bluuebunny/crossref_metadata_2025 huggingface dataset:
A systematic review of treatments for alcohol-related cognitive impairment: lessons from the past and gaps for future interventions
Authors: Caballeria Elsa , Oliveras Clara , Nuño Laura , Balcells-Oliveró Mercedes , Gual Antoni , López-Pelayo Hugo
Published: August 2020

Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol dependence. Although it negatively influences treatment outcome, this condition is underdiagnosed and undertreated. The aim of this systematic review is to investigate the existing evidence regarding both cognitive and pharmacological interventions for ARCI. We systematically reviewed PubMed, Scopus and Science direct databases up to May 2019 and followed the PRISMA guidelines. The quality of the studies was assessed using the Jadad Scale. Twenty-six studies were eligible for inclusion (14 referring to neuropsychological interventions and 12 to pharmacological treatments). Among neuropsychological interventions, computerised treatments, errorless learning and component method showed positive effects on working memory, memory measures and general cognitive function. On the other hand, thiamine, memantine and methylphenidate improved working memory, long-term memory and general cognitive function. Nevertheless, these studies have several limitations, such as small sample size, lack of replication of the results or low specificity of the interventions. Therefore, no gold-standard intervention can yet be recommended for clinical practice, and further research based on promising strategies (e.g. digital interventions, thiamine) is required.
‘It gives you a reason to be in this world’: the interdependency of communities, environments and social justice for quality of life in older people
Authors: Robertson Jane M. , Gibson Grant , Greasley-Adams Corinne , McCall Vikki , Gibson Joan , Mason-Duff Janice , Pengelly Ro
Published: August 2020

Research regarding quality of life among older people has predominantly focused on functional elements experienced at individual or dyadic level despite the complex interplay of factors that contribute to quality of life. Perspectives which explore interdependencies within communities and the intersecting environments in which older people exercise agency have seen less study. They do, however, play an important role in influencing quality of life as experienced by older people across community settings. Qualitative data from a co-produced study of dimensions influencing quality of life in older people was subjected to secondary analysis using a critical human ecological approach. Findings demonstrate the importance of community interdependencies in supporting individual quality of life, the expression of active agency to foster quality of life within and across communities, and the importance of state infrastructures and service provision within these interdependencies. This article argues for a movement beyond functional conceptualisations of quality of life towards the inclusion of perspectives regarding communal wellbeing, alongside the role differing types of community play in influencing quality of life. Through developing conceptions of quality of life in social relations and community cohesion, in particular how quality of life is influenced by perceptions of solidarity and social justice including across generations, assessing quality of life at community level will assist in driving cultural change in policy making and practice.
Sentinel surveillance strategies for early detection of coronavirus disease in fever clinics: experience from China
Authors: Lai Rongtao , Chen Erzhen , Gao Weiyi , Cheng Chengwei , Xie Qing
Published: August 2020

Sentinel surveillance system plays a key role in screening and monitoring emerging and acute infectious diseases in order to identify the suspected cases in time. During SARS period in 2003, fever clinics emerged in many cities in mainland China with the purpose to screen the suspected SARS patients and to transfer the confirmed cases to designated hospitals for professional management. Shanghai city has reserved the fever clinics and the designated hospitals since then. Hence, clinicians in the front line are able to respond quickly to the emerging COVID-19 outbreak with their accumulated knowledge and experiences from the past. One hundred seventeen fever clinics distributed in various district areas in Shanghai have played a vital ‘sentinel’ role to fight against the COVID-19 epidemic. Most of suspected patients were identified in fever clinics and thereafter among these suspected patients the COVID-19 cases were confirmed and were isolated quickly to avoid the spread. We would like to share the sentinel roadmap for screening and diagnosis of COVID-19 to medical healthcare workers around the world, especially countries who are facing great challenges to cope with COVID-19 and meanwhile with limited medical resources. These sentinel surveillance strategies will certainly provide insight into the early detection and timely isolation of suspected cases from the others.
A TWO-DIMENSIONAL LOGIC FOR TWO PARADOXES OF DEONTIC MODALITY
Authors: FUSCO MELISSA , KOCUREK ALEXANDER W.
Published: August 2020

In this paper, we axiomatize the deontic logic in Fusco (2015), which uses a Stalnaker-inspired account of diagonal acceptance and a two-dimensional account of disjunction to treat Ross’s Paradox and the Puzzle of Free Choice Permission. On this account, disjunction-involving validities are a priori rather than necessary. We show how to axiomatize two-dimensional disjunction so that the introduction/elimination rules for boolean disjunction can be viewed as one-dimensional projections of more general two-dimensional rules. These completeness results help make explicit the restrictions Fusco’s account must place on free-choice inferences. They are also of independent interest, as they raise difficult questions about how to “lift” a Kripke frame for a one-dimensional modal logic into two dimensions.
Vertical mobility and cotton tolerance to trifludimoxazin, a new protoporphyrinogen oxidase-inhibiting herbicide, in three West Texas soils
Authors: Asher B. Scott , Dotray Peter A. , Liebl Rex A. , Keeling J. Wayne , Ritchie Glen D. , Udeigwe Theophilus K. , Reed Jacob D. , Keller Kyle E. , Bowe Steve J. , Aldridge Ryan B. , Simon Anja
Published: August 2020

