bluuebunny/crossref_metadata_2025 huggingface dataset:
Policy feedback in the local context: analysing fairness perceptions of public childcare fees in a German town
Authors: Busemeyer Marius R. , Goerres Achim
Published: February 2019

This article studies local processes of policy feedback by analysing citizens’ fairness perceptions of public childcare fees in a German town. Employing an experimental vignette study, we uncover complex feedback effects: first, citizens in the study regard a fee level as fair that is close to the actual fee level in the city, suggesting self-reinforcing feedback effects. Second, citizens strongly support a fee structure in which fees vary according to parental income. As this preferred fee structure differs from the local fee structure in the town itself, we interpret the citizens’ preference as evidence for self-undermining policy feedback. Finally, the actual characteristics of the respondents matter less than the fictitious characteristics of the parents in the vignettes, which points to the importance of interpretive rather than resource-based feedback effects. In concluding, we highlight the relevance of these findings for broader debates about policy feedback.
CUMULATED SUM OF SQUARES STATISTICS FOR NONLINEAR AND NONSTATIONARY REGRESSIONS
Authors: Berenguer-Rico Vanessa , Nielsen Bent
Published: February 2019

We show that the cumulated sum of squares statistic has a standard Brownian bridge–type asymptotic distribution in nonlinear regression models with (possibly) nonstationary regressors. This contrasts with cumulated sum statistics which have been previously studied and whose asymptotic distribution has been shown to depend on the functional form and the stochastic properties, such as persistence and stationarity, of the regressors. A recursive version of the test is also considered. A local power analysis is provided, and through simulations, we show that the test has good size and power properties across a variety of situations.
Invasive pneumococcal disease in hospitalised children from Lima, Peru before and after introduction of the 7-valent conjugated vaccine
Authors: Luna-Muschi A. , Castillo-Tokumori F. , Deza M. P. , Mercado E. H. , Egoavil M. , Sedano K. , Castillo M. E. , Reyes I. , Chaparro E. , Hernández R. , Silva W. , Del Aguila O. , Campos F. , Saenz A. , Ochoa T. J.
Published: February 2019

The objective of this study was to determine the serotype distribution and antibiotic resistance of invasive pneumococcal disease (IPD) strains in children from Lima, Peru, before and after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7), which was introduced in the national immunisation program on 2009. We conducted a prospective, multicentre, passive surveillance IPD study during 2006–2008 and 2009–2011, before and right after the introduction of PCV7 in Peru. The study was performed in 11 hospitals and five private laboratories in Lima, Peru, in patients <18 years old, with sterile site cultures yielding Streptococcus pneumoniae. In total 159 S. pneumoniae isolates were recovered. There was a decrease in the incidence of IPD in children <2 years old after the introduction of PCV7 (18.4/100 000 vs. 5.1/100 000, P = 0.004). Meningitis cases decreased significantly in the second period (P = 0.036) as well as the overall case fatality rate (P = 0.025), including a decreased case fatality rate of pneumonia (16.3% to 0%, P = 0.04). PCV7 serotypes showed a downward trend. Vaccine-preventable serotypes caused 78.9% of IPD cases, mainly 14, 6B, 5, 19F and 23F. A non-significant increase in erythromycin resistance was reported. Our findings suggest that the introduction of PCV7 led to a significant decrease of IPD in children under 2 years old and in the overall case fatality rate.
Gender and time delays in diagnosis of pulmonary tuberculosis: a cross-sectional study from China
Authors: Chen H. G. , Wang T. W. , Cheng Q. X.
Published: February 2019

Gender inequality has severe consequences on public health in terms of delay in diagnosis of pulmonary tuberculosis (PTB). In order to explore gender-related differences in diagnosis delay, a cross-sectional study of 10 686 patients diagnosed with PTB in Yulin from 1 January 2009 to 31 December 2014 was conducted. Diagnosis delay was categorised into ‘short delay’ and ‘long delay’ by four commonly used cut-off points of 14, 30, 60 and 90 days. Logistic regression analysis was used to analyse gender differences in diagnostic delay. Stratified analyses by smear results, age, urban/rural were performed to examine whether the effect persisted across the strata. The median delay was 31 days (interquartile range 13–65). Diagnostic delay in females at cut-off points of 14, 30, 60 and 90 days had odds ratios (OR) of 0.99 (95% CI 0.91–1.09), 1.09 (95% CI 1.01–1.18), 1.15 (95% CI 1.05–1.26) and 1.18 (95% CI 1.06–1.31), respectively, compared with males. Stratified analysis showed that females were associated with increased risk of longer delay among those aged 30–60 years, smear positive and living in the rural areas (P < 0.05). The female-to-male OR increased along with increased delay time. Further inquiry into the underlying reasons for gender differences should be urgently addressed to improve the current situation.
Differential detection ofEntamoeba histolytica,Entamoeba disparandEntamoeba moshkovskiiin faecal samples using nested multiplex PCR in west of Iran
Authors: Bahrami Fares , Haghighi Ali , Zamini Ghasem , Khademerfan Mohammadbagher
Published: February 2019

