bluuebunny/crossref_metadata_2025 huggingface dataset:
Reply to Comment by Peterie Et Al. on “Accelerated Fill‐Up of the Arbuckle Group Aquifer and Links to U.S. Midcontinent Seismicity”
Authors: Ansari Esmail , Bidgoli Tandis S.
Published: October 2020

Peterie et al. question one observation in our paper: associating pressure increases to injection volumes at distances of up to 25 km from an injection well. In this reply, we show that the comment misunderstands our analysis and the evidence that led to this conclusion. We also show that gauge‐depth‐corrected pressures, used by the authors to produce statewide pressure maps, are discrepant with the static fluid level data, provided in our original compilation and analysis. The discrepancies are a result of the pressure correction method employed, which naïvely substitutes formation pressure for bottomhole pressure to calculate wellbore fluid density. Their linearly interpolated pressure maps, based on sparse data, contain interpolation and extrapolation artifacts that contradict injection trends in the state, the Theis solution, and the superposition principle. We reiterate that pressure and static fluid level increases in Class I wells existed prior to 2013, most notably in central Kansas, where recent earthquakes are cited in the comment as evidence of a pressure plume emanating from the Kansas‐Oklahoma border, 90 km away. We show that the space‐time pattern of seismicity in this area is inconsistent with a northward propagating pressure plume and, instead, seismicity appears to be centered on and near a cluster of high‐rate injection wells, two of which are among the highest rate wells in the state. These observations, along with recent M4 + earthquakes during continued decreases in wastewater injection in southern Kansas and northern Oklahoma, question the usefulness of the comment for understanding and managing societally significant earthquakes.
Long‐Wavelength Gravity Field Constraint on the Lower Mantle Viscosity in North America
Authors: Reusen J. M. , Root B. C. , Szwillus W. , Fullea J. , van der Wal W.
Published: October 2020

The long‐wavelength negative gravity anomaly over Hudson Bay coincides with the area depressed by the Laurentide Ice Sheet during the Last Glacial Maximum, suggesting that it is, at least partly, caused by glacial isostatic adjustment (GIA). Additional contributions to the static gravity field stem from surface dynamic topography, core‐mantle boundary (CMB) topography, and density anomalies in the subsurface. Previous estimates of the contribution of GIA to the gravity anomaly range from 25% to more than 80%. However, these estimates did not include uncertainties in all components that contribute to the gravity field. In this study, we develop a forward model for the gravity anomaly based on density models and dynamic models, investigating uncertainty in all components. We derive lithospheric densities from equilibrium constraints but extend the concept of lithospheric isostasy to a force balance that includes the dynamic models. The largest uncertainty in the predicted gravity anomaly is due to the lower mantle viscosity, uncertainties in the ice history, the crustal model, the lithosphere‐asthenosphere boundary, and the conversion from seismic velocities to density have a smaller effect. A preference for lower mantle viscosities >1022 Pa s is found, in which case at least 60% of the observed long‐wavelength gravity anomaly can be attributed to GIA. This lower bound on the lower mantle viscosity has implications for inferences based on models for mantle convection and GIA.
Prolonged Lifetime of the Transient Ionized Layer in the Martian Atmosphere Caused by Comet Siding Spring
Authors: Luppen Z. A. , Girazian Z. , Morgan D. D. , Kopf A. J. , Chu F. , Halekas J. S. , Gurnett D. A.
Published: October 2020

In October 2014, the close encounter between Mars and comet Siding Spring produced a transient ionized layer in the upper atmosphere composed primarily of Mg+ and Fe+ ions. The layer was detected by instruments on three spacecraft, including the Mars Advanced Radar for Subsurface and Ionosphere Sounding (MARSIS) on Mars Express. Analyses of the MARSIS data indicated the transient layer persisted up to 19 h after the comet's closest approach. We report MARSIS observations that suggest the transient layer lasted at least 7 days—and potentially as long as 32 days—after closest approach. During this period, the transient layer was mostly confined to a narrow latitude range between 20°N and 60°N and a longitude range spanning 275°E to 95°E. Since this period coincided with a highly active Sun, we discuss how solar flares may have contributed to the layer's prolonged lifetime.
Exploring the Interactions Between Rift Propagation and Inherited Crustal Fabrics Through Experimental Modeling
Authors: Maestrelli Daniele , Montanari Domenico , Corti Giacomo , Del Ventisette Chiara , Moratti Giovanna , Bonini Marco
Published: October 2020

Continental rifting is a geodynamic process that involves the breakup of the crust and may eventually evolve to seafloor spreading. Although it is often assumed to be a product of orthogonal divergence, continental rifting may result from oblique extension, and in several cases, it is related to the rotation of plates or crustal blocks about a vertical axis. This implies the occurrence of rifts with straight but not parallel margins and rift axis‐parallel gradients in extension velocity and amount of strain. The effects of rift propagation through the continental crust has only recently started to be addressed, and even less investigated is the interaction between rift propagation and inherited crustal fabrics. We have studied this issue by carrying out a series of analog laboratory experiments. Modeling results suggest that inherited linear discontinuities in the model brittle upper crust that are oriented above a threshold angle (≥45°) from the orthogonal to the rift axis have the ability to interact with rift‐related structures. Depending on their orientation, such inherited discontinuities are reactivated as either transfer zones or rift‐bounding faults. We compare our models with four natural prototypes in which rift propagation is likely to have occurred (the Trans Mexican Volcanic belt, the Gofa Province, the Gulf of Suez, and the Kenya Rift). For each case study, we show how the kinematics of propagating rifts is comparable to our model results, and we provide insights into how rift‐related deformation may interact with inherited crustal fabrics.
Why Is the Terrestrial Water Storage in Dryland Regions Declining? A Perspective Based on Gravity Recovery and Climate Experiment Satellite Observations and Noah Land Surface Model With Multiparameterization Schemes Model Simulations
Authors: Chang Li‐Ling , Yuan Ruiqiang , Gupta Hoshin V. , Winter C. Larrabee , Niu Guo‐Yue
Published: October 2020

