bluuebunny/crossref_metadata_2025 huggingface dataset:
Of hands, tools, and exploding dots: How different action states and effects separate visuomotor memories
Authors: Schween Raphael , Langsdorf Lisa , Taylor Jordan A , Hegele Mathias
Published: February 2019

Humans can operate a variety of modern tools, which are often associated with different visuomotor transformations. Studies investigating this ability have repeatedly found that the simultaneous acquisition of different transformations appears inextricably tied to distinct states associated with movement, such as different postures or action plans, whereas abstract contextual associations can be leveraged by explicit aiming strategies. It still remains unclear how different transformations are remembered implicitly when target postures are similar. We investigated if features of planning to manipulate a visual tool, such as its visual identity or the intended effect enable implicit learning of opposing visuomotor rotations. Both cues only affected implicit aftereffects indirectly through generalization around explicit strategies. In contrast, practicing transformations with different hands resulted in separate aftereffects. It appears that different (intended) body states are necessary to separate aftereffects, supporting the idea that underlying implicit adaptation is limited to the recalibration of a body model.
Metabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development
Authors: Lampe Lena , Jentzsch Marius , Levashina Elena A
Published: February 2019

Anopheles mosquitoes are obligate vectors of the human malaria parasite Plasmodium falciparum. The blood-feeding behavior of Anopheles females delivers essential nutrients for egg development and drives transmission from one human host to another. Plasmodium growth is adapted to the vector reproductive cycle, but how changes in the reproductive cycle impact parasite development is poorly understood. Here, we show that the blood meal-induced miR-276-5p fine-tunes the duration of the mosquito reproductive cycle. Silencing of miR-276 prolonged amino acid catabolism and increased female fertility rates, suggesting that timely termination of the reproductive cycle restricts mosquito investment into reproduction. Prolongation of the reproductive period in P. falciparum-infected females compromised the development of the transmissible parasite form called sporozoite. Our results suggest that Plasmodium sporogony exploits surplus resources after mosquito reproductive investment and demonstrate the crucial role of the mosquito amino acid metabolism in parasite within-vector proliferation and malaria transmission.
Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukaemia cells
Authors: Jiang Liren , Malik Natasha , Acedo Pilar , Zawacka-Pankau Joanna
Published: February 2019

p53 is a tumor suppressor, which belongs to the p53 family of proteins. The family consists of p53, p63 and p73 proteins, which share similar structure and function. Activation of wild-type p53 or TAp73 in tumors leads to tumor regression, and small molecules restoring the p53 pathway are in clinical development.

Protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid, is a clinically approved drug applied in photodynamic diagnosis and therapy. PpIX induces p53- and TAp73-dependent apoptosis and inhibits TAp73/MDM2 and TAp73/MDM4 interactions. Here we demonstrate that PpIX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and activates apoptosis in B-cell chronic lymphocytic leukaemia cells without illumination and without affecting normal cells. PpIX stabilizes p53 and TAp73 proteins, induces p53-downstream apoptotic targets and provokes cancer cell death at doses non-toxic to normal cells.

Our findings open up new opportunities for repurposing PpIX for treating lymphoblastic leukaemias withwtTP53.
Activity-dependent regulation of the proapoptotic BH3-only geneegl-1in a living neuron pair inC. elegans
Authors: Cohn Jesse , Dwivedi Vivek , Zarate Nicole , Horvitz H Robert , Pierce Jonathan T
Published: February 2019

The BH3-only family of proteins is key for initiating apoptosis in a variety of contexts, and may also contribute to non-apoptotic cellular processes. Historically, the nematodeCaenorhabditis eleganshas provided a powerful system for studying and identifying conserved regulators of BH3-only proteins. InC. elegans, the BH3-only protein EGL-1 is expressed during development to cell-autonomously trigger most developmental cell deaths. Here we provide evidence thategl-1is also transcribed after development in the sensory neuron pair URX without inducing apoptosis. We used genetic screening and epistasis analysis to determine that its transcription is regulated in URX by neuronal activity and/or in parallel by orthologs of Protein Kinase G and the Salt-Inducible Kinase family. Because several BH3-only family proteins are also expressed in the adult nervous system of mammals, we suggest that studyingegl-1expression in URX may shed light on mechanisms that regulate conserved family members in higher organisms.
Metacognition facilitates the exploitation of unconscious brain states
Authors: Cortese Aurelio , Lau Hakwan , Kawato Mitsuo
Published: February 2019