This study aimed to determine the prevalence ofEntamoeba histolytica,Entamoeba disparandEntamoeba moshkovskii(collectively referred to asEntamoebacomplex), using microscopic and molecular methods in Kurdistan Province, northwest of Iran. The relationship between positiveEntamoebaspecies and clinical symptoms was also investigated. Eight positiveEntamoebacomplex, as well as fourEntamoebacomplex-like isolates, were detected by microscopic stool examination. DNA was extracted from all positive and from 55 randomly selected negative stool samples. PCR was performed using species-specific 18S rRNA primers for theEntamoebacomplex. All positive PCR samples were sequenced. In total, 14 (1.01%) out of 1383 isolates, i.e. 12 microscopy-positive andEntamoebacomplex-like isolates and two out of 55 microscopy-negative isolates, were identified via PCR and sequencing. Overall, 0.58% (8/1383) of the isolates wereE.dispar, 0.14% (2/1383)E.histolytica, 0.07% (1/1383)E.moshkovskiiand 0.22% (3/1383) were mixed ofE.histolyticaandE.dispar. Based on our findings, the prevalence ofE. disparis greater than that ofE. histoltyica. On the other hand, a case ofE. moshkovskiiwas reported for the first time in this region. It seems that some gastrointestinal symptoms may be attributed toEntamoebaspecies.
Feral cats do not play a major role in leptospirosis epidemiology on Reunion Island
Authors: Gomard Y. , Lagadec E. , Humeau L. , Pinet P. , Bureau S. , Da Silva D. , Turpin M. , Soulaimana Mattoir Y. , Georger S. , Mavingui P. , Tortosa P.
Published: February 2019

Although previous studies have reported Leptospira carriage in kidneys and urine of cats, the role of these animals in leptospirosis epidemiology remains poorly understood. Using molecular methods, we investigated Leptospira renal carriage in 172 feral cats from Reunion Island, an oceanic geographically isolated island located in the South West Indian Ocean. Only one out of the 172 analysed specimens tested positive for Leptospira DNA through quantitative real-time polymerase chain reaction. Using this positive sample, we could obtain sequences at three Leptospira loci (rrs2, lipL32 and lipL41) allowing to report for the first time Leptospira borgpetersenii naturally infecting cats. Comparisons with bacterial sequences from both acute human cases and animal reservoirs revealed similarities with Leptospira sequences previously reported on Reunion Island. However, the low prevalence (0.6%) reported herein does not support any major role of feral cats in leptospirosis epidemiology on Reunion Island, contrasting with results recently reported on another Indian Ocean Island, Christmas Island. The significance of these discrepancies is discussed.
A NOTE ON INFLATION DYNAMICS, PRICE VOLATILITY, AND FISCAL ACTIVISM
Authors: Afonso António , Jalles João Tovar
Published: February 2019

Using a panel of 54 countries between 1980 and 2013, we find empirical support for the view that changes in the fiscal policy stance (year-on-year change in the cyclically adjusted primary balance) have a significant positive correlation with inflation volatility. An increase in the volatility of discretionary fiscal policies by one standard deviation raises inflation volatility by about 6%. Moreover, results using alternative inflation volatility proxies confirm that an expansionary fiscal stance increases price volatility. Another relevant outcome is that in a context of economic expansions (recessions) the harmful impact of fiscal activism on price volatility is soft (heightened), while the negative impact of fiscal activism on price stability is higher when fiscal policy is expansionary. Finally, fiscal activism fuels inflation volatility much more pronouncedly in emerging market economies vis-à-vis advanced economies.
A new method for path-loss modeling
Authors: Li Qiang , Zhang Hongxin , Lu Yang , Zheng Tianyi , Lv Yinghua
Published: February 2019

In this paper, a new path-loss model for electromagnetic wave in an indoor multipath environment is proposed based on matching coefficient, polarization matching factor, and normalized field intensity direction function. This model is called the Friis-extension (Friis-EXT) model, because it operates as the Friis model under certain conditions. In addition, in the modeling process of the path-loss in an indoor environment, the reflective surfaces in the environment and form of the antenna are considered. Afterwards, the path-loss data in an indoor corridor environment are measured, and the maximum error between the theoretical value and the measured data is <7.5 dB. Finally, the Friis-EXT model is compared with some other traditional models, and the results show that the Friis-EXT model is the best one that matches the measurement data.
Magma Chamber Growth During Intercaldera Periods: Insights From Thermo‐Mechanical Modeling With Applications to Laguna del Maule, Campi Flegrei, Santorini, and Aso
Authors: Townsend Meredith , Huber Christian , Degruyter Wim , Bachmann Olivier
Published: February 2019

Crustal magma chambers can grow to be hundreds to thousands of cubic kilometers, potentially feeding catastrophic caldera‐forming eruptions. Smaller volume chambers are expected to erupt frequently and freeze quickly; a major outstanding question is how magma chambers ever grow to the sizes required to sustain the largest eruptions on Earth. We use a thermo‐mechanical model to investigate the primary factors that govern the extrusive:intrusive ratio in a chamber, and how this relates to eruption frequency, eruption size, and long‐term chamber growth. The model consists of three fundamental timescales: the magma injection timescale τin, the cooling timescale τcool, and the timescale for viscous relaxation of the crust τrelax. We estimate these timescales using geologic and geophysical data from four volcanoes (Laguna del Maule, Campi Flegrei, Santorini, and Aso) to compare them with the model. In each of these systems, τin is much shorter than τcool and slightly shorter than τrelax, conditions that in the model are associated with efficient chamber growth and simultaneous eruption. In addition, the model suggests that the magma chambers underlying these volcanoes are growing at rates between ~10−4 and 10−2 km3/year, speeding up over time as the chamber volume increases. We find scaling relationships for eruption frequency and size that suggest that as chambers grow and volatiles exsolve, eruption frequency decreases but eruption size increases. These scaling relationships provide a good match to the eruptive history from the natural systems, suggesting that the relationships can be used to constrain chamber growth rates and volatile saturation state from the eruptive history alone.
Two‐Dimensional Reconstruction of Magnetic Mirror Structures With Pressure Anisotropy: Theory and Application
Authors: Teh Wai‐Leong
Published: February 2019

