bluuebunny/crossref_metadata_2025 huggingface dataset:
Legume consumption and risk of hypertension in a prospective cohort of Chinese men and women
Authors: Guo Fang , Zhang Qiang , Yin Yue , Liu Yan , Jiang Hong , Yan Ni , Lin Jing , Liu Xiao-hong , Ma Le
Published: November 2019

Prior data on long-term association between legume consumption and hypertension risk are sparse. We aimed to evaluate whether total legume and subtype intakes prospectively associate with hypertension incidence among 8758 participants (≥30 years) from the China Health and Nutrition Survey 2004–2011. Diet was assessed by interviews combining 3-d 24-h food recalls and household food inventory weighing at each survey round. Incident hypertension was identified by self-reports or blood pressure measurements. We applied multivariable Cox regressions to estimate hazard ratios (HR) with corresponding 95 % CI for hypertension across increasing categories of cumulatively averaged legume intakes. For 35 990 person-years (median 6·0 years apiece), we documented 944 hypertension cases. After covariate adjustment, higher total legume intakes were significantly associated with lower hypertension risks, with HR comparing extreme categories being 0·56 (95 % CI 0·43, 0·71;Ptrend< 0·001). Then we found that intakes of dried legumes (HR 0·53 (95 % CI 0·43, 0·65);Ptrend< 0·001) and fresh legumes (HR 0·67 (95 % CI 0·55, 0·81);Ptrend< 0·001) were both related to decreased hypertension hazards. However, further dried legume classification revealed that negative association with hypertension substantially held for soyabean (HR 0·51 (95 % CI 0·41, 0·62);Ptrend< 0·001) but not non-soyabean intakes. In stratified analyses, the association of interest remained similar within strata by sex, BMI, physical activity, smoking and drinking status; rather, significant heterogeneity showed across age strata (Pinteraction= 0·02). Total legume consumption among the over-65s was related to a more markedly reduced hypertension risk (HR 0·47 (95 % CI 0·30, 0·73);Ptrend< 0·001). Our findings suggest an inverse association of all kinds of legume (except non-soyabean) intakes with hypertension risks.
Towards a Cyber Secure Shipboard Radar
Authors: Svilicic Boris , Rudan Igor , Frančić Vlado , Mohović Djani
Published: November 2019

This paper presents a comparative cyber security resilience estimation of shipboard radars that are implemented on two oil/chemical tankers certified as SOLAS ships. The estimated radars were chosen from the same manufacturer, but belonged to different generations. The estimation was conducted by means of ships' crew interviews and computational testing of the radars using a widely deployed vulnerability scanning software tool. The identified cyber threats were analysed qualitatively in order to gain a holistic understanding of cyber risks threatening shipboard radar systems. The results obtained experimentally indicate that potential cyber threats mainly relate to maintenance of the radars' underlying operating system, suggesting the need for regulatory standardisation of periodic cyber security testing of radar systems.
Provisional checklist of terrestrial heterotrophic protists from Antarctica
Authors: Thompson Andrew R. , Powell Gareth S. , Adams Byron J.
Published: November 2019

Heterotrophic soil protists encompass lineages that are both evolutionarily ancient and highly diverse, providing an untapped wealth of scientific insight. Yet the diversity of free-living heterotrophic terrestrial protists is still largely unknown. To contribute to our understanding of this diversity, we present a checklist of heterotrophic protists currently reported from terrestrial Antarctica, for which no comprehensive evaluation currently exists. As a polar continent, Antarctica is especially susceptible to rising temperatures caused by anthropogenic climate change. Establishing a baseline for future conservation efforts of Antarctic protists is therefore important. We performed a literature search and found 236 taxa identified to species and an additional 303 taxa identified to higher taxonomic levels in 54 studies spanning over 100 years of research. Isolated by distance, climate and the circumpolar vortex, Antarctica is the most extreme continent on Earth: it is not unreasonable to think that it may host physiologically and evolutionarily unique species of protists, yet currently most species discovered in Antarctica are considered cosmopolitan. Additional sampling of the more extreme intra-continental zones will probably result in the discovery of more novel and unique taxa.
Introduction: special issue on the economics of climate change and sustainability (Part A)
Authors: Agliardi Elettra , Casari Marco , Xepapadeas Anastasios
Published: November 2019

Climate change is one of the most significant and complex challenges facing the world's economies. The necessity to enlarge the knowledge base regarding climate change and its impacts and to design efficient policies is widely accepted by the scientific community, the decision makers and the general public. This special issue, which will be published in two parts in the current and subsequent issue of Environment and Development Economics, is a selection of papers related to the topic of the international workshop on ‘The Economics of Climate Change and Sustainability’ organized by the Economics Department of the University of Bologna in April 2018. The papers in this special issue cover a wide range of climate-change-related topics, which include endogenous growth and overlapping generation models; climate-related financing and green bonds; demographics; location decisions; technology diffusion; quantitative relationships and experimental approaches. We hope that this special issue will provide some new insights into the economics of climate change and help to identify new directions for future research.
Short-term nutrition and growth indicators in 6-month- to 6-year-old children are improved following implementation of a multidisciplinary community-based programme in a chronic conflict setting
Authors: Simonyan Hambardzum , Sargsyan Aelita , Balalian Arin A , Davtyan Karapet , Gupte Himanshu A
Published: November 2019

Objective:

We investigated short- and long-term indicators of malnutrition and diet before and after the community-based ‘Breaking the Cycle of Poverty’ multidisciplinary intervention.

