bluuebunny/crossref_metadata_2025 huggingface dataset:
Large-scale simulations of biological cell sorting driven by differential adhesion follow diffusion-limited domain coalescence regime
Authors: Durand Marc
Published: December 2020

Cell sorting, whereby a heterogeneous cell mixture segregates and forms distinct homogeneous tissues, is one of the main collective cell behaviors at work during development. Although differences in interfacial energies are recognized to be a possible driving source for cell sorting, no clear consensus has emerged on the kinetic law of cell sorting driven by differential adhesion. Using a modified Cellular Potts Model algorithm that allows for efficient simulations while preserving the connectivity of cells, we numerically explore cell-sorting dynamics over unprecedentedly large scales in space and time. For a binary mixture of cells surrounded by a medium, increase of domain size follows a power-law with exponentn= 1/4 independently of the mixture ratio, revealing that the kinetics is dominated by the diffusion and coalescence of rounded domains. We compare these results with recent numerical and experimental studies on cell sorting, and discuss the importance of boundary conditions, space dimension, initial cluster geometry, and finite size effects on the observed scaling.

Author summary

Cell sorting describes the spontaneous segregation of identical cells in biological tissues. This phenomenon is observed during development or organ regeneration in a variety of biological systems. Minimization of the total surface energy of a tissue, in which adhesion strengh between homotypic and heterotypic cells are different, is one of the mechanisms that explain cell sorting. This mechanism is then similar to the one that drives demixing of two immiscible fluids. Because of the high sensibility of this process to finite-size and finite-time effects, no clear consensus has emerged on the scaling law of cell sorting driven by differential adhesion. Using an efficient numerical code, we were able to investigate this scaling law on very large binary mixtures of cells. We show that on long times, cell sorting obeys a universal power law, which is independent of the mixture ratio.
From random to predictive: a context-specific interaction framework improves selection of drug protein-protein interactions for unknown drug pathways
Authors: Wilson Jennifer L. , Gravina Alessio , Grimes Kevin
Published: December 2020

With high drug attrition, interaction network methods are increasingly attractive as quick and inexpensive methods for prediction of drug safety and efficacy effects when a drug pathway is unknown. However, these methods suffer from high false positive rates for selecting drug phenotypic effects, their performance is often no better than random (AUROC ~0.5), and this limits the use of network methods in regulatory and industrial decision making. In contrast to many network engineering approaches that apply mathematical thresholds to discover phenotype associations, we hypothesized that interaction networks associated with true positive drug phenotypes are context specific. We tested this hypothesis on 16 designated medical event (DMEs) phenotypes which are a subset of adverse events that are of upmost concern to FDA review using a novel data set extracted from drug labels. We demonstrated that context-specific interactions (CSIs) distinguished true from false positive DMEs with an 50% improvement over non-context-specific approaches (AUROC 0.77 compared to 0.51). By reducing false positives, CSI analysis has the potential to advance network techniques to influence decision making in regulatory and industry settings.

Author summary

Drugs bind proteins that interact with multiple downstream proteins and these protein networks are responsible for drug efficacy and safety. Protein interaction network methods predict drug effects aggregating information about proteins around drug-binding protein targets. However, many frameworks exist for identifying proteins relevant to a drug’s effect. We consider three frameworks for selecting these proteins and show increased performance from a context-specific approach on selecting proteins relevant to severe drug side effects. The context-specific approach leverages the idea that the proteins responsible for a drug side effect are specific to each side-effect. By discovering the relevant proteins, we can better understand downstream effects of drugs and better anticipate drug side effects for new drugs in development. Further, we focus on designated medical events, a subset of the most severe drug side-effects that are high priority for regulatory review.
ChameleonmicroRNAs in breast cancer: their elusive role as regulatory factors in cancer progression
Authors: Miglioli Cesare , Bakalli Gaetan , Orso Samuel , Karemera Mucyo , Molinari Roberto , Guerrier Stéphane , Mili Nabil
Published: December 2020

Breast cancer is one of the most frequent cancers affecting women. Non-coding micro RNAs (miRNAs) seem to play an important role in the regulation of pathways involved in tumor occurrence and progression. Extending on the research in Haakensenet al., where significant miRNAs were selected as being associated with the progression from normal breast tissue to breast cancer, in this work we put forward 112 sets of miRNA combinations, each including at most 5 expressions with high accuracy in discriminating healthy breast tissue from breast carcinoma. Our results are based on a recently developed machine learning technique which, instead of selecting a single model (or combination of features), delivers a set of models with equivalent predictive capabilities that allow to interpret and visualize the interaction of these features. These results shed new light on the biological action of the selected miRNAs which can behave in different ways according to the miRNA network with which they interact.

Indeed, these revealed connections may contribute to explain why, in some cases, different studies attribute opposite functions to the same miRNA. It is therefore possible to understand how the role of a genomic variable may change when considered in interaction with other sets of variables, as opposed to only considering its effect when it is evaluated within a unique combination of features. The approach proposed in this work provides a statistical basis for the notion ofchameleonmiRNAs and is inspired by the emerging field of systems biology.

