bluuebunny/crossref_metadata_2025 huggingface dataset:
PathExt: a general framework for path-based mining of omics-integrated biological networks
Authors: Sambaturu Narmada , Pusadkar Vaidehi , Hannenhalli Sridhar , Chandra Nagasuma
Published: January 2020

Motivation

Large scale transcriptomic data are routinely used to prioritize genes underlying specific phenotypes. Current approaches largely focus on differentially expressed genes (DEGs), despite the recognition that phenotypes emerge via a network of interactions between genes and proteins, many of which may not be differentially expressed. Furthermore, many practical applications lack sufficient samples or an appropriate control to robustly identify statistically significant DEGs.

Results

We provide a computational tool - PathExt, which, in contrast to differential genes, identifies differentially active paths when a control is available, and most active paths otherwise, in an omics-integrated biological network. The sub-network comprising such paths, referred to as the Top-Net, captures the most relevant genes and processes underlying the specific biological context. The TopNet forms a well-connected graph, reflecting the tight orchestration in biological systems. Two key advantages of PathExt are (i) it can extract characteristic genes and pathways even when only a single sample is available, and (ii) it can be used to study a system even in the absence of an appropriate control. We demonstrate the utility of PathExt via two diverse sets of case studies, to characterize (a) Mycobacterium tuberculosis (M.tb) response upon exposure to 18 antibacterial drugs where only one transcriptomic sample is available for each exposure; and (b) tissue-relevant genes and processes using transcriptomic data from GTEx (Genotype-Tissue Expression) for 39 human tissues. Overall, PathExt is a general tool for prioritizing context-relevant genes in any omics-integrated biological network for any condition(s) of interest, even with a single sample or in the absence of appropriate controls.

Availability

The source code for PathExt is available athttps://github.com/NarmadaSambaturu/PathExt.

Contact

nchandra@iisc.ac.in,sridhar.hannenhalli@nih.gov
A minimal 3D model of mosquito flight behavior around the human baited bed net
Authors: Jones Jeff , Murray Greg , McCall Philip J
Published: January 2020

Advances in digitized video-tracking and behavioral analysis have enabled accurate recording and quantification of mosquito flight and host-seeking behaviors, enabling development of Individual (agent) Based Models at much finer spatial scales than previously possible. We used such quantified behavioral parameters to create a novel virtual testing model, capable of accurately simulating indoor flight behavior by a virtual population of host-seeking mosquitoes as it interacts with and responds to simulated stimuli from a human-occupied bed net. We describe the model, including base mosquito behavior, state transitions, environmental representation and host stimulus representation. In the absence of a bed net and human bait, flight distribution of the model population is relatively uniform in the arena. Introducing an unbaited net induces a change in distribution due to landing events on the net surface, predominantly occurring on the sides and edges of the net. Presence of simulated human baited net strongly impacted flight distribution patterns, exploratory foraging, the number and distribution of net landing sites, depending on the bait orientation. As recorded in live mosquito experiments, contact with baited nets (a measure of exposure to the lethal insecticide) occurred predominantly on the top surface of the net. Number of net contacts and height of contacts decreased with increasing attractant dispersal noise. Results generated by the model are an accurate representation of actual mosquito behavior recorded at and around a human-occupied bed net in untreated and insecticide treated nets. In addition to providing insights into host-seeking behavior of endophilic vectors, this fine-grained model is highly flexible and has significant potential for in silico screening of novel bed net designs, accelerating the deployment of new and more effective tools for protecting against malaria in sub-Saharan Africa.
Functional anatomy of the full length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis
Authors: Stephens Bryan S. , Ngo Tony , Kufareva Irina , Handel Tracy M.
Published: January 2020

Due to their prominent role in development and infamy in cancer and HIV, the chemokine receptor CXCR4 and its ligand, CXCL12, have been the subject of numerous structural and functional studies. Nevertheless, a high resolution structure of the CXCR4-CXCL12 complex has not been reported. Even with several alternative computational models of the complex at hand, the relative contributions of different interaction epitopes to ligand binding, ligand selectivity and signaling are not readily apparent. Here, building upon our latest structural model, we employed a systematic mutagenesis strategy to dissect the functional anatomy of the of CXCR4-CXCL12 complex. Key charge swap mutagenesis experiments supported pairwise interactions between oppositely charged residues in the receptor and chemokine, confirming the accuracy of the predicted orientation of the chemokine relative to the receptor, while also providing insight into ligand selectivity. Progressive deletion of N-terminal residues revealed an unexpected contribution of the receptor N-terminus to chemokine signaling; this finding challenges a longstanding “two-site” hypothesis about the essential features of the receptor-chemokine interaction where the N-terminus is purported to only contribute to binding affinity. The results suggest that while the interaction of the chemokine N-terminus with the receptor binding pocket is the key driver of signaling, the signaling amplitude depends on the extent to which the receptor N-terminus binds the chemokine. Along with systematic characterization of other epitopes, the current data allow us to propose a comprehensive experimentally-consistent structural model for how the chemokine binds CXCR4 and initiates signal transmission through the receptor TM domain.

