bluuebunny/crossref_metadata_2025 huggingface dataset:
Criminal Jurisdiction over Armed Forces Abroad
Authors: Liivoja Rain , Benvenisti Eyal
Published: September 2017

Rain Liivoja explores why, and to what extent, armed forces personnel who commit offences abroad are prosecuted under their own country's laws. After clarifying several conceptual uncertainties in the doctrine of jurisdiction and immunities, he applies the doctrine to the extraterritorial deployment of service personnel. Comparing the law and practice of different states, the author shows the sheer breadth of criminal jurisdiction that countries claim over their service personnel. He argues that such claims disclose a discrete category of jurisdiction, with its own scope and rationale, which can be justified as a matter of international law. By distinguishing service jurisdiction as a distinct category, the analysis explains some of the peculiarities of military criminal law and also provides a basis for extending national criminal law to private military contractors serving the state. This book is essential for scholars and practitioners in international and criminal law, especially in military contexts.
The Ballad in American Popular Music
Authors: Metzer David
Published: September 2017

While ballads have been a cornerstone of popular music for decades, this is the first book to explore the history and appeal of these treasured songs. David Metzer investigates how and why the styles of ballads have changed over a period of more than seventy years, offering a definition of the genre and discussing the influences of celebrated performers including Frank Sinatra, Aretha Franklin, and Whitney Houston. The emotional power of the ballad is strongly linked to the popular mood of the time, and consequently songs can tell us much about how events and emotions were felt and understood in wider culture at specific moments of recent American history. Tracing both the emotional and stylistic developments of the genre from the 1950s to the present day, this lively and engaging volume is as much a musical history as it is a history of emotional life in America.
NATURAL HEDGING IN LONG-TERM CARE INSURANCE
Authors: Levantesi Susanna , Menzietti Massimiliano
Published: September 2017

We investigate the application of natural hedging strategies for long-term care (LTC) insurers by diversifying both longevity and disability risks affecting LTC annuities. We propose two approaches to natural hedging: one built on a multivariate duration, the other on the Conditional Value-at-Risk minimization of the unexpected loss. Both the approaches are extended to the LTC insurance using a multiple state framework. In order to represent the future evolution of mortality and disability transition probabilities, we use the stochastic model of Cairns et al. (2009) with cohort effect under parameter uncertainty through a semi-parametric bootstrap procedure. We calculate the optimal level of a product mix and measure the effectiveness provided by the interaction of LTC stand alone, deferred annuity and whole-life insurance. We compare the results obtained by the two approaches and find that a natural hedging strategy for LTC insurers is attainable with a product mix of LTC and annuities, but including low proportion of LTC.
Applications of 256-Slice, Spiral Computed Tomography Perfusion Scanning in Limb Salvage After High-Voltage Electrical Injury
Authors: Ma Pengcheng , Sun Yong , Zhang Xintang , Liu Hui , Liu Canli , Zhao Jing
Published: September 2017

Objective

This study aimed to investigate the applications of intelligent 256-slice computed tomography (iCT) perfusion imaging in high-voltage electrical injuries (HVEIs).

Methods

256-slice iCT was used to perform perfusion scanning for 48 patients with HVEI to detect the perfusion parameters.

Results

The blood flow (BF) and peak enhancement intensity (PEI) values of the plane lower than the amputation level of the diseased side (ALD) were smaller than those of the corresponding healthy side (P<0.05); therefore, the differences were statistically significant. The BF value of the plane beyond the ALD was bigger than that of the ALD (t=2.99 and P=0.042); therefore, the difference was statistically significant. The BF, PEI, and blood volume values of the plane below the ALD were smaller than those of the ALD (P<0.05); therefore, the differences were statistically significant.

Conclusions

The technique of 256-slice iCT perfusion imaging could provide richer and more comprehensive imaging data for the clinical treatment of HVEIs, thus exhibiting its benefit in reducing the disability of patients with HVEIs. (Disaster Med Public Health Preparedness. 2018;12:478–485)
Microcytosis is associated with low cognitive outcomes in healthy 2-year-olds in a high-resource setting
Authors: McCarthy Elaine K. , Kiely Mairead E. , Hannon Geraldine , Ahearne Caroline , Kenny Louise C. , Hourihane Jonathan O’B. , Irvine Alan D. , Murray Deirdre M.
Published: September 2017