Trifludimoxazin, a new protoporphyrinogen oxidase–inhibiting herbicide, is being evaluated for possible use as a soil-residual active herbicide treatment in cotton for control of small-seeded annual broadleaf weeds. Laboratory and greenhouse studies were conducted to compare vertical mobility and cotton tolerance of trifludimoxazin to flumioxazin and saflufenacil, which are two currently registered protoporphyrinogen oxidase–inhibiting herbicides for use in cotton, in three West Texas soils. Vertical soil mobility of trifludimoxazin was similar to flumioxazin in Acuff loam and Olton loam soils, but was more mobile than flumioxazin in the Amarillo loamy sand soil. The depth of trifludimoxazin movement after a 2.5-cm irrigation event ranged from 2.5 to 5.0 cm in all soils, which would not allow for crop selectivity based on herbicide placement, because ideal cotton seeding depth is from 0.6 to 2.54 cm deep. Greenhouse studies indicated that PRE treatments were more injurious than the 14 d preplant treatment when summarized across soils for the three herbicides (43% and 14% injury, respectively). No differences in visual cotton response or dry weight was observed after trifludimoxazin preplant as compared with the nontreated control within each of the three West Texas soils and was similar to the flumioxazin preplant across soils. On the basis of these results, a use pattern for trifludimoxazin in cotton may be established with the use of a more than 14-d preplant restriction before cotton planting.
Forecasting Global Fire Emissions on Subseasonal to Seasonal (S2S) Time Scales
Authors: Chen Yang , Randerson James T. , Coffield Shane R. , Foufoula‐Georgiou Efi , Smyth Padhraic , Graff Casey A. , Morton Douglas C. , Andela Niels , van der Werf Guido R. , Giglio Louis , Ott Lesley E.
Published: August 2020

Fire emissions of gases and aerosols alter atmospheric composition and have substantial impacts on climate, ecosystem function, and human health. Warming climate and human expansion in fire‐prone landscapes exacerbate fire impacts and call for more effective management tools. Here we developed a global fire forecasting system that predicts monthly emissions using past fire data and climate variables for lead times of 1 to 6 months. Using monthly fire emissions from the Global Fire Emissions Database (GFED) as the prediction target, we fit a statistical time series model, the Autoregressive Integrated Moving Average model with eXogenous variables (ARIMAX), in over 1,300 different fire regions. Optimized parameters were then used to forecast future emissions. The forecast system took into account information about region‐specific seasonality, long‐term trends, recent fire observations, and climate drivers representing both large‐scale climate variability and local fire weather. We cross‐validated the forecast skill of the system with different combinations of predictors and forecast lead times. The reference model, which combined endogenous and exogenous predictors with a 1 month forecast lead time, explained 52% of the variability in the global fire emissions anomaly, considerably exceeding the performance of a reference model that assumed persistent emissions during the forecast period. The system also successfully resolved detailed spatial patterns of fire emissions anomalies in regions with significant fire activity. This study bridges the gap between the efforts of near‐real‐time fire forecasts and seasonal fire outlooks and represents a step toward establishing an operational global fire, smoke, and carbon cycle forecasting system.
Challenges in Specifying and Predicting Space Weather
Authors: Schunk R. W. , Scherliess L. , Eccles V. , Gardner L. C. , Sojka J. J. , Zhu L. , Pi X. , Mannucci A. J. , Komjathy A. , Wang C. , Rosen G.
Published: August 2020

Physics‐based Data Assimilation (DA) has been shown to be a powerful technique for specifying and predicting space weather. However, it is also known that different data assimilation models simulating the same geophysical event can display different space weather features even if the same data are assimilated. In this study, we used our Multimodel Ensemble Prediction System (MEPS) of DA models to elucidate the similarities and differences in the individual DA model reconstructions of the mid‐low latitude ionosphere when the same data are assimilated. Ensemble model averages were also obtained. For this ensemble modeling study, we selected the quiet/storm period of 16 and 17 March 2013 (equinox, solar medium). Five data assimilation models and one physics‐based model were used to produce an ensemble mean output for Total Electron Content (TEC), ionospheric peak density (NmF2), and ionospheric peak height (hmF2) for latitudes less than 60° and all longitudes. The data assimilated included ground‐based Global Positioning Satellite TEC and topside plasma densities near 800 km altitude derived from the COSMIC (Constellation Observing System for Meteorology, Ionosphere, and Climate) satellites. Both a simple average and a weighted average of the models were used in the ensemble averaging in order to determine if there was an improvement of the ensemble averages over the individual models.
Long‐Term Shifts in U.S. Nitrogen Sources and Sinks Revealed by the New TREND‐Nitrogen Data Set (1930–2017)
Authors: Byrnes D. K. , Van Meter K. J. , Basu N. B.
Published: August 2020