Author Summary

The notion of a single predictive genomic (statistical) model is replaced by that of a set of models that can be considered as exchangeable due to their indistinguishable (optimal) predictive abilities;

Our results indicate that the role of miRNAs cannot be interpreted independently from the combination of features with which they interact and can therefore vary considerably when considered in a network of different combinations. Some miRNAs may act aschameleonsand behave in opposite manners thereby showing some kind of antagonistic duality;

Some miRNAs are exchangeable inside models with equivalent predictive ability and seem to point to latent biological functions.
Structural and functional insights into the mechanism of action of plant boron transporters
Authors: Saouros Savvas , Mohan Thotegowdanapalya C. , Cecchetti Cristina , Lehmann Silke , Barritt Joseph D. , Scull Nicola J. , Simpson Paul , Alguel Yilmaz , Cameron Alexander D. , Jones Alexandra M. E. , Byrne Bernadette
Published: December 2020

Boron has essential roles in plant growth and development. BOR proteins are key in the active uptake and distribution of boron, and regulation of intracellular boron concentrations. However, their mechanism of action remains poorly studied. BOR proteins are members of the SLC4 family of transporters and thus homologues of well studied mammalian transporters including the human Anion Exchanger 1 (hAE1). Here we generatedArabidopsis thalianaBOR1 (AtBOR1) variants based i) on known disease causing mutations of hAE1 (S466R, A500R) and ii) a loss of function mutation (D311A) identified in the yeast BOR protein, ScBOR1p. The AtBOR1 variants express in yeast and localise to the plasma membrane, although both S466R and A500R exhibit lower expression than the WT AtBOR1 and D311A. The D311A, S466R and A500R mutations result in a loss of boron efflux activity in a yeastbor1pknockout strain.A. thalianaplants containing these three individual mutations exhibit substantially decreased growth phenotypes in soil under conditions of low boron. These data confirm an important role for D311 in the function of the protein and show that mutations equivalent to disease causing mutations in hAE1 have major effects in AtBOR1. We also obtained a low resolution cryo-EM structure of a BOR protein fromOryza sativa, OsBOR3 lacking the 30 C-terminal amino acids. This structure confirms the gate and core domain organisation previously observed for related proteins, and is strongly suggestive of an inward facing conformation.
Alpha-tubulin acetylation inTrypanosoma cruzi: a dynamic instability of microtubules is required for replication and cell cycle progression
Authors: Alonso Victoria Lucia , Carloni Mara Emilia , Gonçalves Camila Silva , Peralta Gonzalo Martinez , Chesta Maria Eugenia , Pezza Alejandro , Tavernelli Luis Emilio , Motta Maria Cristina M. , Serra Esteban
Published: December 2020

Trypanosomatids have a cytoskeleton arrangement that is simpler than what is found in most eukaryotic cells. However, it is precisely organized and constituted by stable microtubules. Such microtubules compose the mitotic spindle during mitosis, the basal body, the flagellar axoneme and the subpellicular microtubules, which are connected to each other and also to the plasma membrane forming a helical arrangement along the central axis of the parasite cell body. Subpellicular, mitotic and axonemal microtubules are extensively acetylated inTrypanosoma cruzi. Acetylation on lysine (K) 40 of α-tubulin is conserved from lower eukaryotes to mammals and is associated with microtubule stability. It is also known that K40 acetylation occurs significantly on flagella, centrioles, cilia, basal body and the mitotic spindle in eukaryotes. Several tubulin posttranslational modifications, including acetylation of K40, have been catalogued in trypanosomatids, but the functional importance of these modifications for microtubule dynamics and parasite biology remains largely undefined. The primary tubulin acetyltransferase that delivers this modification was recently identified in several eukaryotes as Mec-17/ATAT, a Gcn5-related N-acetyltransferase. Here, we report thatT. cruziATAT acetylates α-tubulinin vivoand is capable of auto-acetylation.TcATAT is located in the cytoskeleton and flagella of epimastigotes and colocalizes with acetylated α-tubulin in these structures. We have expressedTcATAT with an HA tag using the inducible vector pTcINDEX-GW inT. cruzi. Over-expression ofTcATAT causes increased levels of the acetylated isoform, induces morphological and ultrastructural defects, especially in the mitochondrion, and causes a halt in the cell cycle progression of epimastigotes, which is related to an impairment of the kinetoplast division. Finally, as a result ofTcATAT over-expression we observed that parasites became more resistant to microtubule depolymerizing drugs. These results support the idea that α-tubulin acetylation levels are finely regulated for the normal progression ofT. cruzicell cycle.
Characterization of highly proliferative decidual precursor cells during the window of implantation in human endometrium
Authors: Diniz-da-Costa Maria , Kong Chow-Seng , Fishwick Katherine J. , Rawlings Thomas , Brighton Paul J. , Hawkes Amelia , Odendaal Joshua , Quenby Siobhan , Ott Sascha , Lucas Emma S , Vrljicak Pavle , Brosens Jan J
Published: December 2020

Pregnancy depends on the wholesale transformation of the endometrium, a process driven by differentiation of endometrial stromal cells (EnSC) into specialist decidual cells. Upon embryo implantation, decidual cells impart the tissue plasticity needed to accommodate a rapidly growing conceptus and invading placenta, although the underlying mechanisms are unclear. Here we characterize a discrete population of highly proliferative mesenchymal cells (hPMC) in midluteal human endometrium, coinciding with the window of embryo implantation. Single-cell transcriptomics demonstrated that hPMC express genes involved in chemotaxis and vascular transmigration. Although distinct from resident EnSC, hPMC also express genes encoding pivotal decidual transcription factors and markers, most prominently prolactin. We further show that hPMC are enriched around spiral arterioles, scattered throughout the stroma, and occasionally present in glandular and luminal epithelium. The abundance of hPMC correlated with thein vitrocolony-forming unit activity of midluteal endometrium and, conversely, clonogenic cells in culture express a gene signature partially conserved in hPMC. Cross-referencing of single-cell RNA-sequencing data sets indicated that hPMC differentiate into a recently discovered decidual subpopulation in early pregnancy. Finally, we demonstrate that recurrent pregnancy loss is associated with hPMC depletion. Collectively, our findings characterize midluteal hPMC as novel decidual precursors that are likely derived from circulating bone marrow-derived mesenchymal stem/stromal cells and integral to decidual plasticity in pregnancy.