One sentence summary

A systematic structure-guided mutagenesis study of chemokine receptor CXCR4 reveals novel insights into epitopes regulating ligand recognition, ligand specificity and CXCL12-mediated signaling.
Post-prediction inference
Authors: Wang Siruo , McCormick Tyler H , Leek Jeffrey T
Published: January 2020

Many modern problems in medicine and public health leverage machine learning methods to predict outcomes based on observable covariates. In an increasingly wide array of settings, these predicted outcomes are used in subsequent statistical analysis, often without accounting for the distinction between observed and predicted outcomes. We call inference with predicted outcomespost-prediction inference. In this paper, we develop methods for correcting statistical inference using outcomes predicted with an arbitrary machine learning method. Rather than trying to derive the correction from the first principles for each machine learning tool, we make the observation that there is typically a low-dimensional and easily modeled representation of the relationship between the observed and predicted outcomes. We build an approach for thepost-prediction inferencethat naturally fits into the standard machine learning framework, where the data is divided into training, testing, and validation sets. We train the prediction model in the training set,. We estimate the relationship between the observed and predicted outcomes on the testing set and use that model to correct inference on the validation set and subsequent statistical models. We show ourpostpiapproach can correct bias and improve variance estimation (and thus subsequent statistical inference) with predicted outcome data. To show the broad range of applicability of our approach, we showpostpican improve inference in two totally distinct fields: modeling predicted phenotypes in re-purposed gene expression data and modeling predicted causes of death in verbal autopsy data. We have made our method available through an open-source R package: https://github.com/leekgroup/postpi
Mechanism of Action of a Prostaglandin E2Receptor Antagonist with antimicrobial activity againstStaphylococcus aureus
Authors: Lilly Elizabeth A. , Ikeh Mélanie A. C. , Fidel Paul L. , Noverr Mairi C.
Published: January 2020

Our laboratory recently reported that the EP4receptor antagonist, L-161,982, had direct growth-inhibitory effects onStaphylococcus aureus in vitroand in vivo, reducing microbial burden and providing significant protection against lethality in models ofS. aureusmonomicrobial and polymicrobial intra-abdominal infection. This antimicrobial activity was observed with both methicillin-sensitive and methicillin-resistantS. aureus(MRSA), as well as other Gram-positive bacteria. The antimicrobial activity of L-161,982 was independent of EP4receptor inhibitory activity. In this study, we investigated the mechanism of action (MOA) of L-161,982, which contains a sulfonamide functional group. However, results demonstrate L-161,982 does not affect folate synthesis (sulfonamide MOA), oxidative stress, or membrane permeability. Instead, our results suggest that the inhibitor works via effects on inhibition of the electron transport chain (ETC). Similar to other ETC inhibitors, L-161,982 exposure results in a small colony size variant phenotype and inhibition of pigmentation, as well as significantly reduced hemolytic activity, and ATP production. In addition, L-161,982 potentiated the antimicrobial activity of another ETC inhibitor and inhibition was partially rescued by supplementation with nutrients required for ETC auxotrophs. Taken together, these findings demonstrate that L-161,982 exerts antimicrobial activity against MRSA via inhibition the ETC, representing a new member of a potentially novel antimicrobial drug class.
Bcl6 Preserves the Suppressive Function of Regulatory T Cells during Tumorigenesis
Authors: Li Yiding , Wang Zhiming , Lin Huayu , Wang Lisha , Chen Xiangyu , Liu Qiao , Zuo Qianfei , Hu Jianjun , Wang Haoqiang , Guo Junyi , Xie Luoyingzi , Tang Jianfang , Li Zhirong , Hu Li , Ye Lilin , Huang Qizhao , Xu Lifan
Published: January 2020

During tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3+cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.
An enhanced characterization of the human skin microbiome: a new biodiversity of microbial interactions
Authors: Emiola Akintunde , Zhou Wei , Oh Julia
Published: January 2020

