bluuebunny/crossref_metadata_2025 huggingface dataset:
Alzheimer’s disease susceptibility gene apolipoprotein e (APOE) and blood biomarkers in UK Biobank (N=395,769)
Authors: Ferguson Amy C. , Tank Rachana , Lyall Laura M. , Ward Joey , Celis-Morales Carlos , Strawbridge Rona , Ho Frederick , Whelan Christopher D. , Gill Jason , Welsh Paul , Anderson Jana J. , Mark Patrick B. , Mackay Daniel F. , Smith Daniel J. , Pell Jill P. , Cavanagh Jonathan , Sattar Naveed , Lyall Donald M.
Published: February 2020

Background and objective

Alzheimer’s disease (AD) is a neurodegenerative condition where the underlying aetiology is still unclear. Investigating the potential influence of apolipoprotein e (APOE), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank.

Methods

After quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential associations between APOE genotypes and biomarkers.

Results

Several biomarkers significantly associated with APOE e4 ‘risk’ and e2 ‘protective’ genotypes (vs. neutral e3/e3). Most associations supported previous data: for example, e4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p<0.001) and e2 with lower LDL (b = −0.456 SDs, p<0.001). There were however instances of associations found in unexpected directions: e.g. e4 and increased insulin-like growth factor (IGF-1) (standardized beta = 0.017, p<0.001) where lower levels have been previously suggested as an AD risk factor.

Conclusions

These findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence here in supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways.
Estimating the daily trend in the size of the COVID-19 infected population in Wuhan
Authors: Lin Qiushi , Hu Taojun , Zhou Xiao − Hua
Published: February 2020

There has been an outbreak of coronavirus disease (COVID-19) in Wuhan city, Hubei province, China since December 2019. Cases have been exported to other parts of China and more than 20 countries. We provide estimates of the daily trend in the size of the epidemic in Wuhan based on detailed information of 10,940 confirmed cases outside Hubei province.
Effectiveness of interventions targeting air travellers for delaying local outbreaks of SARS-CoV-2
Authors: Clifford Samuel , Pearson Carl A.B. , Klepac Petra , Van Zandvoort Kevin , Quilty Billy J. ,   CMMID COVID-19 working group, Eggo Rosalind M. , Flasche Stefan
Published: February 2020

Background

We evaluated if interventions aimed at air travellers can delay local SARS-CoV-2 community transmission in a previously unaffected country.

Methods

We simulated infected air travellers arriving into countries with no sustained SARS-CoV-2 transmission or other introduction routes from affected regions. We assessed the effectiveness of syndromic screening at departure and/or arrival & traveller sensitisation to the COVID-2019-like symptoms with the aim to trigger rapid self-isolation and reporting on symptom onset to enable contact tracing. We assumed that syndromic screening would reduce the number of infected arrivals and that traveller sensitisation reduces the average number of secondary cases. We use stochastic simulations to account for uncertainty in both arrival and secondary infections rates, and present sensitivity analyses on arrival rates of infected travellers and the effectiveness of traveller sensitisation. We report the median expected delay achievable in each scenario and an inner 50% interval.

Results

Under baseline assumptions, introducing exit and entry screening in combination with traveller sensitisation can delay a local SARS-CoV-2 outbreak by 8 days (50% interval: 3-14 days) when the rate of importation is 1 infected traveller per week at time of introduction. The additional benefit of entry screening is small if exit screening is effective: the combination of only exit screening and traveller sensitisation can delay an outbreak by 7 days (50% interval: 2-13 days). In the absence of screening, with less effective sensitisation, or a higher rate of importation, these delays shrink rapidly to less than 4 days.

Conclusion

Syndromic screening and traveller sensitisation in combination may have marginally delayed SARS-CoV-2 outbreaks in unaffected countries.
Early epidemiological assessment of the transmission potential and virulence of coronavirus disease 2019 (COVID-19) in Wuhan City: China, January-February, 2020
Authors: Mizumoto Kenji , Kagaya Katsushi , Chowell Gerardo
Published: February 2020

Background

Since the first cluster of cases was identified in Wuhan City, China, in December, 2019, coronavirus disease 2019 (COVID-19) rapidly spread around the world. Despite the scarcity of publicly available data, scientists around the world have made strides in estimating the magnitude of the epidemic, the basic reproduction number, and transmission patterns. Accumulating evidence suggests that a substantial fraction of the infected individuals with the novel coronavirus show little if any symptoms, which highlights the need to reassess the transmission potential of this emerging disease. In this study, we derive estimates of the transmissibility and virulence of COVID-19 in Wuhan City, China, by reconstructing the underlying transmission dynamics using multiple data sources.