Design:

A historically and geographically controlled study using data collected in 2013 and 2016. We compared the prevalence of short-term indicators (anaemia, breast-feeding duration and minimum dietary diversity) and long-term indicators (stunting and wasting) in exposed communities at two time points. We then compared these factors in geographic areas exposed or not exposed to intervention. We conducted logistic regression analyses on the 2016 sample to measure associations between living in intervention communities and child growth indicators.

Setting:

Berd region, a chronic conflict zone near the north-eastern border of Armenia and Azerbaijan.

Participants:

Children aged 6 months to 6 years.

Results:

Analyses included data from 2013 comprising 382 children, and data from 2016 comprising 348 children living in communities where the programme was implemented, and 635 children from unexposed communities. Anaemia prevalence in exposed communities was significantly lower in 2016 v. 2013 (10·9 v. 19·1 %, P < 0·01). Minimum dietary diversity (79·0 v. 68·1 %, P < 0·001) and breast-feeding duration (13·0 v. 11·5 months, P < 0·002) were significantly improved in exposed communities. Prevalences of stunting (11·5 v. 10·2 %, P = 0·57) and wasting (4·8 v. 2·0 %, P = 0·07) were not significantly different. Odds of anaemia were significantly lower (OR = 0·24, 95 % CI 0·16, 0·36) in intervention communities.

Conclusions:

Exposure to a community-based multidisciplinary intervention reduced the rate of anaemia and improved dietary indicators.
Imaginary Homelessness Prevention with Prison Leavers in Wales
Authors: Madoc-Jones Iolo , Ahmed Anya , Hughes Caroline , Dubberley Sarah , Gorden Caro , Washington-Dyer Karen , Lockwood Kelly , Wilding Mark
Published: November 2019

In this article we engage in a critical examination of how local authority Housing Solutions staff, newly placed centre stage in preventing homelessness amongst prison leavers in Wales, understand and go about their work. Drawing on Carlen’s concept of ‘imaginary penalities’ and Ugelvik’s notion of ‘legitimation work’ we suggest practice with this group can be ritualistic and underpinned by a focus on prison leavers’ responsibilities over their rights, and public protection over promoting resettlement. In response we advocate for less-punitive justice and housing policies, underpinned by the right to permanent housing for all prison leavers and wherein stable accommodation is understood as the starting point for resettlement. The analysis presented in this article provides insights to how homelessness policies could play out in jurisdictions where more joint working between housing and criminal justice agencies are being pursued and/or preventative approaches to managing homelessness are being considered.
Epidemiology of suicide: recent developments
Authors: Baldessarini Ross J.
Published: November 2019

Suicide and suicide attempts have become more prevalent in recent years, with notable increases in the US in all age groups and geographic locations. Risk of suicide is particularly high among patients diagnosed with bipolar disorder or severe depression, especially when associated with mixed features or agitation, or with co-occurring substance abuse. Factors contributing to such risk include relative social and geographic isolation and low access to sources of support or clinical care. In addition, unemployment, poverty, demoralisation and opioid abuse have been identified as important risk factors. Notably, overall longevity rates in the US, though rising for many decades, have recently been declining, in part owing to suicide and substance overdoses. A particular circumstance associated with strikingly high rates of suicides and attempts is the days and weeks following discharge from psychiatric hospitalisation. Although the incidence of such events is low, there is a need for more secure aftercare planning and implementation. Research on therapeutics aimed at reducing suicidal risk and all-cause mortality among psychiatric patients remains severely under-developed.
Saturn's Open‐Closed Field Line Boundary: A Cassini Electron Survey at Saturn's Magnetosphere
Authors: Jasinski Jamie M. , Arridge Christopher S. , Bader Alexander , Smith Andrew W. , Felici Marianna , Kinrade Joe , Coates Andrew J. , Jones Geraint H. , Nordheim Tom A. , Gilbert Lin , Azari Abigail R. , Badman Sarah V. , Provan Gabrielle , Sergis Nick , Murphy Neil
Published: November 2019