The healthy human skin microbiome is shaped by skin site physiology, individual-specific factors, and is largely stable over time despite significant environmental perturbation. Studies identifying these characteristics used shotgun metagenomic sequencing for high resolution reconstruction of the bacteria, fungi, and viruses in the community. However, these conclusions were drawn from a relatively small proportion of the total sequence reads analyzable by mapping to known reference genomes. ‘Reference-free’ approaches, based onde novoassembly of reads into genome fragments, are also limited in their ability to capture low abundance species, small genomes, and to discriminate between more similar genomes. To account for the large fraction of non-human unmapped reads on the skin—referred to as microbial ‘dark matter’—we used a hybridde novoand reference-based approach to annotate a metagenomic dataset of 698 healthy human skin samples. This approach reduced the overall proportion of uncharacterized reads from 42% to 17%. With our refined characterization, we revisited assumptions about the skin microbiome, and demonstrated higher biodiversity and lower stability, particularly in dry and moist skin sites. To investigate hypotheses underlying stability, we examined growth dynamics and interspecies interactions in these communities. Surprisingly, even though most skin sites were relatively stable, many dominant skin microbes, includingCutibacterium acnesand staphylococci, were actively growing in the skin, with poor or no relationship between growth rate and relative abundance, suggesting that host selection or interspecies competition may be important factors maintaining community homeostasis. To investigate other mechanisms facilitating adaptation to a specific skin site, we identifiedStaphylococcus epidermidisgenes that are likely involved in stress response and provide mechanisms essential for growth in oily sites. Finally, horizontal gene transfer—another mechanism of competition by which strains may swap antagonistic or virulent coding regions—was relatively limited in healthy skin, but suggested exchange of different metabolic and environmental tolerance pathways. Altogether, our findings underscore the value of a combined reference-based andde novoapproach to provide significant new insights into microbial composition, physiology, and interspecies interactions to maintain community homeostasis in the healthy human skin microbiome.
Exploiting toxin internalization receptors to enhance delivery of proteins to lysosomes for enzyme replacement therapy
Authors: Sugiman-Marangos Seiji N. , Beilhartz Greg L. , Zhao Xiaochu , Zhou Dongxia , Hua Rong , Kim Peter K. , Rini James M. , Minassian Berge A. , Melnyk Roman A.
Published: January 2020

Lysosomal storage diseases are a group of over 70 inherited genetic diseases caused by a defect or deficiency in a lysosomal protein. Enzyme replacement therapy, in which a functional copy of the defective enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases; however, the inefficient uptake of recombinant enzymes into cells and tissuesviathe low-affinity mannose-6-phosphate receptor prohibits broader utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endo-lysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that the targeted TPP1 chimera binds with high affinity to target cells and is delivered into lysosomes with much greater efficiency than TPP1 alone. Further, we demonstrate efficient and durable uptake of the chimerain vivofollowing intracerebroventricular injection in mice lacking TPP1. Targeting the highly efficient diphtheria toxin internalization pathway represents a novel approach for improving the efficacy and utility of enzyme replacement therapy for treating lysosomal storage diseases.
The tale of two genes: from next-generation sequencing to phenotype
Authors: Rohanizadegan Mersedeh , Siddharath Aishwarya , Retterer Kyle , Hung Christina , Bodamer Olaf
Published: January 2020

An 18-yr-old man with a history of intellectual disability, craniofacial dysmorphism, seizure disorder, and obesity was identified to carry a de novo, pathogenic variant in ASXL1 (c.4198G>T; p.E1400X) associated with the diagnosis of Bohring–Opitz syndrome based on exome sequencing. In addition, he was identified to carry a maternally inherited and likely pathogenic variant in MC4R (c.817C>T; p.Q273X) associated with monogenic obesity. Dual genetic diagnosis occurs in 4%–6% of patients and results in unique clinical phenotypes that are a function of tissue-specific gene expression, involved pathways, clinical expressivity, and penetrance. This case highlights the utility of next-generation sequencing in patients with an unusual combination of clinical presentations for several pillars of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.
Simplified probabilistic seismic assessment of dampers in tall and braced structures in buildings
Authors: Singh Tanuja , Kalra Megha , Misra Anil Kumar
Published: January 2020

Purpose

The paper aims to focus on adjacent buildings response, equipped with damper, to analyze the vibration reduction in the nearby buildings. The nearby buildings were also equipped with dampers. The occurrence of adjacent buildings with adequate or inadequate space in between is a common phenomenon. However, many a times not much attention is paid to provide or check gap adequacy or to connect the two buildings suitably to avoid pounding of two structures on each other. This study emphasizes the utility of providing a damper in between two adjacent buildings for better performance.

Design/methodology/approach

The two steel structures taken for study are prototype of two structures normally found in industrial structure such as power plant, where in one of boiler structure is often tall and braced and short structure of turbine building which is moment resistant, modeled in SAP. There could be similar such structures which are often connected to a platform or a walkway with a sliding end, so as not to transfer horizontal force to other structures. If the advantage of stiffness of tall braced structure is taken into account, shorter structure can be suitably connected to braced structure to transfer forces during seismic cases under nonlinear conditions, thereby avoiding pounding (incase gap is too less), reducing response and thus optimizing the section sizes. The structures were subjected to El Centro earthquake, to simulate MCE (which could be the other site TH scaled up as desired for real site PGA), and damper location and parameters were varied to find optimum value which offers reduced base shear, reduced top floor displacement and minimum inter story drift and highest energy absorption by fluid viscous dampers.

Findings

The findings show that taller structures, which are braced, have more stiffness; the effect of damper is more pronounced in reducing displacement of shorter moment resistant structure to the tune of 60%, with suitably defined Cd value which is found to be 600 KNs/m for the present study. Thus, advantage of stiffener structure is taken to leverage and reduce the displacement of shorter moment resistant structure in reducing its displacement under nonlinear conditions of seismic case.

