bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of pro‐inflammatory cytokines and mediators induced by Bisphenol A via ERK‐NFκB and JAK1/2‐STAT3 pathways in macrophages
Authors: Huang Fu‐Mei , Chang Yu‐Chao , Lee Shiuan‐Shinn , Yang Ming‐Ling , Kuan Yu‐Hsiang
Published: January 2019

Macrophages not only play an important role in the innate immune response but also participate in many inflammatory and infectious diseases including asthma, diabetes, obesity, cardiovascular diseases, and cancers. Bisphenol A (BPA) is the most commonly used component for plastic products. However, BPA is an endocrine disruptor for mammals and participates in several inflammatory and infectious diseases. Up until now, there are no researches demonstrated the potential role of BPA in macrophage activation and its relative mechanism. BPA promoted the generation of proinflammatory cytokines IL‐1β, IL‐6, and TNFα in a concentration‐dependent manner (P < 0.05). BPA was identified to increase the expression of proinflammatory mediators NO and PGE2, and its upstream factors iNOS, COX2, and cPLA2 in a concentration‐dependent manner (P < 0.05). Phosphorylation and nuclear translocation of NF‐κB p65 were significantly induced by BPA via IκB degradation (P < 0.05). In addition, phosphorylation of ERK significantly induced by BPA at a concentration which was less than that for phosphorylation of p38 MAPK and JNK (P < 0.05). Furthermore, phosphorylation of STAT3 significantly induced by BPA at a concentration lower than that for phosphorylation of STAT1 (P < 0.05). Phosphorylation of JAK1 and JAK2 was also significantly induced by BPA in a concentration‐dependent manner (P < 0.05).
VANET security and forensics: Challenges and opportunities
Authors: Abassi Ryma
Published: January 2019

Vehicular Ad hoc NETworks (VANETs) are a key part of the Intelligent Transport Systems (ITS) as they constitute an intelligent transport network where vehicles and some infrastructure collaborate to exchange messages about traffic, accidents, etc. In such context, security becomes a key component to ensure that exchanged messages were not modified or inserted for example. Consequently, a wide variety of research contributions have been recently presented to cope with this issue. This paper presents a review of most recent papers dealing with security issues in VANETs. Hence, it presents an overview of VANETs and mainly their characteristics as well as their main applications. Then, the main security challenges faced by VANETs are introduced. This is done by first listing their main security requirements, second by establishing attackers' profiles, and their attacks and third by introducing some security solutions. Finally, the opportunities and challenges related to VANETs security are presented such as Trust, Internet of Vehicle, etc.

This article is categorized under:

Digital and Multimedia Science > Vehicle Forensics

Digital and Multimedia Science > Mobile Forensics

Digital and Multimedia Science > IoT Forensics
Fleet-Wide Proactive Maintenance of Machine Tools
Authors: Peysson Flavien , Mozzati Christophe , Leon David , Lafuste Quentin , Leger Jean-Baptiste
Published: January 2019

Fleet-wide proactive maintenance characterizes all services that are made available to the users to help them to operate, supervise and maintain a fleet of systems. These services can be, for a general manager of a fleet, a dashboard of all the systems’ business indicators or, for a technical manager, a dashboard of all the systems’ maintenance and health status. At the bottom level of the pyramidal hierarchy, a technical operator should have a fast overview of the systems’ status and should be alerted at the right time when a system needs to be checked. Nowadays, more and more data and information are available on machine tools which should be treated and analysed to extract the right information for the right people at the right time. To achieve this goal, a fleet-wide proactive maintenance platform requires several main business services to have an understandable view of the system by all users and, thus, save time for decision-making during diagnosis and prognosis analysis.
CP violation in η muonic decays
Authors: Sanchez-Puertas Pablo
Published: January 2019

Abstract

In this study, we investigate the imprints of CP violation in certain η muonic decays that could arise within the Standard Model effective field theory. In particular, we study the sensitivities that could be reached at REDTOP, a proposed η facility. After estimating the bounds that the neutron EDM places, we find still viable to discover signals of CP violation measuring the polarization of muons in η → μ
+
μ
− decays, with a single effective operator as its plausible source.
Racial and Socioeconomic Disparities in the Surgical Management and Outcomes of Patients with Colorectal Carcinoma
Authors: Cairns Ashley L. , Schlottmann Francisco , Strassle Paula D. , Di Corpo Marco , Patti Marco G.
Published: January 2019

Introduction

Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. We aimed to determine racial and socioeconomic disparities in the surgical management and outcomes of patients with CRC in a contemporary, national cohort.

Methods

We performed a retrospective analysis of the National Inpatient Sample for the period 2009–2015. Adult patients diagnosed with CRC and who underwent colorectal resection were included. Multivariable linear and logistic regressions were used to assess the effect of race, insurance type, and household income on patient outcomes.

Results

A total of 100,515 patients were included: 72,552 (72%) had elective admissions and 27,963 (28%) underwent laparoscopic surgery. Patients with private insurance and higher household income were consistently more likely to have laparoscopic procedures, compared to other insurance types and income levels, p < 0.0001. Black patients, compared to white patients, were more likely to have postoperative complications (OR 1.23, 95% CI, 1.17, 1.29). Patients with Medicare and Medicaid, compared to private insurance, were also more likely to have postoperative complications (OR 1.30, 95% CI, 1.24, 1.37 and OR 1.40, 95% CI, 1.31, 1.50). Patients in low‐household‐income areas had higher rates of any complication (OR 1.11, 95% CI 1.06, 1.16).