Can humans be trained to make strategic use of unconscious representations in their own brains? We investigated how one can derive reward-maximizing choices from latent high-dimensional information represented stochastically in neural activity. In a novel decision-making task, reinforcement learning contingencies were defined in real-time by fMRI multivoxel pattern analysis; optimal action policies thereby depended on multidimensional brain activity that took place below the threshold of consciousness. We found that subjects could solve the task, when their reinforcement learning processes were boosted by implicit metacognition to estimate the relevant brain states. With these results we identified a frontal-striatal mechanism by which the brain can untangle tasks of great dimensionality, and can do so much more flexibly than current artificial intelligence.
Alterations of redox and iron metabolism accompany development of HIV latency
Authors: Shytaj IL , Lucic B , Forcato M , Billingsley JM , Bosinger S , Stanic M , Gregoretti F , Antonelli L , Oliva G , Frese CK , Trifunovic A , Galy B , Eibl C , Silvestri G , Bicciato S , Savarino A , Lusic M
Published: February 2019

Metabolic alterations, such as oxidative stress, are hallmarks of HIV-1 infection. However, their influence on the development of viral latency, and thus on HIV-1 persistence during antiretroviral therapy (ART), have just begun to be explored. We analyzed omics profiles of in-vitro and in-vivo models of infection by HIV-1 and its simian homolog SIVmac. We found that cells survive retroviral replication by upregulating antioxidant pathways and intertwined iron import pathways. These changes are associated with remodeling of the redox sensitive promyelocytic leukemia protein nuclear bodies (PML NBs), an important constituent of nuclear architecture and a marker of HIV-1 latency. We found that PML is depleted in productively infected cells and restored by ART. Moreover, we identified intracellular iron as a key link between oxidative stress and PML depletion, thus supporting iron metabolism modulators as pharmacological tools to impair latency establishment.
A Deficiency in SUMOylation Activity Disrupts Multiple Pathways Leading to Neural Tube and Heart Defects inXenopusEmbryos
Authors: Bertke Michelle M. , Dubiak Kyle M. , Cronin Laura , Zeng Erliang , Huber Paul W.
Published: February 2019

Background

Adenovirus protein, Gam1, triggers the proteolytic destruction of the E1 SUMO-activating enzyme. Microinjection of an empirically determined amount of Gam1 mRNA into one-cellXenopusembryos can reduce SUMOylation activity to undetectable, but nonlethal, levels, enabling an examination of the role of this post-translational modification during early vertebrate development.

Results

We find that SUMOylation-deficient embryos consistently exhibit defects in neural tube and heart development. We have measured differences in gene expression between control and embryos injected with Gam1 mRNA at three developmental stages: early gastrula (immediately following the initiation of zygotic transcription), late gastrula (completion of the formation of the three primary germ layers), and early neurula (appearance of the neural plate). Although changes in gene expression are widespread and can be linked to many biological processes, three pathways, non-canonical Wnt/PCP, snail/twist, and Ets-1, are especially sensitive to the loss of SUMOylation activity and can largely account for the predominant phenotypes of Gam1 embryos. SUMOylation appears to generate different pools of a given transcription factor having different specificities with this post-translational modification involved in the regulation of more complex, as opposed to housekeeping, processes.

Conclusions

We have identified changes in gene expression that underlie the neural tube and heart phenotypes resulting from depressed SUMOylation activity. Notably, these developmental defects correspond to the two most frequently occurring congenital birth defects in humans, strongly suggesting that perturbation of SUMOylation, either globally or of a specific protein, may frequently be the origin of these pathologies.
Kevlar: a mapping-free framework for accurate discovery ofde novovariants
Authors: Standage Daniel S. , Brown C. Titus , Hormozdiari Fereydoun
Published: February 2019

Motivation

Discovery of genetic variants by whole genome sequencing has proven a powerful approach to study the etiology of complex genetic disorders. Elucidation of all variants is a necessary step in identifying causative variants and disease genes. In particular, there is an increased interest in detection ofde novovariation and investigation of its role in various disorders. State-of-the-art methods for variant discovery rely on mapping reads from each individual to a reference genome and predicting variants from difference observed between the mapped reads and the reference genome. This process typically results in millions of variant predictions, most of which are inherited and irrelevant to the phenotype of interest. To distinguish between inherited variation and novel variation resulting fromde novogermline mutation, whole-genome sequencing of close relatives (especially parents and siblings) is commonly used. However, standard mapping-based approaches tend to have a high false-discovery rate forde novovariant prediction, which in many cases arises from problems with read mapping. This is a particular challenge in predictingde novoindels and structural variants.

Results

We have developed a mapping-free method, Kevlar, forde novovariant discovery based on direct comparison of sequence content between related individuals. Kevlar identifies high-abundancek-mers unique to the individual of interest and retrieves the reads containing thesek-mers. These reads are easily partitioned into disjoint sets by sharedk-mer content for subsequent locus-by-locus processing and variant calling. Kevlar also utilizes a novel probabilistic approach to score and rank the variant predictions to identify the most likelyde novovariants. We evaluated Kevlar on simulated and real pedigrees, and demonstrate its ability to detect bothde novoSNVs and indels with high sensitivity and specificity.