We investigate the average configuration and structure of Saturn's magnetosphere in the nightside equatorial and high‐latitude regions. Electron data from the Cassini Plasma Spectrometer's Electron Spectrometer (CAPS‐ELS) is processed to produce a signal‐to‐noise ratio for the entire CAPS‐ELS time of operation at Saturn's magnetosphere. We investigate where the signal‐to‐noise ratio falls below 1 to identify regions in the magnetosphere where there is a significant depletion in the electron content. In the nightside equatorial region, we use this to find that the most planetward reconnection x‐line location is at 20–25 RS downtail from the planet in the midnight to dawn sector. We also find an equatorial dawn‐dusk asymmetry at a radial distance of >20 RS, which may indicate the presence of plasma‐depleted flux tubes returning to the dayside after reconnection in the tail. Furthermore, we find that the high‐latitude magnetosphere is predominantly in a state of constant plasma depletion and located on open field lines. We map the region of high‐latitude magnetosphere that is depleted of electrons to the polar cap to estimate the size and open flux content within the polar caps. The mean open flux content for the northern and southern polar caps are found to be 25 ± 5 and 32 ± 5 GWb, respectively. The average location of the open‐closed field boundary is found at invariant colatitudes of 12.7 ± 0.6° and 14.5 ± 0.6°. The northern boundary is modulated by planetary period oscillations more than the southern boundary.
Low‐Resource Technique for Measurement of H+ and O+ in the Terrestrial Magnetosphere
Authors: Fernandes P. A. , Funsten H. O. , Dors E. E. , Harper R. W. , Larsen B. A. , MacDonald E. A. , Reisenfeld D. B. , Skoug R. M. , Steinberg J. T. , Thomsen M. F.
Published: November 2019

Measurement of O+ in the Earth's magnetosphere is important for monitoring and understanding the initiation and evolution of geomagnetic activity. During active times, O+ can be the most abundant ion in the magnetosphere. Furthermore, because O+ and H+ damage exposed spacecraft materials through different processes, measurement and prediction of O+ and H+ fluxes is critical for understanding cumulative damage effects to these materials resulting from the ambient plasma environment of a spacecraft. We describe a simple technique for quantitative, in situ measurement of O+ and H+ fluxes using ultrathin foils. This technique is a low‐resource addition to a standard electrostatic energy‐per‐charge analyzer followed by an array of detectors. H+ and O+ abundances up to a few tens of keV can be determined by comparison of counts in detectors having no ultrathin foil at the detector aperture, in which both H+ and O+ are detected, and adjacent detectors having a foil over the aperture of the appropriate thickness to stop the transmission of O+ but through which H+ can transit. We describe three techniques for implementing this method enabling differentiation of O+ and H+ in an instrument package significantly simpler than traditional mass spectrometers.
High‐Speed Video Observation of a Dart Leader Producing X‐rays
Authors: Saba M. M. F. , Ferro M. A. S. , Cuadros E. T. , Custódio D. M. , Nag A. , Schumann C. , Cooray V. , Paiva A. R. , Lauria P. B. , Medeiros D. S. F. , Hettiarachchi P. , Rassoul H. K.
Published: November 2019

This work presents the first simultaneous X‐ray measurement and high‐speed video observation of the propagation of a lightning leader producing X‐rays. As a result, the three‐dimensional leader distance from the X‐ray measurement and, for the first time, the conditions of the preexisting channel during the leader propagation were observed. Although four leaders in this seven‐stroke flash followed the same path to ground, X‐rays were only observed during the leader before the return stroke with the highest peak current. The fact that the other three leaders following the same path to ground did not produce detectable X‐rays confirms the hypothesis that leader line charge density is an important factor that determines X‐ray production. The fact that X‐rays was recorded only when the leader tip was at a certain portion of the lightning channel confirms that the orientation of the leader plays an important role in the detection of X‐rays.
Open Apatite Sr Isotopic System in Low‐Temperature Hydrous Regimes
Authors: Cao Mingjian , Evans Noreen J. , Qin Kezhang , Danišík Martin , Li Guangming , McInnes Brent I. A.
Published: November 2019

Single crystal in situ Sr and Nd isotopic analysis of apatite permits more accurate interrogation of a variety of geoscience questions, including provenance, petrogenesis, and ore system evolution. However, the degree to which the apatite Sr and Nd isotopic systems remain closed under extended low‐temperature hydrous conditions is not well constrained. Granitoids at the Baogutu deposit in NW China contain veins of low‐temperature H2O‐rich epistilbite and thus provide an excellent opportunity to evaluate isotopic system integrity under low‐temperature hydrous conditions. Apatite from the Late Carboniferous diorite and granodiorite porphyry show variable (87Sr/86Sr)i ratios (0.7042 to 0.7062) but restricted εNd(t) values (+7.0±0.4 and +6.5±0.4, 1σ). The apatite Sr isotope signatures are transitional between whole rock (0.7035) and vein epistilbite (~0.7062), indicating apparent incorporation of radiogenic Sr from the epistilbite‐related hydrothermal fluid into the igneous apatite, whereas εNd values closely match those of the whole rock (+6.9±0.2 and +6.5±0.2, 1σ) and epistilbite (+6.2±0.2, 1σ). Obvious metasomatic textures of apatite were revealed by cathodoluminescence images. The 260 to 300°C formation temperatures for earlier quartz‐sulfide veins and chlorite alteration and homogenization temperature (~190°C) of fluid inclusions in epistilbite‐calcite vein calcite constrain the temperature of the later epistilbite‐related hydrothermal fluid to 190 to 260°C. These results indicate that Sr and likely Nd isotopes in apatite are mobile under low‐temperature (<300°C) hydrous conditions and implies that Rb‐Sr signatures in apatite from hydrothermally altered rocks reveal the presence and characteristics of modifying fluids.
Long‐Term Stability of Tilt‐Controlled gPhoneX Gravimeters
Authors: Fores Benjamin , Klein Gilbert , Le Moigne Nicolas , Francis Olivier
Published: November 2019