Conclusions

The use of laparoscopic surgery in patients with CRC is strongly influenced by insurance type and household income, with Medicare, Medicaid and low‐income patients being less likely to undergo laparoscopic surgery. In addition, black patients, patients with public insurance, and patients with low household income have significant worse surgical outcomes.
Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects
Authors: Muirhead Gary J. , Osterloh Ian H. , Whaley Steven , van den Berg Frans
Published: January 2019

Background

Cligosiban (formerly IX-01) is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE).

Aim

To investigate the plasma pharmacokinetics, safety, and tolerability of multiple oral doses of cligosiban in healthy male subjects; measure the amount of cligosiban in semen; and evaluate the potential of cligosiban to modulate CYP3A4.

Methods

Both studies were double-blind, placebo-controlled, parallel group designs involving sequential cohorts of 12 subjects each. Cligosiban dosage regimens were 100 mg, 400 mg, 800 mg, 1200 mg, 1,600 mg and 2,400 mg once daily for 10 days, administered as an aqueous dispersion.

Outcomes

Blood samplings for cligosiban assays and safety assessments were performed throughout both studies. Semen was collected on day 9 at 2–4 hours postdose in study 1 only. Safety assessments included monitoring of adverse events, 12-lead electrocardiography, vital signs, and laboratory safety assessments. Urine samples for assessment of the 6β-hydroxycortisol/cortisol ratio were collected before dosing on days 1 and 10.

Results

Cligosiban was rapidly absorbed after both single and multiple dosing, with maximum plasma concentrations typically measured at 1–3 hours postdose. The terminal half-life was approximately 12 hours, and steady state was achieved by day 3. Exposure increased approximately proportionally to dose after single dosing but less than proportionally after multiple dosing. Accumulation ratios were higher at the lower doses compared with higher doses (2.3 at 100 mg vs 1.1 at 2,400 mg). The mean amount of cligosiban in semen ranged from 0.22 to 2.01 μg over the 100–1,200 mg dose range (<0.0003% of the administered dose). There were no meaningful differences in the urinary 6β-hydroxycortisol/cortisol ratio after multiple dosing with cligosiban. Cligosiban appeared to be well tolerated at all dose levels.

Clinical Implications

Cligosiban is well tolerated following once-daily dosing over a wide dose range and does not appear to modulate CYP3A4 activity, suggesting limited potential for perpetrating drug–drug interactions via this mechanism.

Strengths & Limitations

The 2 controlled trials show good toleration and pharmacokinetic data, including negligible amounts of cligosiban in semen at doses expected to be therapeutic. Toleration of cligosiban will need to be confirmed in studies in patients with PE.

Conclusion

Cligosiban showed a good safety profile at doses predicted to be therapeutic or supratherapeutic along with a pharmacokinetic profile appropriate for as-required or once-daily dosing. There was no evidence that cligosiban inhibited or induced CYP3A4 at doses up to 2,400 mg.
Wage Exploitation and the Nonworseness Claim: Allowing the Wrong, To Do More Good
Authors: Faraci David
Published: January 2019

Many believe that employment can be wrongfully exploitative, even if it is consensual and mutually beneficial. At the same time, it may seem third parties should not do anything to preclude or eliminate such arrangements, given these same considerations of consent and benefit. I argue that there are perfectly sensible, intuitive ethical positions that vindicate this “Reasonable View.” The view requires such defense because the literature often suggests that there is no theoretical space for it. I respond to arguments for the clearest symptom of this obscuration: the so-callednonworseness claimthat a consensual, mutually beneficial transaction cannot be “morally worse” than its absence. In addition to making space for the Reasonable View, this serves my dialectical goal of encouraging distinct attention to first- and third-party obligations.
Interpreting Life-History Traits of Miconia (Miconia calvescens) through Management over Space and Time in the East Maui Watershed, Hawaii (USA)
Authors: Leary James , Mahnken Brooke , Wada Christopher , Burnett Kimberly
Published: January 2019

Miconia (Miconia calvescensDC) was introduced to the East Maui Watershed (EMW) a half-century ago with more than 25 yr of management recorded. Using a historical spatiotemporal data set, we constructed a leptokurtic dispersal kernel with 99% of progeny confined to within 549 m of the nearest maternal source and the remaining 1% dispersed out to 1,636 m. Seedbank persistence, based on postdated recruitment, displayed an exponential decay projecting extinction beyond 20 yr. These parameters are highly congruent to independent interpretations ofM. calvescensin Australia and Tahiti. In a simulated stage matrix model, we projected management efforts to locally eradicate a small incipient propagule bank wherein optimal management was achieved with an annual harvest rate that eliminated all juvenile recruits before reaching maturity, until extinction. Based on current pricing for helicopter herbicide ballistic technology (HBT) operations, the optimal, variable cost to locally eradicate this incipient propagule bank was estimated to be less than US$42,000, with ~90% of the effort searching for the most distant 1% of the progeny expended within the first 9 yr after the mature discovery. This variable cost was sensitive to seedbank size, recruitment rate, and dispersal range, but was most sensitive to harvest rates between suboptimal and excess. In a scenario prioritizing the upper region of EMW, we retroactively analyzed past HBT efforts eliminating satelliteM. calvescensand determined that 27% of the total effort resulted in 87% of the total protection to this priority asset, with every US$1 invested potentially avoiding US$184 in future costs. Management outside the priority area was less economical, with returns in protection diminishing with distance from the priority upper region.Miconia calvescensis currently not eradicable in the EMW, and full containment of the invasion would require a substantial increase in stable, long-term funding. With limited resources, local eradication of satelliteM. calvescenscould be the most cost-effective alternative to protecting uninvaded areas prioritized for critical ecosystem functions.
ON THE DECOMPOSITION OF OPERATORS WITH SEVERAL ALMOST-INVARIANT SUBSPACES
Authors: ASSADI AMANOLLAH , FARZANEH MOHAMAD ALI , MOHAMMADINEJAD HAJI MOHAMMAD
Published: January 2019