Fe deficiency in early childhood is associated with long-term consequences for cognitive, motor and behavioural development; however explorations in healthy children from low risk, high-resource settings have been limited. We aimed to explore associations between Fe status and neurodevelopmental outcomes in low risk, healthy 2-year-olds. This study was a secondary analysis of a nested case–control subgroup from the prospective, maternal-infant Cork Babies after Screening for Pregnancy Endpoints: Evaluating the Longitudinal Impact using Neurological and Nutritional Endpoints (BASELINE) Birth Cohort Study. At 2 years, serum ferritin, Hb and mean corpuscular volume (MCV) were measured and neurodevelopment was assessed using the Bayley Scales of Infant and Toddler Development (n87). Five children had Fe deficiency (ferritin <12 µg/l) and no child had Fe deficiency anaemia (Hb<110 g/l+ferritin<12 µg/l). Children with microcytosis (MCV<74 fl,n13) had significantly lower mean cognitive composite scores (88·5 (sd13·3)v. 97·0 (sd7·8),P=0·04, Cohen’sdeffect size=0·8) than those without microcytosis. The ferritin concentration which best predicted microcytosis was calculated as 18·4 µg/l (AUC=0·87 (95% CI 0·75, 0·98),P<0·0001, sensitivity 92 %, specificity 75 %). Using 18·5 µg/l as a threshold, children with concentrations <18·5 µg/l had significantly lower mean cognitive composite scores (92·3 (sd10·5)v. 97·8 (sd8·1),P=0·012, Cohen’sdeffect size=0·6) compared with those with ferritin ≥18·5 µg/l. All associations were robust after adjustment for potential confounding factors. Despite a low prevalence of Fe deficiency using current diagnostic criteria in this healthy cohort, microcytosis was associated with lower cognitive outcomes at 2 years. This exploratory study emphasises the need for re-evaluation of the diagnostic criteria for Fe deficiency in young children, with further research in adequately powered studies warranted.
The effect of anthocyanin supplementation in modulating platelet function in sedentary population: a randomised, double-blind, placebo-controlled, cross-over trial
Authors: Thompson Kiara , Hosking Holly , Pederick Wayne , Singh Indu , Santhakumar Abishek B.
Published: September 2017

The anti-thrombotic properties of anthocyanin (ACN) supplementation was evaluated in this randomised, double-blind, placebo (PBO) controlled, cross-over design, dietary intervention trial in sedentary population. In all, sixteen participants (three males and thirteen females) consumed ACN (320 mg/d) or PBO capsules for 28 d followed by a 2-week wash-out period. Biomarkers of thrombogenesis and platelet activation induced by ADP; platelet aggregation induced by ADP, collagen and arachidonic acid; biochemical, lipid, inflammatory and coagulation profile were evaluated before and after supplementation. ACN supplementation reduced monocyte-platelet aggregate formation by 39 %; inhibited platelet endothelial cell adhesion molecule-1 expression by 14 %; reduced platelet activation-dependant conformational change and degranulation by reducing procaspase activating compound-1 (PAC-1) (↓10 %) and P-selectin expression (↓14 %), respectively; and reduced ADP-induced whole blood platelet aggregation by 29 %. Arachidonic acid and collagen-induced platelet aggregation; biochemical, lipid, inflammatory and coagulation parameters did not change post-ACN supplementation. PBO treatment did not have an effect on the parameters tested. The findings suggest that dietary ACN supplementation has the potential to alleviate biomarkers of thrombogenesis, platelet hyperactivation and hyper-aggregation in sedentary population.
Genome-wide analysis of gene expression profile in the respiratory tree of sea cucumber (Apostichopus japonicus) in response to hypoxia conditions
Authors: Zhang Libin , Feng Qiming , Ding Kui , Sun Lina , Huo Da , Fang Yan , Zhang Tao , Yang Hongsheng
Published: September 2017

The sea cucumber Apostichopus japonicus is a deposit-feeder and vital for marine benthic ecosystems. Hypoxia can influence the behaviour and even lead to massive mortality in A. japonicus in the wild. It is important to understand the molecular responses of A. japonicus when exposed to acute changes in dissolved oxygen (DO) concentration. In this study, RNA-seq provided a general overview of the gene expression profiles of the respiratory tree of A. japonicus exposed to DO of 8 mg l−1 (DO8), 4 mg l−1 (DO4) and 2 mg l−1 (DO2) conditions. Differentially expressed genes (DEGs) screening with the NOISeq method identified 51, 59 and 61 DEGs according to the criteria of fold change ≥2 and divergence probability ≥0.8 in the comparisons of DO2 vs DO4, DO2 vs DO8 and DO4 vs DO8, respectively. Gene ontology analysis showed that ‘cellular process’ and ‘binding’ had the most enriched DEGs in the categories of ‘biological process’ and ‘molecular function’, respectively (catalytic activity also had the most enriched DEGs in the category of ‘molecular function’ based on the comparison of DO2 vs DO8), while ‘cell’ and ‘cell part’ had the most enriched DEGs in the category of ‘cellular component’. The DEGs were mapped to 79, 81 and 104 pathways in the KEGG database, and 8, 29 and 16 pathways were significantly enriched, respectively. The DO-specific DEGs identified in this study of the respiratory tree are important targets for further research into the biochemical mechanisms involved in the response of the sea cucumber to changes in the DO concentration.
Laser-generated Richtmyer–Meshkov and Rayleigh–Taylor instabilities. III. Near-peripheral region of Gaussian spot
Authors: Lugomer Stjepan
Published: September 2017