Originality/value

This work shows the original findings, of the adjacent buildings response, equipped with damper, to analyze the vibration reduction on other buildings which were planned to be constructed nearby.
Long-range dependence in the returns and volatility of the Finnish housing market
Authors: Dufitinema Josephine , Pynnönen Seppo
Published: January 2020

Purpose

The purpose of this paper is to examine the evidence of long-range dependence behaviour in both house price returns and volatility for fifteen main regions in Finland over the period of 1988:Q1 to 2018:Q4. These regions are divided geographically into 45 cities and sub-areas according to their postcode numbers. The studied type of dwellings is apartments (block of flats) divided into one-room, two-rooms, and more than three rooms apartments types.

Design/methodology/approach

For each house price return series, both parametric and semiparametric long memory approaches are used to estimate the fractional differencing parameter d in an autoregressive fractional integrated moving average [ARFIMA (p, d,q)] process. Moreover, for cities and sub-areas with significant clustering effects (autoregressive conditional heteroscedasticity [ARCH] effects), the semiparametric long memory method is used to analyse the degree of persistence in the volatility by estimating the fractional differencing parameter d in both squared and absolute price returns.

Findings

A higher degree of predictability was found in all three apartments types price returns with the estimates of the long memory parameter constrained in the stationary and invertible interval, implying that the returns of the studied types of dwellings are long-term dependent. This high level of persistence in the house price indices differs from other assets, such as stocks and commodities. Furthermore, the evidence of long-range dependence was discovered in the house price volatility with more than half of the studied samples exhibiting long memory behaviour.

Research limitations/implications

Investigating the long memory behaviour in both returns and volatility of the house prices is crucial for investment, risk and portfolio management. One reason is that the evidence of long-range dependence in the housing market returns suggests a high degree of predictability of the asset. The other reason is that the presence of long memory in the housing market volatility aids in the development of appropriate time series volatility forecasting models in this market. The study outcomes will be used in modelling and forecasting the volatility dynamics of the studied types of dwellings. The quality of the data limits the analysis and the results of the study.

Originality/value

To the best of the authors’ knowledge, this is the first research that assesses the long memory behaviour in the Finnish housing market. Also, it is the first study that evaluates the volatility of the Finnish housing market using data on both municipal and geographical level.
Molecular epidemiology of clinically high‐risk Pseudomonas aeruginosa strains: Practical overview
Authors: Sawa Teiji , Momiyama Kyoko , Mihara Toshihito , Kainuma Atsushi , Kinoshita Mao , Moriyama Kiyoshi
Published: January 2020

In recent years, numerous outbreaks of multidrug‐resistant Pseudomonas aeruginosa have been reported across the world. Once an outbreak occurs, besides routinely testing isolates for susceptibility to antimicrobials, it is required to check their virulence genotypes and clonality profiles. Replacing pulsed‐field gel electrophoresis DNA fingerprinting are faster, easier‐to‐use, and less expensive polymerase chain reaction (PCR)‐based methods for characterizing hospital isolates. P. aeruginosa possesses a mosaic genome structure and a highly conserved core genome displaying low sequence diversity and a highly variable accessory genome that communicates with other Pseudomonas species via horizontal gene transfer. Multiple‐locus variable‐number tandem‐repeat analysis and multilocus sequence typing methods allow for phylogenetic analysis of isolates by PCR amplification of target genes with the support of Internet‐based services. The target genes located in the core genome regions usually contain low‐frequency mutations, allowing the resulting phylogenetic trees to infer evolutionary processes. The multiplex PCR‐based open reading frame typing (POT) method, integron PCR, and exoenzyme genotyping can determine a genotype by PCR amplifying a specific insertion gene in the accessory genome region using a single or a multiple primer set. Thus, analyzing P. aeruginosa isolates for their clonality, virulence factors, and resistance characteristics is achievable by combining the clonality evaluation of the core genome based on multiple‐locus targeting methods with other methods that can identify specific virulence and antimicrobial genes. Software packages such as eBURST, R, and Dendroscope, which are powerful tools for phylogenetic analyses, enable researchers and clinicians to visualize clonality associations in clinical isolates.
Long‐term deepened snow cover alters litter layer turnover rate in temperate steppes
Authors: Wang Jing , Liu Weixing , Li Ping , Jia Zhou , Deng Meifeng , Yang Sen , Liu Lingli
Published: January 2020

The turnover of litter layer is a biogeochemical process fundamental to carbon and nutrient cycling, influencing seed germination, species coexisting, and carbon storage. Winter snow depth is undergoing increasing trend in Northern China, which has been shown to alter litter decomposition rate of individual species. However, it remains unknown how changes in snow depth affect the turnover rate of the whole litter layer, and whether the responses vary between different steppes. Most current litter decomposition studies are site‐based or short‐term treated, limiting the exploration of the long‐term response of litter layer turnover in regional pattern.

In this study, we selected six long‐term (11–13 years) snow fence sites in Inner Mongolia, with three in the dry steppe and another three in the wet steppe, and investigated the responses of community‐weighted litter residence time (LRT) to long‐term increased snow treatment.

