bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic permeability functions for partially saturated porous media
Authors: Solazzi Santiago G , Rubino J Germán , Jougnot Damien , Holliger Klaus
Published: February 2020

While the frequency-dependence of permeability under fully saturated conditions has been studied for decades, the corresponding characteristics of partially saturated porous media remain unexplored. Notably, it is not clear whether the use of effective pore fluid approaches under such conditions is valid. To address this issue, we propose a method that allows us to obtain dynamic permeability functions for partially saturated porous media. To this end, we conceptualize the considered pore space as a bundle of capillary tubes of different radii saturated by two immiscible fluid phases. We then solve the Navier–Stokes equations within the pore space and define a capillary pressure–saturation relationship, which permits to obtain saturation- and frequency-dependent effective permeability estimates. The application of this method to a realistic model of an unconsolidated granular sediment demonstrates that dynamic effective permeability functions for wetting and non-wetting fluid phases exhibit distinct characteristics, thus rendering effective pore fluid approaches inadequate. Finally, we explore the capability of the seminal dynamic permeability model developed by Johnson et al.[J. Fluid Mech. 176, 379 (1987)] to account for the effects of partial saturation. We find that the frequency scaling proposed by Johnson et al. prevails in partially saturated scenarios. However, the parameters associated with this model need to be redefined to account for saturation-dependent effects.
Term Formation under the Prism of Linguistic Purism: Borrowings in German and Greek
Authors: Koliopoulou Maria
Published: February 2020

The present study investigates the role of borrowing in specialised language and the connection of this crosslinguistically common phenomenon with the attitude of language purism. German and Greek have been selected for the purpose of this study. The selection of these languages is based on their comparable morphological properties, but also on their different terminological characteristics. The data come mainly from the domain of statistics. However, some examples from a different domain, that of computer science, are also discussed. The different terminological profiles of the selected languages are found to coincide with the specific characteristics of the two domains. These characteristics are also linked to their attitudes towards foreign words and especially borrowing. In this respect, this paper investigates borrowed words from a morphological and a sociolinguistic point of view.
Determinants of the Economic Adaptation of Refugees: The Case of Midyat Camp
Authors: Abedtalas Musallam , Toprak Lokman , Aloklah Wissam Aldien , Alawak Abdulhamid , Aljasem Abdulnaser , Aykol Şehmus
Published: February 2020

In the context of the bottom-up approach to development and poverty reduction, this is the first study to use the Sustainable Livelihood Approach (SLA), with a slight adjustment, to study the economic adaptation of refugees within camps. The objective of this study was to explore the factors affecting the economic adaptation of refugees in Midyat Refugee Camp in Turkey. The study used a focus group to help design the questionnaire that was subsequently used to collect data from a sample of 393 households in Midyat Camp. The data was used to estimate a Structural Equations Model. The findings indicated that the most important factors in determining refugees' economic adaptation are human capital, social capital and institutions.
Discussing the Populist Features of Anti-refugee Discourses on Social Media: An Anti-Syrian Hashtag in Turkish Twitter
Authors: Özerim Mehmet Gökay , Tolay Juliette
Published: February 2020

This article discusses whether it is possible to frame anti-refugee discourse on social media as a form of populism by analysing the case study of the hashtag #ülkemdesuriyeliistemiyorum (#IdontwantSyriansinmycountry), which emerged on Twitter in Turkey in 2016. Both network analysis and discourse analysis are used in order to delineate the characteristics of the tropes associated with the hashtag, to identify the existence of populist elements, as well as to scrutinize the linkage of the hashtag with the broader political context. The study shows that some elements of a populist discourse clearly exist (simple and popular discourse, anti-foreigner), while some others are missing (the existence of a leader). Most importantly, the discussion of the other elements (dichotomous views, othering and anti-elite) highlight the need to better conceptualize and contextualize these features to understand the connection between anti-elite (populism) and anti-foreigner discourses (nativism), the impact of tagged tropes such as a hashtag that can poke holes in echo chambers and the distinction between the concepts of anti-elitism and anti-establishment (especially in specific political contexts such as Turkey).
Cloud fragmentation cascades and feedback: on reconciling an unfettered inertial range with a low star formation rate
Authors: Blackman Eric G
Published: February 2020

Molecular cloud complexes exhibit both (i) an unfettered Larson-type spectrum over much of their dynamic range, whilst (ii) still producing a much lower star formation rate than were this cascade to remain unfettered all the way down to star-forming scales. Here we explain the compatibility of these attributes with minimalist considerations of a mass-conserving fragmentation cascade, combined with estimates of stellar feedback. Of importance is that the amount of feedback needed to abate fragmentation and truncate the complex decreases with decreasing scale. The scale at which the feedback momentum matches the free-fall momentum marks a transition scale below most of the cascade is truncated and the molecular cloud complex dissipated. For a 106 M⊙ giant molecular cloud (GMC) complex starting with radius of ∼50 pc, the combined feedback from young stellar objects, supernovae, radiation, and stellar winds for a GMC cloud complex can truncate the cascade within an outer free-fall time but only after the cascade reaches parsec scales.
Parry–Romberg syndrome in an adolescent: a case report on progressive hemifacial atrophy
Authors: Srinivasan Ranjini , Joy Shasta Theresa
Published: February 2020