Dynamics and organization of laser-generated three-dimensional (3D) Richtmyer–Meshkov (RMI) and Rayleigh–Taylor instabilities (RMI and RTI) on metal target in the semiconfined configuration are different in the central region (CR) (Lugomer, 2016), near central region (NCR) (Lugomer, 2017) and the near periphery region (NPR) of the Gaussian-like spot. The RMI/RTI in the NPR evolve from the shock and series of reshocks associated with lateral expansion and increase of the vapor density, decrease of the Atwood number and momentum transfer. Scanning electron micrographs show irregular (chaotic) web of the base-plane walls, and mushroom spikes on its nodal points with disturbed two-dimensional (2D) lattice organization. Lattice disturbance is caused by the incoherent wavy motion of background fluid due to fast reshocks, which after series of reflections change their strength and direction. Reconstruction of the disturbed lattice reveals rectangular lattice of mushroom spikes with p2mm symmetry. The splitting (bifurcation) of mushroom diameter distribution on the large and small mushroom spikes increases with radial distance from the center of Gaussian-like spot. Dynamics of their evolution is represented by the orbits or stable periods in 2D phase space. The constant mushroom diameter – stable circulation or the stable periodic orbits – are the limit cycles between the unstable spiral orbits. Those with increasing periods represent supercritical Hopf bifurcation, while those leading to decrease and disappearance represent subcritical Hopf bifurcation. The empirical models of RMI, although predict dependence of the growth rate on radial distance (distance the reshocks travel to reach the interface), show many limitations. More appropriate interpretation of the simultaneous growth and lattice organization of small and large spikes give the fundamental model based on the interference of the perturbation modes depending on their amplitude, relative phase, and the symmetry. The late-time instability in the base-plane evolves into line solitons, vortex filaments and wave–vortex structures with chaotic rather than stochastic features.
Feeling Modern: The History of Emotions in Urban South Asia
Authors: CHATTERJEE ELIZABETH , KRISHNAN SNEHA , ROBB MEGAN EATON
Published: September 2017

The foundation of history's recent ‘emotional turn’ is thatemotions matterin shaping individual and social motivations. Their importance is not just instrumental: against the explanatory grain of much scholarship since the nineteenth century, the history of emotions recognises that humans are not purely rational “economic subjects in trousers and skirts”— or, as it may be,dhotis andsaris.
Novel Method for Preparing Transmission Electron Microscopy Samples of Micrometer-Sized Powder Particles by Using Focused Ion Beam
Authors: Kim Tae-Hoon , Kang Min-Chul , Jung Ga-Bin , Kim Dong Soo , Yang Cheol-Woong
Published: September 2017

The preparation of transmission electron microscopy (TEM) samples from powders is quite difficult and challenging. For powders with particles in the 1–5μm size range, it is especially difficult to select an adequate sample preparation technique. Epoxy is commonly used to bind powder, but drawbacks, such as differential milling originating from unequal milling rates between the epoxy and powder, remain. We propose a new, simple method for preparing TEM samples. This method is especially useful for powders with particles in the 1–5μm size range that are vulnerable to oxidation. The method uses solder as an embedding agent together with focused ion beam (FIB) milling. The powder was embedded in low-temperature solder using a conventional hot-mounting instrument. Subsequently, FIB was used to fabricate thin TEM samples via the lift-out technique. The solder proved to be more effective than epoxy in producing thin TEM samples with large areas. The problem of differential milling was mitigated, and the solder binder was more stable than epoxy under an electron beam. This methodology can be applied for preparing TEM samples from various powders that are either vulnerable to oxidation or composed of high atomic number elements.
Shifting care from community hospitals to intensive community support: a mixed method study
Authors: Williams Kate S. , Kurtev Stoyan , Phelps Kay , Regen Emma , Conroy Simon , Wilson Andrew
Published: September 2017

Aim

To examine how the introduction of intensive community support (ICS) affected admissions to community hospital (CH) and to explore the views of patients, carers and health professionals on this transition.

Background

ICS was introduced to provide an alternative to CH provision for patients (mostly very elderly) requiring general rehabilitation.

Method

Routine data from both services were analysed to identify the number of admissions and length of stay between September 2012 and September 2014. In total, 10 patients took part in qualitative interviews. Qualitative interviews and focus groups were undertaken with 19 staff members, including managers and clinicians.

Findings

There were 5653 admissions to CH and 1710 to ICS between September 2012 and September 2014. In the five months before the introduction of ICS, admission rates to CH were on average 217/month; in the final five months of the study, when both services were fully operational, average numbers of patients admitted were: CH 162 (a 25% reduction), ICS 97, total 259 (a 19% increase). Patients and carers rated both ICS and CH favourably compared with acute hospital care. Those who had experienced both services felt each to be appropriate at the time; they appreciated the 24 h availability of staff in CH when they were more dependent, and the convenience of being at home after they had improved. In general, staff welcomed the introduction of ICS and appreciated the advantages of home-based rehabilitation. Managers had a clearer vision of ICS than staff on the ground, some of whom felt underprepared to work in the community. There was a consensus that ICS was managing less complex and dependent patients than had been envisaged.

Conclusion

ICS can provide a feasible adjunct to CH that is acceptable to patients. More work is needed to promote the vision of ICS amongst staff in both community and acute sectors.
Silkworm disease incidence trends during the years 1992–2011 in the Murshidabad district of West Bengal, India
Authors: Hossain Zakir , Chakraborty Satadal , Gupta Sunil Kumar , Saha Atul Kumar , Bindroo Bharat Bhushan
Published: September 2017