A new reconstruction method is developed for two‐dimensional (2‐D), steady, magnetohydrostatic structures with anisotropic plasma pressure, which is assumed to be solely dependent on magnetic field strength. This dependence leads to a Poisson‐like partial differential equation that can be solved as a spatial initial‐value problem by use of data taken from a single spacecraft passing through a coherent structure. However, the resulting partial differential equation cannot be reduced to the ordinary Grad‐Shafranov equation with isotropic pressure. The numerical code for new reconstruction is developed and successfully validated against an exact analytical solution. This new reconstruction method is first applied to examine 2‐D geometry of magnetic mirror structures observed by the Magnetospheric Multiscale (MMS) spacecraft in the Earth's magnetosheath. The observed mirror structures satisfy the magnetohydrostatic conditions and are comoving with the average ion bulk flow. Using MMS1 measurements, the reconstruction produces a 2‐D magnetic field map and distribution maps of pressures perpendicular and parallel to the magnetic field. The reconstructed field map reveals magnetic bottle‐like structures as predicted by the mirror‐mode theory. A very good agreement is achieved between observation and reconstruction for the other three MMS spacecraft not used for reconstruction. It is concluded that this new reconstruction is suitable for examining 2‐D geometry of mirror structures.
The Role of Ekman Currents, Geostrophy, and Stokes Drift in the Accumulation of Floating Microplastic
Authors: Onink Victor , Wichmann David , Delandmeter Philippe , van Sebille Erik
Published: February 2019

Floating microplastic in the oceans is known to accumulate in the subtropical ocean gyres, but unclear is still what causes that accumulation. We investigate the role of various physical processes, such as surface Ekman and geostrophic currents, surface Stokes drift, and mesoscale eddy activity, on the global surface distribution of floating microplastic with Lagrangian particle tracking using GlobCurrent and WaveWatch III reanalysis products. Globally, the locations of microplastic accumulation (accumulation zones) are largely determined by the Ekman currents. Simulations of the North Pacific and North Atlantic show that the locations of the modeled accumulation zones using GlobCurrent Total (Ekman+Geostrophic) currents generally agree with observed microplastic distributions in the North Pacific and with the zonal distribution in the North Atlantic. Geostrophic currents and Stokes drift do not contribute to large‐scale microplastic accumulation in the subtropics, but Stokes drift leads to increased microplastic transport to Arctic regions. Since the WaveWatch III Stokes drift and GlobCurrent Ekman current data sets are not independent, combining Stokes drift with the other current components leads to an overestimation of Stokes drift effects and there is therefore a need for independent measurements of the different ocean circulation components. We investigate whether windage would be appropriate as a proxy for Stokes drift but find discrepancies in the modeled direction and magnitude. In the North Pacific, we find that microplastic tends to accumulate in regions of relatively low eddy kinetic energy, indicating low mesoscale eddy activity, but we do not see similar trends in the North Atlantic.
Alleles of Insm1 determine whether RIP1-Tag2 mice produce insulinomas or nonfunctioning pancreatic neuroendocrine tumors
Authors: Kobayashi Shinta , Contractor Tanupriya , Vosburgh Evan , Du Yi-Chieh Nancy , Tang Laura H. , Clausen Richard , Harris Chris R.
Published: February 2019

The two most common types of pancreatic neuroendocrine tumors (PanNETs) are insulinomas and nonfunctioning PanNETs (NF-PanNETs). Insulinomas are small, rarely metastatic tumors that secrete high amounts of insulin, and nonfunctioning PanNETs are larger tumors that are frequently metastatic but that do not secrete hormones. Insulinomas are modeled by the highly studied RIP1-Tag2 (RT2) transgenic mice when bred into a C57Bl/6 (B6) genetic background (also known as RT2 B6 mice). But there has been a need for an animal model of nonfunctioning PanNETs, which in the clinic are a more common and severe disease. Here we show that when bred into a hybrid AB6F1 genetic background, RT2 mice make nonfunctioning PanNETs. Compared to insulinomas produced by RT2 B6 mice, the tumors produced by RT2 AB6F1 mice were larger and more metastatic, and the animals did not suffer from hypoglycemia or hyperinsulinemia. Genetic crosses revealed that a locus in mouse chromosome 2qG1 was linked to liver metastasis and to lack of insulin production. This locus was tightly linked to the gene encoding Insm1, a beta cell transcription factor that was highly expressed in human insulinomas but unexpressed in other types of PanNETs due to promoter hypermethylation. Insm1-deficient human cell lines expressed stem cell markers, were more invasive in vitro, and metastasized at higher rates in vivo when compared to isogenic Insm1-expressing cell lines. These data demonstrate that expression of Insm1 can determine whether a PanNET is a localized insulinoma or a metastatic nonfunctioning tumor.
Health-related quality of life in the ENDEAVOR study: carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed/refractory multiple myeloma
Authors: Ludwig Heinz , Moreau Philippe , Dimopoulos Meletios A. , Mateos Maria-Victoria , Kaiser Martin , Hajek Roman , Feng Shibao , Cocks Kim , Buchanan Jaqueline , Weisel Katja
Published: February 2019

