the electronic properties of molecules through weak non-covalent interaction with suitably functionalized graphene.
SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix
Authors: Fukuda Masatoshi , Yoshizawa Tatsuya , Karim Md. Fazlul , Sobuz Shihab U. , Korogi Wataru , Kobayasi Daiki , Okanishi Hiroki , Tasaki Masayoshi , Ono Katsuhiko , Sawa Tomohiro , Sato Yoshifumi , Chirifu Mami , Masuda Takeshi , Nakamura Teruya , Tanoue Hironori , Nakashima Kazuhisa , Kobashigawa Yoshihiro , Morioka Hiroshi , Bober Eva , Ohtsuki Sumio , Yamagata Yuriko , Ando Yukio , Oike Yuichi , Araki Norie , Takeda Shu , Mizuta Hiroshi , Yamagata Kazuya
Published: July 2018

SP7/Osterix (OSX) is a master regulatory transcription factor that activates a variety of genes during differentiation of osteoblasts. However, the influence of post-translational modifications on the regulation of its transactivation activity is largely unknown. Here, we report that sirtuins, which are NAD(+)-dependent deacylases, regulate lysine deacylation-mediated transactivation of OSX. Germline Sirt7 knockout mice develop severe osteopenia characterized by decreased bone formation and an increase of osteoclasts. Similarly, osteoblast-specific Sirt7 knockout mice showed attenuated bone formation. Interaction of SIRT7 with OSX leads to the activation of transactivation by OSX without altering its protein expression. Deacylation of lysine (K) 368 in the C-terminal region of OSX by SIRT7 promote its N-terminal transactivation activity. In addition, SIRT7-mediated deacylation of K368 also facilitates depropionylation of OSX by SIRT1, thereby increasing OSX transactivation activity. In conclusion, our findings suggest that SIRT7 has a critical role in bone formation by regulating acylation of OSX.
Iridium-catalyzed reductive Ugi-type reactions of tertiary amides
Authors: Xie Lan-Gui , Dixon Darren J.
Published: July 2018

Amides are ubiquitous in the fine chemical, agrochemical and pharmaceutical industries, but are rarely exploited as substrates for homologous amine synthesis. By virtue of their high chemical stability, they are essentially inert to all but the harshest of chemical reagents and to the majority of chemical transformations routinely used in organic synthesis. Accordingly, the development of chemoselective carbon−carbon bond-forming methodologies arising from the functionalization of the amide functionality should find widespread use across academia and industry. We herein present our findings on a series of Ugi-type reactions of tertiary amides enabled by an initial chemoselective iridium-catalyzed partial reduction, followed by reaction with isocyanide and (thio)acetic acid or trimethylsilyl azide, thus providing a multicomponent synthesis of α-amino (thio)amide or α-amino tetrazole derivatives. The reductive Ugi-type reactions are amenable to a broad range of amides and isocyanides, and are applicable to late-stage functionalization of various bioactive molecules and pharmaceutical compounds.
Enzymatic one-step ring contraction for quinolone biosynthesis
Authors: Kishimoto Shinji , Hara Kodai , Hashimoto Hiroshi , Hirayama Yuichiro , Champagne Pier Alexandre , Houk Kendall N. , Tang Yi , Watanabe Kenji
Published: July 2018

The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we report in vitro and computational analyses leading to the discovery of a hemocyanin-like protein AsqI from the Aspergillus nidulans aspoquinolone biosynthetic pathway that forms viridicatins via a conversion of the cyclopenin-type 6,7-bicyclic system into the viridicatin-type 6,6-bicyclic core through elimination of carbon dioxide and methylamine through methyl isocyanate.
Predictable evolution towards larger brains in birds colonizing oceanic islands
Authors: Sayol Ferran , Downing Philip A. , Iwaniuk Andrew N. , Maspons Joan , Sol Daniel
Published: July 2018

Theory and evidence suggest that some selective pressures are more common on islands than in adjacent mainland habitats, leading evolution to follow predictable trends. The existence of predictable evolutionary trends has nonetheless been difficult to demonstrate, mainly because of the challenge of separating in situ evolution from sorting processes derived from colonization events. Here we use brain size measurements of >1900 avian species to reveal the existence of one such trend: increased brain size in island dwellers. Based on sister-taxa comparisons and phylogenetic ancestral trait estimations, we show that species living on islands have relatively larger brains than their mainland relatives and that these differences mainly reflect in situ evolution rather than varying colonization success. Our findings reinforce the view that in some instances evolution may be predictable, and yield insight into why some animals evolve larger brains despite substantial energetic and developmental costs.