Drylands cover over 40% of the global land area and are home to more than 2 billion humans. Here, we use the terrestrial water storage (TWS) anomaly data derived from GRACE satellites to assess water storage changes globally and find that drylands lost ~15.9 ± 9.1 mm of water between April 2002 and January 2017. The TWS trends are more significant and apparent in dry regions than in humid regions. The decrease in TWS occurred mainly in hyperarid and arid regions. Exact causes to the observed declines in TWS remain elusive due to anthropogenic water withdrawals, atmospheric demand (potential evapotranspiration,PET) in contrast to supply (precipitation,P) caused by the warming, and terrestrial ecohydrological responses. Therefore, we use a process‐based model forced by climate data to interpret the causes over three selected dryland regions showing the strongest drying trends. We find that the modeled TWS without considering anthropogenic water withdrawals explains most of the declining GRACE TWS over the southwestern North America (NA) and Middle East but underestimates the drying trend over North China. This suggests that TWS declines in the southwestern NA and the Middle East were primarily driven by the contrast between atmospheric demand and supply, whereas anthropogenic water withdrawals may have played a relatively more dominant role in TWS declines over North China. Additional model experiments indicate that terrestrial ecohydrological processes that help extract deep substrate water are critical for providing water supply additional to precipitation to sustainETin the drying drylands at decadal scales.
Impact of Uncertainty in Precipitation Forcing Data Sets on the Hydrologic Budget of an Integrated Hydrologic Model in Mountainous Terrain
Authors: Schreiner‐McGraw Adam P. , Ajami Hoori
Published: October 2020

Precipitation is a key input variable in distributed surface water‐groundwater models, and its spatial variability is expected to impact watershed hydrologic response via changes in subsurface flow dynamics. Gridded precipitation data sets based on gauge observations, however, are plagued by uncertainty, especially in mountainous terrain where gauge networks are sparse. To examine the mechanisms via which uncertainty in precipitation data propagates through a watershed, we perform a series of numerical experiments using an integrated surface water‐groundwater hydrologic model, ParFlow.CLM. The Kaweah River watershed in California, USA, is used as our virtual catchment laboratory to characterize watershed response to variable precipitation forcing from headwaters to groundwaters. By applying the three‐cornered hat method, we quantify the spatially distributed uncertainty in four publically available precipitation forcing data sets and their simulated hydrology. Simulations demonstrate that uncertainty in the simulated groundwater storage is primarily a result of topographic redistribution of uncertainty in precipitation forcing. Soil water redistribution is the primary pathway that redistributes uncertainty downslope. We also find that topography exerts a larger impact than variable subsurface parameters on propagating uncertainty in simulated fluxes. Finally, we find that improvement in model performance metrics is higher for a single simulation forced with the mean precipitation from the available data sets than the averaged simulated results of separate simulations forced with each data set. Results from this study highlight the importance of topography‐moderated flow through the critical zone in shaping the groundwater response to climate variability.
Groundwater Flow and Moisture Dynamics in the Swash Zone: Effects of Heterogeneous Hydraulic Conductivity and Capillarity
Authors: Geng Xiaolong , Heiss James W. , Michael Holly A. , Boufadel Michel C. , Lee Kenneth
Published: October 2020

A density‐dependent, variably saturated groundwater flow and solute transport model was used to investigate the influence of swash motions on subsurface flow and moisture dynamics in beach aquifers with heterogeneous distributions of hydraulic conductivity (K) and capillarity. The numerical simulations were performed within a Monte Carlo framework using field measurements conducted in the swash zone of a sandy beach. Our results show that heterogeneous capillarity causes spatially variable capillary rise above the groundwater table. In response to swash motions, heterogeneity creates capillary barriers that result in pockets of elevated moisture content beneath the swash zone. These moisture hotspots persist within the unsaturated zone even at ebb tide when the swash motions recede seaward. Heterogeneous capillarity also results in highly tortuous preferential flow paths and alters the flow rates from the sand surface to the water table. Heterogeneous K greatly enhances the seawater infiltration into the swash zone and modulates its spatial distribution along the beach surface. Due to heterogeneous K and capillarity, complex mixing patterns emerge. Both strain‐dominated and vorticity‐dominated flow regions develop and dissipate as tides and waves move across the beach surface. Complex mixing patterns of seawater percolating from the swash zone surface to the water table, with localized areas of high and low mixing intensities, are further demonstrated by analysis of dilution index. Our findings reveal the influence of geologic heterogeneity on swash zone moisture and flow dynamics, which may have important implications for sediment transport and chemical processing in beach aquifers.
Epigenetic silencing of LncRNA LINC00261 promotes c-myc-mediated aerobic glycolysis by regulating miR-222-3p/HIPK2/ERK axis and sequestering IGF2BP1
Authors: Zhai Shuyu , Xu Zhiwei , Xie Junjie , Zhang Jun , Wang Xinjing , Peng Chenghong , Li Hongwei , Chen Hao , Shen Baiyong , Deng Xiaxing
Published: October 2020