Methods

We employ statistical methods and publicly available epidemiological datasets to jointly derive estimates of transmissibility and severity associated with the novel coronavirus. For this purpose, the daily series of laboratory–confirmed COVID-19 cases and deaths in Wuhan City together with epidemiological data of Japanese repatriated from Wuhan City on board government–chartered flights were integrated into our analysis.

Results

Our posterior estimates of basic reproduction number (R) in Wuhan City, China in 2019–2020 reached values at 3.49 (95%CrI: 3.39–3.62) with a mean serial interval of 6.0 days, and the enhanced public health intervention after January 23rd in 2020 was associated with a significantly reduced R at 0.84 (95%CrI: 0.81–0.88), with the total number of infections (i.e. cumulative infections) estimated at 1906634 (95%CrI: 1373500–2651124) in Wuhan City, elevating the overall proportion of infected individuals to 19.1% (95%CrI: 13.5–26.6%). We also estimated the most recent crude infection fatality ratio (IFR) and time–delay adjusted IFR at 0.04% (95% CrI: 0.03%–0.06%) and 0.12% (95%CrI: 0.08–0.17%), respectively, estimates that are several orders of magnitude smaller than the crude CFR estimated at 4.06%

Conclusions

We have estimated key epidemiological parameters of the transmissibility and virulence of COVID-19 in Wuhan, China during January-February, 2020 using an ecological modelling approach. The power of this approach lies in the ability to infer epidemiological parameters with quantified uncertainty from partial observations collected by surveillance systems.
The human small intestine contains two subsets of regulatory Foxp3+ CD4+ T cells with very different life span and functional properties
Authors: Chauhan Sudhir Kumar , Casado Raquel Bartolomé , Landsverk Ole J.B. , Johannessen Hanna , Phung Danh , Sætre Frank , Jahnsen Jørgen , Horneland Rune , Yaqub Sheraz , Aandahl Einar Martin , Lundin Knut E.A. , Bækkevold Espen S. , Jahnsen Frode L.
Published: February 2020

Background

Regulatory CD4 T cells (Tregs) in the mice gut are mainly specific for intestinal antigens and play an important role in the suppression of immune responses against harmless dietary antigens and members of the microbiota. However, information about the phenotype and function of Tregs in the human gut is limited.

Objective

Here, we performed a detailed characterization of Foxp3+ CD4 Tregs in the human small intestine.

Methods

Tregs and conventional CD4 T cells derived from normal intestine as well as from transplanted duodenum and celiac disease lesions were subjected to extensive immunophenotyping and their suppressive activity and ability to produce cytokines were assessed.

Results

Small intestinal Foxp3+ CD4 T cells were CD45RA- CD127- CTLA4+ and suppressed proliferation of autologous T cells. Approximately 60% of the Tregs expressed the transcription factor Helios. When stimulated, Helios- Tregs produced IL-17, IFN-γ and IL-10, whereas Helios+ Tregs produced very low levels of these cytokines. By sampling mucosal tissue from transplanted human duodenum we demonstrated that donor Helios+ Tregs have a short life span whereas Helios- Tregs persisted for at least 1 year post-transplantation. In normal small intestine, Foxp3+ Tregs constituted only 2% of all CD4 T cells, while in active celiac disease both subsets expanded 5-10-fold.