We seek a sufficient condition which preserves almost-invariant subspaces under the weak limit of bounded operators. We study the bounded linear operators which have a collection of almost-invariant subspaces and prove that a bounded linear operator on a Banach space, admitting each closed subspace as an almost-invariant subspace, can be decomposed into the sum of a multiple of the identity and a finite-rank operator.
Climate-change-related long-term historical and projected changes to spring barley phenological development in Lithuania
Authors: Sujetovienė G. , Velička R. , Kanapickas A. , Kriaučiūnienė Z. , Romanovskaja D. , Bakšienė E. , Vagusevičienė I. , Klepeckas M. , Juknys R.
Published: January 2019

Though the number of climate-change-related agro-phenological investigations are growing rapidly, the attention paid to spring crops has been much less than to winter ones. The objective of the current study was to investigate long-term temporal and spatial trends of spring barley phenology and to project changes in the timing and duration of different phenological phases during the current century. Higher temperatures significantly affected the potential scheduling of agricultural practices, accelerating the occurrence of sowing and emergence dates. Historical trends in harvest dates of spring barley showed a slight delay. These changes resulted in the extension of the total vegetative period of spring barley by >12 days over the period investigated (1961–2015). Since Lithuania is situated on the Baltic Sea, an increase in temperature along with an increase in distance from the sea was characteristic over the last 55 years. Projected changes in the occurrence of phenological phases of spring barley differ significantly from analysed historical changes and advancement of all phenological phases have been projected according to both Representative Concentration Pathway (RCP) 2.6 and RCP 8.5 climate change scenarios. Shortening of the total vegetative period by 5 days is foreseen for the far (2071–2100) future according to the pessimistic (RCP 8.5) climate change scenario.
Sul concetto di generazione politica
Authors: Lattes Gianfranco Bettin
Published: January 2019

Introduzione

L'interrogativo principale cui ci si propone di dare una risposta in queste pagine è: perché (e come) riflettere sul concetto di generazione politica? L'interrogativo è apparentemente confinato ad un tema dai contorni piuttosto limitati. Il nodo da sciogliere, in realtà, è assai più complicato ed è da rintracciare nella palese insufficienza dell'armamentario sociologico tradizionalmente adottato per lo studio del mutamento politico. Un esempio di come si pone il problema è forse utile anche ai fini analitici. Nella storia europea uno dei dati ricorrenti è quello di una duplice forma di conflitto che ha sempre agito come motore di mutamento politico: da un lato il conflitto tra le nazioni e dall'altro lato il conflitto tra le classi. Il conflitto tra la coscienza nazionale e la coscienza di classe è stato in generale risolto a vantaggio del valore della nazione; tuttavia oggi questi due tipi di conflitto non hanno molto spazio perché sono mutati – forse in modo irreversibile – i loro fondamenti sociali, culturali e politici.
A FULLY CLASSICAL TRUTH THEORY CHARACTERIZED BY SUBSTRUCTURAL MEANS
Authors: PAILOS FEDERICO MATÍAS
Published: January 2019

We will present a three-valued consequence relation for metainferences, called CM, defined through ST and TS, two well known substructural consequence relations for inferences. While ST recovers every classically valid inference, it invalidates some classically valid metainferences. While CM works as ST at the inferential level, it also recovers every classically valid metainference. Moreover, CM can be safely expanded with a transparent truth predicate. Nevertheless, CM cannot recapture every classically valid meta-metainference. We will afterwards develop a hierarchy of consequence relations CMn for metainferences of level n (for 1 ≤ n < ω). Each CMn recovers every metainference of level n or less, and can be nontrivially expanded with a transparent truth predicate, but cannot recapture every classically valid metainferences of higher levels. Finally, we will present a logic CMω, based on the hierarchy of logics CMn, that is fully classical, in the sense that every classically valid metainference of any level is valid in it. Moreover, CMω can be nontrivially expanded with a transparent truth predicate.
Visualizing the Interconnections Among Climate Risks
Authors: Yokohata T. , Tanaka K. , Nishina K. , Takahashi K. , Emori S. , Kiguchi M. , Iseri Y. , Honda Y. , Okada M. , Masaki Y. , Yamamoto A. , Shigemitsu M. , Yoshimori M. , Sueyoshi T. , Iwase K. , Hanasaki N. , Ito A. , Sakurai G. , Iizumi T. , Nishimori M. , Lim W. H. , Miyazaki C. , Okamoto A. , Kanae S. , Oki T.
Published: January 2019