Long noncoding RNAs have been identified as key regulators in the progression of various cancers. LINC00261 has been reported as a tumor suppressor in multiple cancers. However, its function and underlying mechanisms in pancreatic cancer remain largely unclear. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization was used to discover the subcellular location. The direct binding of LINC00261 to miR-222-3p was verified using a dual-luciferase reporter assay and RNA immunoprecipitation. LINC00261-binding proteins were detected using an RNA pulldown assay. LINC00261 was downregulated in pancreatic cancer tissues and cell lines. Its reduced expression was correlated with advanced pathological stage and poor prognosis. Forced expression of LINC00261 suppressed pancreatic cancer glycolysis and proliferation and induced cell cycle arrest and apoptosis. Mechanistically, downregulation of LINC00261 was caused by hypermethylation of the CpG island in the promoter region and EZH2-mediated histone H3 lysine 27 trimethylation. Moreover, LINC00261 exerted its biological function by binding to miR-222-3p to activate the HIPK2/ERK/c-myc pathway. In addition, LINC00261 could also reduce c-myc expression by sequestering IGF2BP1. Our study suggests that LINC00261 functions as a tumor suppressor in pancreatic cancer and identifies novel epigenetic and posttranscriptional regulatory mechanisms of LINC00261, which contribute to the targeted therapy of pancreatic cancer.
RALB GTPase: a critical regulator of DR5 expression and TRAIL sensitivity in KRAS mutant colorectal cancer
Authors: Khawaja Hajrah , Campbell Andrew , Roberts Jamie Z. , Javadi Arman , O’Reilly Paul , McArt Darragh , Allen Wendy L. , Majkut Joanna , Rehm Markus , Bardelli Alberto , Di Nicolantonio Federica , Scott Christopher J. , Kennedy Richard , Vitale Nicolas , Harrison Timothy , Sansom Owen J. , Longley Daniel B. , Evergren Emma , Van Schaeybroeck Sandra
Published: October 2020

RAS mutant (MT) metastatic colorectal cancer (mCRC) is resistant to MEK1/2 inhibition and remains a difficult-to-treat group. Therefore, there is an unmet need for novel treatment options for RASMT mCRC. RALA and RALB GTPases function downstream of RAS and have been found to be key regulators of several cell functions implicated in KRAS-driven tumorigenesis. However, their role as regulators of the apoptotic machinery remains to be elucidated. Here, we found that inhibition of RALB expression, but not RALA, resulted in Caspase-8-dependent cell death in KRASMT CRC cells, which was not further increased following MEK1/2 inhibition. Proteomic analysis and mechanistic studies revealed that RALB depletion induced a marked upregulation of the pro-apoptotic cell surface TRAIL Death Receptor 5 (DR5) (also known as TRAIL-R2), primarily through modulating DR5 protein lysosomal degradation. Moreover, DR5 knockdown or knockout attenuated siRALB-induced apoptosis, confirming the role of the extrinsic apoptotic pathway as a regulator of siRALB-induced cell death. Importantly, TRAIL treatment resulted in the association of RALB with the death-inducing signalling complex (DISC) and targeting RALB using pharmacologic inhibition or RNAi approaches triggered a potent increase in TRAIL-induced cell death in KRASMT CRC cells. Significantly, high RALB mRNA levels were found in the poor prognostic Colorectal Cancer Intrinsic Subtypes (CRIS)-B CRC subgroup. Collectively, this study provides to our knowledge the first evidence for a role for RALB in apoptotic priming and suggests that RALB inhibition may be a promising strategy to improve response to TRAIL treatment in poor prognostic RASMT CRIS-B CRC.
MicroRNA-200b/c-3p regulate epithelial plasticity and inhibit cutaneous wound healing by modulating TGF-β-mediated RAC1 signaling
Authors: Tang Huiyi , Wang Xueer , Zhang Min , Yan Yuan , Huang Simin , Ji Jiahao , Xu Jinfu , Zhang Yijia , Cai Yongjie , Yang Bobo , Lan Wenqi , Huang Mianbo , Zhang Lin
Published: October 2020

Cutaneous wound healing is pivotal for human skin to regain barrier function against pathogens. MicroRNAs (miRNAs) have been found to play regulatory roles in wound healing. However, the mechanism of miRNA regulation remains largely unknown. In this study, we focused on microRNA-200b/c-3p (miR-200b/c-3p) whose expression was abundant in intact epidermis, but dramatically decreased in skin wounds. In silico prediction identified RAC1 as a potential miR-200b/c-3p target. Luciferase reporter assay confirmed that miR-200b/c-p repressed RAC1 by direct targeting to its mRNA 3′UTR. Consistently, miR-200b/c-3p expression was discordantly related to RAC1 protein level during wound healing. Forced miR-200b/c-3p expression repressed RAC1 and inhibited keratinocyte migration as well as re-epithelialization in a mouse back skin full-thickness wound healing model. Mechanistically, miR-200b/c-3p modulated RAC1 to inhibit cell migration by repressing lamellipodia formation and intercellular adhesion dissolution in keratinocytes. Furthermore, we found that TGF-β1, which was highly expressed in skin wounds, contributed to the downregulation of miR-200b/c-3p in wound edge keratinocytes. Taken together, miR-200b/c-3p-mediated RAC1 repression inhibited keratinocyte migration to delay re-epithelialization. TGF-β1 induction attenuated miR-200b/c-3p regulation of RAC1 signaling in cutaneous wounds and the repression of miR-200b/c-3p accelerated keratinocyte migration to promote wound healing. Our data provide new insight into how miR-200b/c-3p affects keratinocyte migration and highlight the potential of miR-200b/c-3p targeting for accelerating wound healing.
Combating acquired resistance to MAPK inhibitors in melanoma by targeting Abl1/2-mediated reactivation of MEK/ERK/MYC signaling
Authors: Tripathi Rakshamani , Liu Zulong , Jain Aditi , Lyon Anastasia , Meeks Christina , Richards Dana , Liu Jinpeng , He Daheng , Wang Chi , Nespi Marika , Rymar Andrey , Wang Peng , Wilson Melissa , Plattner Rina
Published: October 2020