Reactive nitrogen (N) fluxes have increased tenfold over the last century, driven by increases in population, shifting diets, and increased use of commercial N fertilizers. Runoff of excess N from intensively managed landscapes threatens drinking water quality and disrupts aquatic ecosystems. Excess N is also a major source of greenhouse gas emissions from agricultural soils. While N emissions from agricultural landscapes are known to originate from not only current‐year N input but also legacy N accumulation in soils and groundwater, there has been limited access to fine‐scale, long‐term data regarding N inputs and outputs over decades of intensive agricultural land use. In the present work, we synthesize population, agricultural, and atmospheric deposition data to develop a comprehensive, 88‐year (1930–2017) data set of county‐scale components of the N mass balance across the contiguous United States (Trajectories Nutrient Dataset for nitrogen [TREND‐nitrogen]). Using a machine‐learning algorithm, we also develop spatially explicit typologies for components of the N mass balance. Our results indicate a large range of N trajectory behaviors across the United States due to differences in land use and management and particularly due to the very different drivers of N dynamics in densely populated urban areas compared with intensively managed agricultural zones. Our analysis of N trajectories also demonstrates a widespread functional homogenization of agricultural landscapes. This newly developed typology of N trajectories improves our understanding of long‐term N dynamics, and the underlying data set provides a powerful tool for modeling the impacts of legacy N on past, present, and future water quality.
Topside Ionosphere of NeQuick2 and IRI‐2016 Validated by Using Onboard GPS Observations From Multiple LEO Satellites
Authors: Ren Xiaodong , Chen Jun , Zhang Xiaohong , Yang Pengxin
Published: August 2020

An accurate description of the topside ionosphere is of great importance for space weather applications. Currently, there are two commonly used empirical ionosphere models, that is, NeQuick2 and IRI‐2016, that can be used to describe the topside ionosphere. In this study, topside total electron content (TEC) values derived from low Earth orbit (LEO) satellites are selected to validate the topside ionosphere predictions of the NeQuick2 and IRI‐2016 models from 2008 to 2018. The results show that these two models both underestimate the topside ionosphere. Compared with the global topside ionosphere model estimated by LEO‐based global positioning system (GPS) observations with orbital altitudes of 500 and 800 km, NeQuick2 and IRI‐2016 have similar performances over different latitudes and longitudes. The daily mean root mean square (RMS) values are approximately 4.10 and 2.10 TEC units (TECU) for the region above 500 and 800 km, respectively. The results assessed by the GPS‐TEC technique indicate that the performance of the NeQuick2 model is slightly better than that of the IRI‐2016 model. The daily mean bias mainly ranges from −1.5 to 1.5 and −3.0 to −1.0 TECU for the regions above 500 and 800 km, respectively. The RMS values for the corresponding parts are 3.50 and 2.74 TECU. Finally, the validation results of the dSTEC method show that the mean bias is −0.43 and −0.20 TECU above 500 and 800 km, respectively. The mean RMS values are 2.04 and 0.72 TECU for the corresponding regions.
Formation and Topology of Foreshock Bubbles
Authors: Omidi N. , Lee S. H. , Sibeck D. G. , Turner D. L. , Liu T. Z. , Angelopoulos V.
Published: August 2020

We use global and local hybrid (kinetic ions and fluid electrons) simulations to investigate the conditions under which foreshock bubbles (FBs) form and how their topology changes with solar wind conditions. FBs form as a result of the interaction between solar wind discontinuities and backstreaming ion beams in the foreshock. They consist of an outer shock and its associated sheath plasma and a low density high temperature core with low magnetic field strength. The structure of FBs is determined by the angle between the interplanetary magnetic field and the normal to the solar wind discontinuity. We show that interaction of rotational discontinuities with the foreshock during small angles between the interplanetary magnetic field and discontinuity normal results in the formation of a nearly spherical bubble with a radius that scales with the width of the foreshock. As this angle increases, FBs become more elongated and eventually become nearly planar structures with dimensions that scale with the length of the foreshock. Despite this transformation, the signatures of FBs in spacecraft time series data remain the same in agreement with the observations. Global simulation results show that FBs form when the solar wind flow speed corresponds to high or intermediate Alfvén Mach numbers (approximately >7 MA). In general, this is tied to the relative speed between the solar wind and ion beams and drop in density of the backstreaming ions.
Importance of Regional‐Scale Auroral Precipitation and Electrical Field Variability to the Storm‐Time Thermospheric Temperature Enhancement and Inversion Layer (TTEIL) in the Antarctic E Region
Authors: Wu Haonan , Lu Xian , Lu Gang , Chu Xinzhao , Wang Wenbin , Yu Zhibin , Kilcommons Liam M. , Knipp Delores J. , Wang Boyi , Nishimura Yukitoshi
Published: August 2020