Conclusion

The small intestine contains two subsets of Tregs with different functional capacities and very different life span. Both subsets are scarce in the normal situation but increase dramatically in a chronic inflammatory setting.
Codon-usage optimization in the prokaryotic tree of life: How synonymous codons are differentially selected in sequence domains with different expression levels and degrees of conservation
Authors: López José Luis , Lozano Mauricio Javier , Fabre María Laura , Lagares Antonio
Published: February 2020

Prokaryote genomes exhibit a wide range of GC contents and codon usages, both resulting from an interaction between mutational bias and natural selection. In order to investigate the basis underlying specific codon changes, we performed a comprehensive analysis of 29-different prokaryote families. The analysis of core-gene sets with increasing ancestries in each family lineage revealed that the codon usages became progressively more adapted to the tRNA pools. While, as previously reported, highly-expressed genes presented the more optimized codon usage, the singletons contained the less selectively-favored codons. Results showed that usually codons with the highest translational adaptation were preferentially enriched. In agreement with previous reports, a C-bias in 2- to 3-fold codons, and a U-bias in 4-fold codons occurred in all families, irrespective of the global genomic-GC content. Furthermore, the U-biases suggested that U3-mRNA–U34-tRNA interactions were responsible for a prominent codon optimization in both the more ancestral core and the highly expressed genes. A comparative analysis of sequences that encode conserved-(cr) or variable-(vr) translated products, with each one being under high- (HEP) and low- (LEP) expression levels, demonstrated that the efficiency was more relevant (by a factor of 2) than accuracy to modelling codon usage. Finally, analysis of the third position of codons (GC3) revealed that, in genomes of global-GC contents higher than 35-40%, selection favored a GC3 increase; whereas in genomes with very low-GC contents, a decrease in GC3 occurred. A comprehensive final model is presented where all patterns of codon usage variations are condensed in five-distinct behavioral groups.

IMPORTANCE

The prokaryotic genomes—the current heritage of the more ancient life forms on earth— are comprised of diverse gene sets; all characterized by varied origins, ancestries, and spatial-temporal–expression patterns. Such genetic diversity has for a long time raised the question of how cells shape their coding strategies to optimize protein demands (i.e., product abundance) and accuracy (i.e., translation fidelity) through the use of the same genetic code in genomes with GC-contents that range from less than 20 to over 80%. In this work, we present evidence on how codon usage is adjusted in the prokaryote tree of life, and on how specific biases have operated to improve translation. Through the use of proteome data, we characterized conserved and variable sequence domains in genes of either high- or low-expression level, and quantitated the relative weight of efficiency and accuracy—as well as their interaction—in shaping codon usage in prokaryotes.
Trait-based aerial dispersal of arbuscular mycorrhizal fungi
Authors: Chaudhary V. Bala , Nolimal Sarah , Sosa-Hernández Moisés A. , Egan Cameron , Kastens Jude
Published: February 2020

Dispersal is a key process driving local-scale community assembly and global-scale biogeography of plant symbiotic arbuscular mycorrhizal (AM) fungal communities. A trait-based approach could improve predictions regarding how AM fungal aerial dispersal varies by species.

We conducted month-long collections of aerial AM fungi for 12 consecutive months in an urban mesic environment at heights of 20 m. We measured functional traits of all collected spores and assessed aerial AM fungal community structure both morphologically and with high-throughput sequencing.

Large numbers of AM fungal spores were present in the air over the course of one year and these spores were more likely to exhibit traits that facilitate dispersal. Aerial spores were smaller than average for Glomeromycotinan fungi. Trait-based predictions indicate that nearly 1/3 of described species from diverse genera demonstrate the potential for aerial dispersal. Diversity of aerial AM fungi was relatively high (20 spore species and 17 virtual taxa) and both spore abundance and community structure shifted temporally.

The prevalence of aerial dispersal in arbuscular mycorrhizas is perhaps greater than previously indicated and a hypothesized model of AM fungal dispersal mechanisms is presented. Anthropogenic soil impacts may initiate the dispersal of disturbance-tolerating AM fungal species and facilitate community homogenization.
Osprey: Open-Source Processing, Reconstruction & Estimation of Magnetic Resonance Spectroscopy Data
Authors: Oeltzschner Georg , Zöllner Helge J. , Hui Steve C. N. , Mikkelsen Mark , Saleh Muhammad G. , Tapper Sofie , Edden Richard A. E.
Published: February 2020

Background

Processing and quantitative analysis of magnetic resonance spectroscopy (MRS) data are far from standardized and require interfacing with third-party software. Here, we present Osprey, a fully integrated open-source data analysis pipeline for MRS data, with seamless integration of pre-processing, linear-combination modelling, quantification, and data visualization.