Significance statement

Transformation of cycling endometrium into the decidua of pregnancy requires extensive tissue remodeling. Perturbations in this process lead to breakdown of the maternal-fetal interface and miscarriage. Here we report the characterization of decidual precursor cells during the window of implantation. We demonstrate that decidual precursors are clonogenic and primed for exponential growth. They likely originate from bone marrow-derived MSC and give rise to a distinct decidual subpopulation in pregnancy. Recurrent pregnancy loss is associated with loss of decidual precursor cells prior to conception, raising the possibility that they can be harnessed for the prevention of pregnancy disorders, including miscarriages and preterm labor.
Comprehensive prediction of robust synthetic lethality between paralog pairs in cancer cell lines
Authors: Kegel Barbara De , Quinn Niall , Thompson Nicola A. , Adams David J. , Ryan Colm J.
Published: December 2020

Pairs of paralogs may share common functionality and hence display synthetic lethal interactions. As the majority of human genes have an identifiable paralog, exploiting synthetic lethality between paralogs may be a broadly applicable approach for targeting gene loss in cancer. However only a biased subset of human paralog pairs has been tested for synthetic lethality to date. Here, by analysing genome-wide CRISPR screens and molecular profiles of over 700 cancer cell lines, we identify features predictive of synthetic lethality between paralogs, including shared protein-protein interactions and evolutionary conservation. We develop a machine-learning classifier based on these features to predict which paralog pairs are most likely to be synthetic lethal and to explain why. We show that our classifier accurately predicts the results of combinatorial CRISPR screens in cancer cell lines and furthermore can distinguish pairs that are synthetic lethal in multiple cell lines from those that are cell-line specific.
LAHMA: structure analysis through local annotation of homology-matched amino acids
Authors: van Beusekom Bart , Damaskos George , Hekkelman Maarten L. , Salgado-Polo Fernando , Hiruma Yoshitaka , Perrakis Anastassis , Joosten Robbie P.
Published: December 2020

Comparison of homologous structure models is a key step in analyzing protein structure. With a wealth of homologous structures, comparison becomes a tedious process, and often only a small (user-biased) selection of data is used. A multitude of structural superposition algorithms are then typically used to visualize the structures together in 3D and to compare them. Here, the Local Annotation of Homology-Matched Amino acids (LAHMA) website (https://lahma.pdb-redo.eu) is presented, which compares any structure model with all of its close homologs from the PDB-REDO databank. LAHMA displays structural features in sequence space, allowing users to uncover differences between homologous structure models that can be analyzed for their relevance to chemistry or biology. LAHMA visualizes numerous structural features, also allowing one-click comparison of structure-quality plots (for example the Ramachandran plot) and `in-browser' structural visualization of 3D models.
Complex crystal structure determination and anti-non-small-cell lung cancer activity of the Hsp90N inhibitor Debio0932
Authors: Qin Wei , Yu Feng , Zhou Huan , Li Ping , Zhou Fang , Li Hui-Jin , He Chun-Xia , Xing Lu , Zhou Xin , Zhao Dong , Li Peng-Quan , Jin Xi , Wang Qi-Sheng , He Jian-Hua , Cao Hui-Ling
Published: December 2020

Debio0932 is a promising lead compound in phase I clinical trials targeting the N-terminal ATP-binding pocket of the molecular chaperone heat-shock protein 90 (Hsp90N). The absence of a crystal structure of the Hsp90N–Debio0932 complex, however, has impeded further structural optimization of Debio0932 and understanding of the molecular-interaction mechanism. Here, a high-resolution crystal structure of the Hsp90N–Debio0932 complex was successfully determined (resolution limit 2.20 Å; PDB entry 6lr9) by X-ray diffraction and the molecular-interaction mechanism was analysed in detail, which suggested that Debio0932 suppresses cancer cells by accommodating itself in the ATP-binding pocket of Hsp90N, disabling its molecular-chaperone capability. The results of a thermal shift assay (ΔT
m = 8.83 ± 0.90°C) and isothermal titration calorimetry (K
d = 15.50 ± 1.30 nM) indicated strong binding and favourable thermodynamic changes in the binding of Hsp90N and Debio0932. Based on the crystal structure of the complex and on molecular-interaction analysis, 30 new Debio0932 derivatives were designed and nine new derivatives exhibited increased binding to Hsp90N, as determined by molecular-docking evaluation. Additionally, Debio0932 suppressed cell proliferation (IC50 values of 3.26 ± 2.82 µM for A549, 20.33 ± 5.39 µM for H1299 and 3.16 ± 1.04 µM for H1975), induced cell-cycle arrest and promoted apoptosis in three non-small-cell lung cancer (NSCLC) cell lines. These results provide novel perspectives and guidance for the development of new anti-NSCLC drugs based on the lead compound Debio0932.
ICT infrastructure, innovation development and economic growth: a comparative evidence between two decades in OECD countries
Authors: Kurniawati Meta Ayu
Published: December 2020

Purpose

The objective of this study is to examine the causal relationship between economic growth, information and communication technology (ICT) penetration and innovation development in OECD countries.