It is now widely recognized that climate change affects multiple sectors in virtually every part of the world. Impacts on one sector may influence other sectors, including seemingly remote ones, which we call “interconnections of climate risks.” While a substantial number of climate risks are identified in the Intergovernmental Panel on Climate Change Fifth Assessment Report, there have been few attempts to explore the interconnections between them in a comprehensive way. To fill this gap, we developed a methodology for visualizing climate risks and their interconnections based on a literature survey. Our visualizations highlight the need to address climate risk interconnections in impact and vulnerability studies. Our risk maps and flowcharts show how changes in climate impact natural and socioeconomic systems, ultimately affecting human security, health, and well‐being. We tested our visualization approach with potential users and identified likely benefits and issues. Our methodology can be used as a communication tool to inform decision makers, stakeholders, and the general public of the cascading risks that can be triggered by climate change.
Interbasin and Intrabasin Competitions Control Drainage Network Density
Authors: Hooshyar Milad , Singh Arvind , Wang Dingbao
Published: January 2019

The growth and evolution of drainage networks are controlled by erosional and depositional processes forced by climate and tectonics operating on the landscape. By analyzing the data from 137 natural basins across the United States and an ensemble of synthetic terrains generated by a numerical landscape evolution model, we observed a power law relationship between the characteristic length (the length scale at which the timescales of diffusive and advective transports are equal) and drainage density (total channel length divided by drainage area) with two scaling regimes. The observed regimes exhibit significantly different characteristics in terms of intrabasin (i.e., the interaction between channels and hillslopes) and interbasin (i.e., the interaction between adjacent basins) competitions. Our findings reveal the relationship between drainage density and basic geomorphic and topologic characteristics, which encapsulate the advective and diffusive transport processes acting on the landscape.
Variability of Precipitating Ion Fluxes During the September 2017 Event at Mars
Authors: Martinez A. , Leblanc F. , Chaufray J. Y. , Modolo R. , Romanelli N. , Curry S. , Luhmann J. , Lillis R. , Hara T. , McFadden J. , Halekas J. , Eparvier F. , Larson D. , Connerney J. , Ma Y. J. , Holmström M. , Witasse O. , Jakosky B.
Published: January 2019

In this work, we study the influence of the September 2017 solar event on the precipitating heavy ion fluxes toward Mars' atmosphere as seen by Mars Atmosphere and Volatile EvolutioN/Solar Wind Ion Analyzer, an energy and angular ion spectrometer and by Mars Atmosphere and Volatile EvolutioN/Suprathermal and Thermal Ion Composition instrument, an energy, mass, and angular ion spectrometer. After a careful reconstruction of the background induced by the Solar Energetic Particle event in the Mars Atmosphere and Volatile EvolutioN/Solar Wind Ion Analyzer spectrometer, we investigate the precipitating ion flux responses to the space weather events that took place in September 2017. This period is a unique opportunity to analyze the respective role of various possible drivers of heavy ion precipitation into Mars' atmosphere with a wide range of different space weather events occurring during the same month. This study shows an increase in the precipitation flux by more than 1 order of magnitude during the arrival of the September Interplanetary Coronal Mass Ejection compared to the average flux during quiet solar conditions. We also showed that among the possible solar drivers, the solar wind dynamic pressure is the most significant during September 2017.
The Importance of the Inelastic and Elastic Structures of the Crust in Constraining Glacial Density, Mass Change, and Isostatic Adjustment From Geodetic Observations in Southeast Alaska
Authors: Durkin William , Kachuck Samuel , Pritchard Matthew
Published: January 2019

Elastic deformation of the solid Earth in response to ice mass loss offers a promising constraint on the density of glacial material lost. Further, the elastic response to modern deglaciation is important to constrain for studies of glacial isostatic adjustment to determine the mantle's structure and rheology. Models of this elastic uplift are commonly based on the 1‐D, seismically derived global average Preliminary Reference Earth Model and typically neglect uncertainties that can arise from regional differences in elastic structure from that of the global average, lateral heterogeneities within the region, and inelastic behavior of the crust. We quantify these uncertainties using an ensemble of 1‐D local elastic structure models and empirical relations for the effects of inelasticity in the upper ∼10 km of the crust. In Southeast Alaska, modeling elastic uplift rates with local elastic structures results in up to a 20–40% difference from those modeled with the Preliminary Reference Earth Model. Although these differences are limited to regions near to ice‐covered areas, they are comparable to the differences in uplift rates expected from the loss of firn versus loss of ice. Far from ice‐covered areas, where most of the region's GPS observations were made, these differences become insignificant and do not affect previous glacial isostatic adjustment studies in the region. The methods presented here are based on the globally available LITHO1.0 seismic model and open source software, and the approach of using an ensemble of 1‐D elastic structures can be easily adapted to other regions around the world.
Improving AGCM Hurricane Structure With Two‐Way Nesting
Authors: Gao Kun , Harris Lucas , Chen Jan‐Huey , Lin Shian‐Jiann , Hazelton Andrew
Published: January 2019