New Method

Osprey loads multiple common MRS data formats, performs phased-array coil combination, frequency-and phase-correction of individual transients, signal averaging and Fourier transformation. Linear combination modelling of the processed spectrum is carried out using simulated basis sets and a spline baseline. The MRS voxel is coregistered to an anatomical image, which is segmented for tissue correction and quantification is performed based upon modelling parameters and tissue segmentation. The results of each analysis step are visualized in the Osprey GUI. The analysis pipeline is demonstrated in 12 PRESS, 11 MEGA-PRESS, and 8 HERMES datasets acquired in healthy subjects.

Results

Osprey successfully loads, processes, models, and quantifies MRS data acquired with a variety of conventional and spectral editing techniques.

Comparison with Existing Method(s)

Osprey is the first MRS software to combine uniform pre-processing, linear-combination modelling, tissue correction and quantification into a coherent ecosystem. Compared to existing compiled, often closed-source modelling software, Osprey’s open-source code philosophy allows researchers to integrate state-of-the-art data processing and modelling routines, and potentially converge towards standardization of analysis.

Conclusions

Osprey combines robust, peer-reviewed data processing methods into a modular workflow that is easily augmented by community developers, allowing the rapid implementation of new methods.
Anin vitrovesicle formation assay to analyze protein sorting in the secretory transport pathway
Authors: Huang Yan , Yin Haidi , Tang Xiao , Wu Qian , Wang Mo , Poljak Kristina , Li Baiying , Yang Liu , Wu Zhixiao , Jiang Liwen , Miller Elizabeth A. , Yao Zhong-Ping , Guo Yusong
Published: February 2020

The fidelity of protein transport in the secretory transport pathway relies on the accurate sorting of proteins to their correct destination. To deepen our understanding of the underlying molecular mechanisms, it is important to develop a robust approach to systematically reveal cargo proteins that depend on a specific cargo sorting machinery to be efficiently packaged into vesicles. Here, we used anin vitroassay that reconstitutes packaging of human cargo proteins into vesicles to quantify cargo capture. Quantitative mass spectrometry analyses of the isolated vesicles revealed novel cytosolic proteins that are associated with vesicle membranes in a GTP-dependent manner or that interact with GTP-bound Sar1A on vesicle membranes. Functional analysis indicates that two of them, FAM84B and PRRC1, regulate anterograde trafficking. Comparing control cells with cells depleted of the cargo receptors, SURF4 or ERGIC53, we revealed specific clients of each of these two export adaptors. Moreover, our results indicate that vesicles enriched with a specific cargo protein contain specific transmembrane cargo and SNARE proteins. A SNARE protein, Vti1B, is identified to be in vesicles enriched with a planar cell polarity protein, Frizzled6, and promotes vesicular release of Frizzled6. Our results indicate that the vesicle formation assay in combination with quantitative mass spectrometric analysis is a robust and powerful tool to reveal novel cytosolic and transmembrane proteins that regulate trafficking of a specific cargo protein.
Bacterial flagella disrupt host cell membranes and interact with cytoskeletal components
Authors: Wolfson Eliza. B. , Elvidge Johanna , Tahoun Amin , Gillespie Trudi , Mantell Judith , McAteer Sean P. , Rossez Yannick , Paxton Edith , Lane Fiona , Shaw Darren J. , Gill Andrew C. , Stevens Jo , Verkade Paul , Blocker Ariel , Mahajan Arvind , Gally David L.
Published: February 2020

Bacterial flagella have many established roles beyond swimming motility. Despite clear evidence of flagella-dependent adherence, the specificity of ligands and mechanisms of binding are still debated. In this study, the molecular basis ofE. coliO157:H7 andS. Typhimurium flagella binding to epithelial cell cultures was investigated. Flagella interactions with host cell surfaces were intimate and crossed cellular boundaries as demarcated by actin and membrane labelling. SEM revealed flagella disappearing into cellular surfaces and TEM ofS. Typhiumurium indicated host membrane deformation and disruption in proximity to flagella. Motor mutants ofE. coliO157:H7 andS. Typhimurium caused reduced haemolysis compared to wild-type, indicating that membrane disruption was in part due to flagella rotation. Flagella fromE. coliO157 (H7), EPEC O127 (H6), andS. Typhimurium (P1 & P2 flagella) were shown to bind to purified intracellular components of the actin cytoskeleton and directly increase in vitro actin polymerisation rates.
Stem cell lineage survival as a noisy competition for niche access
Authors: Corominas-Murtra Bernat , Scheele Colinda L.G.J. , Kishi Kasumi , Ellenbroek Saskia I.J. , Simons Benjamin D. , van Rheenen Jacco , Hannezo Edouard
Published: February 2020