We examined effects of carfilzomib-dexamethasone (Kd56) versus bortezomib-dexamethasone (Vd) on health-related quality of life (HR-QoL) in relapsed/refractory multiple myeloma (MM) patients from the ENDEAVOR study. HR-QoL was assessed by the European Organisation for Research and Treatment of Cancer QoL Questionnaire (QLQ-C30), MM-specific module (QLQ-MY20), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx) “Additional Concerns” neurotoxicity subscale. The QLQ-C30 Global Health Status (GHS)/QoL scale and seven prespecified subscales were compared between groups using mixed model for repeated measures. Of 929 randomized patients, 911 with ≥1 post-baseline assessment were included. Kd56 was associated with statistically significant improvements in GHS/QoL, fatigue, pain, side effects, and FACT/GOG-Ntx scores versus Vd, although mean differences did not meet thresholds for clinical significance. The Kd56 group had longer time to deterioration (TTD) in GHS/QoL (median 3.7 versus 2.8 months,p = 0.0046), physical function (5.6 versus 3.7 months,p = 0.0390), nausea/vomiting (17.6 versus 8.2 months,p = 0.0358), side effects (6.4 versus 3.7 monthsp < 0.0001), and FACT/GOG-Ntx (11.1 versus 5.5 months, p = 0.0004). Overall, Kd56 resulted in statistically but not clinically significant improvements in mean GHS/QoL scores versus Vd. Treatment with Kd56 versus Vd also significantly prolonged TTD in GHS/QoL, physical function, nausea/vomiting, side effects, and FACT/GOG-Ntx.
Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells
Authors: Rezuchova Ingeborg , Hudecova Sona , Soltysova Andrea , Matuskova Miroslava , Durinikova Erika , Chovancova Barbora , Zuzcak Michal , Cihova Marina , Burikova Monika , Penesova Adela , Lencesova Lubomira , Breza Jan , Krizanova Olga
Published: February 2019

Although the involvement of type 1 (IP3R1) and type 2 (IP3R2) inositol 1,4,5-trisphosphate receptors in apoptosis induction has been well documented in different cancer cells and tissues, the function of type 3 IP3R (IP3R3) is still elusive. Therefore, in this work we focused on the role of IP3R3 in tumor cells in vitro and in vivo. We determined increased expression of this receptor in clear cell renal cell carcinoma compared to matched unaffected part of the kidney from the same patient. Thus, we hypothesized about different functions of IP3R3 compared to IP3R1 and IP3R2 in tumor cells. Silencing of IP3R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA. As expected, silencing of IP3R3 and subsequent apoptosis induction resulted in increased levels of apoptosis in all these cells. Further, we prepared a DLD1/IP3R3_del cell line using CRISPR/Cas9 gene editing method. These cells were injected into nude mice and tumor's volume was compared with tumors induced by DLD1 cells. Lower volume of tumors originated from DLD1/IP3R3_del cells was observed after 12 days, compared to wild type DLD1 cells. Also, the migration of these cells was lesser compared to wild type DLD1 cells. Apoptosis under hypoxic conditions was more pronounced in DLD1/IP3R3_del cells than in DLD1 cells. These results clearly show that IP3R3 has proliferative and anti-apoptotic effect in tumor cells, on contrary to the pro-apoptotic effect of IP3R1.
Ocean precursors to the extreme Atlantic 2017 hurricane season
Authors: Hallam Samantha , Marsh Robert , Josey Simon A. , Hyder Pat , Moat Ben , Hirschi Joël J.-M.
Published: February 2019

Active Atlantic hurricane seasons are favoured by positive precursor sea surface temperature anomalies (SSTA) in the main development region (MDR, 10–20°N, 20–80°W). Here, we identify a different driving mechanism for these anomalies in 2017 (most costly season on record) compared to the recent active 2005 and 2010 seasons. In 2005 and 2010, a weakened Atlantic Meridional Overturning Circulation is the primary driver of positive SSTA. However, in 2017, reduced wind-driven cold water upwelling and weaker surface net heat loss in the north-eastern MDR were the main drivers. Our results are the first to show that air-sea heat flux and wind stress related processes are important in generating precursor positive SSTAs and that these processes were active pre-determinants of the 2017 season severity. In contrast to other strong seasons, positive SSTA developed later in 2017 (between April and July rather than March) compounding the challenge of predicting Atlantic hurricane season severity.
Characterized cis-FeV(O)(OH) intermediate mimics enzymatic oxidations in the gas phase
Authors: Borrell Margarida , Andris Erik , Navrátil Rafael , Roithová Jana , Costas Miquel
Published: February 2019