Spring relative gravimeters are considered too unstable to provide useful information on long‐term gravity variations. In this paper, we prove that the new generation of spring gravimeter gPhoneX can reach long‐term stability at the μGal level (10 nm s−2) when the verticality of the gravimeter is maintained, if the instrumental drift can be correctly estimated. We conducted two comparisons with different gPhoneXs in different observatories and environmental conditions. In the “Walferdange Underground Laboratory for Geodynamics” in Luxembourg, we compared time series from the gPhoneX (with and without tilt control), with data from a superconducting gravimeter. We found an agreement at the μGal level when the tilt control is switched on. We validated this result by repeating the experiment at the “Geodesy in Karstic Environment” observatory in the south of France. The fit between the superconducting gravimeter and the gPhoneX hourly values gives similar results at all frequencies over 276 days of measurements. The linear correlation coefficient between the gPhoneX and superconducting gravimeter reaches 0.99, with a misfit of 6.0 nm s−2. We demonstrated that tilt‐controlled gPhoneXs are suitable for long‐term gravity monitoring.
Enhanced Snow Absorption and Albedo Reduction by Dust‐Snow Internal Mixing: Modeling and Parameterization
Authors: He Cenlin , Liou Kuo‐Nan , Takano Yoshi , Chen Fei , Barlage Michael
Published: November 2019

We extend a stochastic aerosol‐snow albedo model to explicitly simulate dust internally/externally mixed with snow grains of different shapes and for the first time quantify the combined effects of dust‐snow internal mixing and snow nonsphericity on snow optical properties and albedo. Dust‐snow internal/external mixing significantly enhances snow single‐scattering coalbedo and absorption at wavelengths of <1.0 μm, with stronger enhancements for internal mixing (relative to external mixing) and higher dust concentrations but very weak dependence on snow size and shape variabilities. Compared with pure snow, dust‐snow internal mixing reduces snow albedo substantially at wavelengths of <1.0 μm, with stronger reductions for higher dust concentrations, larger snow sizes, and spherical (relative to nonspherical) snow shapes. Compared to internal mixing, dust‐snow external mixing generally shows similar spectral patterns of albedo reductions and effects of snow size and shape. However, relative to external mixing, dust‐snow internal mixing enhances the magnitude of albedo reductions by 10%–30% (10%–230%) at the visible (near‐infrared) band. This relative enhancement is stronger as snow grains become larger or nonspherical, with comparable influences from snow size and shape. Moreover, for dust‐snow external and internal mixing, nonspherical snow grains have up to ~45% weaker albedo reductions than spherical grains, depending on snow size, dust concentration, and wavelength. The interactive effect of dust‐snow mixing state and snow shape highlights the importance of accounting for these two factors concurrently in snow modeling. For application to land/climate models, we develop parameterizations for dust effects on snow optical properties and albedo with high accuracy.
Response of Convective Boundary Layer and Shallow Cumulus to Soil Moisture Heterogeneity: A Large‐Eddy Simulation Study
Authors: Han Cunbo , Brdar Slavko , Kollet Stefan
Published: November 2019

In this study, the impact of varying soil moisture heterogeneity (spatial variance and structure) on the development of the convective boundary layer and shallow cumulus clouds was investigated. Applying soil moisture heterogeneity generated via spatially correlated Gaussian random fields based on a power law model and idealized atmospheric vertical profiles as initial conditions, three sets of large‐eddy simulations provide insight in the influence of soil moisture heterogeneity on the ensuing growth of the convective boundary layer and development of shallow cumulus clouds. A sensitivity on the strong, weak, and unstructured soil moisture heterogeneity is investigated. The simulation results show that domain‐averaged land surface sensible heat and latent heat flux change strongly with changing soil moisture variance because of the interactions between surface heterogeneity and induced circulations, while domain means of soil moisture are identical. Vertical profiles of boundary layer characteristics are strongly influenced by the surface energy partitioning and induced circulations, especially the profiles of liquid water and liquid water flux. The amount of liquid water and liquid water flux increases with increasing structure. In addition, the liquid water path is higher in case of strongly‐structured heterogeneity because more available energy is partitioned into latent heat and more intensive updrafts exist. Interestingly, the increase of liquid water path with increasing soil moisture variance only occurs in the strongly structured cases, which suggests that soil moisture variance and structure work conjunctively in the surface energy partitioning and the cloud formation.
Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study
Authors:   On behalf of the Grupo Español de Trasplante Hematopoyético (GETH), Escamilla Gómez Virginia , García-Gutiérrez Valentín , López Corral Lucía , García Cadenas Irene , Pérez Martínez Ariadna , Márquez Malaver Francisco J. , Caballero-Velázquez Teresa , González Sierra Pedro A. , Viguria Alegría María C. , Parra Salinas Ingrid M. , Calderón Cabrera Cristina , González Vicent Marta , Rodríguez Torres Nancy , Parody Porras Rocío , Ferra Coll Christelle , Orti Guillermo , Valcárcel Ferreiras David , De la Cámara LLanzá Rafael , Molés Paula , Velázquez-Kennedy Kyra , João Mende María , Caballero Barrigón Dolores , Pérez Estefanía , Martino Bofarull Rodrigo , Saavedra Gerosa Silvanna , Sierra Jorge , Poch Marc , Zudaire Ripa María T. , Díaz Pérez Miguel A. , Molina Angulo Blanca , Sánchez Ortega Isabel , Sanz Caballer Jaime , Montoro Gómez Juan , Espigado Tocino Ildefonso , Pérez-Simón José A
Published: November 2019