Understanding to what extent stem cell potential is a cell-intrinsic property, or an emergent behavior coming from global tissue dynamics and geometry, is a key outstanding question of stem cell biology. Here, we propose a theory of stem cell dynamics as a stochastic competition for access to a spatially-localized niche, giving rise to a “stochastic conveyor-belt” model. Cell divisions produce a steady cellular stream which advects cells away from the niche, while random rearrangements enable cells away from the niche to be favourably repositioned. Importantly, even when assuming that all cells in a tissue molecularly equivalent, the model predicts a common (“universal”) functional dependence of the long-term clonal survival probability on the position within the niche, as well as the emergence of a well-defined number of “functional” stem cells, dependent only on the rate of random movements vs. mitosis-driven advection. We test the predictions of this theory on datasets on pubertal mammary gland tips, embryonic kidney tips as well homeostatic intestinal crypt, and find good quantitative agreement for the number of functional stem cells in each organ, as well as the predicted functional dependence of the competition.
Fatigue behavior of trabecular bone orientation
Authors: Januddi Fatihhi Szali , Harun M.N , Abdullah Jaafar , Mostakhdemin Mohammad , Syahrom Ardiyansyah
Published: February 2020

The present study reports the anisotropy effects of uniaxial and multiaxial loading on cancellous bone in order to mimic true physiological conditions as well as pathological reactions and thereby provides improved data that represents clinical and real life conditions. Cancellous bone samples were CT-scanned for morphological analysis and model construction. The models were then computationally loaded on three different directions; horizontal, vertical, and at 45°. Lower BV/TV, Tb.Th, and Conn.D resulted in lower number of cycles to failure, regardless to the loading conditions. However, the number of cycles to failure was found to be negatively correlated to the value of structural model index. Dramatic increased in effective plastic strain and decrease in cycles to failure were demonstrated by the cancellous bone models under multiaxial loading. The reduction of fatigue life was five times lower in multiaxial condition in comparison to the fatigue life under uniaxial loading. Off-axis orientation effect on the fatigue life of the trabecular bone was demonstrated the worst in horizontal trabecular bone model. Effective plastic strain was recorded the highest in horizontal model, while the model at 45° demonstrated 1.6 times higher effective plastic strain than the vertical ones. This is due to several numbers of thin trabeculae which are susceptible to fatigue at higher stress concentration. In conclusion, the anisotropic effect of uniaxial and multiaxial loading onto the mechanical behaviour of bovine cancellous bone was demonstrated throughout this study. It is apparent that multiaxial with off-axis forces are important to be considered as the loading direction manifests the fatigue lifetime of cancellous bone.
Incidence of atrial septal defects in children attended the Cardiac Center of Ethiopia during January 2016 to December 2018
Authors: Musa Abdu Hassen , Afework Mekbeb , Bedru Mohammed , Tamirat Shibikom ,   on behalf of Cardiac Center of Ethiopia record screener
Published: February 2020

Background

Although it appears that an atrial septal defect (ASD) occurs frequently in Ethiopia there are only a few published studies available so far on this matter. This study is therefore aimed to evaluate the prevalence and echocardiographic characteristics of ASDs in children (aged ≤ 15 years) attended a cardiac referral center in Ethiopia.

Methods

This retrospective study reviewed the sociodemographic data and the initial echocardiographic findings of the children with ASDs who were diagnosed at the Cardiac Center of Ethiopia (CCE), Addis Ababa, from January 2016 to December 2018.

Results

A total of 116 children (56.9% females and 43.1% males) with a mean age of 3.47± 3.72 years (range: 15 days to 15 years) were diagnosed with ASDs. The most prevalent age groups were infancy (50%) and early childhood (29.3%). All the studied cases were diagnosed with ostium secundum ASD while there were no cases with ostium primum, sinus venosus and coronary sinus defects. The most frequent ostium secundum ASD was large size (61.2%) and was more frequent in infants (23.3%) and young children (21.6% of all cases).