We found that LRT increased by 0.02 year for every 10 cm increase in snow depth in the wet steppe, but was not affected in the dry steppe. The lack of effect of deepened snow on LRT in the dry steppe was attributed to the offset between the positive effect of the increased plant community‐weighted height possibly via inhibiting photodegradation and the enhanced litter recalcitrance by producing higher proportion of stem litter, and the negative effect of the increased soil moisture via accelerating microbial decomposition. The significantly positive effect of the deepened snow on LRT in the wet steppe was mainly because the deepened snow increased grass biomass but had no effect on forb biomass, which reduced the degradability of the litter layer.

Overall, our findings indicated that deepened snow changed plant community, which altered environmental conditions and enhanced litter recalcitrance, thereby increasing LRT in temperate steppes. However, this effect was diminished by enhancing microbial decomposition in the dry but not wet steppe, resulting in different overall responses of LRT to deep‐snow in the two steppes. The slow litter turnover rate in the wet steppe might result in greater litter accumulation under future increased snow depth, which could be unfavourable for seed germination and alter plant diversity.

A free Plain Language Summary can be found within the Supporting Information of this article.
Phenolic compounds extraction in enzymatic macerations of grape skins identified as low‐level extractable total anthocyanin content
Authors: Nogales‐Bueno Julio , Baca‐Bocanegra Berta , Heredia Francisco José , Hernández‐Hierro José Miguel
Published: January 2020

Anthocyanins in wine principally depend on grape skin extractable anthocyanin content, that is, the amount of anthocyanins present in grape skin that are released to wine during the maceration stage. This amount of extractable anthocyanins is closely linked to the cell wall degradation of skin cells. Indeed, among other methodologies, the maceration in presence of different enzymes can be used to increase cell wall degradation, and therefore, the amount of anthocyanins extracted from grape skins to wine. Vitis vinifera L. cv. Tempranillo and Syrah red grapes have been identified as samples with low anthocyanin extraction potential by near infrared hyperspectral imaging. Grape skins have been macerated in the presence of cellulase, glucosidase, and pectinase. Then, color of the supernatants and phenolic compounds extracted from grape skins (total phenols, total flavanols, and total and individual anthocyanins) has been determined. Cellulase and glucosidase have shown a positive effect in the extraction of phenolic compounds from these grapes. Macerations carried out in the presence of cellulase have produced supernatants with a more intense color (lower lightness and higher chroma values), and a higher extraction of flavanols and anthocyanins than the respective control essays. However, pectinase treatments have produced the opposite effect, which could be partially explained by an eventual interaction between the cell wall polysaccharides liberated by pectinase and the phenolic compounds extracted. Synergy effects do not appear between cellulase and glucosidase. Moreover, the negative effect of the addition of pectinase might be due to the interactions between the cell wall material liberated by pectinase and the phenolic compounds extracted.

Practical Application

In the present study, grape samples with a low anthocyanin extraction potential have been identified, and these samples have been macerated in the presence of different enzymes. The applied enzymes were three of the most common enzymes that are applied in the wine industry. Individual enzymes and mixtures have been applied to Syrah and Tempranillo grape skin samples and the results have been compared to control macerations. Knowledge in this topic will help the production of quality wines.
steps: Software for spatially and temporally explicit population simulations
Authors: Visintin Casey , Briscoe Natalie J. , Woolley Skipton N. C. , Lentini Pia E. , Tingley Reid , Wintle Brendan A. , Golding Nick
Published: January 2020

Species population dynamics are driven by spatial and temporal changes in the environment, anthropogenic activities and conservation management actions. Understanding how populations will change in response to these drivers is fundamental to a wide range of ecological applications, but there are few open‐source software options accessible to researchers and managers that allow them to predict these changes in a flexible and transparent way.

We introduce an open‐source, multi‐platformrpackage,steps, that models spatial changes in species populations as a function of drivers of distribution and abundance, such as climate, disturbance, landscape dynamics and species ecological and physiological requirements.

To illustrate the functionality ofsteps, we model the population dynamics of the greater gliderPetauroides volans, an arboreal Australian mammal. We demonstrate howstepscan be used to simulate population responses of the glider to forest dynamics and management with the types of data commonly used in ecological analyses.

stepsexpands on the features found in existing software packages, can easily incorporate a range of spatial layers (e.g. habitat suitability, vegetation dynamics and disturbances), facilitates integrated and transparent analyses within a single platform and produces interpretable outputs of changes in species' populations through space and time. Further,stepsoffers both ready‐to‐use, built‐in functionality, as well as the ability for advanced users to define their own modules for custom analyses. Thus, we anticipate thatstepswill be of significant value to environment and wildlife managers and researchers from a broad range of disciplines.
Clinical and experimental validation of a capnodynamic method for end‐expiratory lung volume assessment
Authors: Öhman Tomas , Sigmundsson Thorir S. , Hallbäck Magnus , Suarez Sipmann Fernando , Wallin Mats , Oldner Anders , Björne Håkan , Hällsjö Sander Caroline
Published: January 2020

Introduction

Lung protective ventilation can decrease post‐operative pulmonary complications. The aim of this study was to evaluate a capnodynamic method estimating effective lung volume (ELV) as a proxy for end‐expiratory lung volume in response to PEEP changes in patients, healthy subjects and a porcine model.