FeV(O)(OH) species have long been proposed to play a key role in a wide range of biomimetic and enzymatic oxidations, including as intermediates in arene dihydroxylation catalyzed by Rieske oxygenases. However, the inability to accumulate these intermediates in solution has thus far prevented their spectroscopic and chemical characterization. Thus, we use gas-phase ion spectroscopy and reactivity analysis to characterize the highly reactive [FeV(O)(OH)(5tips3tpa)]2+ (32+) complex. The results show that 32+ hydroxylates C–H bonds via a rebound mechanism involving two different ligands at the Fe center and dihydroxylates olefins and arenes. Hence, this study provides a direct evidence of FeV(O)(OH) species in non-heme iron catalysis. Furthermore, the reactivity of 32+ accounts for the unique behavior of Rieske oxygenases. The use of gas-phase ion characterization allows us to address issues related to highly reactive intermediates that other methods are unable to solve in the context of catalysis and enzymology.
The human gut Firmicute Roseburia intestinalis is a primary degrader of dietary β-mannans
Authors: La Rosa Sabina Leanti , Leth Maria Louise , Michalak Leszek , Hansen Morten Ejby , Pudlo Nicholas A. , Glowacki Robert , Pereira Gabriel , Workman Christopher T. , Arntzen Magnus Ø. , Pope Phillip B. , Martens Eric C. , Hachem Maher Abou , Westereng Bjørge
Published: February 2019

β-Mannans are plant cell wall polysaccharides that are commonly found in human diets. However, a mechanistic understanding into the key populations that degrade this glycan is absent, especially for the dominant Firmicutes phylum. Here, we show that the prominent butyrate-producing Firmicute Roseburia intestinalis expresses two loci conferring metabolism of β-mannans. We combine multi-“omic” analyses and detailed biochemical studies to comprehensively characterize loci-encoded proteins that are involved in β-mannan capturing, importation, de-branching and degradation into monosaccharides. In mixed cultures, R. intestinalis shares the available β-mannan with Bacteroides ovatus, demonstrating that the apparatus allows coexistence in a competitive environment. In murine experiments, β-mannan selectively promotes beneficial gut bacteria, exemplified by increased R. intestinalis, and reduction of mucus-degraders. Our findings highlight that R. intestinalis is a primary degrader of this dietary fiber and that this metabolic capacity could be exploited to selectively promote key members of the healthy microbiota using β-mannan-based therapeutic interventions.
Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses
Authors: Kurelac Ivana , Iommarini Luisa , Vatrinet Renaud , Amato Laura Benedetta , De Luise Monica , Leone Giulia , Girolimetti Giulia , Umesh Ganesh Nikkitha , Bridgeman Victoria Louise , Ombrato Luigi , Columbaro Marta , Ragazzi Moira , Gibellini Lara , Sollazzo Manuela , Feichtinger Rene Gunther , Vidali Silvia , Baldassarre Maurizio , Foriel Sarah , Vidone Michele , Cossarizza Andrea , Grifoni Daniela , Kofler Barbara , Malanchi Ilaria , Porcelli Anna Maria , Gasparre Giuseppe
Published: February 2019

Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inability to respond to hypoxia, concordantly with the persistence of human oncocytomas. We demonstrate that CI-deficient tumors survive and carry out angiogenesis, despite their inability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated macrophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneous pharmacological inhibition of CI function through metformin and macrophage infiltration through PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basis for an efficient combinatorial adjuvant therapy in clinical trials.
Prototype of running clinical trials in an untrustworthy environment using blockchain
Authors: Wong Daniel R. , Bhattacharya Sanchita , Butte Atul J.
Published: February 2019

Monitoring and ensuring the integrity of data within the clinical trial process is currently not always feasible with the current research system. We propose a blockchain-based system to make data collected in the clinical trial process immutable, traceable, and potentially more trustworthy. We use raw data from a real completed clinical trial, simulate the trial onto a proof of concept web portal service, and test its resilience to data tampering. We also assess its prospects to provide a traceable and useful audit trail of trial data for regulators, and a flexible service for all members within the clinical trials network. We also improve the way adverse events are currently reported. In conclusion, we advocate that this service could offer an improvement in clinical trial data management, and could bolster trust in the clinical research process and the ease at which regulators can oversee trials.
Halogen bonding as a supramolecular dynamics catalyst
Authors: Szell Patrick M. J. , Zablotny Scott , Bryce David L.
Published: February 2019

Dynamic processes have many implications in functional molecules, including catalysts, enzymes, host-guest complexes, and molecular machines. Here, we demonstrate via deuterium NMR relaxation experiments how halogen bonding directly impacts the dynamics in solid 2,3,5,6-tetramethylpyrazine cocrystals, catalyzing the methyl group rotation. On average, we observe a reduction of 56% in the rotational activation energy of the methyl groups in the halogen bonded cocrystals, contrasting the reduction of 36% in the hydrogen bonded cocrystals, with respect to pure 2,3,5,6-tetramethylpyrazine. Density functional theory calculations attribute this superior catalytic ability of the halogen bond to the simultaneous destabilization of the staggered conformation and stabilization of the gauche conformation, overall reducing the rotational energy barrier. Furthermore, the calculations suggest that the catalytic ability of the halogen bond may be tuneable, with stronger halogen bond donors acting as superior dynamics catalysts. Thus, halogen bonding may play a role in both assembly and promoting dynamical processes.
Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner
Authors: Bianco Julien N. , Bergoglio Valérie , Lin Yea-Lih , Pillaire Marie-Jeanne , Schmitz Anne-Lyne , Gilhodes Julia , Lusque Amelie , Mazières Julien , Lacroix-Triki Magali , Roumeliotis Theodoros I. , Choudhary Jyoti , Moreaux Jérôme , Hoffmann Jean-Sébastien , Tourrière Hélène , Pasero Philippe
Published: February 2019

Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner.
Bacterial release from pipe biofilm in a full-scale drinking water distribution system
Authors: Chan Sandy , Pullerits Kristjan , Keucken Alexander , Persson Kenneth M. , Paul Catherine J. , Rådström Peter
Published: February 2019

Safe drinking water is delivered to the consumer through kilometres of pipes. These pipes are lined with biofilm, which is thought to affect water quality by releasing bacteria into the drinking water. This study describes the number of cells released from this biofilm, their cellular characteristics, and their identity as they shaped a drinking water microbiome. Installation of ultrafiltration (UF) at full scale in Varberg, Sweden reduced the total cell count to 1.5 × 103 ± 0.5 × 103 cells mL−1 in water leaving the treatment plant. This removed a limitation of both flow cytometry and 16S rRNA amplicon sequencing, which have difficulties in resolving small changes against a high background cell count. Following installation, 58% of the bacteria in the distributed water originated from the pipe biofilm, in contrast to before, when 99.5% of the cells originated from the treatment plant, showing that UF shifts the origin of the drinking water microbiome. The number of bacteria released from the biofilm into the distributed water was 2.1 × 103 ± 1.3 × 103 cells mL−1 and the percentage of HNA (high nucleic acid) content bacteria and intact cells increased as it moved through the distribution system. DESeq2 analysis of 16S rRNA amplicon reads showed increases in 29 operational taxonomic units (OTUs), including genera identified as Sphingomonas, Nitrospira, Mycobacterium, and Hyphomicrobium. This study demonstrated that, due to the installation of UF, the bacteria entering a drinking water microbiome from a pipe biofilm could be both quantitated and described.
ESR1 mutations in metastatic lobular breast cancer patients
Authors: Desmedt Christine , Pingitore Julien , Rothé Françoise , Marchio Caterina , Clatot Florian , Rouas Ghizlane , Richard François , Bertucci François , Mariani Odette , Galant Christine , Fribbens Charlotte , O’Leary Ben , van den Eynden Gert , Salgado Roberto , Turner Nicholas C. , Piccart Martine , Vincent-Salomon Anne , Pruneri Giancarlo , Larsimont Denis , Sotiriou Christos
Published: February 2019

Invasive lobular breast cancer (ILC) represents the second most common histology of breast cancer after invasive ductal breast cancer (IDC), accounts for up to 15% of all invasive cases and generally express the estrogen receptor (ER, coded by the ESR1 gene). ESR1 mutations have been associated with resistance to endocrine therapy, however these have not been specifically evaluated in ILC. We assessed the frequency of ESR1 mutations by droplet digital PCR in a retrospective multi-centric series of matched primary tumor and recurrence samples (n = 279) from 80 metastatic ER-positive ILC patients. We further compared ESR1 mutations between IDC and ILC patients in metastatic samples from MSKCC-IMPACT (n = 595 IDC and 116 ILC) and in ctDNA from the SoFEA and PALOMA-3 trials (n = 416 IDC and 76 ILC). In the retrospective series, the metastases from seven patients (9%) harbored ESR1 mutations, which were absent from the interrogated primary samples. Five patients (6%) had a mutation in the primary tumor or axillary metastasis, which could not be detected in the matched distant metastasis. In the MSKCC-IMPACT cohort, as well as in the SoFEA and PALOMA-3 trials, there were no differences in prevalence and distribution of the mutations between IDC and ILC, with D538G being the most frequent mutation in both histological subtypes. To conclude, no patient had an identical ESR1 mutation in the early and metastatic disease in the retrospective ILC series. In the external series, there was no difference in terms of prevalence and type of ESR1 mutations between ILC and IDC.
Mutations in the palm domain disrupt modulation of acid-sensing ion channel 1a currents by neuropeptides
Authors: Bargeton Benoîte , Iwaszkiewicz Justyna , Bonifacio Gaetano , Roy Sophie , Zoete Vincent , Kellenberger Stephan
Published: February 2019

Modulation by neuropeptides enhances several functions of acid-sensing ion channels (ASICs), such as pain sensation and acid-induced neuronal injury. The acid-induced opening of ASICs is transient, because of a rapid desensitization. Neuropeptides containing an Arg-Phe-amide motif affect ASIC desensitization and allow continuous activity of ASICs. In spite of the importance of the sustained ASIC activity during prolonged acidification, the molecular mechanisms of ASIC modulation by neuropeptides is only poorly understood. To identify the FRRFa (Phe-Arg-Arg-Phe-amide) binding site on ASIC1a, we carried out anin silicodocking analysis and verified functionally the docking predictions. The docking experiments indicated three possible binding pockets, located (1) in the acidic pocket between the thumb, finger, β-ball and palm domains, (2) in a pocket at the bottom of the thumb domain, and (3) in the central vestibule along with the connected side cavities. Functional measurements of mutant ASIC1a confirmed the importance of residues of the lower palm, which encloses the central vestibule and its side cavities, for the FRRFa effects. The combined docking and functional experiments strongly suggest that FRRFa binds to the central vestibule and its side cavities to change ASIC desensitization.
A method to identify respiratory virus infections in clinical samples using next-generation sequencing
Authors: Kustin Talia , Ling Guy , Sharabi Sivan , Ram Daniela , Friedman Nehemya , Zuckerman Neta , Bucris Efrat Dahan , Glatman-Freedman Aharona , Stern Adi , Mandelboim Michal
Published: February 2019