Design/methodology/approach

This study incorporates data for 24 OECD countries from 2000 to 2018, which is divided into the earliest (2000–2009) and the latest (2010–2018) periods. The econometric methodologies of this study employ panel cointegration, estimation procedures and vector error-correction modelling to investigate the potential interconnections between ICT, innovation development and economic growth.

Findings

The results from the latest period illustrate that OECD countries have achieved positive and significant economic development from high ICT penetration, while results from the earliest period show that OECD countries were just beginning to enjoy the benefits of ICT penetration. Moreover, findings show that innovation development is highly significant in the latest period when promoting economic growth.

Practical implications

The policy implications suggest that promoting ICT infrastructure establishment and expanding the innovation development may drive the process of economic development in OECD countries.

Originality/value

This study employs mobile and Internet penetration as the development of telecommunication which is in line with the enlargement of innovation to foster economic growth in OECD countries. Comparing the evidence from two decades provides significant value for policymakers and decision-makers regarding the advantages of technology expansion and innovation development to promote economic growth in recent conditions.
Identification of the piston machine combustion chamber tightness
Authors: Bielawski Piotr Jan
Published: December 2020

Purpose

The lack of integrity of the piston machine combustion chamber manifests itself in leakages of the working fluid between the piston and the cylinder liner, at valves mounted in the cylinder head and between the head and the liner. An untight combustion chamber leads to decreased power output or efficiency of the engine, while leaks of a fluid may cause damage to many components of the chamber. The actual value of working chamber leak is a desired and essential piece of information for planning operations of a given machine.

Design/methodology/approach

This research paper describes causes and mechanisms of leakage from the working chamber of internal combustion engines. Besides, the paper outlines presently used methods and means of leak identification and states that their further development and improvements are needed. New methods and their applicability are presented.

Findings

The methods of leak identification have been divided into diagnostic and non-working machine leak identification methods. The need has been justified for the identification of leakage from the combustion chamber of a non-working machine and for using the leakage measure as the value of the cross-sectional area of the equivalent leak, defined as the sum of cross-section areas of all leaking paths. The analysis of possible developments of tightness assessment methods referring to the combustion chamber of a non-working machine consisted in modelling subsequent combustion chamber leaks as gas-filled tank leak, leak from another element of gas-filled tank and as a regulator of gas flow through a nozzle.

Originality/value

A measurement system was built allowing the measurement of pressure drop in a tank with the connected engine combustion chamber, which indicated the usefulness of the system for leakage measurement in units as defined in applicable standards. A pneumatic sensor was built for measuring the cross-sectional area of the equivalent leak of the combustion chamber connected to the sensor where the chamber functioned as a regulator of gas flow through the sensor nozzle. It has been shown that the sensor can be calibrated by means of reference leaks implemented as nozzles of specific diameters and lengths. The schematic diagram of a system for measuring the combustion chamber leakage and a diagram of a sensor for measuring the cross-sectional area of the equivalent leak of the combustion chamber leakage are presented. The results are given of tightness tests of a small one-cylinder combustion engine conducted by means of the set up measurement system and a pre-prototype pneumatic sensor. The two solutions proved to be practically useful.
A cross‐sectional study of United States Academic‐clinical research collaborations: Characteristics, resources, benefits and outcomes
Authors: Albert Nancy M. , Chipps Esther , Klein Colleen J. , Briskin Isaac , Falkenberg Olson Ann C. , Liu Hand Linda , Harmon Michelle M. , Heitschmidt Mary , Talsma AkkeNeel
Published: December 2020

Aims

The aims of the study were to compare characteristics, resources, benefits and outcomes of academic‐clinical collaborations of nursing researcher leaders from academic, clinical and joint‐employer sites.

Background

Few research‐based publications addressed academic‐clinical research collaborations. New knowledge could increase nursing and multidisciplinary research productivity, including implementation science.

Design

An anonymous survey using a 40‐item questionnaire.

Methods

Information letters with a link to the questionnaire were emailed to United States nursing research leaders. Data were grouped by institution type: academic, clinical or joint‐employer. Analyses included Kruskal–Wallis tests for ordered responses, Pearson's chi‐square test or Fisher's exact test for categorical responses and Cohen's Kappa agreement statistic for expected and actual time devoted to research. STROBE guidelines were followed.

Results

Of 120 respondents from academic (n = 60; 50.0%), clinical (n = 53; 41.2%) and joint‐employer (n = 7; 5.8%) sites, 78.3%, 92.3% and 100%, respectively, were from metropolitan areas. Mean (SD) priority for active collaborations was higher at joint‐employer sites; p = .002. Clinical sites were more likely to have directors of evidence‐based practice (p = .031) and informatics (p = .008) and librarians (p = .029). Sites with collaborations were more likely to have access to research subjects (p = .008) and post‐award research account management (p = .045). By collaboration status, there were no differences in the number of ethics board‐approved studies. Collaborating site benefits were perceived to be executive leadership support (p = .003), greater research engagement by clinical nurses (p = .048), more co‐authored publications (p = .048) and more abstracts accepted at national meetings (p = .044). Despite more resources and perceived benefits, outcomes did not differ by collaboration status.

Conclusions

Sites with and without academic‐clinical research collaborations differed; however, outcomes were similar. Future efforts should focus on nurse scientist collaboration to address important clinical questions aimed at improving clinical outcomes.