The Murshidabad District of West Bengal, India has practised traditional mulberry sericulture since time immemorial. One of the most important aspects for sustainable development of the sericulture industry is the control and prevention of silkworm diseases. The main objective of this study was to determine silkworm disease incidence over the period 1992–2011 in Murshidabad District and how environmental factors have contributed towards their occurrence. Data were collected from a crop-wise survey of silkworm diseases from 25 farmers (five farmers from five villages), who each had a separate rearing house, were progressive and had a capacity of rearing at least 100 disease free layings (dfls) in each crop. Disease incidence was expressed in percentage and calculated taking into consideration 40,000 larvae per 100 dfls. Crop-wise silkworm disease mortality data were correlated with meteorological data. Data collected from the continuous survey conducted in the district during 1992–2011 revealed that there was no set pattern of occurrence of silkworm diseases. However, maximum mortality (up to 30%) of silkworm due to diseases in all the seasons occurred mainly due to grasserie, as relative humidity remains high for most part of the year in this area. However, other than grasserie, for most of the period, disease incidence was below 10%. This observation of the dominance of grasserie over other diseases in causing silkworm mortality calls for renewed emphasis on the preventive measures and development of disease forecasting models, for disease control. Another observation was that since 1993, pebrine, the deadliest disease of the silkworm, has not been reported from the farmers’ fields.
How Much GOTV Mail is Too Much? Results from a Large-Scale Field Experiment
Authors: Green Donald P. , Zelizer Adam
Published: September 2017

This study evaluates the turnout effects of direct mail sent in advance of the 2014 New Hampshire Senate election. Registered Republican women were sent up to 10 mailings from a conservative advocacy group that encouraged participation in the upcoming election. We find that mail raises turnout, but no gains are achieved beyond five mailers. This finding is shown to be consistent with other experiments that have sent large quantities of mail. We interpret these results in light of marketing research on repetitive messaging.
Analysis of the pressure requirements for silk spinning reveals a pultrusion dominated process
Authors: Sparkes James , Holland Chris
Published: September 2017

Silks are remarkable materials with desirable mechanical properties, yet the fine details of natural production remain elusive and subsequently inaccessible to biomimetic strategies. Improved knowledge of the natural processes could therefore unlock development of a host of bio inspired fibre spinning systems. Here, we use the Chinese silkworm Bombyx mori to review the pressure requirements for natural spinning and discuss the limits of a biological extrusion domain. This provides a target for finite element analysis of the flow of silk proteins, with the aim of bringing the simulated and natural domains into closer alignment. Supported by two parallel routes of experimental validation, our results indicate that natural spinning is achieved, not by extruding the feedstock, but by the pulling of nascent silk fibres. This helps unravel the oft-debated question of whether silk is pushed or pulled from the animal, and provides impetus to the development of pultrusion-based biomimetic spinning devices.
Nanopore extended field-effect transistor for selective single-molecule biosensing
Authors: Ren Ren , Zhang Yanjun , Nadappuram Binoy Paulose , Akpinar Bernice , Klenerman David , Ivanov Aleksandar P. , Edel Joshua B. , Korchev Yuri
Published: September 2017

There has been a significant drive to deliver nanotechnological solutions to biosensing, yet there remains an unmet need in the development of biosensors that are affordable, integrated, fast, capable of multiplexed detection, and offer high selectivity for trace analyte detection in biological fluids. Herein, some of these challenges are addressed by designing a new class of nanoscale sensors dubbed nanopore extended field-effect transistor (nexFET) that combine the advantages of nanopore single-molecule sensing, field-effect transistors, and recognition chemistry. We report on a polypyrrole functionalized nexFET, with controllable gate voltage that can be used to switch on/off, and slow down single-molecule DNA transport through a nanopore. This strategy enables higher molecular throughput, enhanced signal-to-noise, and even heightened selectivity via functionalization with an embedded receptor. This is shown for selective sensing of an anti-insulin antibody in the presence of its IgG isotype.
Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis
Authors: Liu Zhiping , Yan Siyuan , Wang Jiaojiao , Xu Yiming , Wang Yong , Zhang Shuya , Xu Xizhen , Yang Qiuhua , Zeng Xianqiu , Zhou Yaqi , Gu Xuejiao , Lu Sarah , Fu Zhongjie , Fulton David J. , Weintraub Neal L. , Caldwell Ruth B. , Zhang Wenbo , Wu Chaodong , Liu Xiao-Ling , Chen Jiang-Fan , Ahmad Aftab , Kaddour-Djebbar Ismail , Al-Shabrawey Mohamed , Li Qinkai , Jiang Xuejun , Sun Ye , Sodhi Akrit , Smith Lois , Hong Mei , Huo Yuqing
Published: September 2017

Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies. Here, we show that the adenosine A2a receptor (ADORA2A) promotes hypoxia-inducible transcription factor-1 (HIF-1)-dependent endothelial cell glycolysis, which is crucial for pathological angiogenesis in proliferative retinopathies. Adora2a expression is markedly increased in the retina of mice with oxygen-induced retinopathy (OIR). Endothelial cell-specific, but not macrophage-specific Adora2a deletion decreases key glycolytic enzymes and reduces pathological neovascularization in the OIR mice. In human primary retinal microvascular endothelial cells, hypoxia induces the expression of ADORA2A by activating HIF-2α. ADORA2A knockdown decreases hypoxia-induced glycolytic enzyme expression, glycolytic flux, and endothelial cell proliferation, sprouting and tubule formation. Mechanistically, ADORA2A activation promotes the transcriptional induction of glycolytic enzymes via ERK- and Akt-dependent translational activation of HIF-1α protein. Taken together, these findings advance translation of ADORA2A as a therapeutic target in the treatment of proliferative retinopathies and other diseases dependent on pathological angiogenesis.
Consolidation of the optoelectronic properties of CH3NH3PbBr3 perovskite single crystals
Authors: Wenger Bernard , Nayak Pabitra K. , Wen Xiaoming , Kesava Sameer V. , Noel Nakita K. , Snaith Henry J.
Published: September 2017