Respiratory virus infections are very common. Such infections impose an enormous economic burden and occasionally lead to death. Furthermore, every few decades, respiratory virus pandemics emerge, putting the entire world population at risk. Thus, there is an urgent need to quickly and precisely identify the infecting agent in a clinical setting. However, in many patients with influenza-like symptoms (ILS) the identity of the underlying pathogen remains unknown. In addition, it takes time and effort to individually identify the virus responsible for the ILS. Here, we present a new next-generation sequencing (NGS)-based method that enables rapid and robust identification of pathogens in a pool of clinical samples without the need for specific primers. The method is aimed at rapidly uncovering a potentially common pathogen affecting many samples with an unidentified source of disease.
Maternal Supplementation of Low Dose Fluoride Alleviates Adverse Perinatal Outcomes Following Exposure to Intrauterine Inflammation
Authors: Jia Bei , Zong Lu , Lee Ji Yeon , Lei Jun , Zhu Yan , Xie Han , Clemens Julia L. , Feller Mia C. , Na Quan , Dong Jie , McLane Michael W. , Jones-Beatty Kimberly , Burd Irina
Published: February 2019

Maternal periodontal disease has been linked to adverse pregnancy sequelae, including preterm birth (PTB); yet, root planing and scaling in pregnancy has not been associated with improved perinatal outcomes. Fluoride, a cariostatic agent, has been added to drinking water and dental products to prevent caries and improve dental health. The objective of this study was to explore the effects of fluoride supplementation using a mouse model of preterm birth and perinatal sequalae. Pregnant mice were fed low dose fluoride (LF−) or high dose fluoride (HF−) and given intrauterine injections of lipopolysaccharide (LPS) or phosphate-buffered saline (PBS). We found that LPS + LF− significantly increased livebirths, pup survival, and litter size compared to LPS alone. Moreover, offspring from the LPS + LF− group exhibited significantly improved neuromotor performance and more neurons compared to those from the LPS group. Additionally, LF− treatment on human umbilical vein endothelial cells (HUVECs) increased cell viability and decreased oxidative stress after treatment with LPS. Collectively, our data demonstrates that maternal LF− supplementation during pregnancy postpones the onset of PTB, acts to increase the liveborn rate and survival time of newborns, and reduces perinatal brain injury in cases of intrauterine inflammation.
Demonstrative operation of four-terminal memristive devices fabricated on reduced TiO2 single crystals
Authors: Takeuchi Shotaro , Shimizu Takuma , Isaka Tsuyoshi , Tohei Tetsuya , Ikarashi Nobuyuki , Sakai Akira
Published: February 2019

Resistive switching (RS) was demonstrated in four-terminal planar memristive devices fabricated on reduced TiO2 (TiO2−x) single crystal substrates. In the device, a pair of diagonally opposing electrode terminals is used to modify the distribution of oxygen vacancies in the region between another pair of diagonally opposing electrode terminals. This allowed microscopic visual observations of the oxygen vacancy distribution based on electrocoloring. The visual contrast observed in the TiO2−x reflects the oxygen vacancy concentration in the electrically active zone of the device, which can be modified by application of various external voltages to the electrodes. The current that flows in the device is significantly dependent on the modified oxygen vacancy distribution and the resultant resistance is switchable when the polarization of the applied external voltage is reversed. The crystallographic orientation of the TiO2−x substrate has a strong influence on the reversible RS phenomenon. Mechanisms behind the voltage-driven resistance change are elaborated with the aid of microscopic analysis for both crystalline and electronic structures in the electrically active zone of the device. Suppression of the formation of irreversible conductive structures comprised of accumulated oxygen vacancies is a key to establishing reversible RS in the device.
Characterization of the mitochondrial genome of an ancient amphipod Halice sp. MT-2017 (Pardaliscidae) from 10,908 m in the Mariana Trench
Authors: Li Jun-yuan , Zeng Cong , Yan Guo-yong , He Li-sheng
Published: February 2019

Small amphipods (Halice sp. MT-2017) with body length <1 cm were collected from the Challenger Deep (~10,920 m below sea level). The divergence time of their lineage was approximately 109 Mya, making this group ancient compared to others under study. The mitochondrial genome of Halice sp. shared the usual gene components of metazoans, comprising 13 protein coding genes (PCGs), 22 transfer RNAs (tRNAs), and 2 ribosomal RNAs (rRNAs). The arrangement of these genes, however, differed greatly from that of other amphipods. Of the 15 genes that were rearranged with respect to the pancrustacean gene pattern, 12 genes (2 PCGs, 2 rRNAs, and 8 tRNAs) were both translocated and strand-reversed. In contrast, the mitochondrial genomes in other amphipods never show so many reordered genes, and in most instances, only tRNAs were involved in strand-reversion-coupled translocation. Other characteristics, including reversed strand nucleotide composition bias, relatively higher composition of non-polar amino acids, and lower evolutionary rate, were also identified. Interestingly, the latter two features were shared with another hadal amphipod, Hirondellea gigas, suggesting their possible associations with the adaptation to deep-sea extreme habitats. Overall, our data provided a useful resource for future studies on the evolutionary and adaptive mechanisms of hadal faunas.
Optical bleaching front in bedrock revealed by spatially-resolved infrared photoluminescence
Authors: Sellwood E. L. , Guralnik B. , Kook M. , Prasad A. K. , Sohbati R. , Hippe K. , Wallinga J. , Jain M.
Published: February 2019