Availability

https://github.com/kevlar-dev/kevlar
SpectralTAD: an R package for defining a hierarchy of Topologically Associated Domains using spectral clustering
Authors: Cresswell Kellen G. , Stansfield John C. , Dozmorov Mikhail G.
Published: February 2019

The three-dimensional (3D) structure of the genome plays a crucial role in regulating gene expression. Chromatin conformation capture technologies (Hi-C) have revealed that the genome is organized in a hierarchy of topologically associated domains (TADs), the fundamental building blocks of the genome. Identifying such hierarchical structures is a critical step in understanding regulatory interactions within the genome. Existing tools for TAD calling frequently require tunable parameters, are sensitive to biases such as sequencing depth, resolution, and sparsity of Hi-C data, and are computationally inefficient. Furthermore, the choice of TAD callers within the R/Bioconductor ecosystem is limited. To address these challenges, we frame the problem of TAD detection in a spectral clustering framework. Our SpectralTAD R package has automatic parameter selection, robust to sequencing depth, resolution and sparsity of Hi-C data, and detects hierarchical, biologically relevant TAD structure. Using simulated and real-life Hi-C data, we show that SpectralTAD outperforms rGMAP and TopDom, two state-of-the-art R-based TAD callers. TAD boundaries that are shared among multiple levels of the hierarchy were more enriched in relevant genomic annotations, e.g., CTCF binding sites, suggesting their higher biological importance. In contrast, boundaries of primary TADs, defined as TADs which cannot be split into sub-TADs, were found to be less enriched in genomic annotations, suggesting their more dynamic role in genome regulation. In summary, we present a simple, fast, and user-friendly R package for robust detection of TAD hierarchies supported by biological evidence. SpectralTAD is available on https://github.com/dozmorovlab/SpectralTAD and Bioconductor (submitted).
Emergence of multidrug-resistantMycobacterium simiae: An in vitro study from a regional tuberculosis reference laboratory in Iran
Authors: Nasiri Mohammad Javad , Amini Sirus , Nikpor Zahra , Arefzadeh Samaneh , Mosavi Mohammad , Dabiri Hossein , Goudarzi Mehdi , Goudarzi Hossein , Tabarsi Payam , Sarokhalil Davood Darban , Fooladi Abbas Ali Imani , Feizabadi Mohammad Mehdi
Published: February 2019

Introduction

Mycobacterium simiaeis an emerging pathogen in Iran and little is known about drug susceptibility patterns of this pathogen.

Materials and methods

Twenty five clinical isolates ofM. simiaefrom 80 patients with confirmed NTM pulmonary disease were included in this study. For drug susceptibility testing (DST), proportional and broth microdilution methods were used according to the clinical and laboratory standards institute (CLSI) guideline.

Results

All clinical isolates ofM. simiaewere resistant to isoniazid, rifampicin, ethambutol, streptomycin, amikacin, kanamycin, ciprofloxacin and clarithromycin. They also were highly resistant to ofloxacin (80%). Susceptibility to ofloxacin was only noted in the 5 isolates.

Conclusions

Clinical isolates ofM.simiaewere multidrug resistant, and had different drug susceptibility patterns than previously published studies. DST results can assist in selecting more appropriate treatment regimens. Newer drugs with proven clinical efficacy correlating with in vitro susceptibility should be substituted with first- and second line anti-TB drug testing.
Comparative genome analysis ofLactobacillus mudanjiangensis, an understudied member of theLactobacillus plantarumgroup
Authors: Wuyts Sander , Allonsius Camille Nina , Wittouck Stijn , Thys Sofie , Lievens Bart , Weckx Stefan , Vuyst Luc De , Sarah Lebeer
Published: February 2019

The genusLactobacillusis known to be extremely diverse and consists of different phylogenetic groups that show a diversity roughly equal to the expected diversity of a typical bacterial genus. One of the most prominent phylogenetic groups within this genus is theLactobacillus plantarumgroup which contains the understudiedLactobacillus mudanjiangensisspecies. Before this study, only oneL. mudanjiangensisstrain, DSM 28402T, was described but without whole-genome analysis. In this study, three strains classified asL. mudanjiangensis, were isolated from three different carrot juice fermentations and their whole-genome sequence was determined, together with the genome sequence of the type strain. The genomes of all four strains were compared with publicly availableL. plantarumgroup genome sequences. This analysis showed thatL. mudanjiangensisharbored the second largest genome size and gene count of the wholeL. plantarumgroup. In addition, all members of this species showed the presence of a gene coding for a putative cellulose-degrading enzyme. Finally, three of the fourL. mudanjiangensisstrains studied showed the presence of pili on scanning electron microscopy (SEM) images, which were linked to conjugative gene regions, coded on plasmids in at least two of the strains studied.