We demonstrate that two‐way nesting significantly improves the structure of simulated hurricane in an atmospheric general circulation model. Two sets of 30‐day hindcast experiments are conducted, one with the global‐uniform‐resolution (approximately 25‐km nominal horizontal resolution) and the other with a regionally refined two‐way nest (approximately 8 km over the tropical North Atlantic). The increase in the horizontal resolution on the nested grid improves the representation of storm intensity and intensification rate. When normalized by the radius of maximum wind (RMW), composite hurricane structures are generally similar in both simulations and compare well to observations. However, the hurricanes in the globally uniform configuration have much larger RMWs than observed, while those in the two‐way‐nested configuration have more realistic RMWs. We also find that the representation of the RMW has a critical impact on the simulation of inertial stability and boundary‐layer convergence in the inner‐core region. The more realistic inner‐core size (indicated by RMW) and structure are possible reasons for the improved intensification rates in the two‐way‐nested configuration.
Applications of Deep Learning to Ocean Data Inference and Subgrid Parameterization
Authors: Bolton Thomas , Zanna Laure
Published: January 2019

Oceanographic observations are limited by sampling rates, while ocean models are limited by finite resolution and high viscosity and diffusion coefficients. Therefore, both data from observations and ocean models lack information at small and fast scales. Methods are needed to either extract information, extrapolate, or upscale existing oceanographic data sets, to account for or represent unresolved physical processes. Here we use machine learning to leverage observations and model data by predicting unresolved turbulent processes and subsurface flow fields. As a proof of concept, we train convolutional neural networks on degraded data from a high‐resolution quasi‐geostrophic ocean model. We demonstrate that convolutional neural networks successfully replicate the spatiotemporal variability of the subgrid eddy momentum forcing, are capable of generalizing to a range of dynamical behaviors, and can be forced to respect global momentum conservation. The training data of our convolutional neural networks can be subsampled to 10–20% of the original size without a significant decrease in accuracy. We also show that the subsurface flow field can be predicted using only information at the surface (e.g., using only satellite altimetry data). Our results indicate that data‐driven approaches can be exploited to predict both subgrid and large‐scale processes, while respecting physical principles, even when data are limited to a particular region or external forcing. Our in‐depth study presents evidence for the successful design of ocean eddy parameterizations for implementation in coarse‐resolution climate models.
David Sandwell Receives 2018 Charles A. Whitten Medal
Authors:   AGU
Published: January 2019

David Sandwell was awarded the 2018 Charles A. Whitten Medal at the AGU Fall Meeting Honors Ceremony, held on 12 December 2018 in Washington, D. C. The medal is for “outstanding achievement in research on the form and dynamics of the Earth and planets.”
White House Science Adviser Seat Filled After 2 Years
Authors: Showstack Randy
Published: January 2019

The Senate’s confirmation of Kelvin Droegemeier to head the White House Office of Science and Technology Policy is a win for the science community. But will Trump take his advice?
Correction: Connectomics of bipolar disorder: a critical review, and evidence for dynamic instabilities within interoceptive networks
Authors: Perry Alistair , Roberts Gloria , Mitchell Philip B. , Breakspear Michael
Published: January 2019

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.
Niche-directed evolution modulates genome architecture in freshwater Planctomycetes
Authors: Andrei Adrian-Ştefan , Salcher Michaela M , Mehrshad Maliheh , Rychtecký Pavel , Znachor Petr , Ghai Rohit
Published: January 2019

Freshwater environments teem with microbes that do not have counterparts in culture collections or genetic data available in genomic repositories. Currently, our apprehension of evolutionary ecology of freshwater bacteria is hampered by the difficulty to establish organism models for the most representative clades. To circumvent the bottlenecks inherent to the cultivation-based techniques, we applied ecogenomics approaches in order to unravel the evolutionary history and the processes that drive genome architecture in hallmark freshwater lineages from the phylum Planctomycetes. The evolutionary history inferences showed that sediment/soil Planctomycetes transitioned to aquatic environments, where they gave rise to new freshwater-specific clades. The most abundant lineage was found to have the most specialised lifestyle (increased regulatory genetic circuits, metabolism tuned for mineralization of proteinaceous sinking aggregates, psychrotrophic behaviour) within the analysed clades and to harbour the smallest freshwater Planctomycetes genomes, highlighting a genomic architecture shaped by niche-directed evolution (through loss of functions and pathways not needed in the newly acquired freshwater niche).
Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study
Authors: Kaufman Jonathan L. , Mina Roberto , Jakubowiak Andrzej J. , Zimmerman Todd L. , Wolf Jeffrey J. , Lewis Colleen , Gleason Charise , Sharp Cathy , Martin Thomas , Heffner Leonard T. , Nooka Ajay K. , Harvey R. Donald , Lonial Sagar
Published: January 2019

Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m2 (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression. At the MTD, the most common grade 3/4, treatment-related adverse events were thrombocytopenia (41%), fatigue (17%), and nausea/vomiting (12%). The objective response rate (ORR) and clinical benefit rate were 63% and 68%, respectively. Median progression-free survival (PFS) and overall survival (OS) for the entire population were 8 and 23 months, respectively. No differences in terms of ORR (55% vs. 57%), median PFS (months 8 vs. 7 months) and OS (24 vs. 22 months) were observed between bortezomib-sensitive and -refractory patients. CarPan proved to be a safe and effective steroid-sparing regimen in a heavily pre-treated population of MM patients. (Trial registered at ClinicalTrial.gov: NCT01549431)
Oil palm expansion and deforestation in Southwest Cameroon associated with proliferation of informal mills
Authors: Ordway Elsa M. , Naylor Rosamond L. , Nkongho Raymond N. , Lambin Eric F.
Published: January 2019