Conclusion

Ostium secundum ASD is the most prevalent IAS defect and more common among female cases. Large size ostium secundum ASD is more frequent in the studied children and is more prevalent in infants and young children. This survey may provide data for the currently lacking statistics on ASDs at the CCE and might be helpful for the management and follow-up of children with ASDs. Scheduled follow-up and intervention studies are required to evaluate the incidence and patterns of spontaneous and surgical closure of ASD and their outcomes.
The PINK1 – Parkin mitophagy signalling pathway is not functional in peripheral blood mononuclear cells
Authors: Bradshaw Aaron V. , Campbell Philip , Schapira Anthony H. V. , Morris Huw R. , Taanman Jan-Willem
Published: February 2020

Mutations in thePINK1andPRKNgenes are the most common cause of early-onset familial Parkinson disease. These genes code for the PINK1 and Parkin proteins, respectively, which are involved in the degradation of dysfunctional mitochondria through mitophagy. An early step in PINK1 – Parkin mediated mitophagy is the ubiquitination of the mitofusin proteins MFN1 and -2. The ubiquitination of MFN1 and -2 in patient samples may therefore serve as a biomarker to determine the functional effects ofPINK1andPRKNmutations, and to screen idiopathic patients for potential mitophagy defects. We aimed to characterise the expression of the PINK1 – Parkin mitophagy machinery in peripheral blood mononuclear cells (PBMCs) and assess if these cells could serve as a platform to evaluate mitophagy via analysis of MFN1 and -2 ubiquitination. Mitophagy was induced through mitochondrial depolarisation by treatment with the protonophore CCCP and ubiquitinated MFN proteins were analysed by western blotting. In addition,PINK1andPRKNmRNA and protein expression levels were characterised with reverse transcriptase quantitative PCR and western blotting, respectively. Whilst CCCP treatment led to MFN ubiquitination in primary fibroblasts, SH-SY5Y neuroblastoma cells and Jurkat leukaemic cells, treatment of PBMCs did not induce ubiquitination of MFN.PRKNmRNA and protein was readily detectable in PBMCs at comparable levels to those observed in Jurkat and fibroblast cells. In contrast, PINK1 protein was undetectable andPINK1mRNA levels remarkably low in control PBMCs. Our findings suggest that the PINK1 – Parkin mitophagy signalling pathway is not functional in PBMCs. Therefore, PBMCs are not a suitable biosample for analysis of mitophagy function in Parkinson disease patients.
Antagonistic roles of NOT1 paralogues in the timing of gene expression inPlasmodium falciparum
Authors: Liu Ying , Rai Ragini , Zhu Lei , Zhang Changqing , Rocamora Frances , Featherstone Mark , Bozdech Zbynek
Published: February 2020

NOT1 is the scaffold of the CCR4-NOT complex, a highly conserved multi-protein complex that regulates gene expression in eukaryotes. As opposed to most eukaryotes in which NO1 is encoded by a single gene, malaria parasites,Plasmodium falciparum,carry two NOT1 paralogues, PfNOT1.1 and PfNOT1.2. Here we showed that the two PfNOT1 proteins function as mutually exclusive scaffolds within the PfCCR4-NOT protein complexes that are abundantly located in the parasite cytoplasm. Intriguingly, the two PfNOT1 paralogues appear to have directly opposing functions in regulation of mRNA abundance across theP. falciparumIDC, in which PfNTO1.1 and PfNOT1.2 induces and suppresses transcript abundance during their active transcription, respectively. Targeted disruption of either of thePfNOT1gene causes defective growth and lower invasion rates presumably due to the deregulation theP. falciparumIDC transcriptional cascade. We also demonstrate that the regulatory function of both PfNOT1.1 and PfNOT1.2 are related to another PfCCR4-NOT subunit,PfCaf1,which indicates their activity during post-transcriptional regulation. Indeed RNA decay studies suggest the active role of both PfNOT1 proteins in regulation of mRNA stability in a directly opposing manner.