Metastatic melanoma remains an incurable disease for many patients due to the limited success of targeted and immunotherapies. BRAF and MEK inhibitors reduce metastatic burden for patients with melanomas harboring BRAF mutations; however, most eventually relapse due to acquired resistance. Here, we demonstrate that ABL1/2 kinase activities and/or expression are potentiated in cell lines and patient samples following resistance, and ABL1/2 drive BRAF and BRAF/MEK inhibitor resistance by inducing reactivation of MEK/ERK/MYC signaling. Silencing/inhibiting ABL1/2 blocks pathway reactivation, and resensitizes resistant cells to BRAF/MEK inhibitors, whereas expression of constitutively active ABL1/2 is sufficient to promote resistance. Significantly, nilotinib (2nd generation ABL1/2 inhibitor) reverses resistance, in vivo, causing prolonged regression of resistant tumors, and also, prevents BRAFi/MEKi resistance from developing in the first place. These data indicate that repurposing the FDA-approved leukemia drug, nilotinib, may be effective for prolonging survival for patients harboring BRAF-mutant melanomas.
Electro-reduction of carbon dioxide at low over-potential at a metal–organic framework decorated cathode
Authors: Kang Xinchen , Li Lili , Sheveleva Alena , Han Xue , Li Jiangnan , Liu Lifei , Tuna Floriana , McInnes Eric J. L. , Han Buxing , Yang Sihai , Schröder Martin
Published: October 2020

Electrochemical reduction of carbon dioxide is a clean and highly attractive strategy for the production of organic products. However, this is hindered severely by the high negative potential required to activate carbon dioxide. Here, we report the preparation of a copper-electrode onto which the porous metal–organic framework [Cu2(L)] [H4L = 4,4′,4″,4′′′-(1,4-phenylenebis(pyridine-4,2,6-triyl))tetrabenzoic acid] can be deposited by electro-synthesis templated by an ionic liquid. This decorated electrode shows a remarkable onset potential for reduction of carbon dioxide to formic acid at −1.45 V vs. Ag/Ag+, representing a low value for electro-reduction of carbon dioxide in an organic electrolyte. A current density of 65.8 mA·cm−2 at −1.8 V vs. Ag/Ag+ is observed with a Faradaic efficiency to formic acid of 90.5%. Electron paramagnetic resonance spectroscopy confirms that the templated electro-synthesis affords structural defects in the metal–organic framework film comprising uncoupled Cu(II) centres homogenously distributed throughout. These active sites promote catalytic performance as confirmed by computational modelling.
Acute EPA-induced learning and memory impairment in mice is prevented by DHA
Authors: Liu Ji-Hong , Wang Qian , You Qiang-Long , Li Ze-Lin , Hu Neng-Yuan , Wang Yan , Jin Zeng-Lin , Li Shu-Ji , Li Xiao-Wen , Yang Jian-Ming , Zhu Xin-Hong , Dai Yi-Fan , Xu Jiang-Ping , Bai Xiao-Chun , Gao Tian-Ming
Published: October 2020

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). However, the impact of EPA and DHA supplementation on normal cognitive function and the molecular targets of EPA and DHA are still unknown. We show that acute administration of EPA impairs learning and memory and hippocampal LTP in adult and prepubescent mice. Similar deficits are duplicated by endogenously elevating EPA in the hippocampus in the transgenic fat-1 mouse. Furthermore, the damaging effects of EPA are mediated through enhancing GABAergic transmission via the 5-HT6R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT2CR. We conclude that EPA exhibits an unexpected detrimental impact on cognitive functions, suggesting that caution must be exercised in omega-3 fatty acid supplementation and the combination of EPA and DHA at a natural ratio is critical for learning and memory and synaptic plasticity.
Engineered fluoride sensitivity enables biocontainment and selection of genetically-modified yeasts
Authors: Yoo Justin I. , Seppälä Susanna , OʼMalley Michelle A.
Published: October 2020

Biocontainment systems are needed to neutralize genetically modified organisms (GMOs) that pose ecological threats outside of controlled environments. In contrast, benign selection markers complement GMOs with reduced fitness. Benign selection agents serve as alternatives to antibiotics, which are costly and risk spread of antibiotic resistance. Here, we present a yeast biocontainment strategy leveraging engineered fluoride sensitivity and DNA vectors enabling use of fluoride as a selection agent. The biocontainment system addresses the scarcity of platforms available for yeast despite their prevalent use in industry and academia. In the absence of fluoride, the biocontainment strain exhibits phenotypes nearly identical to those of the wildtype strain. Low fluoride concentrations severely inhibit biocontainment strain growth, which is restored upon introduction of fluoride-based vectors. The biocontainment strategy is stringent, easily implemented, and applicable to several eukaryotes. Further, the DNA vectors enable genetic engineering at reduced costs and eliminate risks of propagating antibiotic resistance.
Molecular mechanism of the MORC4 ATPase activation
Authors: Tencer Adam H. , Cox Khan L. , Wright Gregory M. , Zhang Yi , Petell Christopher J. , Klein Brianna J. , Strahl Brian D. , Black Joshua C. , Poirier Michael G. , Kutateladze Tatiana G.
Published: October 2020