Oil palm expansion resulted in 2 million hectares (Mha) of forest loss globally in 2000–2010. Despite accounting for 24% (4.5 Mha) of the world’s total oil palm cultivated area, expansion dynamics in sub-Saharan Africa have been overlooked. We show that in Southwest Cameroon, a top producing region of Africa, 67% of oil palm expansion from 2000–2015 occurred at the expense of forest. Contrary to the publicized narrative of industrial-scale expansion, most oil palm expansion and associated deforestation is occurring outside large agro-industrial concessions. Expansion and deforestation carried out by non-industrial producers is occurring near low-efficiency informal mills, unconstrained by the location of high-efficiency company-owned mills. These results highlight the key role of a booming informal economic sector in driving rapid land use change. High per capita consumption and rising palm oil demands in sub-Saharan Africa spotlight the need to consider informal economies when identifying regionally relevant sustainability pathways.
A disinhibitory mechanism biases Drosophila innate light preference
Authors: Zhao Weiqiao , Zhou Peipei , Gong Caixia , Ouyang Zhenhuan , Wang Jie , Zheng Nenggan , Gong Zhefeng
Published: January 2019

Innate preference toward environmental conditions is crucial for animal survival. Although much is known about the neural processing of sensory information, how the aversive or attractive sensory stimulus is transformed through central brain neurons into avoidance or approaching behavior is largely unclear. Here we show that Drosophila larval light preference behavior is regulated by a disinhibitory mechanism. In the disinhibitory circuit, a pair of GABAergic neurons exerts tonic inhibition on one pair of contralateral projecting neurons that control larval reorientation behavior. When a larva enters the light area, the reorientation-controlling neurons are disinhibited to allow reorientation to occur as the upstream inhibitory neurons are repressed by light. When the larva exits the light area, the inhibition on the downstream neurons is restored to repress further reorientation and thus prevents the larva from re-entering the light area. We suggest that disinhibition may serve as a common neural mechanism for animal innate preference behavior.
Long-term functional and structural preservation of precision-cut human myocardium under continuous electromechanical stimulation in vitro
Authors: Fischer Carola , Milting Hendrik , Fein Evelyn , Reiser Elisabeth , Lu Kun , Seidel Thomas , Schinner Camilla , Schwarzmayr Thomas , Schramm Rene , Tomasi Roland , Husse Britta , Cao-Ehlker Xiaochun , Pohl Ulrich , Dendorfer Andreas
Published: January 2019

In vitro models incorporating the complexity and function of adult human tissues are highly desired for translational research. Whilst vital slices of human myocardium approach these demands, their rapid degeneration in tissue culture precludes long-term experimentation. Here, we report preservation of structure and performance of human myocardium under conditions of physiological preload, compliance, and continuous excitation. In biomimetic culture, tissue slices prepared from explanted failing human hearts attain a stable state of contractility that can be monitored for up to 4 months or 2000000 beats in vitro. Cultured myocardium undergoes particular alterations in biomechanics, structure, and mRNA expression. The suitability of the model for drug safety evaluation is exemplified by repeated assessment of refractory period that permits sensitive analysis of repolarization impairment induced by the multimodal hERG-inhibitor pentamidine. Biomimetic tissue culture will provide new opportunities to study drug targets, gene functions, and cellular plasticity in adult human myocardium.
Post-exposure immunotherapy for two ebolaviruses and Marburg virus in nonhuman primates
Authors: Brannan Jennifer M. , He Shihua , Howell Katie A. , Prugar Laura I. , Zhu Wenjun , Vu Hong , Shulenin Sergey , Kailasan Shweta , Raina Henna , Wong Gary , Rahim Md Niaz , Banadyga Logan , Tierney Kevin , Zhao Xuelian , Li Yuxing , Holtsberg Frederick W. , Dye John M. , Qiu Xiangguo , Aman M. Javad
Published: January 2019

The 2013–2016 Ebola virus (EBOV) disease epidemic demonstrated the grave consequences of filovirus epidemics in the absence of effective therapeutics. Besides EBOV, two additional ebolaviruses, Sudan (SUDV) and Bundibugyo (BDBV) viruses, as well as multiple variants of Marburg virus (MARV), have also caused high fatality epidemics. Current experimental EBOV monoclonal antibodies (mAbs) are ineffective against SUDV, BDBV, or MARV. Here, we report that a cocktail of two broadly neutralizing ebolavirus mAbs, FVM04 and CA45, protects nonhuman primates (NHPs) against EBOV and SUDV infection when delivered four days post infection. This cocktail when supplemented by the anti-MARV mAb MR191 exhibited 100% efficacy in MARV-infected NHPs. These findings provide a solid foundation for clinical development of broadly protective immunotherapeutics for use in future filovirus epidemics.
Bifurcation-based embodied logic and autonomous actuation
Authors: Jiang Yijie , Korpas Lucia M. , Raney Jordan R.
Published: January 2019

Many plants autonomously change morphology and function in response to environmental stimuli or sequences of stimuli. In contrast with the electronically-integrated sensors, actuators, and microprocessors in traditional mechatronic systems, natural systems embody these sensing, actuation, and control functions within their compositional and structural features. Inspired by nature, we embody logic in autonomous systems to enable them to respond to multiple stimuli. Using 3D printable fibrous composites, we fabricate structures with geometries near bifurcation points associated with a transition between bistability and monostability. When suitable stimuli are present, the materials swell anisotropically. This forces a key geometric parameter to pass through a bifurcation, triggering rapid and large-amplitude self-actuation. The actuation time can be programmed by varying structural parameters (from 0.6 to 108 s for millimeter-scale structures). We demonstrate this bioinspired control strategy with examples that respond to their environment according to their embodied logic, without electronics, external control, or tethering.
Phase self-aligned continuous-variable measurement-device-independent quantum key distribution
Authors: Yin Hua-Lei , Zhu Wei , Fu Yao
Published: January 2019