A dramatic thermospheric temperature enhancement and inversion layer (TTEIL) was observed by the Fe Boltzmann lidar at McMurdo, Antarctica during a geomagnetic storm (Chu et al. 2011, https://doi.org/10.1029/2011GL050016). The Thermosphere‐Ionosphere‐Electrodynamics General Circulation Model (TIEGCM) driven by empirical auroral precipitation and background electric fields cannot adequately reproduce the TTEIL. We incorporate the Defense Meteorological Satellite Program (DMSP)/Special Sensor Ultraviolet Spectrographic Imager (SSUSI) auroral precipitation maps, which capture the regional‐scale features into TIEGCM and add subgrid electric field variability in the regions with strong auroral activity. These modifications enable the simulation of neutral temperatures closer to lidar observations and neutral densities closer to GRACE satellite observations (~475 km). The regional scale auroral precipitation and electric field variabilities are both needed to generate strong Joule heating that peaks around 120 km. The resulting temperature increase leads to the change of pressure gradients, thus inducing a horizontal divergence of air flow and large upward winds that increase with altitude. Associated with the upwelling wind is the adiabatic cooling gradually increasing with altitude and peaking at ~200 km. The intense Joule heating around 120 km and strong cooling above result in differential heating that produces a sharp TTEIL. However, vertical heat advection broadens the TTEIL and raises the temperature peak from ~120 to ~150 km, causing simulations deviating from observations. Strong local Joule heating also excites traveling atmospheric disturbances that carry the TTEIL signatures to other regions. Our study suggests the importance of including fine‐structure auroral precipitation and subgrid electric field variability in the modeling of storm‐time ionosphere‐thermosphere responses.
Transition of Low Clouds in the East China Sea and Kuroshio Region in Winter: A Regional Atmospheric Model Study
Authors: Long Jingchao , Wang Yuqing , Zhang Suping , Liu Jingwu
Published: August 2020

Bias in simulating the stratocumulus‐to‐cumulus transition remains a main source of uncertainties in climate projection and can significantly affect the energy budget in climate models. To gain insights into the transition, this study investigates the cloud transition forced by the sea surface temperature (SST) front and synoptic disturbances in the East China Sea and Kuroshio region in winter based on both observations and regional atmospheric model simulations. The Kuroshio SST front greatly accelerates cloud transition by enhancing surface latent heat flux, marine atmospheric boundary layer (MABL) dynamical adjustment, and cloud top entrainment. With the sharp SST increase from the cold flank to the Kuroshio SST warm tongue (KWT), surface wind convergence (SWC) over the KWT induced by the SST front and synoptic disturbances enhances the coupling between the cloud layer and subcloud layer. An underlying positive feedback between the SWC and latent heating in the cloud layer can enhance abrupt change in cloud properties and maintain cloud band over the KWT against the decoupling through the so‐called “Deepening‐Warming” mechanism induced by latent heating. From the KWT downwind southward, the surface layer turbulent mixing weakens, while latent heating in the cloud layer and cloud top longwave radiative cooling enhance buoyancy and vertical mixing in the cloud layer. This difference in vertical mixing between the cloud layer and subcloud layer facilitates the MABL decoupling and impedes upward moisture transport. Meanwhile, decreasing lower tropospheric stability is conducive to the entrainment of drier and warmer air from above into the cloud layer, strengthening cloud evaporation.
Hydrometeor Size Sorting in the Asymmetric Eyewall of Hurricane Matthew (2016)
Authors: Laurencin Chelsey N. , Didlake Anthony C. , Loeffler Scott D. , Kumjian Matthew R. , Heymsfield Gerald M.
Published: August 2020

Polarimetric radar observations of Hurricane Matthew's asymmetric eyewall were captured by WSR‐88D radars from 1500 UTC on 7 October 2016 to 0000 UTC on 8 October 2016. Raindrop size sorting was observed within the eyewall, marked by a differential reflectivity (ZDR) enhancement region situated upwind of a specific differential phase (KDP) enhancement region, both overlapping the maximum reflectivity. This signature indicated that the largest raindrops fell out of the eyewall updrafts faster than the smaller, abundant drops that were advected further downstream by the primary circulation. Airborne Doppler radar observations revealed an updraft structure in an azimuthal location consistent with the size‐sorting signature and previous observational studies of eyewall kinematic asymmetries.

Given that a tropical cyclone's environment or internal dynamics can modulate the eyewall's kinematic and microphysical structure, we used a simple size‐sorting model that only includes sedimentation and advection of raindrops by the axisymmetric tangential wind to examine how an eyewall size‐sorting signature responds to artificial changes in the tangential wind speed and initial raindrop size distributions (DSDs). The axisymmetric tangential wind was retrieved from WSR‐88D radar observations using the Ground‐Based Velocity Track Display technique. The simple model was capable of producing an eyewall size‐sorting signature with an azimuthal separation between the simulated ZDR and KDP enhancements in general agreement with the observed separation (~20°) at low levels. Sensitivity tests showed that the azimuthal separation between the ZDR and KDP enhancements responded to changes in the tangential wind speed, but not to changes in the initial DSDs aloft.
The Surface Warming Attributable to Stratospheric Water Vapor in CO2‐Caused Global Warming
Authors: Wang Yuwei , Huang Yi
Published: August 2020