Human Microrchidia 4 (MORC4) is associated with acute and chronic pancreatitis, inflammatory disorders and cancer but it remains largely uncharacterized. Here, we describe the structure–function relationship of MORC4 and define the molecular mechanism for MORC4 activation. Enzymatic and binding assays reveal that MORC4 has ATPase activity, which is dependent on DNA-binding functions of both the ATPase domain and CW domain of MORC4. The crystal structure of the ATPaseCW cassette of MORC4 and mutagenesis studies show that the DNA-binding site and the histone/ATPase binding site of CW are located on the opposite sides of the domain. The ATPase and CW domains cooperate in binding of MORC4 to the nucleosome core particle (NCP), enhancing the DNA wrapping around the histone core and impeding binding of DNA-associated proteins, such as transcription factors, to the NCP. In cells, MORC4 mediates formation of nuclear bodies in the nucleus and has a role in the progression of S-phase of the cell cycle, and both these functions require CW and catalytic activity of MORC4. Our findings highlight the mechanism for MORC4 activation, which is distinctly different from the mechanisms of action observed in other MORC family members.
Sex-specific outcome disparities in very old patients admitted to intensive care medicine: a propensity matched analysis
Authors: Wernly Bernhard , Bruno Raphael Romano , Kelm Malte , Boumendil Ariane , Morandi Alessandro , Andersen Finn H. , Artigas Antonio , Finazzi Stefano , Cecconi Maurizio , Christensen Steffen , Faraldi Loredana , Lichtenauer Michael , Muessig Johanna M. , Marsh Brian , Moreno Rui , Oeyen Sandra , Öhman Christina Agvald , Pinto Bernado Bollen , Soliman Ivo W. , Szczeklik Wojciech , Niederseer David , Valentin Andreas , Watson Ximena , Leaver Susannah , Boulanger Carole , Walther Sten , Schefold Joerg C. , Joannidis Michael , Nalapko Yuriy , Elhadi Muhammed , Fjølner Jesper , Zafeiridis Tilemachos , De Lange Dylan W. , Guidet Bertrand , Flaatten Hans , Jung Christian
Published: October 2020

Female and male very elderly intensive patients (VIPs) might differ in characteristics and outcomes. We aimed to compare female versus male VIPs in a large, multinational collective of VIPs with regards to outcome and predictors of mortality. In total, 7555 patients were included in this analysis, 3973 (53%) male and 3582 (47%) female patients. The primary endpoint was 30-day-mortality. Baseline characteristics, data on management and geriatric scores including frailty assessed by Clinical Frailty Scale (CFS) were documented. Two propensity scores (for being male) were obtained for consecutive matching, score 1 for baseline characteristics and score 2 for baseline characteristics and ICU management. Male VIPs were younger (83 ± 5 vs. 84 ± 5; p < 0.001), less often frail (CFS > 4; 38% versus 49%; p < 0.001) but evidenced higher SOFA (7 ± 6 versus 6 ± 6 points; p < 0.001) scores. After propensity score matching, no differences in baseline characteristics could be observed. In the paired analysis, the mortality in male VIPs was higher (mean difference 3.34% 95%CI 0.92–5.76%; p = 0.007) compared to females. In both multivariable logistic regression models correcting for propensity score 1 (aOR 1.15 95%CI 1.03–1.27; p = 0.007) and propensity score 2 (aOR 1.15 95%CI 1.04–1.27; p = 0.007) male sex was independently associated with higher odds for 30-day-mortality. Of note, male gender was not associated with ICU mortality (OR 1.08 95%CI 0.98–1.19; p = 0.14). Outcomes of elderly intensive care patients evidenced independent sex differences. Male sex was associated with adverse 30-day-mortality but not ICU-mortality. Further research to identify potential sex-specific risk factors after ICU discharge is warranted.

Trial registration: NCT03134807 and NCT03370692; Registered on May 1, 2017 https://clinicaltrials.gov/ct2/show/NCT03370692.
Impact of road network structure on dementia-related missing incidents: a spatial buffer approach
Authors: Puthusseryppady Vaisakh , Manley Ed , Lowry Ellen , Patel Martyn , Hornberger Michael
Published: October 2020

Dementia-related missing incidents are a highly prevalent issue worldwide. Despite being associated with potentially life-threatening consequences, very little is still known about what environmental risk factors may potentially contribute to these missing incidents. The aim of this study was to conduct a retrospective, observational analysis using a large sample of police case records of missing individuals with dementia (n = 210). Due to the influence that road network structure has on our real world navigation, we aimed to explore the relationship between road intersection density, intersection complexity, and orientation entropy to the dementia-related missing incidents. For each missing incident location, the above three variables were computed at a 1 km radius buffer zone around these locations; these values were then compared to that of a set of random locations. The results showed that higher road intersection density, intersection complexity, and orientation entropy were all significantly associated with dementia-related missing incidents. Our results suggest that these properties of road network structure emerge as significant environmental risk factors for dementia-related missing incidents, informing future prospective studies as well as safeguarding guidelines.
Topoisomerase IIβ targets DNA crossovers formed between distant homologous sites to induce chromatin opening
Authors: Miyaji Mary , Furuta Ryohei , Hosoya Osamu , Sano Kuniaki , Hara Norikazu , Kuwano Ryozo , Kang Jiyoung , Tateno Masaru , Tsutsui Kimiko M. , Tsutsui Ken
Published: October 2020