Relevance to Clinical Practice

Despite some successful outcomes, potential benefits of academic‐clinical research collaborations have not been fully actualised.
THE APPLICATION OF PYRAMID LUCAS-KANADE OPTICAL FLOW METHOD FOR TRACKING RAIN MOTION USING HIGH-RESOLUTION RADAR IMAGES
Authors: Hambali Roby , Legono Djoko , Jayadi Rachmad
Published: December 2020

Short-duration rainfall characteristics in the form of certain intensity, time, and spatial distribution become valuable contribution for lahar flow disaster mitigation in a mountainous region. Due to mitigation purpose, such information can be provided through the rainfall nowcasting process. One of the promising rainfall nowcasting applications is the extrapolation-based method. Rain motion tracking is a crucial part of the rainfall nowcasting based on this method. This paper discusses the application of Pyramid Lucas-Kanade Optical Flow (PLKOF) method on the rain motion tracking analysis using 150x150m resolution radar image. The study of rain motion tracking is carried out using 112 successive rainfall images with 10-minutes time interval originating from Mt. Merapi X-band multiparameter radar. The rainfall movement patterns in short duration are presented in the displacement vector (u,v) images and scatter diagrams of rain motions at x- and y-directions. From the simulations, it was found that the average displacement of rain motions in the Mt. Merapi region is 9 pixels (8.3 km/h) with the dominant direction is northeast. The results show that PLKOF is relatively good at detecting small displacements, yet unable to identify the occurrence of rain growth and decay properly. The ability of PLKOF method in predicting the position of rain cell displacement is satisfied as indicated by the POD, CSI, and FAR indexes.
IDENTIFYING SHALLOW SUBSURFACE CHARACTERISTICS VIA COMPRESSIONAL TO SHEAR WAVES VELOCITY RATIO (VP/VS) FROM SEISMIC REFRACTION TOMOGRAPHY
Authors: Syukri Muhammad , M. Muztaza Nordiana , Ismail Nur Azwin , Fadhli Zul , Saad Rosli
Published: December 2020

This study was conducted in Banda Aceh district by utilizing seismic refraction P- and S-waves methods on three similar profile lines, with the aim to identify subsurface characteristic. The seismic data were acquired using ABEM TERRALOC MK8 system with 28 Hz vertical and 6 Hz horizontal geophones, and suitable seismic sources. Software used for processing to produce 2-D tomography sections and interpretations are IXRefract, Microsoft Excel, SeisOpt@2D v6.0 and Surfer 8. The results show the study area comprises of four subsurface layers with strong to very strong relation between Vp and Vs (R2 is >0.7509) for each layer. Ratio value of Vp and Vs (Vp/Vs) for each layer (1st to 4th) was calculated to be 4.75 – 5.79; 6.50 – 8.89; 6.57 – 12.17 and 6.08 – 8.21 respectively. This study concluded that the ground subsurface in Banda Aceh district is made up of water saturated unconsolidated sediments that was identified to be a mixture of clay and silt at depth up to 55 m.
ENDOPHYTIC BACTERIA DIVERSITY FROM ZINGIBERACEAE AND ANTICANDIDAL CHARACTERIZATION PRODUCED BY Pseudomonas helmanticensis
Authors: Sulistiyani Tri Ratna , Masrukhin Masrukhin , Purnaningsih Ismu , Pangihotan Napitupulu Toga , Budiyanto Agus , Kanti Atit , Sudiana I Made
Published: December 2020

Endophytic microbes are sources for the novel antibiotic. We isolated endophytic bacteria from Zingiberaceae collected from West Sulawesi, Indonesia, and investigated their anticandidal activity. Molecular identification of the isolates was done using 16S rRNA gene sequence analysis. The antimicrobial activity was tested against four bacteria and one yeast. The anticandidal compound of selected bacteria was extracted using three different solvents (chloroform, ethyl acetate, and methanol), and each fraction was tested for their anticandidal activity. Anticandidal minimum inhibitory concentration (MIC) was determined with concentration ranging from 300 to 18.75 μg/mL, and the morphology of the Candida cells after treatment was confirmed by scanning electron microscope (SEM). The identification of anticandidal compounds was conducted using GC-MS. A total of 24 isolates were collected from Zingiberaceae plants. There were 14 genera and 19 species belonging to Gammaproteobacteria (66.67%), Alphaproteobacteria (25.00%), Actinobacteria (4.17%), Bacteriodetes (4.17%), and a new record for Lelliottia aquatilis as an endophytic bacteria. One of 24 isolates identified as Pseudomonas helmanticensis isolated from Alpinia melichroa showed anticandidal activity. Ethyl acetate was the appropriate solvent to extract the anticandidal compounds. Diisooctyl phthalate was found as the most abundant compound in the extract for the anticandidal activity. An increase in extract concentration did not reduce the Candida cell number. The extract treatment showed membrane disruption of Candida albicans cells. We propose that active compounds from P. helmanticensis are potential as anticandidal sources and could be explored more for the pharmaceutical industry.
New Family of Carbohydrate-Binding Modules Defined by a Galactosyl-Binding Protein Module from a Cellvibrio japonicus Endo-Xyloglucanase
Authors: Attia Mohamed A. , Brumer Harry
Published: December 2020

This study reveals carbohydrate-binding module family 88 (CBM88) as a new family of galactose-binding protein modules, which are found in series with diverse microbial glycoside hydrolases, polysaccharide lyases, and carbohydrate esterases. The definition of CBM88 in the carbohydrate-active enzymes classification (
http://www.cazy.org/CBM88.html
) will significantly enable future microbial (meta)genome analysis and functional studies.
Human milk oligosaccharide DSLNT and gut microbiome in preterm infants predicts necrotising enterocolitis
Authors: Masi Andrea C , Embleton Nicholas D , Lamb Christopher A , Young Gregory , Granger Claire L , Najera Julia , Smith Daniel P , Hoffman Kristi L , Petrosino Joseph F , Bode Lars , Berrington Janet E , Stewart Christopher J
Published: December 2020

Objective

Necrotising enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm infants. The underlying mechanisms are poorly understood: mother’s own breast milk (MOM) is protective, possibly relating to human milk oligosaccharide (HMO) and infant gut microbiome interplay. We investigated the interaction between HMO profiles and infant gut microbiome development and its association with NEC.