Graft-versus-host disease is the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. First-line treatment is based on the use of high doses of corticosteroids. Unfortunately, second-line treatment for both acute and chronic graft-versus-host disease, remains a challenge. Ruxolitinib has been shown as an effective and safe treatment option for these patients. Seventy-nine patients received ruxolitinib and were evaluated in this retrospective and multicenter study. Twenty-three patients received ruxolitinib for refractory acute graft-versus-host disease after a median of 3 (range 1–5) previous lines of therapy. Overall response rate was 69.5% (16/23) which was obtained after a median of 2 weeks of treatment, and 21.7% (5/23) reached complete remission. Fifty-six patients were evaluated for refractory chronic graft-versus-host disease. The median number of previous lines of therapy was 3 (range 1–10). Overall response rate was 57.1% (32/56) with 3.5% (2/56) obtaining complete remission after a median of 4 weeks. Tapering of corticosteroids was possible in both acute (17/23, 73%) and chronic graft-versus-host disease (32/56, 57.1%) groups. Overall survival was 47% (CI: 23–67%) at 6 months for patients with aGVHD (62 vs 28% in responders vs non-responders) and 81% (CI: 63–89%) at 1 year for patients with cGVHD (83 vs 76% in responders vs non-responders). Ruxolitinib in the real life setting is an effective and safe treatment option for GVHD, with an ORR of 69.5% and 57.1% for refractory acute and chronic graft-versus-host disease, respectively, in heavily pretreated patients.
Tomorou attenuates progression of rheumatoid arthritis through alteration in ULK-1 independent autophagy pathway in collagen induced arthritis mice model
Authors: Jannat Arooma , John Peter , Bhatti Attya , Hayat Muhammad Qasim
Published: November 2019

Rheumatoid arthritis (RA) is a multifactorial disease which is complicated by apoptosis resistance. Autophagy is one of the key mechanisms which are involved in the development of resistance to apoptosis as well as to the standard therapies against RA. Aberration in autophagy and apoptosis homeostasis results in the development of oxidative stress thus complicates the pathogenesis of RA. In the given study, tomorou, an indigenous herb of Hunza-Nagar Valley, has been evaluated for its pro-apoptotic, anti-inflammatory, and anti-rheumatic activity. Several major classes of bioactive phytochemicals including steroids, terpenoids, phenols, flavonoids, and essential oils have been detected in the aqueous and ethyl acetate extracts of tomorou through phytochemical analysis. Plant extracts depicted enhanced free radical scavenging activity through di-phenyl-2-picryl hydrazyl hydrate (DPPH) assay and ameliorated the symptoms of arthritis in collagen induced arthritic (CIA) mice model. Moreover, the 6 week extract treatment resulted in the reduction of IL-6 serum levels thus making it an effective anti-inflammatory agent. Upregulation of microtubule-associated proteins light chain 3b (LC3b) and downregulation of UNC51-like kinase 1 (ULK-1) in arthritic mice proposed a ULK-1 independent non-canonical autophagy pathway. Treatment with extracts upregulated the expression of caspase 3 which in turn inhibited the activity of LC3b thus altering the autophagy pathway. However, ULK-1 expression was restored to normal in aqueous extract treated group whereas it was upregulated in ethyl acetate extract treated group. On the other hand, a novel LC3b-independent autophagy pathway was observed in mice treated with ethyl acetate extract due to ULK-1 upregulation. Despite of significantly high IL-6 levels, the arthritic symptoms waned off which suggested the participation of IL-6 in LC3b-independent autophagy pathway in the extract prepared in ethyl acetate. Conclusively, the study established pro-apoptotic, antioxidant, anti-inflammatory and anti-rheumatic activity of tomorou and suggested an intricate autophagy pathway shift.
Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma
Authors: Su Dan , Zhang Dadong , Jin Jiaoyue , Ying Lisha , Han Miao , Chen Kaiyan , Li Bin , Wu Junzhou , Xie Zhenghua , Zhang Fanrong , Lin Yihui , Cheng Guoping , Li Jing-Yu , Huang Minran , Wang Jinchao , Wang Kailai , Zhang Jianjun , Li Fugen , Xiong Lei , Futreal Andrew , Mao Weimin
Published: November 2019

Previous studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.
Foxp1 controls brown/beige adipocyte differentiation and thermogenesis through regulating β3-AR desensitization
Authors: Liu Pei , Huang Sixia , Ling Shifeng , Xu Shuqin , Wang Fuhua , Zhang Wei , Zhou Rujiang , He Lin , Xia Xuechun , Yao Zhengju , Fan Ying , Wang Niansong , Hu Congxia , Zhao Xiaodong , Tucker Haley O. , Wang Jiqiu , Guo Xizhi
Published: November 2019