Type II DNA topoisomerases (topo II) flip the spatial positions of two DNA duplexes, called G- and T- segments, by a cleavage-passage-resealing mechanism. In living cells, these DNA segments can be derived from distant sites on the same chromosome. Due to lack of proper methodology, however, no direct evidence has been described so far. The beta isoform of topo II (topo IIβ) is essential for transcriptional regulation of genes expressed in the final stage of neuronal differentiation. Here we devise a genome-wide mapping technique (eTIP-seq) for topo IIβ target sites that can measure the genomic distance between G- and T-segments. It revealed that the enzyme operates in two distinctive modes, termed proximal strand passage (PSP) and distal strand passage (DSP). PSP sites are concentrated around transcription start sites, whereas DSP sites are heavily clustered in small number of hotspots. While PSP represent the conventional topo II targets that remove local torsional stresses, DSP sites have not been described previously. Most remarkably, DSP is driven by the pairing between homologous sequences or repeats located in a large distance. A model-building approach suggested that topo IIβ acts on crossovers to unknot the intertwined DSP sites, leading to chromatin decondensation.
Ischemia reperfusion-induced metastasis is resistant to PPARγ agonist pioglitazone in a murine model of colon cancer
Authors: Tashiro Yoshihiko , Nishino Hiroto , Higuchi Takashi , Sugisawa Norihiko , Fukuda Yasunari , Yamamoto Jun , Inubushi Sachiko , Aoki Takeshi , Murakami Masahiko , Singh Shree Ram , Bouvet Michael , Hoffman Robert M.
Published: October 2020

Ischemia reperfusion injury (IRI) during liver-metastasis resection for treatment of colon cancer may increase the risk of further metastasis. Peroxisome proliferator-activated receptor-γ (PPARγ) activation has been observed to exert a protective effect against IRI and IRI-induced metastasis of hepatocellular carcinoma. The present study aimed to investigate the effect of the PPARγ agonist pioglitazone on tumor metastasis and liver injury following IRI in a mouse model of colon cancer. Pioglitazone (30 mg/kg weight) was administered orally 1.5 h before and 2 h after the initiation of ischemia and was orally administrated daily to mice from day 0–21. SL4-cancer cells expressing red fluorescent protein (SL4-RFP) (1 × 106) were injected into the spleen. Fifteen minutes after injection, the hepatoduodenal ligament was clamped with a vessel clip, and released 5 min later. Liver, blood and tumor samples were taken from mice in order to determine if inflammation was induced by IRI. The effect of pioglitazone on liver metastasis was assessed. Furthermore, the effect of pioglitazone to control the inflammatory response during IRI progression was examined. Liver metastasis along with MMP-9 activation and the production of inflammatory cytokines were resistant to pioglitazone. Our results indicate that liver metastasis and associated inflammation in mice were resistant to pioglitazone.
Using proximity extension proteomics assay to identify biomarkers associated with infarct size and ejection fraction after ST-elevation myocardial infarction
Authors: Mohammad Moman A. , Koul Sasha , Egerstedt Anna , Smith J. Gustav , Noc Marko , Lang Irene , Holzer Michael , Clemmensen Peter , Gidlöf Olof , Metzler Bernhard , Engstrøm Thomas , Erlinge David
Published: October 2020

Plasma concentrations of many cardiovascular and inflammatory proteins are altered after ST-elevation myocardial infarction (STEMI) and may provide prognostic information. We conducted a large-scale proteomic analysis in patients with STEMI, correlating protein levels to infarct size and left ventricular ejection fraction (LVEF) determined with cardiac magnetic resonance imaging. We analysed 131 cardiovascular and inflammatory proteins using a multiplex proximity extension assay and blood samples obtained at baseline, 6, 24, and 96 h from the randomised clinical trial CHILL-MI. Cardiac magnetic resonance imaging data at 4 ± 2 days and 6 months were available as per trial protocol. Using a linear regression model with bootstrap resampling and false discovery rate adjustment we identified five proteins (ST2, interleukin-6, pentraxin-3, interleukin-10, renin, and myoglobin) with elevated values corresponding to larger infarct size or worse LVEF and four proteins (TNF-related apoptosis-inducing ligand, TNF-related activation induced cytokine, interleukin-16, and cystatin B) with values inversely related to LVEF and infarct size, concluding that among 131 circulating inflammatory and cardiovascular proteins in the acute and sub-acute phase of STEMI, nine showed a relationship with infarct size and LVEF post-STEMI, with IL-6 and ST2 exhibiting the strongest association.
Exploring the long-term changes in the Madden Julian Oscillation using machine learning
Authors: Dasgupta Panini , Metya Abirlal , Naidu C. V. , Singh Manmeet , Roxy M. K.
Published: October 2020