Author summary

Lactobacillus mudanjiangensisis an understudied species within theLactobacillus plantarumgroup. Since its first description, no other studies have reported its isolation. Here, we present the first four genome sequences of this species, which include the genome sequence of the type strain and three newL. mudanjiangensisstrains isolated from fermented carrot juice. The genomes of all four strains were compared with publicly availableL. plantarumgroup genome sequences. We found that this species harbored the second largest genome size and gene count of the wholeL. plantarumgroup. Furthermore, we present the first scanning electron microscopy (SEM) images ofL. mudanjiangensis, which showed the formation of pili in three strains that we linked to genes related to conjugation. Finally, we found the presence of a unique putative cellulose-degrading enzyme, opening the door for different industrial applications of theseLactobacillusstrains.
Dynamics of visual contextual interactions is altered in Parkinson’s disease
Authors: Vanegas M. Isabel , Blangero Annabelle , Galvin James E , Rocco Alessandro Di , Quartarone Angelo , Ghilardi M. Felice , Kelly Simon P.
Published: February 2019

Over the last decades, psychophysical and electrophysiological studies in patients and animal models of Parkinson’s disease (PD), have consistently revealed a number of visual abnormalities. In particular, specific alterations of contrast sensitivity curves, electroretinogram (ERG), and visual evoked potentials (VEP), have been attributed to dopaminergic retinal depletion. However, fundamental mechanisms of cortical visual processing, such as normalization or “gain-control” computations, have not yet been examined in PD patients. Here we measured electrophysiological indices of gain control in both space (surround suppression) and time (sensory adaptation) in PD patients based on steady-state VEP (ssVEP). Compared to controls, patients exhibited a significantly higher initial ssVEP amplitude that quickly decayed over time, and greater relative suppression of ssVEP amplitude as a function of surrounding stimulus contrast. Meanwhile, EEG frequency spectra were broadly elevated in patients relative to controls. Thus, contrary to what might be expected given the reduced contrast sensitivity often reported in PD, visual neural responses are not weaker; rather, they are initially larger but undergo an exaggerated degree of spatial and temporal gain control and are embedded within a greater background noise level. We conclude that compensatory cortical mechanisms may play a role in determining dysfunctional center-surround interactions at the retinal level.
Cannabis use, depression and self-harm: phenotypic and genetic relationships
Authors: Hodgson K , Coleman JRI , Hagenaars SP , Purves KL , Glanville K , Choi SW , O’Reilly P , Breen G ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Lewis CM
Published: February 2019

Background and Aims

The use of cannabis has previously been linked to both depression and self-harm, however the role of genetics in this relationship are unclear. We aimed to examine the phenotypic and genetic relationships between these traits.

Design

Genetic and cross-sectional phenotypic data collected through UK Biobank, together with consortia genome-wide association study summary statistics. These data were used to assess the phenotypic and genetic relationship between cannabis use, depression and self harm.

Setting

UK, with additional international consortia data

Participants

N=126,291 British adults aged between 40 and 70 years, recruited into UK Biobank

Measurements

Genome-wide genetic data, phenotypic data on lifetime history of cannabis use, depression and self-harm.

Findings

In UK Biobank, cannabis use is associated with increased likelihood of depression (OR=1.64, 95% CI=1.59-1.70, p=1.19×10−213) and self-harm (OR=2.85, 95% CI=2.69-3.01, p=3.46×10−304). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Additionally, significant genetic correlations are seen between cannabis use and depression using consortia summary statistics (rg=0.289, SE=0.036, p=1.45×10−15). Polygenic risk scores for cannabis use and depression both explain a small but significant proportion of variance in cannabis use, depression and self harm within a UK Biobank target sample. However, two-sample Mendelian randomisation analyses were not significant.

Conclusions

Cannabis use is both phenotypically and genetically associated with depression and self harm. Future work dissecting the causal mechanism linking these traits may have implications for cannabis users.
Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2)
Authors: Chaikuad Apirat , Koschade Sebastian E. , Stolz Alexandra , Zivkovic Katarina , Pohl Christian , Shaid Shabnam , Ren Huiyu , Lambert Lester J. , Cosford Nicholas D.P. , Brandts Christian H. , Knapp Stefan
Published: February 2019

Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the other closely related kinase ULK2. Here we present the crystal structure of ULK2 in complex with ATP competitive inhibitors. Surprisingly, the ULK2 structure revealed a dimeric assembly reminiscent of dimeric arrangements of auto-activating kinases suggesting a role for this association in ULK activation. Screening of a kinase focused library of pre-clinical and clinical compounds revealed several potent ULK1/2 inhibitors and good correlation of inhibitor binding behavior with both ULK kinases. Aurora A was identified as a major off-target of currently used ULK1 inhibitors. Autophagic flux assays demonstrated that this off-target activity by strongly inducing autophagy in different cellular systems conferred an additional layer of complexity in the interpretation of cellular data. The data presented here provides structural models and chemical starting points for the development of ULK1/2 dual inhibitors with improved selectivity for future exploitation of autophagy inhibition.
Survey of severe fever with thrombocytopenia syndrome virus covert infection for healthy people in Henan Province, China
Authors: Du Yanhua , Cheng Ningning , Li Yi , Wang Haifeng , You Aiguo , Su Jia , Nie Yifei , Ma Hongxia , Xu Bianli , Huang Xueyong
Published: February 2019

Background:

Severe fever with thrombocytopenia syndrome (SFTS) is a severe emerging disease, and its incidence has been increasing in recent years. A cross-sectional study was conducted for healthy people in high SFTS endemic areas of Henan province in 2016.