Stratospheric water vapor (SWV) is recognized as a potentially important positive feedback in global warming. The SWV change induces significant downward radiative flux perturbation at the tropopause and therefore is hypothesized to substantially amplify the surface warming. To test this hypothesis, we use a global climate model to quantify the surface warming contributed by the SWV change in the context of the quadrupled CO2. By prescribing the SWV increase as an external forcing, we find that SWV only accounts for 0.42 K surface warming, making up merely 5.4% of the total CO2‐caused surface warming (7.7 K). The efficacy of the stratosphere‐adjusted SWV forcing is small (38%), where the efficacy is defined as the ratio of the global temperature response per unit radiative forcing relative to that of the CO2 forcing. With the aid of a series of auxiliary experiments, we find that although the stratosphere‐adjusted SWV forcing at the top of atmosphere (TOA) is significant (1.13 W m−2), more than half of the forcing is offset by a high‐cloud decrease and an upper tropospheric warming in the tropospheric adjustment. The direct radiative impact of the SWV increase on surface temperature is negligible, and the SWV‐induced surface temperature change is a result of interactions between the radiative and nonradiative processes.
Black Carbon Emission and Wet Scavenging From Surface to the Top of Boundary Layer Over Beijing Region
Authors: Liu Dantong , Ding Shuo , Zhao Delong , Hu Kang , Yu Chenjie , Hu Dawei , Wu Yunfei , Zhou Chang , Tian Ping , Liu Quan , Wu Yangzhou , Zhang Jiale , Kong Shaofei , Huang Mengyu , Ding Deping
Published: August 2020

The heating impacts caused by black carbon (BC) may modify the atmospheric dynamics of planetary boundary layer (PBL), essentially determined by its vertical distribution. In this study we performed simultaneous measurements of detailed BC properties at both surface (50 m) and mountain sites (1,344 m) over Beijing region. The latter represents the top of PBL and was influenced by surface anthropogenic emissions, particularly around midday when PBL was developed, allowing continuous investigations on the evolution of BC during vertical transport in the PBL. Experiments in cold and warm seasons were performed to reflect seasonal difference in emission and meteorology: Winter had additional emission of residential heating and dry air; summer had moist air with more precipitation. The net ratio of BC/CO relative to background (ΔBC/ΔCO) is used to indicate the emission signature and scavenging of BC. At surface, both seasons peaked at similar ΔBC/ΔCO, however showed contrast shifts between both sites. In winter, mountain showed slightly higher ΔBC/ΔCO than surface due to receiving sources from wider area, whereas in summer, a refractory black carbon (rBC) mass scavenging efficiency of 35–62% was derived from the significantly lowered ΔBC/ΔCO on mountain. This scavenging process could incorporate BC into the summer moist air or low‐level clouds on a daily basis, exerting potential indirect effects. The resultant BC after scavenging exhibited smaller core size and increased coatings, leading to higher absorption efficiency by 45%. These factors should improve the representation of boundary layer processing of BC in evaluating its direct and indirect radiative impacts over the anthropogenically influenced region.
IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas
Authors: Wang Qing , Zhang Yan , Zhu Jiang , Zheng Honggang , Chen Shuntai , Chen Li , Yang Hsin-Sheng
Published: August 2020

The insulin-like growth factor 1 receptor (IGF-1R) governs several signaling pathways for cell proliferation, survival, and anti-apoptosis. Thus, targeting IGF-1R appears as a reasonable rationale for tumor treatment. However, clinical studies showed that inhibition of IGF-1R has very limited efficacy due to the development of resistance to IGF-1R blockade in tumor cells. Here, we discovered that prolonged treatment of colon cancer cells with IGF-1R inhibitors (BMS-754807 and GSK1838705A) stimulates p70 KDa ribosomal protein S6 kinase 1 (p70S6K1) activation, a well-known kinase signaling for cell survival. We also found that p70S6K1 activation by IGF-1R inhibition is independent of K-Ras and PIK3CA mutations that frequently occur in colon cancer. Besides the increased p70S6K1 phosphorylation, the phosphorylation of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) was elevated in the cells treated with BMS-754807. Interestingly, the increases in MEK1/2 and p70S6K1 phosphorylation were also observed when cells were subjected to the treatment of AKT inhibitor or genetic knockdown of AKT2 but not AKT1, suggesting that AKT2 inhibition stimulates MEK1/2 phosphorylation to activate p70S6K1. Conversely, inhibition of MEK1/2 by MEK1/2 inhibitor (U0126) or knockdown of MEK1 and MEK2 by corresponding mek1 and mek2 siRNA enhanced AKT phosphorylation, indicating mutual inhibition between AKT and MEK. Furthermore, the combination of BMS-754807 and U0126 efficiently decreased the cell viability and increased cleaved caspase 3 and apoptosis in vitro and in vivo. Our data suggest that the treatment of colon tumor cells with IGF-1R inhibitors stimulates p70S6K1 activity via MEK1/2 to promote survival, providing a new strategy for colorectal cancer therapeutics.
Author Correction: Machine-learned impurity level prediction for semiconductors: the example of Cd-based chalcogenides
Authors: Mannodi-Kanakkithodi Arun , Toriyama Michael Y. , Sen Fatih G. , Davis Michael J. , Klie Robert F. , Chan Maria K. Y.
Published: August 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Inferring clonal composition from multiple tumor biopsies
Authors: Manica Matteo , Kim Hyunjae Ryan , Mathis Roland , Chouvarine Philippe , Rutishauser Dorothea , De Vargas Roditi Laura , Szalai Bence , Wagner Ulrich , Oehl Kathrin , Saba Karim , Pati Arati , Saez-Rodriguez Julio , Roy Angshumoy , Parsons Donald W. , Wild Peter J. , Martínez María Rodríguez , Sumazin Pavel
Published: August 2020