β-Adrenergic receptor (β-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the β3-adrenergic receptor (β3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses β3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity.
Homogentisic acid-derived pigment as a biocompatible label for optoacoustic imaging of macrophages
Authors: Weidenfeld Ina , Zakian Christian , Duewell Peter , Chmyrov Andriy , Klemm Uwe , Aguirre Juan , Ntziachristos Vasilis , Stiel Andre C.
Published: November 2019

Macrophages are one of the most functionally-diverse cell types with roles in innate immunity, homeostasis and disease making them attractive targets for diagnostics and therapy. Photo- or optoacoustics could provide non-invasive, deep tissue imaging with high resolution and allow to visualize the spatiotemporal distribution of macrophages in vivo. However, present macrophage labels focus on synthetic nanomaterials, frequently limiting their ability to combine both host cell viability and functionality with strong signal generation. Here, we present a homogentisic acid-derived pigment (HDP) for biocompatible intracellular labeling of macrophages with strong optoacoustic contrast efficient enough to resolve single cells against a strong blood background. We study pigment formation during macrophage differentiation and activation, and utilize this labeling method to track migration of pro-inflammatory macrophages in vivo with whole-body imaging. We expand the sparse palette of macrophage labels for in vivo optoacoustic imaging and facilitate research on macrophage functionality and behavior.
Independent control of the thermodynamic and kinetic properties of aptamer switches
Authors: Wilson Brandon D. , Hariri Amani A. , Thompson Ian A. P. , Eisenstein Michael , Soh H. Tom
Published: November 2019

Molecular switches that change their conformation upon target binding offer powerful capabilities for biotechnology and synthetic biology. Aptamers are useful as molecular switches because they offer excellent binding properties, undergo reversible folding, and can be engineered into many nanostructures. Unfortunately, the thermodynamic and kinetic properties of the aptamer switches developed to date are intrinsically coupled, such that high temporal resolution can only be achieved at the cost of lower sensitivity or high background. Here, we describe a design strategy that decouples and enables independent control over the thermodynamics and kinetics of aptamer switches. Starting from a single aptamer, we create an array of aptamer switches with effective dissociation constants ranging from 10 μM to 40 mM and binding kinetics ranging from 170 ms to 3 s. Our strategy is broadly applicable to other aptamers, enabling the development of switches suitable for a diverse range of biotechnology applications.
Evidence for a causal role by mouse mammary tumour-like virus in human breast cancer
Authors: Lawson James S. , Glenn Wendy K.
Published: November 2019

We have reviewed the evidence relevant to mouse mammary tumour viruses (MMTV) and human breast cancer. The prevalence of MMTV- like gene sequences is 15-fold higher in human breast cancer than in normal human breast tissue controls and is present in up to 40% of human breast cancers. MMTV-like gene sequences can be identified in benign breast tissues 1–11 years before the development of positive MMTV-like breast cancer in the same women. The prevalence of MMTV antibodies in sera from women with breast cancer is 5-fold higher than in normal women. MMTV can infect human breast epithelial cells and integrate at random into the human genome located in those cells. MMTV-like gene sequences are present in human milk from normal lactating women and with increased prevalence in milk from women at risk of breast cancer. MMTV-like virus associated human breast cancer has strikingly similar features to MMTV-associated mouse mammary tumours. These features include almost identical nucleotide sequences and structure of the MMTV genome, histology, superantigen expression, MMTV infection of B and T lymphocytes and hormone dependence. MMTV-like gene sequences have also been identified in dogs, cats, monkeys, mice and rats. Saliva has been identified as the most plausible means of transmission from human to human and possibly from dogs to humans. The evidence meets the classic causal criteria. A causal role for MMTV-like viruses in human breast cancer is highly likely.
Viral emergence in marine mammals in the North Pacific may be linked to Arctic sea ice reduction
Authors: VanWormer E. , Mazet J. A. K. , Hall A. , Gill V. A. , Boveng P. L. , London J. M. , Gelatt T. , Fadely B. S. , Lander M. E. , Sterling J. , Burkanov V. N. , Ream R. R. , Brock P. M. , Rea L. D. , Smith B. R. , Jeffers A. , Henstock M. , Rehberg M. J. , Burek-Huntington K. A. , Cosby S. L. , Hammond J. A. , Goldstein T.
Published: November 2019