Methods:

This study used stratified random sampling method and finally 14 natural villages were selected as the investigation site. The questionnaire survey and serum collection were carried out from April to May in 2016. All the serum samples were detected by SFTSV IgM and IgG antibodies by ELISA. Only positive samples of SFTSV IgM antibody need be tested SFTSV RNA and virus cultured. A month after the specimen collection, all persons positive for IgM antibody were followed up one by one to confirm whether he or she was recessive infection.

Results:

1463 healthy persons were investigated in total. The average seropositive rates of SFTS virus specific IgG and IgM antibodies were 10.46% (153/1463) and 0.82% (12/1463), respectively. IgM antibody was positive in 12 individuals, and 6 of them SFTS virus RNA were also detected. In addition, 5 SFTS virus were isolated from the 6 SFTS virus RNA (+) individuals. By genomic sequencing and phylogenetic analysis, 5 new isolates from healthy crowd all belonged to groups A, which were similar to other isolates from SFTS patients. After one month, all people with SFTS virus IgM antibody had no illness or symptoms.

Conclusions:

This study confirmed there is SFTS recessive infection in human, and it is the first report about SFTS virus isolation in healthy people.

Author Summary:

Severe fever with thrombocytopenia syndrome (SFTS), a severe emerging infectious disease, was discovered in rural areas of China. The first SFTS case was found in Henan province, which has had the largest number of SFTS cases in China every year since the disease was discovered. However, as a high incidence area of SFTS in Henan province, the serum prevalence rate of the virus in healthy people is still not clear. Therefore, a cross-sectional survey was performed in high endemic areas and epidemic seasons in 2016. The results showed that the level of specific SFTS seroprevlence was relatively higher and possibility increasing. SFTS RNA were positive and SFTS virus was isolated from the specimens of healthy people. This study confirmed there is SFTS recessive infection in human, and it is the first report about SFTS virus isolation in healthy people.
The essential role played by B cells in supporting protective immunity againstTrichuris murisinfection is dependent on host genetic background and is independent of antibody
Authors: Sahputra Rinal , Ruckerl Dominik , Couper Kevin , Muller Werner , Else Kathryn J
Published: February 2019

This study investigates the role of B cells in immunity toTrichuris muris(T. muris) infection in two genetically distinct strains of mouse, using anti-CD20 monoclonal antibody (mAb) (Genentech-clone 5D2) to deplete B cells. Data is presented for the mouse strains: C57BL/6 and BALB/c, which mount mixed Th1/Th2, and highly polarised Th2 immune responses toT. muris, respectively. C57BL/6 mice receiving anti-CD20 treatment prior to and during, or anti-CD20 treatment that commenced two weeks post infection (p.i.), were susceptible toT. muris. Parasite-specific IgG1 antibodies were absent and Th2 type cytokines produced by mesenteric lymph nodes cells from mice receiving α-CD20 mAb treatment were significantly lower than produced by cells from isotype control treated mice. T follicular helper cells were also significantly reduced. Importantly, and in complete contrast, BALB/c mice were still able to expelT.murisin the absence of B cells, revealing that the essential role played by B cells in protective immunity was dependent on genetic background. To explore whether the important role played by the B cell in the protective immune response of C57BL/6 mice was in enabling strong Th2 responses in the presence of IFN-γ, IFN-γ was blocked using anti-IFN-γ mAb post B cell depletion. Depleting IFN-γ, in the absence of B cells restored worm expulsion in the absence of parasite-specific IgG1/IgG2c and partially rescued theT. murisspecific IL-13 response. Thus, our data suggest an important, antibody independent role for B cells in supporting Th2 type immune responses in mixed IFN-γ-rich Th1/Th2 immune response settings.