Ultralow trap densities, exceptional optical and electronic properties have been reported for lead halide perovskites single crystals; however, ambiguities in basic properties, such as the band gap, and the electronic defect densities in the bulk and at the surface prevail. Here, we synthesize single crystals of methylammonium lead bromide (CH3NH3PbBr3), characterise the optical absorption and photoluminescence and show that the optical properties of single crystals are almost identical to those of polycrystalline thin films. We observe significantly longer lifetimes and show that carrier diffusion plays a substantial role in the photoluminescence decay. Contrary to many reports, we determine that the trap density in CH3NH3PbBr3 perovskite single crystals is 1015 cm−3, only one order of magnitude lower than in the thin films. Our enhanced understanding of optical properties and recombination processes elucidates ambiguities in earlier reports, and highlights the discrepancies in the estimation of trap densities from electronic and optical methods.
The brain is required for normal muscle and nerve patterning during early Xenopus development
Authors: Herrera-Rincon Celia , Pai Vaibhav P. , Moran Kristine M. , Lemire Joan M. , Levin Michael
Published: September 2017

Possible roles of brain-derived signals in the regulation of embryogenesis are unknown. Here we use an amputation assay in Xenopus laevis to show that absence of brain alters subsequent muscle and peripheral nerve patterning during early development. The muscle phenotype can be rescued by an antagonist of muscarinic acetylcholine receptors. The observed defects occur at considerable distances from the head, suggesting that the brain provides long-range cues for other tissue systems during development. The presence of brain also protects embryos from otherwise-teratogenic agents. Overexpression of a hyperpolarization-activated cyclic nucleotide-gated ion channel rescues the muscle phenotype and the neural mispatterning that occur in brainless embryos, even when expressed far from the muscle or neural cells that mispattern. We identify a previously undescribed developmental role for the brain and reveal a non-local input into the control of early morphogenesis that is mediated by neurotransmitters and ion channel activity.
Predictors of responses to immune checkpoint blockade in advanced melanoma
Authors: Jacquelot N. , Roberti M. P. , Enot D. P. , Rusakiewicz S. , Ternès N. , Jegou S. , Woods D. M. , Sodré A. L. , Hansen M. , Meirow Y. , Sade-Feldman M. , Burra A. , Kwek S. S. , Flament C. , Messaoudene M. , Duong C. P. M. , Chen L. , Kwon B. S. , Anderson A. C. , Kuchroo V. K. , Weide B. , Aubin F. , Borg C. , Dalle S. , Beatrix O. , Ayyoub M. , Balme B. , Tomasic G. , Di Giacomo A. M. , Maio M. , Schadendorf D. , Melero I. , Dréno B. , Khammari A. , Dummer R. , Levesque M. , Koguchi Y. , Fong L. , Lotem M. , Baniyash M. , Schmidt H. , Svane I. M. , Kroemer G. , Marabelle A. , Michiels S. , Cavalcanti A. , Smyth M. J. , Weber J. S. , Eggermont A. M. , Zitvogel L.
Published: September 2017

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.
Human stem cells alter the invasive properties of somatic cells via paracrine activation of mTORC1
Authors: Rosner Margit , Pham Ha Thi Thanh , Moriggl Richard , Hengstschläger Markus
Published: September 2017

Controlled invasion is essential during many physiological processes, whereas its deregulation is a hallmark of cancer. Here we demonstrate that embryonic, induced pluripotent and amniotic fluid stem cells share the property to induce the invasion of primary somatic cells of various origins through insulin-like growth factor I (IGF-I)- or II (IGF-II)-mediated paracrine activation of mechanistic target of rapamycin complex 1 (mTORC1). We propose a model in which downstream of mTORC1 this stem cell-induced invasion is mediated by hypoxia-inducible factor 1-alpha (HIF-1α)-regulated matrix metalloproteinases. Manipulating the IGF signalling pathway in the context of teratoma formation experiments demonstrates that human stem cells use this mechanism to induce invasion and thereby attract cells from the microenvironment in vivo. In this study we have identified a so far unknown feature of human stem cells, which might play a role for the development of stem cell-derived tumours.
Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis
Authors: Trabanelli Sara , Chevalier Mathieu F. , Martinez-Usatorre Amaia , Gomez-Cadena Alejandra , Salomé Bérengère , Lecciso Mariangela , Salvestrini Valentina , Verdeil Grégory , Racle Julien , Papayannidis Cristina , Morita Hideaki , Pizzitola Irene , Grandclément Camille , Bohner Perrine , Bruni Elena , Girotra Mukul , Pallavi Rani , Falvo Paolo , Leibundgut Elisabeth Oppliger , Baerlocher Gabriela M. , Carlo-Stella Carmelo , Taurino Daniela , Santoro Armando , Spinelli Orietta , Rambaldi Alessandro , Giarin Emanuela , Basso Giuseppe , Tresoldi Cristina , Ciceri Fabio , Gfeller David , Akdis Cezmi A. , Mazzarella Luca , Minucci Saverio , Pelicci Pier Giuseppe , Marcenaro Emanuela , McKenzie Andrew N. J. , Vanhecke Dominique , Coukos George , Mavilio Domenico , Curti Antonio , Derré Laurent , Jandus Camilla
Published: September 2017