Author summary

CCR4-NOT complex is a highly conserved multi-protein complex that regulates gene expression in eukaryotes. NOT1 serves as the scaffold of the complex and plays important roles in gene regulation both transcriptionally and post-transcriptionally. As opposed to other eukaryotes,P. falciparumencodes two paralogues of PfNOT1, raising the question as to the significance to possess an additional copy of PfNOT1 in the parasite. Here we described antagonistic regulatory functions of two PfNOT1 paralogues in gene expression during the 48-hour intraerythrocytic developmental cycle. We also reported that their regulatory functions are predominantly post-transcriptional and proposed a model in which distinct PfCCR4-NOT complexes defined by mutually exclusive PfNOT1 scaffolds differentially regulate PfCAF1 function in mRNA decay. This study highlights the importance of post-transcriptional regulation inP. falciparumand provides novel insights into mechanisms of gene regulation in this organism. The unique presence of two PfNOT1 paralogues may also open avenues for the development of new drug targets for anti-malarial control.
PCNA activates the MutLγ endonuclease to promote meiotic crossing over
Authors: Kulkarni Dhananjaya S. , Owens Shannon , Honda Masayoshi , Ito Masaru , Yang Ye , Corrigan Mary W. , Chen Lan , Quan Aric L. , Hunter Neil
Published: February 2020

During meiosis, crossover recombination connects homologous chromosomes to direct their accurate segregation1. Defects in crossing over cause infertility, miscarriage and congenital disease. Accordingly, each pair of chromosomes attains at least one crossover through processes that designate and then implement crossing over with high efficiency2. At the DNA level, crossing over is implemented through the formation and biased resolution of double-Holliday Junction intermediates3–5. A central tenet of crossover resolution is that the two Holliday junctions are resolved in opposite planes by targeting nuclease incisions to specific DNA strands6. Although the endonuclease activity of the MutLγ complex has been implicated in crossover-biased resolution7–12, the mechanisms that activate and direct strand-specific cleavage remain unknown. Here we show that the sliding clamp, PCNA, is important for crossover-biased resolution.In vitroassays with human enzymes show that hPCNA and its loader hRFC are sufficient to activate the hMutLγ endonuclease under physiological conditions. In this context, the hMutLγ endonuclease is further stimulated by a co-dependent activity of the pro-crossover factors hEXO1 and hMutSγ, the latter of which binds Holliday junctions13. hMutLγ also specifically binds a variety of branched DNAs, including Holliday junctions, but canonical resolvase activity is not observed implying that the endonuclease incises adjacent to junction branch points to effect resolution.In vivo, we show that budding yeast RFC facilitates MutLγ-dependent crossing over. Furthermore, PCNA localizes to prospective crossover sites along synapsed chromosomes. These data highlight similarities between crossover-resolution and DNA mismatch repair14–16and evoke a novel model for crossover-specific dHJ resolution during meiosis.
Regulation of the MLH1-MLH3 endonuclease in meiosis
Authors: Cannavo Elda , Sanchez Aurore , Anand Roopesh , Ranjha Lepakshi , Hugener Jannik , Adam Céline , Acharya Ananya , Weyland Nicolas , Aran-Guiu Xavier , Charbonnier Jean-Baptiste , Hoffmann Eva R. , Borde Valérie , Matos Joao , Cejka Petr
Published: February 2020