Author summary

How B cells contribute to protective immunity against parasitic nematodes remains unclear, with their importance as accessory cells under-explored. This study reveals that, on some genetic backgrounds, B cells are important for the expulsion ofT. murisby acting as accessory cells, supporting Th2 immune responses.
Anopheles gambiae TEP1 forms a complex with the coiled-coil domain of LRIM1/APL1C following a conformational change in the thioester domain
Authors: Williams Marni , Contet Alicia , Levashina Elena A. , Baxter Richard H. G.
Published: February 2019

The complement-like protein thioester-containing protein 1 (TEP1) is a key factor in the immune response of the malaria vector Anopheles gambiae to pathogens. Multiple allelic variants of TEP1 have been identified in laboratory strains and in the field, and are correlated with distinct immunophenotypes. TEP1 is tightly regulated by conformational changes induced by cleavage in a protease-sensitive region. Cleaved TEP1 forms a soluble complex with a heterodimer of two leucine-rich repeat proteins, LRIM1 and APL1C, and precipitates in the absence of this complex. The molecular structure and oligomeric state of the TEP1/LRIM1/APL1C complex is unclear. We have analyzed the stability of the cleaved form of four TEP1 alleles. Soluble TEP1 forms exhibit significant variation in stability from hours to days at room temperature. Stability is correlated with allelic variation within two specific loops in direct proximity to the thioester bond. The variable loops are part of an interface between the TED and MG8 domains TEP1 that protect the thioester from hydrolysis. Engineering specific disulfide bonds to prevent separation of the TED-MG8 interface stabilizes the cleaved form of TEP1 for months at room temperature. The C-terminal coiled-coil domain of the LRIM1/APL1C complex is sufficient to stabilize the cleaved form of TEP1 in solution but cleaved forms of disulfide-stabilized TEP1 do not interact with LRIM1/APL1C. This implies that formation of the TEP1cut/LRIM1/APL1C complex is dependent on the same conformational change that induces the precipitation of cleaved TEP1.

Author Summary

The mosquito Anopheles gambiae is the principal vector for malaria in Sub-Saharan Africa. A mosquito’s own immune system affects how readily it transmits disease. A protein in A. gambiae called TEP1 is responsible for targeting malaria parasites that traverse the mosquito’s midgut. TEP1 has multiple alleles and some are associated with a stronger immune response to malaria than others. How genetic variability in TEP1 is linked to phenotypic diversity is not understood. We show that the variation between TEP1 alleles affects the stability of the protein in solution. We also show that the different TEP1 alleles have a wide range in stability of the protein, from hours to days. Engineering disulfide bonds into TEP1 can increase this stability to months. TEP1 activity in vivo is maintained by a complex of two leucine-rich proteins called LRIM1 and APL1C, which binds TEP1 through its C-terminal coiled-coil domain. We found that LRIM1/APL1C does not bind disulfide-stabilized TEP1, suggesting that LRIM1/APL1C binds to activated TEP1. This research advances our molecular understanding of a key immune response that affects the capacity of A. gambiae mosquitoes to transmit malaria.
Dilated Saliency U-Net for White Matter Hyperintensities Segmentation using Irregularity Age Map
Authors: Jeong Yunhee , Rachmadi Muhammad Febrian , Valdés-Hernández Maria del C. , Komura Taku
Published: February 2019

White matter hyperintensities(WMH) appear as regions of abnormally high signal intensity on T2-weighted magnetic resonance image(MRI) sequences. In particular, WMH have been noteworthy in age-related neuroscience for being a crucial biomarker for Alzheimer’ s disease and brain aging processes. However, the automatic WMH segmentation is challenging because of the variable intensity range, size and shape. U-Net tackled this problem through the dense prediction and showed competitive performances on not only WMH segmentation/detection but also on varied image segmentation tasks, but it still accompanies a high complexity of the network architecture. In this study, we propose to use Saliency U-Net architecture and irregularity age map(IAM) to decrease the U-Net complexity without a performance loss. We trained Saliency U-Net using both T2-FLAIR MRI sequence and IAM. Since IAM guides where irregularities, in which WMH is possibly included, exist on the MRI slice, Saliency U-Net performs better than the original U-Net trained only using T2-FLAIR. The better performance was achieved with fewer parameters and shorter training time. Moreover, the application of dilated convolution enhanced Saliency U-Net to recognise the shape of large WMH more accurately by learning multi-context on MRI slices. This network named Dilated Saliency U-Net improved Dice coefficient score to 0.5588 which is the best score among our experimental models, and recorded a relatively good sensitivity of 0.4747 with the shortest train time and the least number of parameters. In conclusion, based on the experimental results, incorporating IAM through Dilated Saliency U-Net resulted an appropriate approach for WMH segmentation.
Effects of mass ratios on salt spray corrosion and electrochemical corrosion behaviors of laser cladded Cr–Ni coatings
Authors: Jiahong Li , Dejun Kong
Published: February 2019

Purpose

The purpose of this paper is to improve the salt spray corrosion and electrochemical corrosion performances of H13 hot work mould steel, Cr–Ni coatings with the different Cr and Ni mass ratios are fabricated using a laser cladding (LC), which provides an experimental basis for the surface modification treatment of H13 steel.

Design/methodology/approach

Cr–Ni coatings with the different Cr and Ni mass ratios were firstly fabricated on H13 hot work mould steel using a laser cladding (LC). The salt spray corrosion (SSC) and electrochemical corrosion performances of Cr–Ni coatings in 3.5 Wt.% NaCl solution were investigated to analyze the corrosion mechanism, and the effect of mass ratios of Cr and Ni on their corrosion mechanism was discussed.