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.
RNA localization is a key determinant of neurite-enriched proteome
Authors: Zappulo Alessandra , van den Bruck David , Ciolli Mattioli Camilla , Franke Vedran , Imami Koshi , McShane Erik , Moreno-Estelles Mireia , Calviello Lorenzo , Filipchyk Andrei , Peguero-Sanchez Esteban , Müller Thomas , Woehler Andrew , Birchmeier Carmen , Merino Enrique , Rajewsky Nikolaus , Ohler Uwe , Mazzoni Esteban O. , Selbach Matthias , Akalin Altuna , Chekulaeva Marina
Published: September 2017

Protein subcellular localization is fundamental to the establishment of the body axis, cell migration, synaptic plasticity, and a vast range of other biological processes. Protein localization occurs through three mechanisms: protein transport, mRNA localization, and local translation. However, the relative contribution of each process to neuronal polarity remains unknown. Using neurons differentiated from mouse embryonic stem cells, we analyze protein and RNA expression and translation rates in isolated cell bodies and neurites genome-wide. We quantify 7323 proteins and the entire transcriptome, and identify hundreds of neurite-localized proteins and locally translated mRNAs. Our results demonstrate that mRNA localization is the primary mechanism for protein localization in neurites that may account for half of the neurite-localized proteome. Moreover, we identify multiple neurite-targeted non-coding RNAs and RNA-binding proteins with potential regulatory roles. These results provide further insight into the mechanisms underlying the establishment of neuronal polarity.
Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90
Authors: Zhang Guohua , Liu Zhelong , Ding Hui , Zhou Yong , Doan Hoang Anh , Sin Ka Wai Thomas , Zhu Zhiren J. , Flores Rene , Wen Yefei , Gong Xing , Liu Qingyun , Li Yi-Ping
Published: September 2017

Cachexia, characterized by muscle wasting, is a major contributor to cancer-related mortality. However, the key cachexins that mediate cancer-induced muscle wasting remain elusive. Here, we show that tumor-released extracellular Hsp70 and Hsp90 are responsible for tumor’s capacity to induce muscle wasting. We detected high-level constitutive release of Hsp70 and Hsp90 associated with extracellular vesicles (EVs) from diverse cachexia-inducing tumor cells, resulting in elevated serum levels in mice. Neutralizing extracellular Hsp70/90 or silencing Hsp70/90 expression in tumor cells abrogates tumor-induced muscle catabolism and wasting in cultured myotubes and in mice. Conversely, administration of recombinant Hsp70 and Hsp90 recapitulates the catabolic effects of tumor. In addition, tumor-released Hsp70/90-expressing EVs are necessary and sufficient for tumor-induced muscle wasting. Further, Hsp70 and Hsp90 induce muscle catabolism by activating TLR4, and are responsible for elevation of circulating cytokines. These findings identify tumor-released circulating Hsp70 and Hsp90 as key cachexins causing muscle wasting in mice.
Metabolic shift in sugars and amino acids regulates sprouting in Saffron corm
Authors: Bagri Jayram , Yadav Anupama , Anwar Khalid , Dkhar Jeremy , Singla-Pareek Sneh Lata , Pareek Ashwani
Published: September 2017

Saffron is one of the most expensive spices of the world. Since this spice is triploid and meiosis is unusual, it cannot reproduce sexually like other plants; rather, it is propagated vegetatively via an underground corm, which can withstand a long dry dormant period before sprouting. Thus, corms are indispensable to saffron propagation. To identify and analyse signature metabolites associated with the ‘dormancy-sprouting’ process, non-targeted GC-MS was performed at different stages of corm development. Comparative metabolite profiling reflected dissimilar profiles among the stages as portrayed by differential cluster patterns of metabolites in the PCA and PLS-DA analysis. Correlation analysis revealed the interdependencies of individual metabolites and metabolic pathway. At the onset of stage 2, characterized by the initiation and differentiation of leaf primordia, a shift from dormancy to active metabolism occurred as derived from the increased abundance of sugars and other metabolites involved in the tricarboxylic acid cycle, glycolytic, amino acid and fatty acid pathways. These changes contribute to sprouting and vegetative growth of the corm. The present study provides new insights into saffron corm composition and metabolite changes associated with various stages of corm development and may pave the way for achieving agronomical improvements in this economically important spice.
Fibromyalgia and microglial TNF-α: Translational research using human blood induced microglia-like cells
Authors: Ohgidani Masahiro , Kato Takahiro A. , Hosoi Masako , Tsuda Makoto , Hayakawa Kohei , Hayaki Chie , Iwaki Rie , Sagata Noriaki , Hashimoto Ryota , Inoue Kazuhide , Sudo Nobuyuki , Kanba Shigenobu
Published: September 2017