Climate change-driven alterations in Arctic environments can influence habitat availability, species distributions and interactions, and the breeding, foraging, and health of marine mammals. Phocine distemper virus (PDV), which has caused extensive mortality in Atlantic seals, was confirmed in sea otters in the North Pacific Ocean in 2004, raising the question of whether reductions in sea ice could increase contact between Arctic and sub-Arctic marine mammals and lead to viral transmission across the Arctic Ocean. Using data on PDV exposure and infection and animal movement in sympatric seal, sea lion, and sea otter species sampled in the North Pacific Ocean from 2001–2016, we investigated the timing of PDV introduction, risk factors associated with PDV emergence, and patterns of transmission following introduction. We identified widespread exposure to and infection with PDV across the North Pacific Ocean beginning in 2003 with a second peak of PDV exposure and infection in 2009; viral transmission across sympatric marine mammal species; and association of PDV exposure and infection with reductions in Arctic sea ice extent. Peaks of PDV exposure and infection following 2003 may reflect additional viral introductions among the diverse marine mammals in the North Pacific Ocean linked to change in Arctic sea ice extent.
Cellular elements in the developing caecum of Japanese quail (Coturnix coturnix japonica): morphological, morphometrical, immunohistochemical and electron-microscopic studies
Authors: AbuAli Aalaa M. , Mokhtar Doaa M. , Ali Reda A. , Wassif Ekbal T. , Abdalla K. E. H
Published: November 2019

The present study aims to investigate the histological, histochemical and electron microscopic changes of the caecal proximal part of Japanese quail during both pre- and post-hatching periods starting from the 2ndembryonic day (ED) until four weeks post-hatching. On the 2ndand 3rdED, the primordia of caeca appeared as bilateral swelling on the wall of the hindgut. On the 7thED, the lamina propria/submucosa contained the primordia of glands. On the 8thED, rodlet cells could be observed amongst the epithelial cells. On the 9thED, the caeca began to divide into three parts with more developed layers. With age, the height and number of villi increased. On the 13thED, immature microfold cells (M-cells) could be identified between the surface epithelium of the villi. The caecal tonsils (CTs) appeared in the form of aggregations of lymphocytes, macrophages, dendritic cells and different types of leukocytes. Telocytes and crypts of Lieberkuhn were observed at this age. On hatching day, the crypts of Lieberkuhn were well-defined and formed of low columnar epithelium, goblet cells, and enteroendocrine cells. Post-hatching, the lumen was filled with villi that exhibited two forms: (1) tongue-shaped villi with tonsils and (2) finger-shaped ones without tonsils. The villi lining epithelium contained simple columnar cells with microvilli that were dispersed with many goblet cells, in addition to the presence of a high number of intra-epithelial lymphocytes and basophils. Moreover, the submucosa was infiltrated by numerous immune cells. CD3 immunomarker was expressed in intraepithelial lymphocytes, while CD20 immunomarker showed focal positivity in CTs. In conclusion, the caecal immune structures of quails at post-hatching were more developed than those in pre-hatching life. The high frequency of immune cells suggests that this proximal part may be a site for immunological surveillance in the quail caecum. The cellular organisation of the caecum and its relation to the immunity was discussed.
Novel QUEST MRI In Vivo Measurement of Noise-induced Oxidative Stress in the Cochlea
Authors: Kühl André , Dixon Angela , Hali Mirabela , Apawu Aaron K. , Muca Antonela , Sinan Moaz , Warila James , Braun Rod D. , Berkowitz Bruce A. , Holt Avril Genene
Published: November 2019

Effective personalized therapeutic treatment for hearing loss is currently not available. Cochlear oxidative stress is commonly identified in the pathogenesis of hearing loss based upon findings from excised tissue, thus suggesting a promising druggable etiology. However, the timing and site(s) to target for anti-oxidant treatment in vivo are not clear. Here, we address this long-standing problem with QUEnch-assiSTed Magnetic Resonance Imaging (QUEST MRI), which non-invasively measures excessive production of free radicals without an exogenous contrast agent. QUEST MRI is hypothesized to be sensitive to noise-evoked cochlear oxidative stress in vivo. Rats exposed to a loud noise event that resulted in hair cell loss and reduced hearing capability had a supra-normal MRI R1 value in their cochleae that could be corrected with anti-oxidants, thus non-invasively indicating cochlear oxidative stress. A gold-standard oxidative damage biomarker [heme oxidase 1 (HO-1)] supported the QUEST MRI result. The results from this study highlight QUEST MRI as a potentially transformative measurement of cochlear oxidative stress in vivo that can be used as a biomarker for improving individual evaluation of anti-oxidant treatment efficacy in currently incurable oxidative stress-based forms of hearing loss.
Considerations for ultrasound exposure during transcranial MR acoustic radiation force imaging
Authors: Phipps M. Anthony , Jonathan Sumeeth V. , Yang Pai-Feng , Chaplin Vandiver , Chen Li Min , Grissom William A. , Caskey Charles F.
Published: November 2019

The aim of this study was to improve the sensitivity of magnetic resonance-acoustic radiation force imaging (MR-ARFI) to minimize pressures required to localize focused ultrasound (FUS) beams, and to establish safe FUS localization parameters for ongoing ultrasound neuromodulation experiments in living non-human primates. We developed an optical tracking method to ensure that the MR-ARFI motion-encoding gradients (MEGs) were aligned with a single-element FUS transducer and that the imaged slice was prescribed at the optically tracked location of the acoustic focus. This method was validated in phantoms, which showed that MR-ARFI-derived displacement sensitivity is maximized when the MR-ARFI MEGs were maximally aligned with the FUS propagation direction. The method was then applied in vivo to acquire displacement images in two healthy macaque monkeys (M fascicularis) which showed the FUS beam within the brain. Temperature images were acquired using MR thermometry to provide an estimate of in vivo brain temperature changes during MR-ARFI, and pressure and thermal simulations of the acoustic pulses were performed using the k-Wave package which showed no significant heating at the focus of the FUS beam. The methods presented here will benefit the multitude of transcranial FUS applications as well as future human applications.
Predation on endangered species by human-subsidized domestic cats on Tokunoshima Island
Authors: Maeda Tamao , Nakashita Rumiko , Shionosaki Kazumi , Yamada Fumio , Watari Yuya
Published: November 2019