Findings

The laser cladded Cr–Ni coatings with the different Cr and Ni mass ratios are composed of Cr–Ni compounds, which are metallurgically combined with the substrate. The SSC resistance of Cr–Ni coating with the Cr and Ni mass ratios of 24:76 is the highest. The electrochemical corrosion resistance of Cr–Ni coating with the Cr and Ni mass ratio of 24:76 is the best among the three kinds of coatings.

Originality/value

In this study, the corrosion resistance of laser cladded Cr–Ni coatings with the Cr and Ni mass ratios of 17: 83, 20: 80 and 24: 76 was first evaluated using salt spray corrosion (SSC) and electrochemical tests, and the effect of mass ratios of Cr and Ni on their corrosion mechanism was discussed.
Initiatives to integrate operational knowledge in design: a building client perspective
Authors: Rasmussen Helle Lohmann , Jensen Per Anker , Nielsen Susanne Balslev , Kristiansen Anders Højen
Published: February 2019

Purpose

This paper aims to focus on deliberate actions by the building client to integrate knowledge of facilities management, in particular building operation, in design and construction of sustainable facilities. Examples of current practices are studied to answer the following questions: Which initiatives to enable operational friendly and sustainable buildings are currently used by building clients in Denmark? Which initiatives could be appropriate to use in the future, and which parties are in the best position to implement the various initiatives?

Design/methodology/approach

The study is a hermeneutic multi-method study, which consists of a review of former research, a case study and a survey. It starts with theoretical background based on earlier research with the aim to identify initiatives to ensure the use of operational knowledge in building design. Hereafter, the paper presents, analyses and discusses two studies: a case study of current practices at a university campus organisation and a survey of five swimming facilities. All cases are from Denmark.

Findings

In all, 31 initiatives to enable use of operational knowledge in building design were initially identified. In the case study, 11 additional initiatives were found. The case study and the survey of swimming facilities show different degrees of implementation, varying from 18 to 31 initiatives implemented. However, the studies show that introducing the initiatives is not sufficient; it takes deliberate actions to get the initiatives well implemented. Within the building client organisation, three main actors should care for implementing the initiatives: Top management, building client division and operation division.

Originality/value

Research-based literature on practices in relation to knowledge transfer from operation to design is limited. This paper provides insights into deliberate efforts on transferring knowledge from operation to design among Danish building clients.
Patient-centered communication: dissecting provider communication
Authors: Platonova Elena A. , Qu Haiyan , Warren-Findlow Jan
Published: February 2019

Purpose

The purpose of this paper is to examine the relationship between patients’ provider communication effectiveness and courteousness with patients’ satisfaction and trust at free clinics.

Design/methodology/approach

This cross-sectional survey (n=507), based on the Consumer Assessment of Healthcare Providers and Systems instrument, was conducted in two Southeastern US free clinics. Latent class analysis (LCA) was used to identify patient subgroups (clusters) with similar but not immediately visible characteristics.

Findings

Across the items assessing provider communication effectiveness and courteousness, five distinct clusters based on patient satisfaction, trust and socio-demographics were identified. In clusters where communication and courteousness ratings were consistent, trust and satisfaction ratings were aligned with these domains, e.g., 54 percent rated communication and courteousness highly, which was associated with high patient satisfaction and trust. When communication effectiveness and courteousness ratings diverged (e.g., low communication effectiveness but high courteousness), patient trust and satisfaction ratings aligned with communication effectiveness ratings. In all clusters, the association was greater for communication effectiveness than for provider courteousness. Thus, provider courteousness was important but secondary to communication effectiveness.

Practical implications

Investment in patient-centered communication training for providers will improve patient satisfaction and trust.

Originality/value

The study is the first to examine individual provider communication components and how they relate to patient satisfaction and trust in free clinics. LCA helped to more fully examine communication constructs, which may be beneficial for more nuanced quality improvement efforts.
Primary healthcare accreditation standards: a systematic review
Authors: Tabrizi Jafar Sadegh , Gharibi Farid
Published: February 2019

Purpose

Accreditation is an essential component in primary healthcare (PHC) systems. The purpose of this paper is to investigate the most suitable PHC accreditation models and standards, worldwide, and to prepare a comprehensive and unbiased summary from research on these models.

Design/methodology/approach

A systematic search was undertaken using Web of Science, Scopus, Science Direct, Springer, PubMed and ProQuest databases in August 2016 and updated in January 2018. English language studies addressing PHC accreditation standards and models, published between 1995 and January 2018, were included, resulting in 9051 citations. After excluding duplicates and irrelevant studies, 19 were included in the final review. Two independent reviewers critically appraised the studies. Consequently, accreditation standards in the models were extracted and compared.