Parry–Romberg syndrome is a rare degenerative disorder causing progressive atrophy of skin and soft tissues of the face and neck, which is usually unilateral. The mean age of onset is usually in the second decade of life and the disease causes functional, aesthetic and psychological disabilities in the affected individual. We present a 14-year-old boy with this disorder. The diagnosis was based on clinical characteristics. A multidisciplinary team approach involving rheumatologists, dermatologists, maxillofacial surgeons, dentists and psychologists is required for the management of this problem, which is mainly targeted at controlling active inflammation with the use of immunosuppressive agents in addition to possible surgical correction of repositioning of adipose tissue that is lost due to atrophy.
Effects of symmetry energy on the radius and tidal deformability of neutron stars in the relativistic mean-field model
Authors: Hu Jinniu , Bao Shishao , Zhang Ying , Nakazato Ken’ichiro , Sumiyoshi Kohsuke , Shen Hong
Published: February 2020

The radii and tidal deformabilities of neutron stars are investigated in the framework of the relativistic mean-field (RMF) model with different density-dependent behaviors of symmetry energy. To study the effects of symmetry energy on the properties of neutron stars, $\omega$ meson and $\rho$ meson coupling terms are included in a popular RMF Lagrangian, i.e., the TM1 parameter set, which is adopted for the widely used supernova equation of state (EoS) table. The coupling constants relevant to the vector–isovector meson, $\rho$, are refitted by a fixed symmetry energy at subsaturation density and its slope at saturation density, while other coupling constants remain the same as the original ones in TM1 so as to update the supernova EoS table. The radius and mass of maximum neutron stars are not so sensitive to the symmetry energy in these family TM1 parameterizations. However, the radii in the intermediate-mass region are strongly correlated with the slope of symmetry energy. Furthermore, the dimensionless tidal deformabilities of neutron stars are also calculated within the associated Love number, which is related to the quadrupole deformation of the star in a static external tidal field and can be extracted from the observation of a gravitational wave generated by a binary star merger. We find that its value at $1.4 \mathrm{M}_\odot$ has a linear correlation to the slope of symmetry energy, unlike that previously studied. With the latest constraints of tidal deformabilities from the GW170817 event, the slope of symmetry energy at nuclear saturation density should be smaller than $60$ MeV in the family TM1 parameterizations. This fact supports the usage of a lower symmetry energy slope for the updated supernova EoS, which is applicable to simulations of neutron star mergers. Furthermore, an analogous analysis is also done within the family IUFSU parameter sets. It is found that the correlations between the symmetry energy slope with the radius and tidal deformability at $1.4 \mathrm{M}_\odot$ have very similar linear relations in these RMF models.
Long-Run Effects of Lottery Wealth on Psychological Well-Being
Authors: Lindqvist Erik , Östling Robert , Cesarini David
Published: February 2020

We surveyed a large sample of Swedish lottery players about their psychological well-being 5–22 years after a major lottery event and analysed the data following pre-registered procedures. Relative to matched controls, large-prize winners experience sustained increases in overall life satisfaction that persist for over a decade and show no evidence of dissipating over time. The estimated treatment effects on happiness and mental health are significantly smaller. Follow-up analyses of domain-specific aspects of life satisfaction implicate financial life satisfaction as an important mediator for the long-run increase in overall life satisfaction.
Adaptations and patient responses to behavioral intervention components in a depression-focused chronic disease care model implemented in India
Authors: Johnson Leslie C M , Chwastiak Lydia , Poongothai Subramani , Tandon Nikhil , Anjana Ranjit Mohan , Aravind Sosale , Sridhar Gumpeny Ramachandra , Rao Deepa , Mohan Viswanathan , Ali Mohammed K
Published: February 2020

Integrated care models offer one approach to treat patients with chronic multimorbidity. However, because these models consist of multiple components designed to provide individualized care, they should be adapted to best meet the needs of patients in diverse settings. This paper presents qualitative and quantitative data from a realist process evaluation embedded in the INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study to uncover what worked, for whom, how, and in what circumstances. We aimed to examine adaptations made to a care coordinator-led behavioral intervention, and how patients responded to adaptations, through a secondary analysis of these data. A purposive sample of 62 patients and 3 care coordinators were recruited based on their involvement with the INDEPENDENT care model across two clinics. Patients were interviewed and surveyed about their experiences in the care model and care coordinators were interviewed about their experiences implementing intervention components. Interview data were coded for reported modifications in intervention content, tools, and delivery; then, these adaptations were categorized by how they served to enhance implementation in the Indian context. Adaptations made in the delivery of this care model served two functions: (a) to improve health promotion communication between care coordinators and patients and (b) to improve patient engagement. Patients’ expressed needs were consistent with what care coordinators perceived. Patients were satisfied with adaptations designed to improve intervention fit for local contexts. Study findings demonstrate that adapting components of an integrated care model can enhance patient satisfaction and engagement with behavioral interventions.
Solution-based science to prevent and control diabetes in underserved communities around the world (commentary, for Diabetes special section)
Authors: King Abby C
Published: February 2020

Despite the numerous successful behavioral interventions that have been published in the behavioral medicine field over a number of decades, surprisingly few have been translated and adapted for real-world settings using participatory research methods. The purpose of this commentary is to highlight the advances in participatory behavioral medicine reflected in the articles contained in the Diabetes special section. The articles contained in the Diabetes special section were reviewed, with a focus on the advances made with this type of research and the challenges that came to light. Numerous strengths of the large-scale translational studies were identified. The studies also highlighted important areas meriting further attention, including exploration of additional dissemination pathways, and further piloting and refinement of program components for different population segments. The articles in this special section represent major advances in implementing successful, impactful programs for diabetes prevention and control in low- and middle-income countries.
Impact of Cardiovascular Disease Risk Factors on Subfoveal Choroidal Thickness by Enhanced-depth Spectral Domain Optical Coherence Tomography
Authors: Druckenbrod Rachel C. , Asefzadeh Baharak , Bertolet Anne
Published: February 2020

SIGNIFICANCE

Risk stratification plays a large role in cardiovascular disease (CVD) management. Spectral-domain optical coherence tomography (SD-OCT) allows for noninvasive analysis of the ophthalmic vasculature, with potential for systemic disease surveillance. Subfoveal choroidal thickness (SFCT) may serve as a marker for CVD risk and play a role in risk stratification.

PURPOSE

This study aimed to explore the association of major CVD risk factors on SFCT measured from SD-OCT images in a general population of U.S. veterans.

METHODS

One hundred fifty veterans were prospectively recruited at the Jamaica Plain VA Hospital (Boston, MA). A total of 143 participants were included in the final analysis. The SFCT was manually measured from Spectralis SD-OCT macular scans, and medical chart review was analyzed for CVD data. The SFCT measurements were correlated with CVD risk factors and CVD clinical makers while controlling for age and refractive error. Mean differences in SFCT between those with and without CVD risk factors were analyzed.

RESULTS

In multivariate analysis, diabetes diagnosis was independently associated with thinner subfoveal choroid (P = .001) and hypertension and hyperlipidemia with thicker subfoveal choroid (P = .006 and P = .05). After adjusting for age and refractive error, veterans with diabetes had thinner choroids than those without (P = .02), and veterans with hypertension and hyperlipidemia had thicker choroids than those without, although these differences did not reach statistical significance (P = .07 and P = .1).

CONCLUSIONS

Comorbid risk factors for CVD are independently associated with optical coherence tomography–derived measurements of subfoveal choroidal thickness in a vasculopathic population of U.S. veterans, and there are detectable differences in subfoveal choroidal thickness between groups with and without CVD risk factors. Larger studies with adequate controls and longitudinal design are necessary to assess the clinical role of SFCT measurements in CVD risk analysis.
Case Report: Evaluating Intraocular Foreign Bodies After Corneal Perforation Using Swept Source Anterior Segment Optical Coherence Tomography
Authors: Rahhal-Ortuño Miriam , Monferrer-Adsuara Clara , Fernández-Santodomingo Alex Samir , Martínez-Rubio Clara , Carpintero-Sanchez Jesús María , Vila-Arteaga Jorge
Published: February 2020

SIGNIFICANCE

Use of anterior segment optical coherence tomography (OCT) is reported, exploring its advantages over other examination techniques.

PURPOSE

The purpose of this study was to report a case in which anterior segment OCT was used to evaluate the presence of intraocular bodies after corneal perforation.

CASE REPORT

A 33-year-old man was referred to our ophthalmology department after traumatic ocular injury. Swept-source anterior segment was carried out showing corneal perforation and anterior lens capsule rupture.

CONCLUSIONS

Evaluating the integrity of posterior capsule and iris after traumatic ocular injury with corneal perforation using anterior segment OCT is a valuable tool to rule out the presence of intraocular foreign bodies without contact and without using radiating imaging techniques.
When good bacteria behave badly: a case report of Bacillus clausii sepsis in an immunocompetant adult
Authors: Princess Isabella , Natarajan T. , Ghosh Siddhartha
Published: February 2020

Reports of unusual microorganisms causing human infections are on the rise due to transitions in epidemiological trends. Commensal/normal flora which are otherwise termed as ‘good bacteria’ are now causing infections in different group of patients, mostly immunocompromised individuals. Various host and environmental factors play a pivotal role in microbial transmigration from their normal habitat into the blood and other body sites. We report one such ‘good bacterium’ associated with sepsis in a patient who was given the same bacterium in the form of probiotics.
Blood Levels of NLRP3 Inflammasome Components is Associated with Obsessive Compulsive Disorder
Authors: Tetik Melike , Direk Nese , Onder Betul , Aykac Cansu , Ekinci Burcu , Yaras Tutku , Kuruoglu Aykut , Ermis Cagatay , Alkin Tunc , Oktay Yavuz
Published: February 2020

Background

Inflammation has a well-known role in the pathogenesis of a range of neuropsychiatric disorders such as major depressive disorder and schizophrenia. Previous studies provided evidence regarding its possible involvement in the etiology of obsessive-compulsive disorder (OCD). However, mechanisms explaining the association of inflammation with OCD are lacking. The NLRP3 inflammasome complex initiates and mediates inflammatory response, which explain one of the most important key mechanisms behind inflammatory response. In this study, we aimed to determine a possible association between NLRP3 inflammasome and OCD, and to evaluate its relationship with clinical features.

Methods

This case-control study included 103 participants (51 OCD and 52 healthy controls). OCD patients were diagnosed using DSM-IV criteria. All participants were evaluated by psychiatric inventories, i.e. Yale Brown Obsessive Compulsive Scale, Hamilton Depression Scale, and Hewitt Multidimensional Perfectionism Scale. Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood samples. RNA and protein were extracted from PBMCs and expression of NLRP3 inflammasome components were evaluated by quantitative real-time PCR (qPCR) and Western blotting. Serum IL-1beta and IL-18 cytokine levels were determined by ELISA.

Results

NEK7 and CASP1 mRNA levels were significantly higher in OCD patients, compared to controls. Pro-Caspase-1 protein levels were elevated, as well. Regression analysis showed that NEK7 mRNA and Caspase-1 protein levels can differentiate OCD and healthy control groups.

Discussion

pro-Caspase-1 mRNA and protein levels in PBMCs, as well as NEK7 mRNA levels are potential biomarker candidates in OCD. Our results may prompt research into possible role of NLRP3 inflammasome in OCD etiology.
Measuring Nestedness: A comparative study of the performance of different metrics
Authors: Payrató-Borràs Clàudia , Hernández Laura , Moreno Yamir
Published: February 2020

Nestedness is a property of interaction networks widely observed in natural mutualistic communities, like plant-pollinators or plant-seed dispersers, among other systems. A perfectly nested network is characterized by the peculiarity that the interactions of any node form a subset of the interactions of all nodes with higher degree. Despite a widespread interest on this pattern, no general consensus exists on how to measure it. Instead, several metrics aiming at quantifying nestedness, based on different but not necessarily independent properties of the networks, coexist in the literature blurring the comparison between ecosystems.

In this work we present a detailed critical study of the behavior of six popular nestedness metrics and the variants of two of them. In order to evaluate their performance, we compare the obtained values of the nestedness of a large set of real networks among them and against a maximum entropy and maximum likelihood null model. We also analyze the dependencies of each metrics on different network parameters as size, fill and eccentricity.

Our results point out, first, that the metrics do not rank the degree of nestedness of networks universally. Furthermore, several metrics show significant undesired dependencies on the network properties considered. The study of these dependencies allows us to understand some of the systematic shifts between the real values of nestedness and the average over the null model.

This paper intends to provide readers with a critical guide on how to measure nestedness patterns, by explaining the functioning of six standard metrics and two of its variants, and then disclosing its qualities and flaws. By doing so, we also aim to extend the application of the recently proposed null models based on maximum entropy to the still largely unexplored area of ecological networks.

Finally, to complement the guide, we provide a fully-documented repository namednullnestwhich gathers the codes to produce the null model and calculate the nestedness index -both the real value and the null expectation-using the studied metrics. The repository contains, moreover, the main results of the null model applied to a large dataset of more than 200 bipartite networks.
Multi-modal meta-analysis of cancer cell line omics profiles identifies ECHDC1 as a novel breast tumor suppressor
Authors: Jaiswal Alok , Gautam Prson , Pietilä Elina A , Timonen Sanna , Nordström Nora , Sipari Nina , Tanoli Ziaurrehman , Lehti Kaisa , Wennerberg Krister , Aittokallio Tero
Published: February 2020

A caveat of cancer cell line models is that their molecular and functional profiling is subject to laboratory-specific experimental practices and data analysis protocols. The current challenge is how to make an integrated use of omics profiles of cancer cell lines for reliable discoveries. Here, we carried out a systematic analysis of nine types of data modalities using meta-analysis of 53 omics profiling studies across 12 research laboratories for 2018 cell lines. To account for relatively low consistency observed for certain data modalities, we developed a robust data integration approach that identifies reproducible signals shared among multiple data modalities and studies. We demonstrated the power of the integrative analyses by identifying a novel driver gene, ECHDC1, with tumor suppressive role validated both in breast cancer cells and patient tumors. Extension of the approach identified synthetic lethal partners of cancer drivers, including a co-dependency of PTEN deficient cells on RNA helicases.

Highlights

A comprehensive meta-analysis of 53 multi-modal omics profiles of >2000 cancer cell lines from 12 research laboratories

An unexpected lack of consistency between TMT-labelled and non-labelled global proteomic profiles

A non-parametric approach to integrate omics profiles from multiple laboratories and to identify robust molecular patterns in individual cell lines

The multi-modal data integration reveals novel drivers and potential therapeutic targets, including ECHDC1 in breast cancers and DDX27 in PTEN mutant cancers.
Dissolved oxygen dynamics reveal biogeochemical tipping points driven by river corridor hydrology
Authors: Kaufman Matthew H , Ghosh Ruby N , Grate Jay , Shooltz Dean D , Freeman Michael J , Ball Terry M , Loloee Reza , McIntire Charles W , Wells Jackie , Strickland Chris , Vermeul Vince , Rod Kenton A. , Mackley Rob , Lin Xinming , Ren Huiying , Stegen James
Published: February 2020

Riverbeds can have an important impact on large-scale fluxes of biogeochemically active solutes in river corridor systems. The hyporheic zone is an important area of both hydrology and biogeochemistry, particularly in a hydropeaked river system where rapid variations in river stage height, hydraulic gradients, and residence times occur. We measured several biogeochemical and hydrological parameters at three different subsurface depths in the riverbed of the Columbia River in Washington state, a complex hydropeaked river system with significant subsurface heterogeneity. During the study, episodes of significant dissolved oxygen (DO) change were observed. The DO signal changes were the most apparent, compared to more modest changes in other biogeochemical markers. While DO is often associated with biological activity, we ultimately found that the notable DO excursions were associated with hydrologic gradients. Here we describe hydrologic perturbations and biogeochemical responses in terms of hydrobiogeochemical regimes. Two different forms of DO response to hydraulic gradient perturbation were observed, defining different hydrobiogeochemical regimes. The system tips abruptly from one regime to the other, exhibiting threshold behavior that is uncaptured in current estimations of cumulative influences of subsurface processes from reach to earth system scales.

Plain language summary

The water in a river is constantly flowing in and out of the river’s bed. While it is in the bed, microbes process environmentally and ecologically important nutrients and other compounds. The exchange of water between the river and the riverbed is largely controlled by the stage of the river. Many processes, both natural and human, can cause rapid changes in the river stage. These rapid stage changes can cause abrupt changes in the riverbed’s ability to process nutrients and other compounds. In this study, we use dissolved oxygen as a window into riverbed microbial and chemical processing. We see that relatively rapid changes in river stage can cause abrupt changes in the concentrations of chemicals in the riverbed, indicating fundamental changes in how the riverbed processes are occurring. Understanding these abrupt and fundamental changes is important to our overall understanding of the ecological function of river corridor systems.

3 key points

A hydrobiogeochemical regime is defined by the functional form of the relationship of a hydrologic perturbation and biogeochemical marker.

Short-term hydrologic perturbations drive tipping points between distinct hydrobiogeochemical regimes.

Linear and hysteretic dissolved oxygen dynamics define distinct regimes as observed throughout the hyporheic zone.
ShearFAST: a user-friendlyin vitrotoolset for high throughput, inexpensive fluid shear stress experiments
Authors: Smith Thomas Brendan , De Nunzio Alessandro Marco , Patel Kamlesh , Munford Haydn , Alam Tabeer , Powell Ohema , Heneghan Nicola , Ready Andrew , Nath Jay , Ludwig Christian
Published: February 2020

Fluid shear stress is a key modulator of cellular physiologyin vitroandin vivo, but its effects are under-investigated due to requirements for complicated induction methods.

Herein we report the validation of ShearFAST; a smartphone application that measures the rocking profile on a standard laboratory cell rocker and calculates the resulting shear stress arising in tissue culture plates.

ShearFAST measured rocking profiles were validated against a graphical analysis and also against measures reported by an 8-camera motion tracking system.

ShearFAST angle assessments correlated well with both analyses (r ≥0.99, p ≤0.001) with no significant differences in pitch detected across the range of rocking angles tested.

Rocking frequency assessment by ShearFAST also correlated well when compared to the two independent validatory techniques (r ≥0.99, p ≤0.0001), with excellent reproducibility between ShearFAST and video analysis (mean frequency measurement difference of 0.006 ± 0.005Hz) and motion capture analysis (mean frequency measurement difference of 0.008 ± 0.012Hz) These data make the ShearFAST assisted cell rocker model make it an attractive approach for economical, high throughput fluid shear stress experiments.

Abstract Figure
Layer-dependent multiplicative effects of spatial attention on contrast responses in human early visual cortex
Authors: Guo Fanhua , Liu Chengwen , Qian Chencan , Zhang Zihao , Sun Kaibao , Wang Danny JJ , He Sheng , Zhang Peng
Published: February 2020

Attention mechanisms at different cortical layers of human visual cortex remain poorly understood. Using submillimeter-resolution fMRI at 7T, we investigated the effects of top-down spatial attention on the contrast responses across different cortical depths in human early visual cortex. Gradient echo (GE) T2* weighted BOLD signal showed an additive effect of attention on contrast responses across cortical depths. Compared to the middle cortical depth, attention modulation was stronger in the superficial and deep depths of V1, and also stronger in the superficial depth of V2 and V3. Using ultra-high resolution (0.3mm in-plane) balanced steady-state free precession (bSSFP) fMRI, a multiplicative scaling effect of attention was found in the superficial and deep layers, but not in the middle layer of V1. Attention modulation of low contrast response was strongest in the middle cortical depths, indicating baseline enhancement or contrast gain of attention modulation on feedforward input. Finally, the additive effect of attention on T2* BOLD can be explained by strong nonlinearity of BOLD signals from large blood vessels, suggesting multiplicative effect of attention on neural activity. These findings support that top-down spatial attention mainly operates through feedback connections from higher order cortical areas, and a distinct mechanism of attention may also be associated with feedforward input through subcortical pathway.

Highlights

Response or activity gain of spatial attention in superficial and deep layers

Contrast gain or baseline shift of attention in V1 middle layer

Nonlinearity of large blood vessel causes additive effect of attention on T2* BOLD
Engineering Selective Molecular Tethers to Enhance Suboptimal Drug Properties
Authors: Dogan Alan B. , von Recum Horst A.
Published: February 2020

Small-molecule drugs are utilized in a wide variety of clinical applications, however, many of these drugs suffer from one or more suboptimal property that can hinder its delivery or cellular action in vivo, or even shelf an otherwise biologically tolerable drug. While high-throughput screening provides a method to discover drugs with altered chemical properties, directly engineering small-molecule bioconjugates provides an opportunity to specifically modulate drug properties rather than sifting through large drug libraries with seemingly ‘random’ drug properties. Herein, we propose that selectively “tethering” a drug molecule to an additional group with favorable properties will improve the drug conjugate’s overall properties, such as solubility. Specifically, we outlined the site-specific chemical conjugation of rapamycin (RAP) to an additional “high-affinity” group to increase the overall affinity the drug has for cyclodextrin-based polymers (pCD). By doing so, we found that RAP’s affinity for pCD and RAP’s window of delivery from pCD microparticles was tripled without sacrificing RAP’s cellular action. This synthesis method was applied to the concept of “affinity” for pCD, but other prosthetic groups can be used in a similar manner to modify other drug properties. This study displays potential for increasing drug delivery windows of small-molecule drugs in pCD systems for chronic drug therapies and introduces the idea of altering drug properties to tune polymer-drug interactions.
Cytoskeletal Tubulin Competes with Actin to Increase Deformability of Metastatic Melanoma Cells
Authors: Higgins Ghodeejah , Peres Jade , Abdalrahman Tamer , Zaman Muhammad H , Lang Dirk M , Prince Sharon , Franz Thomas
Published: February 2020

The formation of membrane protrusions during migration is reliant upon the cells’ cytoskeletal structure and stiffness. It has been reported that actin disruption blocks protrusions and decreases cell stiffness whereas microtubule disruption blocks protrusion but increases stiffness in several cell types. In melanoma, cell migration is of concern as this cancer spreads unusually rapidly during early tumour development. The aim of this study was to characterise motility, structural properties and stiffness of human melanoma cells at radial growth phase (RGP), vertical growth phase (VGP), and metastatic stage (MET) in two-dimensionalin vitroenvironments. Wound assays, western blotting and mitochondrial particle tracking were used to assess cell migration, cytoskeletal content and intracellular fluidity. Our results indicate that cell motility increase with increasing disease stage. Despite their different motility, RGP and VGP cells exhibit similar fluidity, actin and tubulin levels. MET cells, however, display increased fluidity which was associated with increased actin and tubulin content. Our findings demonstrate an interplay between actin and microtubule activity and their role in increasing motility of cells while minimizing cell stiffness at advanced disease stage. In earlier disease stages, cell stiffness may however not serve as an indicator of migratory capabilities.
Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiate the DNA damage response and repair
Authors: Meng Fanbiao , Qian Minxian , Peng Bin , Wang Xiaohui , Peng Linyuan , Zheng Kang , Liu Zuojun , Tang Xiaolong , Zhang Shuju , Sun Shimin , Cao Xinyue , Pang Qiuxiang , Zhao Bosheng , Ma Wenbin , Songyang Zhou , Xu Bo , Zhu Wei-Guo , Xu Xingzhi , Liu Baohua
Published: February 2020

The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result ofSIRT1deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair.
A guided approach for subtomogram averaging of challenging macromolecular assemblies
Authors: Grotjahn Danielle , Chowdhury Saikat , Lander Gabriel C.
Published: February 2020

Cryo-electron tomography is a powerful biophysical technique enabling three-dimensional visualization of complex biological systems. Macromolecular targets of interest identified within cryo-tomograms can be computationally extracted, aligned, and averaged to produce a better-resolved structure through a process called subtomogram averaging (STA). However, accurate alignment of macromolecular machines that exhibit extreme structural heterogeneity and conformational flexibility remains a significant challenge with conventional STA approaches. To expand the applicability of STA to a broader range of pleomorphic complexes, we developed a user-guided, focused refinement approach that can be incorporated into the standard STA workflow to facilitate the robust alignment of particularly challenging samples. We demonstrate that it is possible to align visually recognizable portions of multi-subunit complexes by providinga prioriinformation regarding their relative orientations within cryo-tomograms, and describe how this strategy was applied to successfully elucidate the first three-dimensional structure of the dynein-dynactin motor protein complex bound to microtubules. Our approach expands the application of STA for solving a more diverse range of heterogeneous biological structures, and establishes a conceptual framework for the development of automated strategies to deconvolve the complexity of crowded cellular environments and improve in situ structure determination technologies.
Metastatic signaling of hypoxia-related genes across TCGA Pan-Cancer types
Authors: López-Cortés Andrés , Guevara-Ramírez Patricia , Guerrero Santiago , Ortiz-Prado Esteban , García-Cárdenas Jennyfer M. , Zambrano Ana Karina , Armendáriz-Castillo Isaac , Pérez-Villa Andy , Yumiceba Verónica , Varela Nelson , Córdova-Bastidas Daniel , Leone Paola E. , Paz-y-Miño César
Published: February 2020

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis. Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Here we focused on elucidating the molecular hallmarks of tumor hypoxia that remains poorly defined. To fill this gap, we analyzed the genomic alterations and hypoxia score of 233 hypoxia-related genes of 6,343 individuals across 17 TCGA Pan-Cancer types. In addition, we analyzed a protein-protein interactome (PPi) network and the shortest paths from hypoxic proteins to metastasis. As results, mRNA high alteration was prevalent in all cancer types. Genomic alterations and hypoxia score presented a highest frequency in tumor stage 4 and positive metastasis status in all cancer types. The most significant signaling pathways were HIF-1, ErbB, PI3K-Akt, FoxO, mTOR, Ras and VEGF. The PPi network revealed a strong association among hypoxic proteins, cancer driver proteins and metastasis driver proteins. The analysis of shortest paths revealed 99 ways to spread metastasis signaling from hypoxic proteins. Additionally, we proposed 62 hypoxic genes strongly associated with metastasis and 27 of them with high amount of genomic alterations. Overall, tumor hypoxia may drive aggressive molecular features across cancer types. Hence, we identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at improving novel drug development and treating metastasis.
Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels
Authors: Payne Alexander , Holmes Nadine , Clarke Thomas , Munro Rory , Debebe Bisrat , Loose Matthew
Published: February 2020

Nanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores. Thus DNA molecules can be rejected and replaced with new molecules enabling targeted sequencing to enrich, deplete or achieve specific coverage in a set of reads to address a biological question. We previously demonstrated this method worked using dynamic time warping mapping signal to reference, but required significant compute and did not scale to gigabase references. Using direct base calling with GPU we can now scale to gigabase references. We enrich for specific chromosomes mapping against the human genome and we develop pipelines enriching low abundance organisms from mixed populations without prior knowledge of sample composition. Finally, we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer. Using this approach we identify PML-RARA fusions in the NB4 cell line in under 15 hours sequencing. These methods can be used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.
Dynamic High-Content Imaging Reveals Surface Exposure of VirulentLeishmaniaAmastigotes in Infected Macrophages Undergoing Pyroptosis
Authors: Rosazza Thibault , Lecoeur Hervé , Blisnick Thierry , Moya-Nilges Maryse , Pescher Pascale , Bastin Phillipe , Prina Eric , Späth Gerald F.
Published: February 2020

Leishmaniaspp are obligate intracellular parasites that infect vertebrate phagocytes, notably macrophages. We previously reported thatLeishmania amazonensis(L. am) subvert the host cell pro-inflammatory response by dampening the macrophage NLRP3 inflammasome. No information is available on howLeishmaniainfection affects inflammatory cell death termed pyroptosis, known to limit microbial infection. Here, we provide first evidence thatL. amazonensis-infected macrophages can undergo pyroptosis when subjected to pro-inflammatory stimuli. We analyzed the dynamics of the pyroptotic process and the fate of intracellular amastigotes at the single cell level using spinning disk confocal microscopy and high-content, real-time imaging. Bone marrow-derived macrophages (BMDMs) were infected withL. amamastigotes isolated from footpad lesions and sequentially treated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) for canonical NLRP3 inflammasome priming and activation. Real-time monitoring was performed for 240 min post ATP addition. Longitudinal analyses revealed distinct phases of the pyroptotic process, including rapid decay of the parasitophorous vacuole (PV) as monitored by the pH-sensitive lysotracker fluid phase marker, progressive decrease in macrophage viability as monitored by accumulation of the nuclear dye YO-PRO-1, followed by translocation of the luminal PV membrane to the cell surface observed for 40% of macrophages, resulting in the extracellular exposure of amastigotes that remained anchored to the PV membrane. Scanning and transmission electron microscopy analyses revealed a highly polarized orientation of parasites with exclusive exposure of the anterior pole toward the extracellular milieu, and an attachment site forming a potential biological junction between the parasite posterior pole and the PV membrane. We showed that the exposed parasites are resistant to the cytolytic host cell activities linked to pyroptosis and retain their full infectious potential in reinfection experiments using naïve macrophages. Together these data uncover a novelLeishmaniaimmune subversion strategy that may allow stealthy parasite dissemination via the uptake of pyroptotic host debris by uninfected phagocytes.
Structure of the AAVhu.37 capsid by cryoelectron microscopy
Authors: Kaelber Jason T. , Yost Samantha A. , Webber Keith A. , Firlar Emre , Liu Ye , Danos Olivier , Mercer Andrew C.
Published: February 2020