Methods

Agreement and trending ability for ELV in anaesthetized patients and agreement in awake subjects were evaluated using nitrogen multiple breath wash‐out/in and plethysmography as a reference respectively. Agreement and trending ability were evaluated in pigs during PEEP elevations with inert gas wash‐out as reference.

Results

In anaesthetized patients bias (95% limits of agreement [LoA]) and percentage error (PE) at PEEP 0 cm H2O were 133 mL (−1049 to 1315) and 71%, at PEEP 5 cm H2O 161 mL (−1291 to 1613 mL) and 66%. In healthy subjects: 21 mL (−755 to 796 mL) and 26%. In porcines, at PEEP 5‐20 cm H2O bias decreased from 223 mL to 136 mL LoA (34‐412) to (−30 to 902) and PE 29%‐49%. Trending abilities in anaesthetized patients and porcines were 100% concordant.

Conclusion

The ELV‐method showed low bias but high PE in anaesthetized patients. Agreement was good in awake subjects. In porcines, agreement was good at lower PEEP levels. Concordance related to PEEP changes reached 100% in all settings. This method may become a useful trending tool for monitoring lung function during mechanical ventilation, if findings are confirmed in other clinical contexts.
An instructive case of amlodipine‐induced reversible granulomatous CD30+T‐cell pseudolymphoma
Authors: Cheong Kah Wai , Lim Gareth Zigui , Tan Kong Bing , Lim Joel Hua‐Liang
Published: January 2020

We report an unusual case of drug‐associated granulomatous CD30+T‐cell pseudolymphoma secondary to amlodipine. A 55‐year‐old Chinese man presented with a 6‐month eruption of disseminated erythematous dermal papulonodules and annular infiltrated plaques over his neck and limbs symmetrically. Histopathology revealed a perivascular and interstitial infiltrate of histiocytes, eosinophils and morphologically normal lymphocytes associated with CD30 expression. The eruption improved rapidly after discontinuation of amlodipine and did not recur.
Local anaesthesia for haemorrhoidal rubber band ligation reduces immediate post‐operative recovery time and use of opioid analgesia
Authors: Behrenbruch Corina , Kong Joseph , Chen Frank
Published: January 2020

Background

Haemorrhoidal rubber band ligation (RBL) is a well‐established, safe and cost‐effective treatment for bleeding haemorrhoids. It is generally well tolerated; however, some patients may require narcotic analgesia or even admission to hospital for pain management. This comparative cohort study reports on the difference in peri‐procedural analgesia administration and post‐operative recovery time between patients who received local anaesthetic (LA) infiltration in addition to RBL, compared with patients treated only with RBL.

Methods

Consecutive patients with haemorrhoids treated over a 3‐month period with LA infiltration in addition to RBL were compared to a consecutive control group who received RBL alone in the preceding 3 months. Clinical data were collected prospectively for LA group and retrospectively for the control group. Data collected included analgesia administered during the procedure and in recovery, as well as the mean time to discharge.

Results

A total of 32 patients treated with LA infiltration following RBL for haemorrhoids were compared with 22 patients who were treated with RBL alone. There was a reduction in the administration of intra‐procedural parecoxib in the LA group (P < 0.001). Following the procedure, there was a reduction in the administration of both oral and intravenous opioid analgesia (P = 0.009) and reduced mean time to discharge in the LA group (P < 0.001).

Conclusion

Infiltration of LA proximal to the band following RBL for haemorrhoids reduced the administration of analgesia both during the procedure and in recovery, as well as mean time to discharge following the procedure.
A systematic review of prevention and treatment of infant behavioural sleep problems
Authors: Reuter Antonia , Silfverdal Sven‐Arne , Lindblom Kristin , Hjern Anders
Published: January 2020

Aim

The aim of this review was to evaluate the evidence for interventions for behavioural sleep problem in infants.

Methods

Systematic review based on a search in MEDLINE, Web of Science and PsychINFO in December 2017 for articles published in English during 2007‐2017 about preventive and treatment interventions for sleep problems in infants. The review included controlled trials and meta‐analyses with at least 20 infants in study groups assessed according to the Grading of Recommendations Assessment, Development and Evaluation criteria.

Results

Out of 476 original articles assessed for eligibility, 12 studies were included in the synthesis. Interventions with behavioural, educational and massage strategies were evaluated. No intervention was evaluated in more than one trial. Five interventions with behavioural methods for establishing consistent routines or controlled crying showed modest short‐term effects, while the evidence for elements of education was inconsistent. Studies of massage were of poor quality. Knowledge gaps were identified regarding interventions in cross‐cultural context, involving fathers, in children below six months of age, in high‐risk populations and consequences of interventions that include extinction.