Knowledge about the clonal evolution of a tumor can help to interpret the function of its genetic alterations by identifying initiating events and events that contribute to the selective advantage of proliferative, metastatic, and drug-resistant subclones. Clonal evolution can be reconstructed from estimates of the relative abundance (frequency) of subclone-specific alterations in tumor biopsies, which, in turn, inform on its composition. However, estimating these frequencies is complicated by the high genetic instability that characterizes many cancers. Models for genetic instability suggest that copy number alterations (CNAs) can influence mutation-frequency estimates and thus impede efforts to reconstruct tumor phylogenies. Our analysis suggested that accurate mutation frequency estimates require accounting for CNAs—a challenging endeavour using the genetic profile of a single tumor biopsy. Instead, we propose an optimization algorithm, Chimæra, to account for the effects of CNAs using profiles of multiple biopsies per tumor. Analyses of simulated data and tumor profiles suggested that Chimæra estimates are consistently more accurate than those of previously proposed methods and resulted in improved phylogeny reconstructions and subclone characterizations. Our analyses inferred recurrent initiating mutations in hepatocellular carcinomas, resolved the clonal composition of Wilms’ tumors, and characterized the acquisition of mutations in drug-resistant prostate cancers.
910 metagenome-assembled genomes from the phytobiomes of three urban-farmed leafy Asian greens
Authors: Bandla Aditya , Pavagadhi Shruti , Sridhar Sudarshan Ashwin , Poh Miko Chin Hong , Swarup Sanjay
Published: August 2020

The genome sequences of many microbial species from the phytobiomes of several leafy Asian greens remain unknown. Here, we address this gap by reconstructing 910 prokaryotic draft genomes from 24 leaf, 65 root, 12 soil, and 6 compost metagenomes from the seedling and adult developmental stages of three leafy Asian greens –Brassica rapavar.parachinensis,Brassica oleraceavar.alboglabraandAmaranthusspp. – grown in a commercial, soil-based urban farm. Of these, 128 are near-complete (>90% completeness, <5% redundancy), 540 are substantially complete (≥70% completeness, <10%, redundancy), while the rest have a completeness ≥50% and redundancy <10%. The draft genomes together span 292 bacterial and 3 archaeal species, a subset of which are from underrepresented genus-level lineages in public databases. We expect our dataset to facilitate a wide range of comparative studies that seek to understand the different functional aspects of vegetable crop phytobiomes and for devising new strategies for microbial cultivation in the future.
Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity
Authors: Bonache M.Ángeles , Martín-Escura Cristina , de la Torre Martínez Roberto , Medina Alicia , González-Rodríguez Sara , Francesch Andrés , Cuevas Carmen , Roa Ana María , Fernández-Ballester Gregorio , Ferrer-Montiel Antonio , Fernández-Carvajal Asia , González-Muñiz Rosario
Published: August 2020

The cool sensor transient receptor potential melastatin channel 8 (TRPM8) is highly expressed in trigeminal and dorsal root ganglia, playing a key role in cold hypersensitivity associated to different peripheral neuropathies. Moreover, these channels are aberrantly expressed in different cancers, and seem to participate in tumor progression, survival and invasion. Accordingly, the search for potent and selective TRPM8 modulators attracted great interest in recent years. We describe new heterocyclic TRPM8 antagonist chemotypes derived from N-cloroalkyl phenylalaninol-Phe conjugates. The cyclization of these conjugates afforded highly substituted β-lactams and/or 2-ketopiperazine (KP) derivatives, with regioselectivity depending on the N-chloroalkyl group and the configuration. These derivatives behave as TRPM8 antagonists in the Ca2+ microfluorometry assay, and confirmed electrophysiologically for the best enantiopure β-lactams 24a and 29a (IC50, 1.4 and 0.8 µM). Two putative binding sites by the pore zone, different from those found for typical agonists and antagonists, were identified by in silico studies for both β-lactams and KPs. β-Lactams 24a and 29a display antitumor activity in different human tumor cell lines (micromolar potencies, A549, HT29, PSN1), but correlation with TRPM8 expression could not be established. Additionally, compound 24a significantly reduced cold allodynia in a mice model of oxaliplatin-induced peripheral neuropathy.
Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway
Authors: Zou Zhiyuan V. , Gul Nadia , Lindberg Markus , Bokhari Abdulmalik A. , Eklund Ella M. , Garellick Viktor , Patel Angana A. H. , Dzanan Jozefina J. , Titmuss Ben O. , Le Gal Kristell , Johansson Inger , Tivesten Åsa , Forssell-Aronsson Eva , Bergö Martin O. , Staffas Anna , Larsson Erik , Sayin Volkan I. , Lindahl Per
Published: August 2020