Design

We performed HMO profiling of MOM in a large cohort of infants with NEC (n=33) with matched controls (n=37). In a subset of 48 infants (14 with NEC), we also performed longitudinal metagenomic sequencing of infant stool (n=644).

Results

Concentration of a single HMO, disialyllacto-N-tetraose (DSLNT), was significantly lower in MOM received by infants with NEC compared with controls. A MOM threshold level of 241 nmol/mL had a sensitivity and specificity of 0.9 for NEC. Metagenomic sequencing before NEC onset showed significantly lower relative abundance of Bifidobacterium longum and higher relative abundance of Enterobacter cloacae in infants with NEC. Longitudinal development of the microbiome was also impacted by low MOM DSLNT associated with reduced transition into preterm gut community types dominated by Bifidobacterium spp and typically observed in older infants. Random forest analysis combining HMO and metagenome data before disease accurately classified 87.5% of infants as healthy or having NEC.

Conclusion

These results demonstrate the importance of HMOs and gut microbiome in preterm infant health and disease. The findings offer potential targets for biomarker development, disease risk stratification and novel avenues for supplements that may prevent life-threatening disease.
Variations in knowledge, awareness and treatment of hypertension and stroke risk by country income level
Authors: O' Donnell Martin , Hankey Graeme J , Rangarajan Sumathy , Chin Siu Lim , Rao-Melacini Purnima , Ferguson John , Xavier Denis , Lisheng Liu , Zhang Hongye , Pais Prem , Lopez-Jaramillo Patricio , Damasceno Albertino , Langhorne Peter , Rosengren Annika , Dans Antonio L , Elsayed Ahmed , Avezum Alvaro , Mondo Charles , Smyth Andrew , Judge Conor , Diener Hans-Christoph , Ryglewicz Danuta , Czlonkowska Anna , Pogosova Nana , Weimar Christian , Iqbal Romana , Diaz Rafael , Yusoff Khalid , Yusufali Afzalhussein , Oguz Aytekin , Wang Xingyu , Penaherrera Ernesto , Lanas Fernando , Ogah Okechukwu Samuel , Ogunniyi Adensola , Iversen Helle K , Malaga German , Rumboldt Zvonko , Oveisgharan Shahram , AlHussain Fawaz , Daliwonga Magazi , Nilanont Yongchai , Yusuf Salim
Published: December 2020

Objective

Hypertension is the most important modifiable risk factor for stroke globally. We hypothesised that country-income level variations in knowledge, detection and treatment of hypertension may contribute to variations in the association of blood pressure with stroke.

Methods

We undertook a standardised case-control study in 32 countries (INTERSTROKE). Cases were patients with acute first stroke (n=13 462) who were matched by age, sex and site to controls (n=13 483). We evaluated the associations of knowledge, awareness and treatment of hypertension with risk of stroke and its subtypes and whether this varied by gross national income (GNI) of country. We estimated OR and population attributable risk (PAR) associated with treated and untreated hypertension.

Results

Hypertension was associated with a graded increase in OR by reducing GNI, ranging from OR 1.92 (99% CI 1.48 to 2.49) to OR 3.27 (2.72 to 3.93) for highest to lowest country-level GNI (p-heterogeneity<0.0001). Untreated hypertension was associated with a higher OR for stroke (OR 5.25; 4.53 to 6.10) than treated hypertension (OR 2.60; 2.32 to 2.91) and younger age of first stroke (61.4 vs 65.4 years; p<0.01). Untreated hypertension was associated with a greater risk of intracerebral haemorrhage (OR 6.95; 5.61 to 8.60) than ischaemic stroke (OR 4.76; 3.99 to 5.68). The PAR associated with untreated hypertension was higher in lower-income regions, PAR 36.3%, 26.3%, 19.8% to 10.4% by increasing GNI of countries. Lifetime non-measurement of blood pressure was associated with stroke (OR 1.80; 1.32 to 2.46).

Conclusions

Deficits in knowledge, detection and treatment of hypertension contribute to higher risk of stroke, younger age of onset and larger proportion of intracerebral haemorrhage in lower-income countries.
Prognostic value of automated longitudinal strain measurements in asymptomatic aortic stenosis
Authors: Kitano Tetsuji , Nabeshima Yosuke , Negishi Kazuaki , Takeuchi Masaaki
Published: December 2020

Objective

Two-dimensional (2D) longitudinal strain (LS) predicts cardiac events in aortic stenosis (AS). However, it requires manual editing, which affects its accuracy and reliability. We investigated whether left ventricular (LV), left atrial (LA) and right ventricular (RV) LSs using fully automated 2D strain software provide useful prognostic information in asymptomatic AS.

Methods

We performed LS analyses in 340 asymptomatic patients with AS using novel, fully automated 2D strain analytical software (AutoStrain, Philips) to obtain LV global LS (LVGLS), LALS, RV free wall LS and RVLS. The primary end point was a composite of cardiac events, including cardiac death, heart failure hospitalisation, myocardial infarction or ventricular tachyarrhythmia.

Results

During a median of 24 months follow-up, 46 patients reached a primary end point. 62 patients had aortic valve surgery. All four LSs were significantly associated with the primary end point using univariate analysis (HR 0.821 to 0.951, p<0.05). Multivariate analysis revealed that LVGLS (HR 0.873 to 0.888, p<0.05) remained significantly associated with cardiac events, even after adjusting haemodynamic measures of AS severity and LV ejection fraction. Kaplan-Meier survival curve showed median values of both LVGLS (cut-off: 15.1%) and LALS (cut-off: 22.3%) provide a significant difference in cardiac event rate (3-year event-free rate; LVGLS: 89% vs 76%, p=0.002; LALS: 89% vs 76%, p=0.001). Classification and regression-tree analysis, including four LSs, clinical characteristics and traditional echocardiographic parameters, selected LVGLS and E/ε’ for stratifying a high-risk group of patients with cardiac events.

Conclusions

Fully automated 2D LS analysis, especially LVGLS provides useful prognostic information in asymptomatic AS.
Dysfunction of VIPR2 leads to myopia in humans and mice
Authors: Zhao Fuxin , Li Qihang , Chen Wei , Zhu He , Zhou Dengke , Reinach Peter Sol , Yang Zhenglin , He Mingguang , Xue Anquan , Wu Deng , Liu Tianzi , Fu Qian , Zeng Changqing , Qu Jia , Zhou Xiangtian
Published: December 2020

Background

Myopia is the leading cause of refractive errors. As its pathogenesis is poorly understood, we determined if the retinal VIP-VIPR2 signalling pathway axis has a role in controlling signalling output that affects myopia development in mice.

Methods

Association analysis meta-study, single-cell transcriptome, bulk RNA sequencing, pharmacological manipulation and VIPR2 gene knockout studies were used to clarify if changes in the VIP-VIPR2 signalling pathway affect refractive development in mice.

Results

The SNP rs6979985 of the VIPR2 gene was associated with high myopia in a Chinese Han cohort (randomceffect model: p=0.013). After either 1 or 2 days’ form deprivation (FD) retinal VIP mRNA expression was downregulated. Retinal single-cell transcriptome sequencing showed that VIPR2 was expressed mainly by bipolar cells. Furthermore, the cAMP signalling pathway axis was inhibited in some VIPR2+ clusters after 2 days of FD. The selective VIPR2 antagonist PG99-465 induced relative myopia, whereas the selective VIPR2 agonist Ro25-1553 inhibited this response. In Vipr2 knockout (Vipr2-KO) mice, refraction was significantly shifted towards myopia (p<0.05). The amplitudes of the bipolar cell derived b-waves in 7-week-old Vipr2-KO mice were significantly larger than those in their WT littermates (p<0.05).

Conclusions

Loss of VIPR2 function likely compromises bipolar cell function based on presumed changes in signal transduction due to altered signature electrical wave activity output in these mice. As these effects correspond with increases in form deprivation myopia (FDM), the VIP-VIPR2 signalling pathway axis is a viable novel target to control the development of this condition.
Military metaphors and pandemic propaganda: unmasking the betrayal of ‘Healthcare Heroes’
Authors: Khan Zahra , Iwai Yoshiko , DasGupta Sayantani
Published: December 2020

Dr Caitríona L Cox’s recent article expounds the far-reaching implications of the ‘Healthcare Hero’ metaphor. She presents a detailed overview of heroism in the context of clinical care, revealing that healthcare workers, when portrayed as heroes, face challenges in reconciling unreasonable expectations of personal sacrifice without reciprocity or ample structural support from institutions and the general public. We use narrative medicine, a field primarily concerned with honouring the intersubjective narratives shared between patients and providers, in our attempt to deepen the discussion about the ways Healthcare Heroes engenders military metaphor, antiscience discourse, and xenophobia in the USA. We argue that the militarised metaphor of Healthcare Heroes not only robs doctors and nurses of the ability to voice concerns for themselves and their patients, but effectively sacrifices them in a utilitarian bargain whereby human life is considered the expendable sacrifice necessary to ‘open the U.S. economy’. Militaristic metaphors in medicine can be dangerous to both doctors and patients, thus, teaching and advocating for the critical skills to analyse and alter this language prevents undue harm to providers and patients, as well as our national and global communities.
Differential effect of mechanical thrombectomy and intravenous thrombolysis in atrial fibrillation associated stroke
Authors: Akbik Feras , Alawieh Ali , Cawley C Michael , Howard Brian M , Tong Frank C , Nahab Fadi , Saad Hassan , Dimisko Laurie , Mustroph Christian , Samuels Owen B , Pradilla Gustavo , Maier Ilko , Goyal Nitin , Starke Robert M , Rai Ansaar , Fargen Kyle M , Psychogios Marios N , Jabbour Pascal , De Leacy Reade , Giles James , Dumont Travis M , Kan Peter , Arthur Adam S , Crosa Roberto Javier , Gory Benjamin , Spiotta Alejandro M , Grossberg Jonathan A
Published: December 2020

Background

Atrial fibrillation (AF) associated ischemic stroke has worse functional outcomes, less effective recanalization, and increased rates of hemorrhagic complications after intravenous thrombolysis (IVT). Limited data exist about the effect of AF on procedural and clinical outcomes after mechanical thrombectomy (MT).