Continuous-variable measurement-independent-device quantum key distribution (CV-MDI-QKD) can offer high secure key rate at metropolitan distance and remove all side channel loopholes of detection as well. However, there is no in-field experimental demonstration of CV-MDI-QKD due to the remote distance phase-locking techniques challenge. Here, we present a new optical scheme to overcome this difficulty and also removes the requirement of two identical independent lasers. Furthermore, we give an alternate but detailed proof of the minimized key rate condition to extract the secure key rate. We anticipate that our new scheme can be used to demonstrate the in-field CV-MDI-QKD experiment and build the CV-MDI-QKD network with untrusted source.
Pangenome of Serratia marcescens strains from nosocomial and environmental origins reveals different populations and the links between them
Authors: Abreo Eduardo , Altier Nora
Published: January 2019

Serratia marcescensis a Gram-negative bacterial species that can be found in a wide range of environments like soil, water and plant surfaces, while it is also known as an opportunistic human pathogen in hospitals and as a plant growth promoting bacteria (PGPR) in crops. We have used a pangenome-based approach, based on publicly available genomes, to apply whole genome multilocus sequence type schemes to assess whether there is an association between source and genotype, aiming at differentiating between isolates from nosocomial sources and the environment, and between strains reported as PGPR from other environmental strains. Most genomes from a nosocomial setting and environmental origin could be assigned to the proposed nosocomial or environmental MLSTs, which is indicative of an association between source and genotype. The fact that a few genomes from a nosocomial source showed an environmental MLST suggests that a minority of nosocomial strains have recently derived from the environment. PGPR strains were assigned to different environmental types and clades but only one clade comprised strains accumulating a low number of known virulence and antibiotic resistance determinants and was exclusively from environmental sources. This clade is envisaged as a group of promissory MLSTs for selecting prospective PGPR strains.
Induced cross-resistance of BRAFV600E melanoma cells to standard chemotherapeutic dacarbazine after chronic PLX4032 treatment
Authors: Erdmann Sarah , Seidel Diana , Jahnke Heinz-Georg , Eichler Marie , Simon Jan-Christoph , Robitzki Andrea A.
Published: January 2019

The maximum response and 10-year survival rate for metastatic melanoma patients treated with standardised chemotherapy is still less than 15% and 10%, respectively. In contrast, oncogene targeting was found a promising tool for killing of BRAFV600 mutated melanoma cells. Nevertheless, despite improved response and survival rates, resistance acquisition remains an ongoing problem. In this context, the impact of chronic BRAF inhibition on the efficacy of commonly applied cytostatics is still unknown. In our study, human melanoma cells with BRAFV600E mutation were treated with chemotherapeutics and a BRAF inhibitor. Resistance patterns were analysed by microelectrode array-based impedance spectroscopy, XTT and flow cytometric apoptosis/proliferation assay. BRAFV600E melanoma cells acquired a time- and concentration-dependent desensitisation up to 100-fold towards oncogene-specific PLX4032 and chemotherapeutic dacarbazine after twelve months treatment. The impact of multiple drug insensitivity on molecular melanoma characteristics was elaborated via mRNA and protein quantification. Following BRAFV600E targeting, melanoma cells developed an increasingly aggressive, dacarbazine-insensitive phenotype. Thereby, hyperactivated canonical alternative MAPK and bypass PI3K/AKT signalling caused cross-resistance of differently acting drugs. With these results, we are the first to show that long-term melanoma therapy with BRAF inhibitors can prevent further therapeutic success with dacarbazine due to acquisition of cross-resistance.
Nickel-catalyzed remote and proximal Wacker-type oxidation
Authors: Liu Binbin , Hu Penghui , Xu Fangning , Cheng Lu , Tan Mingxi , Han Wei
Published: January 2019

Wacker oxidation chemistry is widely applied to oxidation of olefins to carbonyls in the synthesis of pharmaceuticals, natural products, and commodity chemicals. However, in this chemistry efficient oxidation of internal olefins and highly selective oxidation of unbiased internal olefins without reliance upon suitable coordinating groups have remained significant challenges. Here we report a nickel-catalyzed remote Wacker-type oxidation where reactions occur at remote and less-reactive sp3 C–H sites in the presence of a priori more reactive ones through a chain-walking mechanism with excellent regio- and chemo- selectivity. This transformation has attractive features including the use of ambient air as the sole oxidant, naturally-abundant nickel as the catalyst, and polymethylhydrosiloxane as the hydride source at room temperature, allowing for effective oxidation of challenging olefins. Notably, this approach enables direct access to a broad array of complex, medicinally relevant molecules from structurally complex substrates and chemical feedstocks.
Total glycerol analysis in biodiesel samples using solid phase extraction coupled with enzymatic-spectrophotometric determination
Authors: Muniz Renan de Oliveira , Martins Sheila Barbosa , Honório Gláucio Gualtieri , da Cunha Jéssica Nogueira , de Souza Cristiane Gimenes , de Andrade Débora França , Pradelle Renata Norah Chaar , Turkovics Franck , Neto Rafael Serralvo , d'Avila Luiz Antonio , D'Elia Eliane
Published: January 2019