Recent data suggest that the transcription factor Zfp148 represses activation of the tumor suppressor p53 in mice and that therapeutic targeting of the human orthologue ZNF148 could activate the p53 pathway without causing detrimental side effects. We have previously shown that Zfp148 deficiency promotes p53-dependent proliferation arrest of mouse embryonic fibroblasts (MEFs), but the underlying mechanism is not clear. Here, we showed that Zfp148 deficiency downregulated cell cycle genes in MEFs in a p53-dependent manner. Proliferation arrest of Zfp148-deficient cells required increased expression of ARF, a potent activator of the p53 pathway. Chromatin immunoprecipitation showed that Zfp148 bound to the ARF promoter, suggesting that Zfp148 represses ARF transcription. However, Zfp148 preferentially bound to promoters of other transcription factors, indicating that deletion of Zfp148 may have pleiotropic effects that activate ARF and p53 indirectly. In line with this, we found no evidence of genetic interaction between TP53 and ZNF148 in CRISPR and siRNA screen data from hundreds of human cancer cell lines. We conclude that Zfp148 deficiency, by increasing ARF transcription, downregulates cell cycle genes and cell proliferation in a p53-dependent manner. However, the lack of genetic interaction between ZNF148 and TP53 in human cancer cells suggests that therapeutic targeting of ZNF148 may not increase p53 activity in humans.
Immunoinformatic identification of B cell and T cell epitopes in the SARS-CoV-2 proteome
Authors: Crooke Stephen N. , Ovsyannikova Inna G. , Kennedy Richard B. , Poland Gregory A.
Published: August 2020

A novel coronavirus (SARS-CoV-2) emerged from China in late 2019 and rapidly spread across the globe, infecting millions of people and generating societal disruption on a level not seen since the 1918 influenza pandemic. A safe and effective vaccine is desperately needed to prevent the continued spread of SARS-CoV-2; yet, rational vaccine design efforts are currently hampered by the lack of knowledge regarding viral epitopes targeted during an immune response, and the need for more in-depth knowledge on betacoronavirus immunology. To that end, we developed a computational workflow using a series of open-source algorithms and webtools to analyze the proteome of SARS-CoV-2 and identify putative T cell and B cell epitopes. Utilizing a set of stringent selection criteria to filter peptide epitopes, we identified 41 T cell epitopes (5 HLA class I, 36 HLA class II) and 6 B cell epitopes that could serve as promising targets for peptide-based vaccine development against this emerging global pathogen. To our knowledge, this is the first study to comprehensively analyze all 10 (structural, non-structural and accessory) proteins from SARS-CoV-2 using predictive algorithms to identify potential targets for vaccine development.
Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
Authors: Morgan Daniel , Studham Matthew , Tjärnberg Andreas , Weishaupt Holger , Swartling Fredrik J. , Nordling Torbjörn E. M. , Sonnhammer Erik L. L.
Published: August 2020

The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
Risk factors for retinopathy in hemodialysis patients with type 2 diabetes mellitus
Authors: Müller Michael , Schönfeld Carl-Ludwig , Grammer Tanja , Krane Vera , Drechsler Christiane , Genser Bernd , Kohnen Thomas , Wanner Christoph , März Winfried
Published: August 2020

There is limited knowledge on the prevalence and risk factors of diabetic retinopathy (DR) in dialysis patients. We have investigated the association between diabetes mellitus and lipid-related biomarkers and retinopathy in hemodialysis patients. We reviewed 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) who participated in the German Diabetes and Dialysis Study (4D Study). Associations between categorical clinical, biochemical variables and diabetic retinopathy were examined by logistic regression. On average, patients were 66 ± 8 years of age, 54% were male and the HbA1c was 6.7% ± 1.3%. DR, found in 71% of the patients, was significantly and positively associated with fasting glucose, HbA1c, time on dialysis, age, systolic blood pressure, body mass index and the prevalence of other microvascular diseases (e.g. neuropathy). Unexpectedly, DR was associated with high HDL cholesterol and high apolipoproteins AI and AII. Patients with coronary artery disease were less likely to have DR. DR was not associated with gender, smoking, diastolic blood pressure, VLDL cholesterol, triglycerides, and LDL cholesterol. In summary, the prevalence of DR in patients with type 2 diabetes mellitus requiring hemodialysis is higher than in patients suffering from T2DM, who do not receive hemodialysis. DR was positively related to systolic blood pressure (BP), glucometabolic control, and, paradoxically, HDL cholesterol. This data suggests that glucose and blood pressure control may delay the development of DR in patients with diabetes mellitus on dialysis.
Strain-specific anti-biofilm and antibiotic-potentiating activity of 3′,4′-difluoroquercetin
Authors: Kho Wonyoung , Kim Mi Kyoung , Jung Minji , Chong Yong Pil , Kim Yang Soo , Park Ki-Ho , Chong Youhoon
Published: August 2020