Fibromyalgia is a refractory disease characterized by chronic intractable pain and psychological suffering, the cause of which has not yet been elucidated due to its complex pathology. Activation of immune cells in the brain called microglia has attracted attention as a potential underlying pathological mechanism in chronic pain. Until recently, however, technological and ethical considerations have limited the ability to conduct research using human microglia. To overcome this limitation, we have recently developed a technique to create human-induced microglia-like (iMG) cells from human peripheral blood monocytes. In this study, we created the iMG cells from 14 patients with fibromyalgia and 10 healthy individuals, and compared the activation of iMG cells between two groups at the cellular level. The expression of tumor necrosis factor (TNF)-α at mRNA and protein levels significantly increased in ATP-stimulated iMG cells from patients with fibromyalgia compared to cells from healthy individuals. Interestingly, there was a moderate correlation between ATP-induced upregulation of TNF-α expression and clinical parameters of subjective pain and other mental manifestations of fibromyalgia. These findings suggest that microglia in patients with fibromyalgia are hypersensitive to ATP. TNF-α from microglia may be a key factor underlying the complex pathology of fibromyalgia.
A high-conductance chemo-optogenetic system based on the vertebrate channel Trpa1b
Authors: Lam Pui-Ying , Mendu Suresh K. , Mills Robert W. , Zheng Baohui , Padilla Hugo , Milan David J. , Desai Bimal N. , Peterson Randall T.
Published: September 2017

Optogenetics is a powerful research approach that allows localized optical modulation of selected cells within an animal via the expression of genetically encoded photo-excitable ion channels. Commonly used optogenetic techniques rely on the expression of microbial opsin variants, which have many excellent features but suffer from various degrees of blue spectral overlap and limited channel conductance. Here, we expand the optogenetics toolbox in the form of a tunable, high-conductance vertebrate cation channel, zTrpa1b, coupled with photo-activated channel ligands, such as optovin and 4g6. Our results demonstrate that zTrpa1b/ligand pairing offers high light sensitivity, millisecond-scale response latency in vivo, as well as adjustable channel off latency. Exogenous in vivo expression of zTrpa1b in sensory neurons allowed subcellular photo-activation, enabling light-dependent motor control. zTrpa1b/ligand was also suitable for cardiomyocyte pacing, as shown in experiments performed on zebrafish hearts in vivo as well as in human stem cell-derived cardiomyocytes in vitro. Therefore, zTrpa1b/optovin represents a novel tool for flexible, high-conductance optogenetics.
Balance between hydration enthalpy and entropy is important for ice binding surfaces in Antifreeze Proteins
Authors: Schauperl Michael , Podewitz Maren , Ortner Teresa S. , Waibl Franz , Thoeny Alexander , Loerting Thomas , Liedl Klaus R.
Published: September 2017

Antifreeze Proteins (AFPs) inhibit the growth of an ice crystal by binding to it. The detailed binding mechanism is, however, still not fully understood. We investigated three AFPs using Molecular Dynamics simulations in combination with Grid Inhomogeneous Solvation Theory, exploring their hydration thermodynamics. The observed enthalpic and entropic differences between the ice-binding sites and the inactive surface reveal key properties essential for proteins in order to bind ice: While entropic contributions are similar for all sites, the enthalpic gain for all ice-binding sites is lower than for the rest of the protein surface. In contrast to most of the recently published studies, our analyses show that enthalpic interactions are as important as an ice-like pre-ordering. Based on these observations, we propose a new, thermodynamically more refined mechanism of the ice recognition process showing that the appropriate balance between entropy and enthalpy facilitates ice-binding of proteins. Especially, high enthalpic interactions between the protein surface and water can hinder the ice-binding activity.
Bistability and up/down state alternations in inhibition-dominated randomly connected networks of LIF neurons
Authors: Tartaglia Elisa M. , Brunel Nicolas
Published: September 2017

Electrophysiological recordings in cortex in vivo have revealed a rich variety of dynamical regimes ranging from irregular asynchronous states to a diversity of synchronized states, depending on species, anesthesia, and external stimulation. The average population firing rate in these states is typically low. We study analytically and numerically a network of sparsely connected excitatory and inhibitory integrate-and-fire neurons in the inhibition-dominated, low firing rate regime. For sufficiently high values of the external input, the network exhibits an asynchronous low firing frequency state (L). Depending on synaptic time constants, we show that two scenarios may occur when external inputs are decreased: (1) the L state can destabilize through a Hopf bifucation as the external input is decreased, leading to synchronized oscillations spanning d δ to β frequencies; (2) the network can reach a bistable region, between the low firing frequency network state (L) and a quiescent one (Q). Adding an adaptation current to excitatory neurons leads to spontaneous alternations between L and Q states, similar to experimental observations on UP and DOWN states alternations.
Dynamics of water bound to crystalline cellulose
Authors: O’Neill Hugh , Pingali Sai Venkatesh , Petridis Loukas , He Junhong , Mamontov Eugene , Hong Liang , Urban Volker , Evans Barbara , Langan Paul , Smith Jeremy C. , Davison Brian H.
Published: September 2017