It is important to unravel how invasive species impact native ecosystems in order to control them effectively. The presence of abundant exotic prey promotes population growth of invasive predators, thereby enhancing the predation pressure on native prey (hyper-predation). Not only the exotic prey but also feeding by humans is likely to cause “hyper-predation”. However, the contribution of artificial resources to this was underestimated in previous studies. Here, we combined fecal and stable isotope analyses to reveal short- and long-term food habits of free-ranging cats on Tokunoshima Island. Although 20.1% of the feral cat feces contained evidence of forest-living species, stable isotope analysis suggested that the cats were mostly dependent on artificial resources. In addition, a general linear model analysis showed that their diet was strongly correlated with landscape variables. These results indicate that the invasive free-ranging cats are aided by anthropogenic feeding, and they move from the human habituated area to natural areas with high biodiversity. These findings suggest the possibility of human feeding indirectly accelerates the effect of cat predation, and call for a further study on their demography. Cat management mainly involves trapping, but our findings show that educating local residents to stop feeding free-ranging cats and keeping pet cats indoors are also important.
Ligand-Induced Conformational Dynamics of A Tyramine Receptor from Sitophilus oryzae
Authors: Braza Mac Kevin E. , Gazmen Jerrica Dominique N. , Yu Eizadora T. , Nellas Ricky B.
Published: November 2019

Tyramine receptor (TyrR) is a biogenic amine G protein-coupled receptor (GPCR) associated with many important physiological functions in insect locomotion, reproduction, and pheromone response. Binding of specific ligands to the TyrR triggers conformational changes, relays the signal to G proteins, and initiates an appropriate cellular response. Here, we monitor the binding effect of agonist compounds, tyramine and amitraz, to aSitophilus oryzaetyramine receptor (SoTyrR) homology model and their elicited conformational changes. All-atom molecular dynamics (MD) simulations of SoTyrR-ligand complexes have shown varying dynamic behavior, especially at the intracellular loop 3 (IL3) region. Moreover, in contrast to SoTyrR-tyramine, SoTyrR-amitraz and non-liganded SoTyrR shows greater flexibility at IL3 residues and were found to be coupled to the most dominant motion in the receptor. Our results suggest that the conformational changes induced by amitraz are different from the natural ligand tyramine, albeit being both agonists of SoTyrR. This is the first attempt to understand the biophysical implication of amitraz and tyramine binding to the intracellular domains of TyrR. Our data may provide insights into the early effects of ligand binding to the activation process of SoTyrR.
Gemcitabine plus nab-paclitaxel for locally advanced or borderline resectable pancreatic cancer
Authors: Tsujimoto Akiko , Sudo Kentaro , Nakamura Kazuyoshi , Kita Emiri , Hara Ryusuke , Takayama Wataru , Ishii Hiroshi , Yamaguchi Taketo
Published: November 2019

Overall survival in a phase III study for metastatic pancreatic cancer has significantly improved with gemcitabine (GEM) plus nab-paclitaxel. However, to date, there is limited data on the efficacy and safety of its use for patients with locally advanced (LA) or borderline resectable pancreatic cancer (BRPC). Here, we investigated the efficacy and safety of first-line GEM plus nab-paclitaxel for LA or BRPC. We retrospectively analysed consecutive patients with pathologically confirmed, untreated LA or BRPC who started receiving first-line GEM plus nab-paclitaxel. A total of 30 patients (LA, n = 22; BRPC, n = 8) were analysed. Twelve patients (40%) without distant metastasis received additional chemoradiotherapy using S-1. Laparotomy was performed on 8 patients and 6 (20%; LA, n = 3; BR, n = 3) achieved R0 resection. Objective response rate was 44.8%. For all patients, median progression-free survival and overall survival were 14.8 and 29.9 months, respectively. Median overall survival for LA was 24.1 months with a 2-year survival rate of 50.8%. The most frequently observed grade 3 or 4 toxicities were neutropenia (73%) and biliary infection (13%). First-line GEM plus nab-paclitaxel was well-tolerated and feasible with an encouraging survival for LA or BRPC.
The Cholesteryl Ester Transfer Protein Inhibitor, des-Fluoro-Anacetrapib, Prevents Vein Bypass-induced Neointimal Hyperplasia in New Zealand White Rabbits
Authors: Wu Ben J. , Li Yue. , Ong Kwok-Leung , Sun Yidan , Johns Douglas , Barter Philip J. , Rye Kerry-Anne
Published: November 2019

Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.