In this work, a method was developed for the quantification of total glycerol in biodiesel using solid phase extraction (SPE) coupled with enzymatic-spectrophotometric determination.
The hydrogen atom transfer reactivity of a porphyrinoid cobalt superoxide complex
Authors: Sacramento Jireh Joy D. , Goldberg David P.
Published: January 2019

The H-atom transfer reactivity of a porphyrinoid cobalt superoxide complex with weak O–H and N–H substrates has been demonstrated.
High proton conduction in an excellent water-stable gadolinium metal–organic framework
Authors: Xing Xiu-Shuang , Fu Zhi-Hua , Zhang Ning-Ning , Yu Xiao-Qing , Wang Ming-Sheng , Guo Guo-Cong
Published: January 2019

Proton conductivity of a new gadolinium(iii) metal–organic framework, is among the highest values for proton-conducting MOFs.
Isolation of U(ii) compounds using strong donor ligands, C5Me4H and N(SiMe3)2, including a three-coordinate U(ii) complex
Authors: Ryan Austin J. , Angadol Mary A. , Ziller Joseph W. , Evans William J.
Published: January 2019

New examples of uranium in the +2 oxidation state have been isolated by reduction of Cptet3U (Cptet = C5Me4H) and U(NR2)3 (R = SiMe3). Results show that more donating ligands as well as lower coordination number complexes are viable for U(ii) and suggest new targets for An(ii) complexes involving Np, Pu, and Am.
Trastuzumab gold-conjugates: synthetic approach and in vitro evaluation of anticancer activities in breast cancer cell lines
Authors: Curado Natalia , Dewaele-Le Roi Guillaume , Poty Sophie , Lewis Jason S. , Contel Maria
Published: January 2019

Trojan horse based design affords antibody gold conjugates containing linkers that display HER2-mediated toxicity in breast cancer cell lines.
Light-mediated copper-catalyzed phosphorus/halogen exchange in 1,1-difluoroalkylphosphonium salts
Authors: Panferova Liubov I. , Levin Vitalij V. , Struchkova Marina I. , Dilman Alexander D.
Published: January 2019

Phosphorus/halogen exchange in fluorinated phosphonium salts is promoted by light and catalyzed by copper(i) halides.
New half-sandwich ruthenium(ii) complexes as proteosynthesis inhibitors in cancer cells
Authors: Ballester Francisco J. , Ortega Enrique , Porto Vanesa , Kostrhunova Hana , Davila-Ferreira Nerea , Bautista Delia , Brabec Viktor , Domínguez Fernando , Santana M. Dolores , Ruiz José
Published: January 2019

New Ru(ii) arene anticancer complexes with a non-coordinated CHO group that are able to inhibit the protein synthesis; this is a new mode of action for half-sandwich metal complexes.
Directing GDNF-mediated neuronal signaling with proactively programmable cell-surface saccharide-free glycosaminoglycan mimetics
Authors: Cai Shuting , Lukamto Daniel H. , Toh Jerry K. C. , Huber Roland G. , Bond Peter J. , Jee Joo-Eun , Lim Teck Chuan , Liu Pei , Chen Liwei , Qu Qianqian Vicky , Lee Su Seong , Lee Song-Gil
Published: January 2019

We report tailorable glycocalyx engineering where {Z}12 imparts the recruitment of GDNF to the cell surface and promotes GDNF-mediated neuronal differentiation.
Atomic zinc dispersed on graphene synthesized for active CO2fixation to cyclic carbonates
Authors: Wang Congwei , Song Qingwen , Zhang Kan , Liu Ping , Wang Junying , Wang Jianmei , Zhang Hengxuan , Wang Junzhong
Published: January 2019

Zn based single atom catalyst could boost the CO2fixation to cyclic carbonates both economically and environmentally.
Iron gall ink revisited: hierarchical formation of Fe(iii)–tannic acid coacervate particles in microdroplets for protein condensation
Authors: Kim Beom Jin , Lee Jungkyu K. , Choi Insung S.
Published: January 2019

We report a hierarchical self-assembly approach to form Fe(iii)–tannic acid particles in microdroplets and its application to protein condensation.
Pressure-induced thermoelectric properties of strongly reduced titanium oxides
Authors: Liu Haiqiang , Ma Hongan , Chen Lixue , Wang Fei , Liu Baomin , Chen Jiaxiang , Ji Guangyao , Zhang Yuewen , Jia Xiaopeng
Published: January 2019

This is the first systematic investigations about thermoelectric properties of strongly reduced titanium oxides, accomplished by high-pressure and high-temperature method.
Modulating the intrinsic reactivity of molecules through non-covalent interactions
Authors: Montero-Campillo M. Merced , Brea Oriana , Mó Otilia , Alkorta Ibon , Elguero José , Yáñez Manuel
Published: January 2019

Non-covalent interactions as tools for modifying molecular properties.
Unexpected trends in the hydrophobicity of fluorinated amino acids reflect competing changes in polarity and conformation
Authors: Robalo João R. , Vila Verde Ana
Published: January 2019

The hydration free energy of fluorinated amino acids is calculated with molecular simulations and explained with an analytical model.