Antibacterial properties of 3′,4′-difluoroquercetin (di-F-Q), a fluorine-substituted stable quercetin derivative, were investigated. Even though di-F-Q itself did not show interesting antibacterial activity, treatment of the Staphylococcus aureus strains with di-F-Q resulted in a dose-dependent reduction in biofilm formation with IC50 values of 1.8 ~ 5.3 mg/L. Also, the antibacterial activity of ceftazidime (CAZ) against carbapenem-resistant Pseudomonas aeruginosa (CRPA) showed eightfold decrease upon combination with di-F-Q. Assessment of the antimicrobial activity of CAZ in combination with di-F-Q against 50 clinical isolates of P. aeruginosa confirmed 15.7% increase in the percentages of susceptible P. aeruginosa isolates upon addition of di-F-Q to CAZ. Further mechanistic studies revealed that di-F-Q affected the antibiotics efflux system in CRPA but not the β-lactamase activity. Thus, di-F-Q was almost equally effective as carbonyl cyanide m-chlorophenyl hydrazine in inhibiting antibiotic efflux by P. aeruginosa. In vivo evaluation of the therapeutic efficacy of CAZ-(di-F-Q) combination against P. aeruginosa showed 20% of the mice treated with CAZ-(di-F-Q) survived after 7 days in IMP carbapenemase-producing multidrug-resistant P. aeruginosa infection group while no mice treated with CAZ alone survived after 2 days. Taken together, di-F-Q demonstrated unique strain-specific antimicrobial properties including anti-biofilm and antibiotic-potentiating activity against S. aureus and P. aeruginosa, respectively.
Accuracy for diagnosis of periapical cystic lesions
Authors: Tsesis Igor , Krepel Gal , Koren Tal , Rosen Eyal , Kfir Anda
Published: August 2020

Clinical differentiation between cystic lesions of endodontic and non-endodontic origin is of importance because correct diagnosis may affect treatment decision making. Most radicular cysts are treated with conservative approaches and, therefore, are not surgically removed. The objective of this study was to determine the accuracy of clinical diagnosis of periapical lesions as compared to the histological findings, and to evaluate various associated factors. All biopsy specimens submitted for histological evaluation from 2002 to 2009 were assessed. Only cases of periapical lesions with complete patient data and clinical diagnosis were included. Sensitivity, specificity and accuracy of the clinical diagnosis were calculated and various patient-related factors were evaluated. Of the 4,908 cases, 183 met inclusion criteria. Histologically, there were 171 lesions of radicular cysts and 12 cases of non-endodontic cysts, including OKC and Incisive Canal Cyst. The diagnostic accuracy for clinical diagnosis for radicular cysts was 91.84% and 91.84% for non-endodontic cysts. There was a high accuracy of clinical differentiation between cystic lesions of endodontic and non-endodontic origin. However, some non-endodontic lesions may be incorrectly diagnosed clinically as lesions of endodontic origin. Histological evaluation may be necessary for the correct diagnosis. Further clinical studies are needed to evaluate clinical examination and histological diagnosis of periapical lesions.
An extended logistic model of photodynamic inactivation for various levels of irradiance using the example of Streptococcus agalactiae
Authors: Brasel Michal , Pieranski Michal , Grinholc Mariusz
Published: August 2020

Irradiance is an important factor influencing the acceleration of microorganism mortality in photodynamic inactivation (PDI) processes. Experimental observations of PDI processes indicate that the greater the irradiation power is, the faster the decrease in the population size of microorganisms. However, commonly used mathematical models of PDI processes usually refer only to specific values of irradiance without taking into account the influence of change in irradiance on the dynamic properties of inactivation. The main goal of this paper is to analyze the effect of irradiance on the PDI process and attempt to mathematically model the obtained dependencies. The analysis was carried out using the example of photodynamic inactivation of the bacterium Streptococcus agalactiae with the adopted Logistic PDI model optimized for several selected levels of irradiance. To take into account the impact of changes in irradiation power on the PDI model, the selected parameters were made appropriately dependent on this factor. The paper presents several variants of parameter modification with an evaluation of the model fitting quality criterion. The discussion on appropriate selection of parameters to be modified was carried out as a comparative analysis of several case studies. The extended logistic PDI model obtained in the conducted research effectively describes the dynamics of microorganism mortality in the whole tested irradiation power range.
Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice
Authors: Acklin Scarlett , Zhang Manchao , Du Wuying , Zhao Xin , Plotkin Matthew , Chang Jianhui , Campisi Judith , Zhou Daohong , Xia Fen
Published: August 2020

Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16INK4A and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological ‘senolytic’ agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN.