bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of polygenic risk profiling for primary open-angle glaucoma in the United Kingdom and Australia
Authors: Liu Qinqin , Davis John , Han Xikun , Mackey David A , MacGregor Stuart , Craig Jamie E , Si Lei , Hewitt Alex W
Published: February 2021

Objective

Primary open-angle glaucoma (POAG) is the most common subtype of glaucoma worldwide. Early diagnosis and intervention is proven to slow disease progression and reduce disease burden. Currently, population-based screening for POAG is not generally recommended due to cost. In this study, we evaluate the cost-effectiveness of polygenic risk profiling as a screening tool for POAG.

Methods and Analysis

We used a Markov cohort model to evaluate the cost-effectiveness of implementing polygenic risk profiling as a new POAG-screening approach in the UK and Australia. Six health states were included in this model: death, early, mild, moderate, severe, and healthy individuals. The evaluation was conducted from the healthcare payer’s perspective. We used the best available published data to calculate prevalence, transition probabilities, utility and other parameters for each health state and age group. The study followed the CHEERS checklist. Our main outcome measure was the incremental cost-effectiveness ratio (ICER) and secondary outcomes were years of blindness avoided per person and a ‘Blindness ICER’. We did one-way and two-way deterministic and probabilistic sensitivity analyses to reflect the uncertainty around predicting ICERs.

Results

Our proposed genetic screening programme for POAG in Australia is predicted to result in ICER of AU$34,252 (95% CI AU$21,324-95,497) and would avoid 1 year of blindness at ICER of AU$13,359 (95% CI: AU$8,143-37,448). In the UK, this screening is predicted to result in ICER of £24,783 (13,373-66,960) and would avoid 1 year of blindness at ICER of £10,095 (95%CI: £5,513-27,656). Findings were robust in all sensitivity analyses. Using the willingness to pay thresholds of $54,808 and £30,000, the proposed screening model is 79.2% likely to be cost-effective in Australia and is 60.2% likely to be cost-effective in the UK, respectively.

Conclusions

We describe and model the cost-efficacy of incorporating a polygenic risk score for POAG screening in Australia and the UK. Although the level of willingness to pay for Australian Government is uncertain, and the ICER range for the UK is broad, we showed a clear target strategy for early detection and prevention of advanced POAG in these developed countries.

Copyright

the Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence.
A NOVEL AIR-DRIED MULTIPLEX HIGH RESOLUTION MELT ASSAY FOR THE DETECTION OF EXTENDED SPECTRUM BETA-LACTAMASE AND CARBAPENEMASE GENES
Authors: Cubas-Atienzar Ana I. , Williams Christopher T. , Karkey Abhilasha , Dongol Sabina , Sulochana Manandhar , Rajendra Shrestha , Hobbs Glyn , Evans Katie , Musicha Patrick , Feasey Nicholas , Cuevas Luis E. , Adams Emily R. , Edwards Thomas
Published: February 2021

Here we describe the development and evaluation of a novel an air-dried high-resolution melt (HRM) assay to detect eight major extended spectrum beta-Lactamase (ESBL) (SHV and CTXM groups 1 and 9) and Carbapenemase (NDM, IMP, KPC, VIM and OXA-48) genes that cause antimicrobial resistance. The assay was evaluated using 440 DNA samples extracted from bacterial isolates from Nepal, Malawi and UK and 390 clinical Enterobacteriaceae isolates with known resistance phenotypes from Nepal. The sensitivity and specificity for detecting the ESBL and Carbapenemase genes in comparison to the reference gel-base PCR and sequencing was 94.7% (95%CI: 92.5%-96.5%) and 99.2% (95%CI: 98.8%-99.5%) and 98.5% (95%CI: 97.0%-99.4%) and 98.5% (95%CI: 98.0%-98.9%) when compared to the original wet format. The overall phenotypic agreement was 91.1% (95%CI: 90.0%-92.9%) on predicting resistance to cefotaxime and carbapenems. We observed good inter-machine reproducibility of the air-dried HRM assay using the Rotor-Gene Q, QuantStudio™ 5, CFX96, LightCycler® 480 and MIC. Assay stability upon storage in the fridge (6.2°C ± 0.9), room temperature (20.35°C ± 0.7) and oven (29.7°C ± 1.4) were assessed at six time points for eight months and no loss of sensitivity occurred under all conditions. We present here a ready-to-use air-dried HRM-PCR assay that offers an easy, thermostable, fast and accurate tool for the detection of ESBL and Carbapenamase genes to improve AMR diagnosis and treatment.
Mobility and COVID-19 in Andorra: Country-scale analysis of high-resolution mobility patterns and infection spread
Authors: Doorley Ronan , Berke Alex , Noyman Ariel , Alonso Luis , Ribó Josep , Arroyo Vanesa , Pons Marc , Larson Kent
Published: February 2021

In the absence of effective vaccines, non-pharmaceutical interventions, such as mobility restrictions, were globally adopted as critically important strategies for curbing the spread of COVID-19. However, such interventions come with immense social and economic costs and the relative effectiveness of different mobility restrictions are not well understood. This study analyzed uniquely comprehensive datasets for the entirety of a small country, consisting of serology data, telecoms data, and COVID-19 case reports, in order to examine the relationship between mobility and transmission of COVID-19.

Andorra is a small European country where tourism is a large part of the economy. Stringent mobility restrictions were put in place in Spring 2020. Additionally, 91% of the population participated in a voluntary COVID-19 serology testing programme and those data were made available for this study. Furthermore, high resolution telecoms data for the entire population were available for analysis of mobility and proximity patterns. A set of mobility metrics were developed to indicate levels of crowding, stay-at-home rates, trip-making and contact with tourists. Mobility metrics were compared to infection rates across communities and transmission rate over time.

Several of these metrics were highly correlated with transmission rate, with a lead time of approximately 18 days, with some metrics more highly correlated than others. There was a stronger correlation for measures of crowding and inter-community trip-making, and a weaker correlation for total trips (including intra-community trips) and stay-at-homes rates.
Conservation and Convergence of Genetic Architecture in the Adaptive Radiation ofAnolisLizards
Authors: McGlothlin Joel W. , Kobiela Megan E. , Wright Helen V. , Kolbe Jason J. , Losos Jonathan B. , Brodie Edmund D.
Published: February 2021

TheGmatrix, which quantifies the genetic architecture of traits, is often viewed as an evolutionary constraint. However,Gcan evolve in response to selection and may also be viewed as a product of adaptive evolution. Convergent evolution ofGin similar environments would suggest thatGevolves adaptively, but it is difficult to disentangle such effects from phylogeny. Here, we use the adaptive radiation ofAnolislizards to ask whether convergence ofGaccompanies the repeated evolution of habitat specialists, or ecomorphs, across the Greater Antilles. We measuredGin seven species representing three ecomorphs (trunk-crown, trunk- ground, and grass-bush). We found that the overall structure ofGdoes not converge. Instead, the structure ofGis well conserved and displays a phylogenetic signal consistent with Brownian motion. However, several elements ofGshowed signatures of convergence, indicating that some aspects of genetic architecture have been shaped by selection. Most notably, genetic correlations between limb traits and body traits were weaker in long-legged trunk-ground species, suggesting effects of recurrent selection on limb length. Our results demonstrate that common selection pressures may have subtle but consistent effects on the evolution ofG, even as its overall structure remains conserved.
Magnetically-Propelled Fecal Surrogates for Modeling the Impact of Solid-Induced Shear Forces on Primary Colonic Epithelial Cells
Authors: Hinman Samuel S. , Huling Jennifer , Wang Yuli , Wang Hao , Bretherton Ross C. , DeForest Cole A. , Allbritton Nancy L.
Published: February 2021

The colonic epithelium is continuously exposed to an array of biological and mechanical stimuli as its luminal contents are guided over the epithelial surface through regulated smooth muscle contraction. In this report, the propulsion of solid fecal contents over the colonic epithelium is recapitulated through noninvasive actuation of magnetic agarose hydrogels over primary intestinal epithelial cultures, in contrast to the vast majority of platforms that apply shear forces through liquid microflow. Software-controlled magnetic stepper motors enable experimental control over the frequency and velocity of these events to matchin vivopropulsive contractions, while the integration of standardized well plate spacing facilitates rapid integration into existing assay pipelines. The application of these solid-induced shear forces did not deleteriously affect cell monolayer surface coverage, viability, or transepithelial electrical resistance unless the device parameters were raised to a 50× greater contraction frequency and 4× greater fecal velocity than those observed in healthy humans. At a frequency and velocity that is consistent with average human colonic motility, differentiation of the epithelial cells into absorptive and goblet cell phenotypes was not affected. Protein secretion was modulated with a two-fold increase in luminal mucin-2 secretion and a significant reduction in basal interleukin-8 secretion. F-actin, zonula occludens-1, and E-cadherin were each present in their proper basolateral locations, similar to those of static control cultures. While cellular height was unaffected by magnetic agarose propulsion, several alterations in lateral morphology were observed including decreased circularity and compactness, and an increase in major axis length, which align with surface epithelial cell morphologies observedin vivoand may represent early markers of luminal exfoliation. This platform will be of widespread utility for the investigation of fecal propulsive forces on intestinal physiology, shedding light on how the colonic epithelium responds to mechanical cues.

HIGHLIGHTS

Magnetic nanoparticle-embedded agarose hydrogels were developed as surrogates for human feces

Software-controlled magnetic motors enable programmable studies of colonic motility

Propulsive shear forces were optimized for primary cell viability, surface coverage, and electrical resistance

Mucus production and cytokine secretion were modulated by magnetic agarose propulsion

Structural and cytoskeletal proteins remain properly distributed with alterations in lateral cell morphology
Optogenetic silencing of neurotransmitter release with a naturally occurring invertebrate rhodopsin
Authors: Mahn Mathias , Saraf-Sinik Inbar , Patil Pritish , Pulin Mauro , Bitton Eyal , Karalis Nikolaos , Bruentgens Felicitas , Palgi Shaked , Gat Asaf , Dine Julien , Wietek Jonas , Davidi Ido , Levy Rivka , Litvin Anna , Zhou Fangmin , Sauter Kathrin , Soba Peter , Schmitz Dietmar , Lüthi Andreas , Rost Benjamin R. , Wiegert J. Simon , Yizhar Ofer
Published: February 2021

Information is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways in cognitive and behavioral processes requires temporally precise manipulation of their activityin vivo. However, existing optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals, while chemogenetic tools are difficult to control in space and time. Here, we show that a targeting-enhanced mosquito homologue of the vertebrate encephalopsin (eOPN3) can effectively suppress synaptic transmission through the Gi/osignaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutesin vitroas well asin vivo. In freely moving mice, eOPN3-mediated suppression of dopaminergic nigrostriatal afferents leads to an ipsiversive rotational bias. We conclude that eOPN3 can be used to selectively suppress neurotransmitter release at synaptic terminals with high spatiotemporal precision, opening new avenues for functional interrogation of long-range neuronal circuitsin vivo.
Effects of early geometric confinement on the transcriptomic profile of human cerebral organoids
Authors: Sen Dilara , Voulgaropoulos Alexis , Keung Albert J.
Published: February 2021

Background

Biophysical factors such as shape and mechanical forces are known to play crucial roles in stem cell differentiation, embryogenesis and neurodevelopment. However, the complexity and experimental challenges capturing such early stages of development, and ethical concerns associated with human embryo and fetal research, limit our understanding of how these factors affect human brain organogenesis. Human cerebral organoids (hCO) are attractive models due to their ability to model important brain regions and transcriptomics of earlyin vivobrain development. Furthermore, they provide three-dimensional environments that better mimic the in vivo environment. To date, they have been used to understand the effects of genetics and soluble factors on neurodevelopment. Establishing links between spatial factors and hCO development will require the development of new approaches.

Results

Here, we investigated the effects of early geometric confinements on transcriptomic changes during hCO differentiation. Using a custom and tunable agarose microwell platform we generated embryoid bodies (EB) of diverse shapes and then further differentiated those EBs to whole brain hCOs. Our results showed that the microwells did not have negative gross impacts on the ability of the hCOs to differentiate generally towards neural fates, and there were clear shape dependent effects on neural lineage specification. In particular, we observed that non-spherical shapes showed signs of altered neurodevelopmental kinetics and favored the development of medial ganglionic eminence-associated brain regions and cell types over cortical regions.

Conclusions

The findings presented here suggest a role for spatial factors in brain region specification during hCO development. Understanding these spatial patterning factors will not only improve understanding ofin vivodevelopment and differentiation, but also provide important handles with which to advance and improve control over human model systems forin vitroapplications.
Toxoplasma gondiiinjected neurons localize to the cortex and striatum and have altered firing
Authors: Mendez Oscar A. , Machado Emiliano Flores , Lu Jing , Koshy Anita A.
Published: February 2021

Toxoplasma gondiiis an intracellular parasite that causes a long-term latent infection of neurons. Using a custom MATLAB-based mapping program in combination with a mouse model that allows us to permanently mark neurons injected with parasite proteins, we found thatToxoplasma-injected neurons (TINs) are heterogeneously distributed in the brain, primarily localizing to the cortex followed by the striatum. Using immunofluorescence co-localization assays, we determined that cortical TINs are commonly (>50%) excitatory neurons (FoxP2+) and that striatal TINs are often (>65%) medium spiny neurons (MSNs) (FoxP2+). As MSNs have highly characterized electrophysiology, we usedex vivoslices from infected mice to perform single neuron patch-clamping on striatal TINs and neighboring uninfected MSNs (bystander MSNs). These studies demonstrated that TINs have highly abnormal electrophysiology, while the electrophysiology of bystander MSNs was akin to that of MSNs from uninfected mice. Collectively, these data offer new neuroanatomic and electrophysiologic insights into CNS toxoplasmosis.
BRAF inhibitors reprogram cancer-associated fibroblasts to drive matrix remodeling and therapeutic escape in melanoma
Authors: Liu Tianyi , Zhou Linli , Xiao Yao , Andl Thomas , Zhang Yuhang
Published: February 2021

The tumor stroma and its cellular components are known to play an important role in tumor resilience towards treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitors (BRAFi)-induced non-canonical nuclear β-catenin signaling in cancer-associated fibroblasts (CAFs). Our study reveals that BRAFi leads to an expanded CAF population with increased β-catenin nuclear accumulation and enhances their biological properties. This CAF subpopulation is essential for melanoma cells to grow and resist to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF and CRAF dimerization and subsequently the activation of ERK signaling in CAFs, leading to the inactivation of the β-catenin destruction complex. By RNA-Seq, periostin (POSTN) is identified as a major downstream effector of β catenin in CAFs and can compensate for the loss of β-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. Moreover, POSTN reactivates the ERK pathway, which is inhibited by BRAFi/MEKi, in melanoma cells through PI3K/AKT signaling. Our data underscore the roles of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma.
Viral route of infection determines the effect ofDrosophila melanogastergut bacteria on host resistance and tolerance to disease
Authors: Landum Miguel , Silva Marta Salvado , Martins Nelson , Teixeira Luís
Published: February 2021

The microbial community interacting with a host can modulate the outcome of pathogenic infections. For instance,Wolbachia, one of the most prevalent invertebrate endosymbionts, strongly increases resistance ofDrosophila melanogasterand other insect hosts, to many RNA viruses.D. melanogasteris also in continuous association with gut bacteria, whose role in antiviral immunity is poorly characterized. Here we asked how gut-colonizing bacteria impact viral titres and host survival, and how these interact with route of infection orWolbachiapresence. We compared germ-free flies and flies associated with two gut bacteria species recently isolated from wild flies (Acetobacter thailandicus and Lactobacillus brevis). We found thatWolbachia-conferred protection to both DCV or FHV is not affected by the presence or absence of these gut bacteria. Flies carryingA. thailandicushave lower DCV loads than germ-free flies, upon systemic infection, but reduced survival, indicating that these bacteria increase resistance to virus and decrease disease tolerance. Association withL. brevis, alone or in combination withA. thailandicus, did not lead to changes in survival to systemic infection. In contrast to the effect on systemic infection, we did not observe an impact of these bacteria on survival or viral loads after oral infection. Overall, the impact of gut-associated bacteria in resistance and tolerance to viruses was mild, when compared withWolbachia. These results indicate that the effect of gut-associated bacteria to different viral infections, and different routes of infection, is complex and understanding it requires a detailed characterization of several parameters of infection.
Familial prion disease-related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM
Authors: Wang Li-Qiang , Zhao Kun , Yuan Han-Ye , Li Xiang-Ning , Dang Hai-Bin , Ma Yeyang , Wang Qiang , Wang Chen , Sun Yunpeng , Chen Jie , Li Dan , Zhang Delin , Yin Ping , Liu Cong , Liang Yi
Published: February 2021

Prion diseases are caused by the conformational conversion of prion protein (PrP) from its cellular form (PrPC) into a protease-resistant, aggregated form (PrPSc). 42 different familial mutations were identified in human PrP, which lead to genetic prion diseases with distinct clinical syndromes. Here we report cryo-EM structure of an amyloid fibril formed by full-length human PrP with E196K mutation, a familial Creutzfeldt-Jakob disease-related mutation. This mutation disrupts key interactions in wild-type PrP fibril and results in a rearrangement of the overall structure, forming an amyloid fibril with a conformation distinct from wild-type PrP fibril. The E196K fibril consists of two protofibrils intertwined into a left-handed helix. Each subunit forms five β-strands stabilized by a disulfide bond and an unusual hydrophilic cavity. Two pairs of amino acids (Lys194 and Glu207; Lys196 and Glu200) from opposing subunits form four salt bridges to stabilize the zigzag interface of the two protofibrils. Furthermore, the E196K fibril exhibits a significantly lower conformational stability and protease resistance activity than the wild-type fibril. Our results provide direct structural evidences of the diverse mammalian prion strains and fibril polymorphism of PrP, and highlight the importance of familial mutations in determining the different prion strains.
Cellular, Circuit and Transcriptional Framework for Modulation of Itch in the Central Amygdala
Authors: Samineni Vijay K , Grajales-Reyes Jose G. , Grajales-Reyes Gary E , Tycksen Eric , Copits Bryan A , Pedersen Christian , Ankudey Edem S , Sackey Julian N , Sewell Sienna B , Bruchas Michael R , Gereau Robert W.
Published: February 2021

Itch is an unpleasant sensation that elicits robust scratching and active avoidance. However, the identity of the cells and neural circuits that organize this information remains elusive. Here we show the necessity and sufficiency of itch-activated neurons in the central amygdala (CeA) for both itch sensation and active avoidance. Further, we show that itch-activated CeA neurons play important roles in itch-related comorbidities, including anxiety-like behaviors, but not in some aversive and appetitive behaviors previously ascribed to CeA neurons. RNA-sequencing of itch-activated CeA neurons identified several differentially expressed genes as well as potential key signaling pathways in regulating pruritis. Finally, viral tracing experiments demonstrate that these neurons send a critical projection to the periaqueductal gray to mediate modulation of itch. These findings reveal a cellular and circuit signature of CeA neurons orchestrating behavioral and affective responses to pruritus in mice.
Detailed characterization of the UMAMITs provides insight into their evolution, functional properties as amino acid transporters and role in the plant
Authors: Zhao Chengsong , Pratelli Réjane , Yu Shi , Shelley Brett , Collakova Eva , Pilot Guillaume
Published: February 2021

Amino acid transporters play a critical role in distributing amino acids within the cell compartments and between the plant organs. Despite this importance, relatively few amino acid transporter genes have been characterized and their role elucidated with certainty. Two main families of proteins encode amino acid transporters in plants: the Amino Acid-Polyamine-Organocation superfamily, containing mostly importers, and the Usually Multiple Acids Move In and out Transporter family, apparently encoding exporters, totaling about 100 genes in Arabidopsis alone. Knowledge on UMAMITs is scarce, focused on six Arabidopsis genes and a handful of genes from other species. To get insight into the role of the members of this family and provide data to be used for future characterization, we studied the evolution of the UMAMITs in plants, and determined the functional properties, the structure, and the localization of the 44 Arabidopsis UMAMITs. Our analysis showed that the AtUMAMIT are essentially localized at the tonoplast or the plasma membrane, and that most of them are able to export amino acids from the cytosol, confirming a role in intra- and inter-cellular amino acid transport. As an example, this set of data was used to hypothesize the role of a few AtUMAMITs in the plant and the cell.
Light and noise pollution impacts specialist wildlife species disproportionately
Authors: Ditmer Mark A. , Francis Clinton D. , Barber Jesse R. , Stoner David C. , Seymoure Brett M. , Fristrup Kurt M. , Carter Neil H.
Published: February 2021

Global expansion of lighting and noise pollution alters how animals receive and interpret environmental cues. Yet we lack a cross-taxon understanding of how animal traits influence species vulnerability to this growing phenomenon. This knowledge is needed to improve the design and implementation of policies that mitigate or reduce sensory pollutants. We present results from an expert knowledge survey that quantified the relative influence of several ecological, anatomical, and physiological traits on the vulnerability of terrestrial vertebrates to elevated levels of anthropogenic lighting and noise. Our findings, based on 280 responses, highlight the increasing recognition among experts that sensory pollutants are important to consider in management and conservation decisions. Participant responses show mounting threats to species with narrow niches; especially habitat specialists, nocturnal species, and those with the greatest ability to differentiate environmental visual and auditory cues. Our results call attention to the threat specialist species face and provide a generalizable understanding of which species require additional considerations when developing conservation policies and mitigation strategies in a world altered by expanding sensory pollutant footprints. We provide a step-by-step example for translating these results to on-the-ground conservation planning using two species as case studies.
Glioblastoma remodeling of neural circuits in the human brain decreases survival
Authors: Krishna Saritha , Choudhury Abrar , Seo Kyounghee , Ni Lijun , Kakaizada Sofia , Lee Anthony , Aabedi Alexander , Cao Caroline , Sudharshan Rasika , Egladyous Andrew , Almeida Nyle , Venkatesh Humsa S. , Findlay Anne , Nagarajan Srikantan , Raleigh David , Brang David , Monje Michelle , Hervey-Jumper Shawn L.
Published: February 2021

Gliomas synaptically integrate into neural circuits. Prior work has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. In this study we wanted to know how glioma induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. We use intracranial brain recordings during lexical retrieval language tasks in awake humans in addition to site specific tumor tissue biopsies and cell biology experiments. We find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumor-infiltrated cortex, beyond cortical excitation normally recruited in the healthy brain. Site-directed biopsies from functionally connected regions within the tumor are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumor cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumor regions compared to tumor regions with less functional connectivity. The degree of functional connectivity between glioblastoma and the normal brain negatively impacts both patient survival and language task performance. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumor proliferation and impairs cognition.
Inferring Ecosystem Networks as Information Flows
Authors: Li Jie , Convertino Matteo
Published: February 2021

The detection of causal interactions is of great importance when inferring complex ecosystem functional and structural networks for basic and applied research. Convergent cross mapping (CCM) based on nonlinear state-space reconstruction made substantial progress about network inference by measuring how well historical values of one variable can reliably estimate states of other variables. Here we investigate the ability of a developed Optimal Information Flow (OIF) ecosystem model to infer bidirectional causality and compare that to CCM. Results from synthetic datasets generated by a simple predator-prey model, data of a real-world sardine-anchovy-temperature system and of a multispecies fish ecosystem highlight that the proposed OIF performs better than CCM to predict population and community patterns. Specifically, OIF provides a larger gradient of inferred interactions, higher point-value accuracy and smaller fluctuations of interactions andα-diversity including their characteristic time delays. We propose an optimal threshold on inferred interactions that maximize accuracy in predicting fluctuations of effectiveα-diversity, defined as the count of model-inferred interacting species. Overall OIF outperforms all other models in assessing predictive causality (also in terms of computational complexity) due to the explicit consideration of synchronization, divergence and diversity of events that define model sensitivity, uncertainty and complexity. Thus, OIF offers a broad ecological information by extracting predictive causal networks of complex ecosystems from time-series data in the space-time continuum. The accurate inference of species interactions at any biological scale of organization is highly valuable because it allows to predict biodiversity changes, for instance as a function of climate and other anthropogenic stressors. This has practical implications for defining optimal ecosystem management and design, such as fish stock prioritization and delineation of marine protected areas based on derived collective multispecies assembly. OIF can be applied to any complex system and used for model evaluation and design where causality should be considered as non-linear predictability of diverse events of populations or communities.
ESC - a comprehensive resource for SARS-CoV-2 immune escape variants
Authors: Rophina Mercy , Pandhare Kavita , Shamnath Afra , Imran Mohamed , Jolly Bani , Scaria Vinod
Published: February 2021

Ever since the breakout of COVID-19 disease, ceaseless genomic research to inspect the epidemiology and evolution of the pathogen has been undertaken globally. Large scale viral genome sequencing and analysis have uncovered the functional impact of numerous genetic variants in disease pathogenesis and transmission. Emerging evidence of mutations in spike protein domains escaping antibody neutralization is reported. We have built a database with precise collation of manually curated variants in SARS-CoV-2 from literature with potential escape mechanisms from a range of neutralizing antibodies. This comprehensive repository encompasses a total of 5258 variants accounting for 2068 unique variants tested against 230 antibodies, patient convalescent plasma and vaccine breakthrough events. This resource enables the user to gain access to an extensive annotation of SARS-CoV-2 escape variants which would contribute to exploring and understanding the underlying mechanisms of immune response against the pathogen. The resource is available athttp://clingen.igib.res.in/esc/

GRAPHICAL ABSTRACT
Concentration and dosage sensitivity of proteins driving liquid-liquid phase separation
Authors: Farahi Nazanin , Lazar Tamas , Wodak Shoshana J. , Tompa Peter , Pancsa Rita
Published: February 2021

Liquid-liquid phase separation (LLPS) is a molecular process that leads to the formation of membraneless organelles (MLOs), i.e. functionally specialized liquid-like cellular condensates formed by proteins and nucleic acids. Integration of data on LLPS-associated proteins from dedicated databases revealed only modest overlap between them and resulted in a confident set of 89 human LLPS driver proteins. Since LLPS is highly concentration-sensitive, the underlying experiments are often criticized for applying higher-than-physiological protein concentrations. To clarify this issue, we performed anaivecomparison ofin vitroapplied and quantitative proteomics-derived protein concentrations and discuss a number of considerations that rationalize the choice of apparently highin vitroconcentrations in most LLPS studies. The validity ofin vitroLLPS experiments is further supported byin vivophase-separation experiments and by the observation that the corresponding genes show a strong propensity for dosage sensitivity. This observation implies that the availability of the respective proteins is tightly regulated in cells to avoid erroneous condensate formation. In all, we propose that although local protein concentrations are practically impossible to determine in cells, proteomics-derived cellular concentrations should rather be considered as lower limits of protein concentrations, than strict upper bounds, to be respected byin vitroexperiments.
Analysis of motor unit spike trains estimated from high-density surface electromyography is highly reliable across operators
Authors: Hug François , Avrillon Simon , Del Vecchio Alessandro , Casolo Andrea , Ibanez Jaime , Nuccio Stefano , Rossato Julien , Holobar Aleš , Farina Dario
Published: February 2021

There is a growing interest in decomposing high-density surface electromyography (HDsEMG) into motor unit spike trains to improve knowledge on the neural control of muscle contraction. However, the reliability of decomposition approaches is sometimes questioned, especially because they require manual editing of the outputs. We aimed to assess the inter-operator reliability of the identification of motor unit spike trains. Eight operators with varying experience in HDsEMG decomposition were provided with the same data extracted using the convolutive kernel compensation method. They were asked to manually edit them following established procedures. Data included signals from three lower leg muscles and different submaximal intensities. After manual analysis, 126 ± 5 motor units were retained (range across operators: 119-134). A total of 3380 rate of agreement values were calculated (28 pairwise comparisons × 11 contractions/muscles × 4-28 motor units). The median rate of agreement value was 99.6%. Inter-operator reliability was excellent for both mean discharge rate and time at recruitment (intraclass correlation coefficient > 0.99). These results show that when provided with the same decomposed data and the same basic instructions, operators converge toward almost identical results. Our data have been made available so that they can be used for training new operators.
Somatic hypomethylation of pericentromeric SST1 repeats and tetraploidization in human colorectal cancer cells
Authors: González Beatriz , Navarro-Jiménez Maria , Alonso-De Gennaro María José , Jansen Sanne Marcia , Granada Isabel , Perucho Manuel , Alonso Sergio
Published: February 2021

Somatic DNA hypomethylation and aneuploidy are hallmarks of cancer, and there is evidence for a causal relationship between them in knockout mice, but not in human cancer. The non-mobile pericentromeric repetitive elements SST1 are hypomethylated in about 17% of human colorectal cancers (CRC) with some 5-7% exhibiting a more severe age-independent demethylation. Tetraploidy is a common and early event in solid tumors generating subsequent aneuploidy. We compared the relative frequency of chromosomal variations during culture of randomly selected single cell clones of diploid LS174T human CRC cells differing in their levels of SST1 demethylation. Diploid cells underwent frequent genome reduplication events generating tetraploid clones that correlated with SST1 demethylation. In primary CRC, severe SST1 hypomethylation was significantly associated with global genomic hypomethylation and mutations inTP53. This work uncovers the association of the naturally occurring demethylation of the SST1 pericentromeric repeat with the onset of spontaneous tetraploidization in human CRC cells in culture, and withTP53mutations in primary CRCs. Altogether, our findings provide further support for an oncogenic pathway linking somatic epigenetic and genetic alterations in a subset of human CRC.
Combined Metabolic Activators decrease liver steatosis by activating mitochondrial metabolism in a Golden Syrian hamster study
Authors: Yang Hong , Mayneris-Perxachs Jordi , Boqué Noemí , del Bas Josep M , Arola Lluís , Yuan Meng , Turkez Hasan , Uhlén Mathias , Borén Jan , Cheng Zhang , Mardinoglu Adil , Caimari Antoni
Published: February 2021

The prevalence of non-alcohol fatty liver disease (NAFLD), defined as the liver’s excessive fat accumulation, continues to increase dramatically. We have recently revealed the molecular mechanism underlying NAFLD using in-depth multi-omics profiling and identified that combined metabolic activators (CMA) could be administered to decrease the amount of hepatic steatosis (HS) in mouse model and NAFLD patients based on systems analysis. Here, we investigated the effects of a CMA including L-carnitine, N-acetyl-l-cysteine, nicotinamide riboside and betaine on a Golden Syrian hamster NAFLD model fed with HFD, and found that HS was decreased with the administration of CMA. To explore the mechanisms involved in the clearance HS, we generated liver transcriptomics data before and after CMA administration, and integrated these data using liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMAs and found that it activates mitochondria in the liver tissue by modulating the global fatty acid, amino acids, antioxidant and folate metabolism.
Molecular insights into malignant progression of atypical choroid plexus papilloma
Authors: Yankelevich Maxim , Finlay Jonathan L. , Gorsi Hamza , Kupsky William , Boue Daniel R. , Koschmann Carl J. , Kumar-Sinha Chandan , Mody Rajen
Published: February 2021

Choroid plexus tumors are rare pediatric neoplasms ranging from low-grade papillomas to overtly malignant carcinomas. They are commonly associated with Li–Fraumeni syndrome and germline TP53 mutations. Choroid plexus carcinomas associated with Li–Fraumeni syndrome are less responsive to chemotherapy, and there is a need to avoid radiation therapy leading to poorer outcomes and survival. Malignant progression from choroid plexus papillomas to carcinomas is exceedingly rare with only a handful of cases reported, and the molecular mechanisms of this progression remain elusive. We report a case of malignant transformation of choroid plexus papilloma to carcinoma in a 7-yr-old male with a germline TP53 mutation in which we present an analysis of molecular changes that might have led to the progression based on the next-generation genetic sequencing of both the original choroid plexus papilloma and the subsequent choroid plexus carcinoma. Chromosomal aneuploidy was significant in both lesions with mostly gains present in the papilloma and additional significant losses in the carcinoma. The chromosomal loss that occurred, in particular loss of Chromosome 13, resulted in the losses of two critical tumor suppressor genes, RB1 and BRCA2, which might play a possible role in the observed malignant transformation.
Protecting vulnerable people during pandemics through home delivery of essential supplies: a distribution logistics model
Authors: Breitbarth Eric , Groβ Wendelin , Zienau Alexander
Published: February 2021

Purpose

This paper studies a concept for protecting vulnerable population groups during pandemics using direct home deliveries of essential supplies, from a distribution logistics perspective. The purpose of this paper is to evaluate feasible and resource-efficient home delivery strategies, including collaboration between retailers and logistics service providers based on a practical application.

Design/methodology/approach

A food home delivery concept in urban areas during pandemics is mathematically modeled. All seniors living in a district of Berlin, Germany, represent the vulnerable population supplied by a grocery distribution center. A capacitated vehicle routing problem (CVRP) is developed in combination with a k-means clustering algorithm. To manage this large-scale problem efficiently, mixed-integer programming (MIP) is used. The impact of collaboration and additional delivery scenarios is examined with a sensitivity analysis.

Findings

Roughly 45 medically vulnerable persons can be served by one delivery vehicle in the baseline scenario. Operational measures allow a drastic decrease in required resources by reducing service quality. In this way, home delivery for the vulnerable population of Berlin can be achieved. This requires collaboration between grocery and parcel services and public authorities as well as overcoming accompanying challenges.

Originality/value

Developing a home delivery concept for providing essential goods to urban vulnerable groups during pandemics creates a special value. Setting a large-scale CVRP with variable fleet size in combination with a clustering algorithm contributes to the originality.
Accountability for climate change: a research synthesis through the lenses of the integrated thinking approach
Authors: Brunelli Sandro , Falivena Camilla , Carlino Chiara , Venuti Francesco
Published: February 2021

Purpose

The increasing responsibility of organisations towards society and the environment has inverted the relationship between accounting and accountability, leading to accountability-based accounting systems. This study aims to explore the debate on accountability for climate change within the integrating thinking (IT) perspective. Ascertaining the most significant trends in the debate around purposes and performance that characterise climate mitigation engagement and their connections, the study would explore if and to what extent organisations are tackling climate actions.

Design/methodology/approach

A narrative review of the extensive academic literature developed from the Kyoto Protocol to date was performed. After selecting a representative sample, papers were analysed with the support of a new analytical framework that involves three dimensions – answerability, enforcement and outcome – and governance schemes that emerge from the involvement of the private and public sector and civil society. With the support of NVivo software, themes arisen were analysed and coded. Key items were labelled, creating specific nodes and synthesised into the proposed framework.

Findings

A “silo approach” largely characterises the debate on accountability for climate change. The most significant reasons behind the shortcomings of extant climate actions may be retrieved firstly in the weakness of the motivations that guide organisations to operate in a climate-friendly way.

Social implications

This study underlines the need for a 360° integrated approach for strategically tackling climate actions.

Originality/value

This study would represent a further step towards an integrated approach for studying organisations behaviours in the “climate war”, embracing the connectivity between purposes and outcomes, capitals and the relationships amongst the various stakeholders.
Emergence of circular economy research: a systematic literature review
Authors: Lahane Swapnil , Prajapati Himanshu , Kant Ravi
Published: February 2021

Purpose

This paper aims to examine the current status and trends in circular economy (CE) research. The state of CE research is assessed by critically examining the field by considering diverse dimensions.

Design/methodology/approach

The systematic literature review (SLR) of CE research articles is analyzed using the content analysis methodology. The articles are selected from the Scopus database containing the keyword “Circular economy” in its title, abstract and keywords. In total, 587 research articles published on CE in various reputed peer-reviewed journals over 15 years (2005–2020) are selected for review.

Findings

The research in the domain of CE is in the beginning phase. It has numerous quantitative modeling opportunities, value creation and propositions aspects and application in real-life case problems. One of the significant findings is that the CE research field is more inclined toward the implication of the empirical qualitative research. The identified research gaps and future opportunities could provide further direction to broaden CE research.

Research limitations/implications

The review focuses on publications published in peer-reviewed journals in the English language only. It restricts the recognition of relevant articles published in conference proceedings and languages other than English.

Originality/value

This research study will provide a deeper understanding of CE research's existing status and highlights the research trends, gap and its applicability in real-life case problems and setting up future research directions in the CE field.
Exchange rate volatility and Turkish–German commodity trade: an asymmetry analysis
Authors: Bahmani-Oskooee Mohsen , Karamelikli Huseyin
Published: February 2021

Purpose

The purpose of this paper is to show that in some industries the linear model may not reveal any significance link between exchange rate volatility and trade flows but once nonlinear adjustment of exchange rate volatility is introduced, the nonlinear model reveals significant link.

Design/methodology/approach

This paper uses the linear ARDL approach of Pesaranet al.(2001) and the nonlinear ARDL approach of Shinet al.(2014) to assess asymmetric effects of exchange rate volatility on trade flows between Germany and Turkey.

Findings

This paper consider the experiences of 75 2-digit industries that trade between Turkey and Germany. When the study assumed the effects of volatility to be symmetric, the study found short-run effects in 31 (30) Turkish (German) exporting industries that lasted into the long run in only 10 (13) Turkish (German) exporting industries. However, when the study assumed asymmetric effects and relied upon a nonlinear model, the study found short-run asymmetric effects of volatility on exports of 55 (56) Turkish (German) industries. Short-run asymmetric effects lasted into long-run asymmetric effects in 10 (25) Turkish (German) exporting industries. All in all, we found that almost 25% of trade is hurt by exchange rate volatility.

Originality/value

This is the first paper that assesses the possibility of asymmetric effects of exchange rate volatility on German–Turkish commodity trade.
The experiences of older carers of people with learning disabilities: “I just carry on with it”
Authors: Forrester-Jones Rachel
Published: February 2021

Purpose

Because people with learning disabilities (LD) are living longer, their family carers are likely to continue their caring role for longer. This study aims to explore the experiences of older carers of people with LD.

Design/methodology/approach

In total, 16 interviews with older carers were carried out and analysed qualitatively.

Findings

Three main themes emerged from the data: “transition to retirement is a misnomer”; “impact of caring role”; and “fears for the future”.

Originality/value

Previous studies have not focussed on the specific experiences of “older” carers and their situation risks going unnoticed. Their experiences should be acknowledged by services and society and meaningful support provided.