Optically stimulated luminescence (OSL) dating of sediment, based on the accumulation of trapped charge in natural crystals since their last exposure to daylight, has revolutionised our understanding of the late Quaternary period. Recently, a complementary technique called luminescence rock surface dating (RSD), which uses differential spatial eviction of trapped charges in rocks exposed to daylight, has been developed to derive exposure and burial ages, and hard-rock erosion rates. In its current form, the RSD technique suffers from labour intensive sample preparation, uncertainties in the depth and dose rate estimates, and poor resolution of the luminescence-depth profile. Here, we develop a novel, 2D luminescence imaging technique for RSD of large rock slabs (3 × 5 cm) to overcome these challenges. We utilize the recently discovered infrared photoluminescence (IRPL) signal for direct, non-destructive imaging of the luminescence-depth profile in a sub-aerially exposed granitic rock, with an unprecedented spatial resolution of ~140 µm. We further establish a correlation between luminescence and geochemistry using micro X-ray fluorescence (µXRF) spectroscopy. Our study promises a substantial advancement in luminescence imaging and paves the path towards novel applications using 2D dating, micro-dosimetry in mixed composition samples, and portable instrumentation for in-situ luminescence measurements.
KRAS genotyping by digital PCR combined with melting curve analysis
Authors: Tanaka Junko , Nakagawa Tatsuo , Shiratori Akiko , Shimazaki Yuzuru , Uematsu Chihiro , Kamahori Masao , Yokoi Takahide , Harada Kunio , Kohara Yoshinobu
Published: February 2019

Digital PCR (dPCR) has been developed as a method that can quantify nucleic acids more sensitively than real-time PCR. However, dPCR exhibits large fluctuations in the fluorescence intensity of the compartment, resulting in low accuracy. The main cause is most likely due to insufficient PCR. In this study, we proposed a new method that combines dPCR with melting curve analysis and applied that method to KRAS genotyping. Since the melting temperature (Tm) of the PCR product hardly depends on the amplification efficiency, genotyping accuracy is improved by using the Tm value. The results showed that the peaks of the distribution of the Tm values of DNA in the wells were 68.7, 66.3, and 62.6 °C for wild-type KRAS, the G12R mutant, and the G12D mutant, respectively, and the standard deviation of the Tm values was 0.2 °C for each genotype. This result indicates that the proposed method is capable of discriminating between the wild-type sequence and the two mutants. To the best of our knowledge, this is the first demonstration of the genotyping of single mutations by combining melting curve analysis and dPCR. The application of this approach could be useful for the quantification and genotyping of cancer-related genes in low-abundance samples.
Pareto Optimality Explanation of the Glycolytic Alternatives in Nature
Authors: Ng Chiam Yu , Wang Lin , Chowdhury Anupam , Maranas Costas D.
Published: February 2019

The Entner-Doudoroff (ED) and Embden-Meyerhof-Parnas (EMP) glycolytic pathways are largely conserved across glycolytic species in nature. Is this a coincidence, convergent evolution or there exists a driving force towards either of the two pathway designs? We addressed this question by first employing a variant of the optStoic algorithm to exhaustively identify over 11,916 possible routes between glucose and pyruvate at different pre-determined stoichiometric yields of ATP. Subsequently, we analyzed the thermodynamic feasibility of all the pathways at physiological metabolite concentrations and quantified the protein cost of the feasible solutions. Pareto optimality analysis between energy efficiency and protein cost reveals that the naturally evolved ED and EMP pathways are indeed among the most protein cost-efficient pathways in their respective ATP yield categories and remain thermodynamically feasible across a wide range of ATP/ADP ratios and pathway intermediate metabolite concentration ranges. In contrast, pathways with higher ATP yield (>2) while feasible, are bound within stringent and often extreme operability ranges of cofactor and intermediate metabolite concentrations. The preponderance of EMP and ED is thus consistent with not only optimally balancing energy yield vs. enzyme cost but also with ensuring operability for wide metabolite concentration ranges and ATP/ADP ratios.
Impulsivity and body fat accumulation are linked to cortical and subcortical brain volumes among adolescents and adults
Authors: Kakoschke Naomi , Lorenzetti Valentina , Caeyenberghs Karen , Verdejo-García Antonio
Published: February 2019

Obesity is associated not only with metabolic and physical health conditions, but with individual variations in cognition and brain health. This study examined the association between body fat (an index of excess weight severity), impulsivity (a vulnerability factor for obesity), and brain structure among adolescents and adults across the body mass index (BMI) spectrum. We used 3D T1 weighted anatomic magnetic resonance imaging scans to map the association between body fat and volumes in regions associated with obesity and impulsivity. Participants were 127 individuals (BMI: 18–40 kg/m2;M = 25.69 ± 5.15), aged 14 to 45 years (M = 24.79 ± 9.60; female = 64). Body fat was measured with bioelectric impendence technology, while impulsivity was measured with the UPPS-P Impulsive Behaviour Scale. Results showed that higher body fat was associated with larger cerebellar white matter, medial orbitofrontal cortex (OFC), and nucleus accumbens volume, although the latter finding was specific to adolescents. The relationship between body fat and medial OFC volume was moderated by impulsivity. Elevated impulsivity was also associated with smaller amygdala and larger frontal pole volumes. Our findings link vulnerability and severity markers of obesity with neuroanatomical measures of frontal, limbic and cerebellar structures, and unravel specific links between body fat and striatal volume in adolescence.