Objective

To determine whether recanalization efficacy, procedural speed, and clinical outcomes differ in AF associated stroke treated with MT.

Methods

We performed a retrospective cohort study of the Stroke Thrombectomy and Aneurysm Registry (STAR) from January 2015 to December 2018 and identified 4169 patients who underwent MT for an anterior circulation stroke, 1517 (36.4 %) of whom had comorbid AF. Prospectively defined baseline characteristics, procedural outcomes, and clinical outcomes were reported and compared.

Results

AF predicted faster procedural times, fewer passes, and higher rates of first pass success on multivariate analysis (p<0.01). AF had no effect on intracranial hemorrhage (aOR 0.69, 95% CI 0.43 to 1.12) or 90-day functional outcomes (aOR 1.17, 95% CI 0.91 to 1.50) after MT, although patients with AF were less likely to receive IVT (46% vs 54%, p<0.0001).

Conclusions

In patients treated with MT, comorbid AF is associated with faster procedural time, fewer passes, and increased rates of first pass success without increased risk of intracranial hemorrhage or worse functional outcomes. These results are in contrast to the increased hemorrhage rates and worse functional outcomes observed in AF associated stroke treated with supportive care and or IVT. These data suggest that MT negates the AF penalty in ischemic stroke.
Topical intranasal lidocaine is not a sphenopalatine ganglion block
Authors: Narouze Samer
Published: December 2020

There is renewed interest in the central role of the sphenopalatine ganglion (SPG) in cerebrovascular autonomic physiology and the pathophysiology of different primary and secondary headache disorders. There are diverse neural structures (parasympathetic, sympathetic and trigeminal sensory) that convene into the SPG which is located within the pterygopalatine fossa (PPF). This makes the PPF an attractive target to neuromodulatory interventions of these different neural structures. Some experts advocate for the nasal application of local anesthetics as an effective route for SPG block with the belief that the local anesthetic can freely access the PPF. It is time to challenge this historical concept from the early 1900s. In this daring discourse, I will review anatomical studies, CT and MRI reports to debunk this old myth. Will provide anatomical evidence to explain that all these assumptions are untrue and the local anesthetic has to magically ‘travel’ a distance of 4–12 mm of adipose and connective tissue to reach the SPG in sufficient concentration and volume to effectively induce SPG blockade. Future research should focus on assessing a clinical biomarker to confirm SPG blockade. It could be regional cerebral blood flow or lacrimal gland secretion.
Variation in oral microbiome is associated with future risk of lung cancer among never-smokers
Authors: Hosgood H Dean , Cai Qiuyin , Hua Xing , Long Jirong , Shi Jianxin , Wan Yunhu , Yang Yaohua , Abnet Christian , Bassig Bryan A , Hu Wei , Ji Bu-Tian , Klugman Madelyn , Xiang Yongbing , Gao Yu-Tang , Wong Jason YY , Zheng Wei , Rothman Nathaniel , Shu Xiao-Ou , Lan Qing
Published: December 2020

Objective

To prospectively investigate whether diversity in oral microbiota is associated with risk of lung cancer among never-smokers.

Design and setting

A nested case–control study within two prospective cohort studies, the Shanghai Women’s Health Study (n=74 941) and the Shanghai Men’s Health Study (n=61 480).

Participants

Lifetime never-smokers who had no cancer at baseline. Cases were subjects who were diagnosed with incident lung cancer (n=114) and were matched 1:1 with controls on sex, age (≤2 years), date (≤30 days) and time (morning/afternoon) of sample collection, antibiotic use during the week before sample collection (yes/no) and menopausal status (for women).

Main outcomes and measures

Metagenomic shotgun sequencing was used to measure the community structure and abundance of the oral microbiome in pre-diagnostic oral rinse samples of each case and control. Multivariable logistic regression models were used to estimate the association of lung cancer risk with alpha diversity metrics and relative abundance of taxa. The Microbiome Regression-Based Kernel Association Test (MiRKAT) evaluated the association between risk and the microbiome beta diversity.

Results

Subjects with lower microbiota alpha diversity had an increased risk of lung cancer compared with those with higher microbial alpha diversity (Shannon: ptrend=0.05; Simpson: ptrend=0.04; Observed Species: ptrend=0.64). No case–control differences were apparent for beta diversity (pMiRKAT=0.30). After accounting for multiple comparisons, a greater abundance of Spirochaetia (ORlow1.00 (reference), ORmedium0.61 (95% CI 0.32 to 1.18), ORhigh0.42 (95% CI 0.21 to 0.85)) and Bacteroidetes (ORlow1.00 (reference), ORmedium0.66 (95% CI 0.35 to 1.25), ORhigh0.31 (95% CI 0.15 to 0.64)) was associated with a decreased risk of lung cancer, while a greater abundance of the Bacilli class (ORlow1.00 (reference), ORmedium1.49 (95% CI 0.73 to 3.08), ORhigh2.40 (95% CI 1.18 to 4.87)) and Lactobacillales order (ORlow1.00 (reference), ORmedium2.15 (95% CI 1.03 to 4.47), ORhigh3.26 (95% CI 1.58 to 6.70)) was associated with an increased risk of lung cancer.

Conclusions

Our prospective study of never-smokers suggests that lower alpha diversity was associated with a greater risk of lung cancer and the abundance of certain specific taxa was associated with altered risk, providing further insight into the aetiology of lung cancer in the absence of active tobacco smoking.