The Madden Julian Oscillation (MJO), the dominant subseasonal variability in the tropics, is widely represented using the Real-time Multivariate MJO (RMM) index. The index is limited to the satellite era (post-1974) as its calculation relies on satellite-based observations. Oliver and Thompson (J Clim 25:1996–2019, 2012) extended the RMM index for the twentieth century, employing a multilinear regression on the sea level pressure (SLP) from the NOAA twentieth century reanalysis. They obtained an 82.5% correspondence with the index in the satellite era. In this study, we show that the historical MJO index can be successfully reconstructed using machine learning techniques and improved upon. We obtain a significant improvement of up to 4%, using the support vector regressor (SVR) and convolutional neural network (CNN) methods on the same set of predictors used by Oliver and Thompson. Based on the improved RMM indices, we explore the long-term changes in the intensity, phase occurrences, and frequency of the winter MJO events during 1905–2015. We show an increasing trend in MJO intensity (22–27%) during this period. We also find a multidecadal change in MJO phase occurrence and periodicity corresponding to the Pacific Decadal Oscillation (PDO), while the role of anthropogenic warming cannot be ignored.
Author Correction: Effects of different intracranial volume correction methods on univariate sex differences in grey matter volume and multivariate sex prediction
Authors: Sanchis-Segura Carla , Ibañez-Gual Maria Victoria , Aguirre Naiara , Cruz-Gómez Álvaro Javier , Forn Cristina
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Stromal microenvironment promoted infiltration in esophageal adenocarcinoma and squamous cell carcinoma: a multi-cohort gene-based analysis
Authors: Li Jiali , Zeng Zihang , Jiang Xueping , Zhang Nannan , Gao Yanping , Luo Yuan , Sun Wenjie , Li Shuying , Ren Jiangbo , Gong Yan , Xie Conghua
Published: October 2020

The stromal microenvironment has been shown to affect the infiltration of esophageal carcinoma (ESCA), which is linked to prognosis. However, the complicated mechanism of how infiltration is influenced by the stromal microenvironment is not well-defined. In this study, a stromal activation classifier was established with ridge cox regression to calculate stroma scores for training (n = 182) and validation cohorts (n = 227) based on the stroma-related 32 hub genes identified by sequential bioinformatics algorithms. Patients with high stromal activation were associated with high T stage and poor prognosis in both esophagus adenocarcinoma and esophagus squamous cell carcinoma. Besides, comprehensive multi-omics analysis was used to outline stromal characterizations of 2 distinct stromal groups. Patients with activated tumor stoma showed high stromal cell infiltration (fibroblasts, endothelial cells, and monocyte macrophages), epithelial-mesenchymal transition, tumor angiogenesis and M2 macrophage polarization (CD163 and CD206). Tumor mutation burden of differential stromal groups was also depicted. In addition, a total of 6 stromal activation markers in ESCA were defined and involved in the function of carcinoma-associated fibroblasts that were crucial in the differentiation of distinct stromal characterizations. Based on these studies, a practical classifier for the stromal microenvironment was successfully proposed to predict the prognosis of ESCA patients.
A novel classification regression method for gridded electric power consumption estimation in China
Authors: Chen Mulin , Cai Hongyan , Yang Xiaohuan , Jin Cui
Published: October 2020

Spatially explicit information on electric power consumption (EPC) is crucial for effective electricity allocation and utilization. Many studies have estimated fine-scale spatial EPC based on remotely sensed nighttime light (NTL). However, the spatial non-stationary relationship between EPC and NTL at prefectural level tends to be overlooked in existing literature. In this study, a classification regression method to estimate the gridded EPC in China based on imaging NTL via a Visible Infrared Imaging Radiometer Suite (VIIRS) was described. In addition, owing to some inherent omissions in the VIIRS NTL data, the study has employed the cubic Hermite interpolation to produce a more appropriate NTL dataset for estimation. The proposed method was compared with ordinary least squares (OLS) and geographically weighted regression (GWR) approaches. The results showed that our proposed method outperformed OLS and GWR in relative error (RE) and mean absolute percentage error (MAPE). The desirable results benefited mainly from a reasonable classification scheme that fully considered the spatial non-stationary relationship between EPC and NTL. Thus, the analysis suggested that the proposed classification regression method would enhance the accuracy of the gridded EPC estimation and provide a valuable reference predictive model for electricity consumption.
De-identification of electronic health record using neural network
Authors: Ahmed Tanbir , Aziz Md Momin Al , Mohammed Noman
Published: October 2020

According to a recent study, around 99% of hospitals across the US now use electronic health record systems (EHRs). One of the most common types of EHR is the unstructured textual data, and unlocking hidden details from this data is critical for improving current medical practices and research endeavors. However, these textual data contain sensitive information, which could compromise our privacy. Therefore, medical textual data cannot be released publicly without undergoing any privacy-protective measures. De-identification is a process of detecting and removing all sensitive information present in EHRs, and it is a necessary step towards privacy-preserving EHR data sharing. Over the last decade, there have been several proposals to de-identify textual data using manual, rule-based, and machine learning methods. In this article, we propose new methods to de-identify textual data based on the self-attention mechanism and stacked Recurrent Neural Network. To the best of our knowledge, we are the first to employ these techniques. Experimental results on three different datasets show that our model performs better than all state-of-the-art mechanism irrespective of the dataset. Additionally, our proposed method is significantly faster than the existing techniques. Finally, we introduced three utility metrics to judge the quality of the de-identified data.
Simultaneous analysis of five triterpenes in Centella asiatica by high performance liquid chromatography with cyclodextrins as the mobile phase additives
Authors: Wang Changhe , Zhao Yanan , Yang Ruomeng , Liu Haijing
Published: October 2020