Conclusion

Some support for short‐term effects of behavioural treatment strategies was found, but more studies are needed to establish evidence.
Canine systemic mycosis associated withChaetomium globosumin a dog
Authors: Mesa‐Sánchez I , Jolly‐Frahija IT , Sánchez‐González K , Pumarola‐Batlle M , Cervera‐Castellanos V , Ródenas S
Published: January 2020

Background

Disseminated mycoses other than aspergillosis are infrequently reported in dogs.

Case report

A 4‐year‐old female Labrador retriever was evaluated because of hyperthermia, cough and intermittent lameness. Computed tomography showed a soft tissue mass in the cranioventral mediastinum, severe left and central tracheobronchial lymphadenopathy, and moderate bilateral pleural effusion. Magnetic resonance imaging identified an irregular intra‐axial well‐defined contrast enhancing mass extending from the right frontal lobe to the right thalamus. Fungal culture yielded growth of Chaetomium globosum.

Conclusion

In this case, the authors report a systemic mycosis in a Labrador retriever caused by C. globosum. To the best of authors' knowledge, this is the first report of systemic disease by this species in veterinary medicine.
Evaluation of functional outcomes after a second focal high‐intensity focused ultrasonography (HIFU) procedure in men with primary localized, non‐metastatic prostate cancer: results from the HIFU Evaluation and Assessment of Treatment (HEAT) registry
Authors: Lovegrove Catherine E. , Peters Max , Guillaumier Stephanie , Arya Manit , Afzal Naveed , Dudderidge Tim , Hosking‐Jervis Feargus , Hindley Richard G. , Lewi Henry , McCartan Neil , Moore Caroline M. , Nigam Raj , Ogden Chris , Persad Raj , Virdi Jaspal , Winkler Mathias , Emberton Mark , Ahmed Hashim U. , Shah Taimur T. , Minhas Suks
Published: January 2020

Objectives

To assess change in functional outcomes after a second focal high‐intensity focused ultrasonography (HIFU) treatment compared with outcomes after one focal HIFU treatment.

Patients and Methods

In this multicentre study (2005–2016), 821 men underwent focal HIFU for localized non‐metastatic prostate cancer. The patient‐reported outcome measures of International Prostate Symptom Score (IPSS), pad usage and erectile function (EF) score were prospectively collected for up to 3 years. To be included in the study, completion of at least one follow‐up questionnaire was required. The primary outcome was comparison of change in functional outcomes between baseline and follow‐up after one focal HIFU procedure vs after a second focal HIFU procedure, using IPSS, Expanded Prostate Cancer Index Composite (EPIC) and International Index of Erectile Function (IIEF) questionnaires.

Results

Of 821 men, 654 underwent one focal HIFU procedure and 167 underwent a second focal HIFU procedure. A total of 355 (54.3%) men undergoing one focal HIFU procedure and 65 (38.9%) with a second focal HIFU procedure returned follow‐up questionnaires, respectively. The mean age and prostate‐specific antigen level were 66.4 and 65.6 years, and 7.9 and 8.4 ng/mL, respectively. After one focal HIFU treatment, the mean change in IPSS was −0.03 (P = 0.02) and in IIEF (EF score) it was −0.4 (P = 0.02) at 1–2 years, with no subsequent decline. Absolute rates of erectile dysfunction increased from 9.9% to 20.8% (P = 0.08), leak‐free continence decreased from 77.9% to 72.8% (P = 0.06) and pad‐free continence from 98.6% to 94.8% (P = 0.07) at 1–2 years, respectively. IPSS prior to second focal HIFU treatment compared to baseline IPSS prior to first focal HIFU treatment was lower by −1.3 (P = 0.02), but mean IPSS change was +1.4 at 1–2 years (P = 0.03) and +1.2 at 2–3 years (P = 0.003) after the second focal HIFU treatment. The mean change in EF score after the second focal HIFU treatment was −0.2 at 1–2 years (P = 0.60) and −0.5 at 2–3 years (P = 0.10), with 17.8% and 6.2% of men with new erectile dysfunction. The rate of new pad use was 1.8% at 1–2 years and 2.6% at 2–3 years.

Conclusion

A second focal HIFU procedure causes minor detrimental effects on urinary function and EF. These data can be used to counsel patients with non‐metastatic prostate cancer prior to considering HIFU therapy.
“She was accused of colluding with the mother”; the training and support needs of parent‐and‐child foster carers: A qualitative study
Authors: November Lucy , Sandall Jane
Published: January 2020

Parent‐and‐child foster placements are used to accommodate parents with their children, either when the mother is a looked‐after child or as a setting for a parenting assessment. Despite this being a specialized role with significant potential for affecting outcomes for disadvantaged families, there is currently a lack of accessible learning opportunities for foster carers on the physical and mental well‐being of women with complex needs such as a history of domestic abuse, substance abuse, perinatal mental ill‐health, or having a learning disability. Parent‐and‐child carers experience some unique stresses and value the support of others with similar experiences; this kind of peer support is currently largely absent. This qualitative study has used ten focus groups with foster carers, eight interviews with mothers, and nine interviews with supervising social workers, to inform the development of an online learning resource and a social media‐based peer support network for parent‐and‐child foster carers.
Simulating the Evolution of Ancient Fortified Cities
Authors: Mas Albert , Martin Ignacio , Patow Gustavo
Published: January 2020