Interactions of water with cellulose are of both fundamental and technological importance. Here, we characterize the properties of water associated with cellulose using deuterium labeling, neutron scattering and molecular dynamics simulation. Quasi-elastic neutron scattering provided quantitative details about the dynamical relaxation processes that occur and was supported by structural characterization using small-angle neutron scattering and X-ray diffraction. We can unambiguously detect two populations of water associated with cellulose. The first is “non-freezing bound” water that gradually becomes mobile with increasing temperature and can be related to surface water. The second population is consistent with confined water that abruptly becomes mobile at ~260 K, and can be attributed to water that accumulates in the narrow spaces between the microfibrils. Quantitative analysis of the QENS data showed that, at 250 K, the water diffusion coefficient was 0.85 ± 0.04 × 10−10 m2sec−1and increased to 1.77 ± 0.09 × 10−10 m2sec−1at 265 K. MD simulations are in excellent agreement with the experiments and support the interpretation that water associated with cellulose exists in two dynamical populations. Our results provide clarity to previous work investigating the states of bound water and provide a new approach for probing water interactions with lignocellulose materials.
Core-shell heterostructured multiwalled carbon nanotubes@reduced graphene oxide nanoribbons/chitosan, a robust nanobiocomposite for enzymatic biosensing of hydrogen peroxide and nitrite
Authors: Mani Veerappan , Govindasamy Mani , Chen Shen-Ming , Chen Tse-Wei , Kumar Annamalai Senthil , Huang Sheng-Tung
Published: September 2017

A robust nanobiocomposite based on core-shell heterostructured multiwalled carbon nanotubes@reduced graphene oxide nanoribbons (MWCNTs@rGONRs)/chitosan (CHIT) was described for the fabrication of sensitive, selective, reproducible and durable biosensor for hydrogen peroxide (H2O2) and nitrite (NO2−). The excellent physicochemical properties of MWCNTs@rGONRs such as, presence of abundant oxygen functionalities, higher area-normalized edge-plane structures and chemically active sites in combination with excellent biocompatibility of CHIT resulting in the versatile immobilization matrix for myoglobin (Mb). The most attractive property of MWCNTs@rGONRs which distinguishes it from other members of graphene family is its rich edge density and edge defects that are highly beneficial for constructing enzymatic biosensors. The direct electron transfer characteristics such as, redox properties, amount of immobilized active Mb, electron transfer efficiency and durability were studied. Being as good immobilization matrix, MWCNTs@rGONRs/CHIT is also an excellent signal amplifier which helped in achieving low detection limits to quantify H2O2 (1 nM) and NO2− (10 nM). The practical feasibility of the biosensor was successfully validated in contact lens cleaning solution and meat sample.
A synthetic cell permeable antioxidant protects neurons against acute oxidative stress
Authors: Drummond Nicola J. , Davies Nick O. , Lovett Janet E. , Miller Mark R. , Cook Graeme , Becker Thomas , Becker Catherina G. , McPhail Donald B. , Kunath Tilo
Published: September 2017

Excessive reactive oxygen species (ROS) can damage proteins, lipids, and DNA, which result in cell damage and death. The outcomes can be acute, as seen in stroke, or more chronic as observed in age-related diseases such as Parkinson’s disease. Here we investigate the antioxidant ability of a novel synthetic flavonoid, Proxison (7-decyl-3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), using a range of in vitro and in vivo approaches. We show that, while it has radical scavenging ability on par with other flavonoids in a cell-free system, Proxison is orders of magnitude more potent than natural flavonoids at protecting neural cells against oxidative stress and is capable of rescuing damaged cells. The unique combination of a lipophilic hydrocarbon tail with a modified polyphenolic head group promotes efficient cellular uptake and moderate mitochondrial enrichment of Proxison. Importantly, in vivo administration of Proxison demonstrated effective and well tolerated neuroprotection against cell loss in a zebrafish model of dopaminergic neurodegeneration.
Role of chemotherapy in dedifferentiated liposarcoma of the retroperitoneum: defining the benefit and challenges of the standard
Authors: Livingston J. A. , Bugano D. , Barbo A. , Lin H. , Madewell J. E. , Wang W. L. , Lazar A. J. , Tseng W. W. , Roland C. L. , Feig B. W. , Pollock R. , Conley A. P. , Benjamin R. S. , Patel S. , Somaiah N.
Published: September 2017

Benefit from chemotherapy for well-differentiated/de-differentiated (WD/DD) liposarcomas has been reported to be minimal, however traditional response criteria may not adequately capture positive treatment effect. In this study, we evaluate benefit from first-line chemotherapy and characterize imaging response characteristics in patients with retroperitoneal (RP) WD/DD liposarcoma treated at The University of Texas MD Anderson Cancer Center. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) and an exploratory analysis of vascular response was characterized. Among 82 patients evaluable for response to first-line therapy, 31 patients received neoadjuvant chemotherapy for localized/locally advanced disease; 51 received chemotherapy for unresectable recurrent/metastatic disease. Median overall survival from the start of chemotherapy was 29 months (95% CI 24–40 months). Response rates by RECIST: partial response (PR) 21% (17/82), stable disease (SD) 40%, and progression (PD) 39%. All RECIST responses were in patients receiving combination chemotherapy. A qualitative vascular response was seen in 24 patients (31%). Combination chemotherapy yields a response rate of 24% and a clinical benefit rate (CR/PR/SD > 6 months) of 44%, higher than previously reported in DD liposarcoma. A higher percentage of patients experience a vascular response with chemotherapy that is not adequately captured by RECIST in these large heterogeneous tumors.