Adeno-associated viruses (AAVs) are used as in vivo gene-delivery vectors in gene-therapy products and have been heavily investigated for numerous indications. Over 100 naturally occurring AAV serotypes and variants have been isolated from primate samples. Many reports have described unique properties of these variants (for instance, differences in potency, target cell or evasion of the immune response), despite high amino-acid sequence conservation. AAVhu.37 is of interest for clinical applications owing to its proficient transduction of the liver and central nervous system. The sequence identity of the AAVhu.37 VP1 to the well characterized AAVrh.10 serotype, for which no structure is available, is greater than 98%. Here, the structure of the AAVhu.37 capsid at 2.56 Å resolution obtained via single-particle cryo-electron microscopy is presented.
Conformational flexibility within the small domain of human serine racemase
Authors: Koulouris Chloe R. , Bax Benjamin D. , Atack John R. , Roe S. Mark
Published: February 2020

Serine racemase (SR) is a pyridoxal 5′-phosphate (PLP)-containing enzyme that converts L-serine to D-serine, an endogenous co-agonist for the N-methyl-D-aspartate receptor (NMDAR) subtype of glutamate ion channels. SR regulates D-serine levels by the reversible racemization of L-serine to D-serine, as well as the catabolism of serine by α,β-elimination to produce pyruvate. The modulation of SR activity is therefore an attractive therapeutic approach to disorders associated with abnormal glutamatergic signalling since it allows an indirect modulation of NMDAR function. In the present study, a 1.89 Å resolution crystal structure of the human SR holoenzyme (including the PLP cofactor) with four subunits in the asymmetric unit is described. Comparison of this new structure with the crystal structure of human SR with malonate (PDB entry 3l6b) shows an interdomain cleft that is open in the holo structure but which disappears when the inhibitor malonate binds and is enclosed. This is owing to a shift of the small domain (residues 78–155) in human SR similar to that previously described for the rat enzyme. This domain movement is accompanied by changes within the twist of the central four-stranded β-sheet of the small domain, including changes in the φ–ψ angles of all three residues in the C-terminal β-strand (residues 149–151). In the malonate-bound structure, Ser84 (a catalytic residue) points its side chain at the malonate and is preceded by a six-residue β-strand (residues 78–83), but in the holoenzyme the β-strand is only four residues (78–81) and His82 has φ–ψ values in the α-helical region of the Ramachandran plot. These data therefore represent a crystallographic platform that enables the structure-guided design of small-molecule modulators for this important but to date undrugged target.
Enhanced static modeling of commercial pneumatic artificial muscles
Authors: Li XueAi , Sun Kui , Guo Chuangqiang , Liu Teng , Liu Hong
Published: February 2020

Purpose

This paper aims to propose an enhanced static model of commercial braided pneumatic artificial muscles (PAMs), which is fully analytical without the need for experimentally determined parameters.

Design/methodology/approach

To address the highly nonlinear issues of PAMs, the enhanced model is derived considering the irregular shapes close to their end-fittings, as well as the elastic energy stored in both their braids and rubber bladders. The hysteresis characteristics of PAMs are also explored by analyzing the friction in the crossovers of the interlacing braided strands, together with that between the strands and their surrounding bladders. The isobaric and isometric experiments of a commercial PAM are conducted to demonstrate the enhancement, and the model accuracy is evaluated and compared with some existing models in terms of root mean square errors (RMSEs). Additionally, the proposed model is simplified to facilitate the applications that entail high computational efficiency.

Findings

The proposed model agrees well with the experimental results, which indicates its viability to accurately predict the static behaviors. An overall RMSE of 5.24 N shows that the enhanced model is capable of providing higher accuracy than the existing analytical models, while keeping the modeling cost at a minimum.

Originality/value

The proposed model, taking account of non-cylindrical shapes, elastic energy and friction, succeeds in enhancing the static predictions of commercial PAMs. The fully analytical model may accelerate the development of novel PAM-based robots for high-precision control, while giving a deeper understanding of commercial PAMs.