Triterpenes are considered the major active components in Centella asiatica (L.) Urb. (C. asiatica), such as asiatic acid, madecassic acid, asiaticoside, madecassoside and asiaticoside B. It is difficult to simultaneously determine five triterpenes because of madecassoside isomers (madecassoside and asiaticoside B), and the great polarity difference between triterpene acid and triterpene glycoside. In this study, a simple high performance liquid chromatography method with isocratic elution employing cyclodextrins (CDs) as the mobile phase additives was developed to determine five triterpenes in C. asiatica. Various factors affecting triterpenes retention in the C18 column, such as the nature of CDs, γ-CD concentration, acetonitrile percentage and temperature, were studied. Experimental results showed that γ-CD, as an effective mobile phase additive, could markedly reduce the retention of triterpenes (especially asiatic acid and madecassic acid), and improve the separation for madecassoside and asiaticoside B. The elution of five triterpenes could be achieved on an ODS C18 column within 30 min using the acetonitrile-0.2% phosphoric acid contained 4.0 mM γ-CD (20:80, v/v) mixture as the mobile phase. The retention modification of triterpenes may be attributed to the formation of the triterpenes-γ-CD inclusion complexes. The optimized method was successfully applied for simultaneous determination of five triterpenes in C. asiatica.
Anemonefish facilitate bleaching recovery in a host sea anemone
Authors: Pryor Sophie H. , Hill Ross , Dixson Danielle L. , Fraser Nicola J. , Kelaher Brendan P. , Scott Anna
Published: October 2020

Ocean warming is causing the symbioses between cnidarians and their algal symbionts to breakdown more frequently, resulting in bleaching. For sea anemones, nutritional benefits derived from hosting anemonefishes increase their algal symbiont density. The sea anemone-anemonefish relationship could, therefore, facilitate bleaching recovery. To test this, bleached and unbleached sea anemones, both with and without anemonefish, were monitored in the laboratory. At the start of our experiment, algal symbiont density and colour score were lower in the bleached than unbleached sea anemones, whereas total chlorophyll remained similar. After 106 days, bleached sea anemones with anemonefish had an algal symbiont density and colour score equal to the controls (unbleached sea anemones and without anemonefish), indicating recovery had occurred. Furthermore, total chlorophyll was 66% higher in the bleached sea anemones with anemonefish than the controls. In contrast, recovery did not occur for the bleached sea anemones without anemonefish as they had 78% fewer algal symbionts than the controls, and colour score remained lower. Unbleached sea anemones with anemonefish also showed positive changes in algal symbiont density and total chlorophyll, which increased by 103% and 264%, respectively. Consequently, anemonefishes give their host sea anemones a distinct ecological advantage by enhancing resilience to bleaching, highlighting the benefits of symbioses in a changing climate.
Functional parameters of small airways can guide bronchodilator use in idiopathic pulmonary fibrosis
Authors: Hu Po-Wei , Ko Hsin-Kuo , Su Kang-Cheng , Feng Jia-Yih , Su Wei-Juin , Hsiao Yi-Han , Perng Diahn-Warng
Published: October 2020

Idiopathic pulmonary fibrosis (IPF) may present comorbid obstructive lung diseases with small airway dysfunction (SAD). Existing guidelines suggest that inhaled bronchodilators should be used if the ratio of forced expiratory volume in the 1st second and forced vital capacity (FEV1/FVC) < 0.7 in IPF. However, most IPF patients have FEV1/FVC > 0.7 even with coexisting emphysema. We retrospectively enrolled IPF patients who were registered at our outpatient clinic. At baseline, 63 patients completed computed tomography (CT) scans, lung function measurements, and symptom questionnaires. Among these patients, 54 (85.71%) underwent antifibrotic treatment and 38 (60.32%) underwent long-acting bronchodilator treatment. The median FEV1/FVC was 0.86. Not all patients treated with bronchodilators showed significant changes in lung function. IPF patients with SAD, determined by IOS parameters, showed significant improvement in FEV1, FEF25–75%, and symptom scores after bronchodilator treatment. Bronchodilator efficacy was not observed in patients without SAD. CT-confirmed emphysema was seen in 34.92% of patients. There were no changes in lung function or symptom scores after bronchodilator treatment in patients with emphysema. In conclusion, FEV1/FVC cannot reflect the airflow limitation in IPF. Emphysema in IPF is not a deciding factor in whether patients should receive bronchodilator treatment. IOS parameters may be useful to guide bronchodilator therapy in patients with IPF coexisting with SAD.
Contribution of Podoviridae and Myoviridae bacteriophages to the effectiveness of anti-staphylococcal therapeutic cocktails
Authors: Kornienko Maria , Kuptsov Nikita , Gorodnichev Roman , Bespiatykh Dmitry , Guliaev Andrei , Letarova Maria , Kulikov Eugene , Veselovsky Vladimir , Malakhova Maya , Letarov Andrey , Ilina Elena , Shitikov Egor
Published: October 2020

Bacteriophage therapy is considered one of the most promising therapeutic approaches against multi-drug resistant bacterial infections. Infections caused by Staphylococcus aureus are very efficiently controlled with therapeutic bacteriophage cocktails, containing a number of individual phages infecting a majority of known pathogenic S. aureus strains. We assessed the contribution of individual bacteriophages comprising a therapeutic bacteriophage cocktail against S. aureus in order to optimize its composition. Two lytic bacteriophages vB_SauM-515A1 (Myoviridae) and vB_SauP-436A (Podoviridae) were isolated from the commercial therapeutic cocktail produced by Microgen (Russia). Host ranges of the phages were established on the panel of 75 S. aureus strains. Phage vB_SauM-515A1 lysed 85.3% and vB_SauP-436A lysed 68.0% of the strains, however, vB_SauP-436A was active against four strains resistant to vB_SauM-515A1, as well as to the therapeutic cocktail per se. Suboptimal results of the therapeutic cocktail application were due to extremely low vB_SauP-436A1 content in this composition. Optimization of the phage titers led to an increase in overall cocktail efficiency. Thus, one of the effective ways to optimize the phage cocktails design was demonstrated and realized by using bacteriophages of different families and lytic spectra.