Ancient cities and castles are ubiquitous cultural heritage structures all over Europe, and countless digital creations (e.g. movies and games) use them for storytelling. However, they got little or no attention in the computer graphics literature. This paper aims to close the gap between historical and geometrical modelling, by presenting a framework that allows the forward and inverse design of ancient city (e.g. castles and walled cities) evolution along history. The main component is an interactive loop that cycles over a number of years simulating the evolution of a city. The user can define events, such as battles, city growth, wall creations or expansions, or any other historical event. Firstly, cities (or castles) and their walls are created, and, later on, expanded to encompass civil or strategic facilities to protect. In our framework, battle simulations are used to detect weaknesses and strengthen them, evolving to accommodate to developments in offensive weaponry. We conducted both forward and inverse design tests on three different scenarios: the city of Carcassone (France), the city of Gerunda (Spain) and the Ciutadella in ancient Barcelona. All the results have been validated by historians who helped fine‐tune the different parameters involved in the simulations.
Family members' experiences with adult participation in weight management programs: Triadic perspectives from patients, partners and children
Authors: Albright Charlotte A. , Pratt Keeley J. , Martin Sarah B. , Hulshult Hannah , Brown Callie L. , Lewis Kristina H. , Skelton Joseph A.
Published: January 2020

Objective

Spouses are known to influence the outcomes of an individual's attempt at weight loss, but little is known about the broader influence of, and on, the family. The objectives were to explore: (a) the effects of an adult weight management program on the family and (b) family factors that help or hinder patient weight loss.

Methods

A qualitative design was employed to explore triadic family members' experiences of patient participation in a weight management program. Semi‐structured interviews were conducted with patients, partners and children (ages 7‐18). Questions included support for patient participation and weight loss, dietary choices, meal preparation, physical activity routines, the home‐food environment, communication about health and family dynamics. Thematic analysis was used, where codes and categories of codes were then grouped together to create themes and subthemes.

Results

Nineteen triadic interviews were conducted (57 total). Seven themes emerged, including four related to Outcomes (objective 1): (a) shift in family dynamics, (b) family behaviour change, (c) child observations of family change, (d) indirect benefit to partner; and three related to Process (objective 2): (e) level of accountability, (f) patient perception of support and (g) support is essential and flexible.

Conclusions

Future research and clinical applications from these themes should seek to determine the positive behaviour change that was evident in the families that were interviewed, where the culmination of family interactions, expectations and concurrent partner weight loss indicates the potential longevity of weight management programs beyond patients' own participation.
Cross talk between RNA N6‐methyladenosine methyltransferase‐like 3 and miR‐186 regulates hepatoblastoma progression through Wnt/β‐catenin signalling pathway
Authors: Cui Xichun , Wang Zhifang , Li Jianhao , Zhu Jianming , Ren Zhigang , Zhang Dandan , Zhao Wei , Fan Yingzhong , Zhang Da , Sun Ranran
Published: January 2020

Objectives

N6‐methyladenosine (m6A) is a ubiquitous epigenetic RNA modification that plays a pivotal role in tumour development and metastasis. In this study, we aimed to investigate the expression profiling, clinical significance, biological function and the regulation of m6A‐related genes in hepatoblastoma (HB).

Materials and Methods

The mRNA and protein expression levels of m6A‐related genes were analysed using Gene Expression Omnibus (GEO) and tissue microarray (TMA) cohort. Kaplan‐Meier analysis was performed to evaluate the prognostic value of m6A‐related genes in HB. Knockdown of m6A‐related genes was conducted to analyse its function on cell proliferation, migration and invasion. Furthermore, bioinformatics analysis and experimental verification were used to explore the potential molecular mechanism and signalling pathway.

Results

We found that most m6A‐related genes were significantly upregulated in HB tumour tissues. High levels of methyltransferase‐like 3 (METTL3, P = .013), YTHDF2 (P = .037) and FTO (P = .032) indicated poor clinical outcomes, and the upregulation of METTL3 was an independent prognostic factor in HB patients. Functional assays showed that knockdown of METTL3 could dramatically suppress the proliferation, migration and invasion of HB cells. In addition, METTL3 was identified to be a direct target of microRNA‐186 (miR‐186). Consistently, miR‐186 was low expressed in HB tumour tissues. Moreover, overexpression of miR‐186 significantly inhibited cell aggressive phenotype both in vitro and in vivo, while the inhibitory effect could be reversed by METTL3 overexpression. Mechanism study indicated that miR‐186/METTL3 axis contributed to the progression of HB via the Wnt/β‐catenin signalling pathway.

Conclusions

M6A‐related genes were frequently dysregulated in HB. miR‐186/METTL3/Wnt/β‐catenin axis might serve as novel therapeutic targets and prognostic biomarkers in HB.