Findings

Results indicate that USA, Australia, Canada, UK and New Zealand (non-eastern Mediterranean regions (EMR)) and Jordan, Saudi Arabia, Lebanon and Egypt (EMR) had well-developed and high-quality PHC accreditation models. The Jordanian, Egyptian and Saudi models had the highest diversity in their PHC standards domains. Community-oriented care, safe care, high-quality care, care continuity and human resource management had the highest priority among PHC accreditation programs.

Originality/value

The authors provide PHC accreditation benchmarks and determine high priority practical domains in accreditation standards. The findings should help health system managers and policymakers design new PHC accreditation programs and promote PHC service quality.
Evaluating and prioritizing hospital service quality
Authors: Torkzad Ahmad , Beheshtinia Mohammad Ali
Published: February 2019

Purpose

Hospital evaluations create competition between healthcare providers. In this study, a multi criteria decision-making (MCDM) method is used to evaluate criteria that affect hospital service quality. The paper aims to discuss these issues.

Design/methodology/approach

Criteria affecting hospital service quality are identified. Four Iranian public hospitals are evaluated using these criteria. Four hybrid methods, including modified digital logic–technique for order of preference by similarity to an ideal solution, analytical hierarchy process–technique for order of preference by similarity to an ideal solution, analytical hierarchy process–elimination and choice expressing reality and modified digital logic–elimination and choice expressing reality are used to evaluate hospital service quality. Results are aggregated using the Copeland method and final ranks are determined.

Findings

The four main criteria for evaluating hospital service quality are: environment; responsiveness; equipment and facilities; and professional capability. Results suggest that professional capability is the most important criterion. The Copeland method, used to integrate four MCDM hybrid methods, provides the final hospital ranks.

Practical implications

The criteria the authors identified and their weight help hospital managers to achieve comprehensive organizational growth and more efficient resource usage. Moreover, the decision matrix helps managers to identify their strengths and weaknesses.

Originality/value

New and comprehensive criteria are proposed for hospital quality assessments. Moreover, a new hybrid MCDM approach is used to achieve final hospital rankings.
Improving healthcare through process standardization: a general hospital case study
Authors: Rusjan Borut , Kiauta Marko
Published: February 2019

Purpose

The purpose of this paper is to analyze two process standardization theoretical conceptual constructs: process variants unification; and distinction between standard, routine and non-routine processes.

Design/methodology/approach

The authors analyze two conceptual constructs based on a single case study representing a general hospital’s (GH) process standardization, approach and results. The authors research whether process standardization implemented in a GH conforms to the process variants unification concept approach and its assumed benefits and whether implemented process standardization enables process management improvement based on distinguishing standard, routine and non-routine processes.

Findings

In accordance with the process variants unification conceptual construct, the hospital task force determined a uniform basic patient comprehensive treatment process at the hospital level, which allows synergy among departments. Uniform process activities reflect the differences between standard, routine and non-routine processes.

Practical implications

Process standardization through unification improves performance by establishing a common framework enabling shared experience based on improved process understanding. Distinguishing standard, routine and non-routine processes is useful for analyzing process management. This distinction provides guidelines for process implementation and measurement improvement. The paper also shows that increased routinization and standardization represent levers for process improvement.

Originality/value

The authors analyze theoretical constructs based on a single case study and confirm that theoretical conceptual construct application can provide better process management, which is important for practitioners.
A decision support simulation model for bed management in healthcare
Authors: Cudney Elizabeth A. , Baru Raja Anvesh , Guardiola Ivan , Materla Tejaswi , Cahill William , Phillips Raymond , Mutter Bruce , Warner Debra , Masek Christopher
Published: February 2019

Purpose

In order to provide access to care in a timely manner, it is necessary to effectively manage the allocation of limited resources. such as beds. Bed management is a key to the effective delivery of high quality and low-cost healthcare. The purpose of this paper is to develop a discrete event simulation to assist in planning and staff scheduling decisions.

Design/methodology/approach

A discrete event simulation model was developed for a hospital system to analyze admissions, patient transfer, length of stay (LOS), waiting time and queue time. The hospital system contained 50 beds and four departments. The data used to construct the model were from five years of patient records and contained information on 23,019 patients. Each department’s performance measures were taken into consideration separately to understand and quantify the behavior of departments individually, and the hospital system as a whole. Several scenarios were analyzed to determine the impact on reducing the number of patients waiting in queue, waiting time and LOS of patients.

Findings

Using the simulation model, it was determined that reducing the bed turnover time by 1 h resulted in a statistically significant reduction in patient wait time in queue. Further, reducing the average LOS by 10 h results in statistically significant reductions in the average patient wait time and average patient queue. A comparative analysis of department also showed considerable improvements in average wait time, average number of patients in queue and average LOS with the addition of two beds.

Originality/value

This research highlights the applicability of simulation in healthcare. Through data that are often readily available in bed management tracking systems, the operational behavior of a hospital can be modeled, which enables hospital management to test the impact of changes without cost and risk.