During prophase of the first meiotic division, cells deliberately break their DNA. These DNA breaks are repaired by homologous recombination, which facilitates proper chromosome segregation and enables reciprocal exchange of DNA segments between homologous chromosomes, thus promoting genetic diversity in the progeny1. A successful completion of meiotic recombination requires nucleolytic processing of recombination intermediates. Genetic and cellular data implicated a pathway dependent on the putative MLH1-MLH3 (MutLγ) nuclease in generating crossovers, but mechanisms that lead to its activation were unclear2–4. Here, we have biochemically reconstituted key elements of this pro-crossover pathway. First, we show that human MSH4-MSH5 (MutSγ), which was known to support crossing over5–7, binds branched recombination intermediates and physically associates with MutLγ. This helps stabilize the ensemble at joint molecule structures and adjacent dsDNA. Second, we show that MutSγ directly stimulates DNA cleavage by the MutLγ endonuclease, which demonstrates a novel and unexpected function for MutSγ in triggering crossing-over. Third, we find that MutLγ activity is further stimulated by EXO1, but only when MutSγ is present. Fourth, we also identify the replication factor C (RFC) and the proliferating cell nuclear antigen (PCNA) as additional components of the nuclease ensemble, and show thatS. cerevisiaestrains expressing PIP box-mutated MutLγ present striking defects in forming crossovers. Finally, we show that the MutLγ-MutSγ-EXO1-RFC-PCNA nuclease ensemble preferentially cleaves DNA with Holliday junctions, but shows no canonical resolvase activity. Instead, the multilayered nuclease ensemble likely processes meiotic recombination intermediates by nicking dsDNA adjacent to junction points8. Since DNA nicking by MutLγ is dependent on its co-factors, the asymmetric distribution of MutSγ and RFC/PCNA on meiotic recombination intermediates may drive biased DNA cleavage. This unique mode of MutLγ nuclease activation might explain crossover-specific processing of Holliday junctions within the meiotic chromosomal context3, 9.
Opposing effects of an F-box protein and the HSP90 chaperone network on microtubule stability and neurite growth inCaenorhabditis elegans
Authors: Zheng Chaogu , Atlas Emily , Lee Ho Ming Terence , Jao Susan Laura Javier , Nguyen Ken C. Q. , Hall David H. , Chalfie Martin
Published: February 2020

Molecular chaperones often work collaboratively with the ubiquitination-proteasome system (UPS) to facilitate the degradation of misfolded proteins, which typically safeguards cellular differentiation and protects cells from stress. In this study, however, we report that the Hsp70/Hsp90 chaperone machinery and an F-box protein, MEC-15, have opposing effects on neuronal differentiation and that the chaperones negatively regulate neuronal morphogenesis and functions. Using the touch receptor neurons (TRNs) ofCaenorhabditis elegans, we find thatmec-15(−)mutants display defects in microtubule formation, neurite growth, synaptic development, and neuronal functions, and these defects can be rescued by the loss of Hsp70/Hsp90 chaperones and cochaperones. MEC-15 likely functions in a SCF complex to degrade DLK-1, which is an Hsp90 client protein stabilized by the chaperones. The abundance of DLK-1, and likely other Hsp90 substrates, is fine-tuned by the antagonism between MEC-15 and chaperones; this antagonism regulates TRN development as well as synaptic functions of GABAergic motor neurons. Therefore, a balance between UPS and chaperones tightly controls neuronal differentiation.

Summary statement

Molecular chaperones are known to protect cells from stress. However, in this study the authors showed that the Hsp90 chaperone negatively regulates neuronal differentiation when the ubiquitination-proteasome system is compromised.
The mechanical inhibition of the isolated Vofrom V-ATPase for proton conductance
Authors: Kishikawa Jun-ichi , Nakanishi Atsuko , Furuta Aya , Kato Takayuki , Namba Keiichi , Tamakoshi Masatada , Mitsuoka Kaoru , Yokoyama Ken
Published: February 2020

V-ATPase is an energy converting enzyme, coupling ATP hydrolysis/synthesis in the hydrophilic V1moiety, with proton flow through the Vomembrane moiety, via rotation of the central rotor complex relative to the surrounding stator apparatus. Upon dissociation from the V1domain, the Voof eukaryotic V-ATPase can adopt a physiologically relevant auto-inhibited form in which proton conductance through the Vois prevented, however the molecular mechanism of this inhibition is not fully understood. Using cryo-electron microscopy, we determined the structure of both theholoV/A-ATPase and the isolated Voat near-atomic resolution, respectively. These structures clarify how the isolated Voadopts the auto-inhibited form and how theholocomplex prevents the formation of this inhibited Voform.

One Sentence Summary

Cryo-EM structures of rotary V-ATPase reveal the ON-OFF switching mechanism of H+translocation in the Vomembrane domain.
Mesoscopic numerical analysis of dynamic tensile fracture of recycled concrete
Authors: Ying Liping , Peng Yijiang , Kamel Mahmoud M.A.
Published: February 2020

Purpose

Based on the random aggregate model of recycled aggregate concrete (RAC), this paper aims to focus on the effect of loading rate on the failure pattern and the macroscopic mechanical properties.

Design/methodology/approach

RAC is regarded as a five-phase inhomogeneous composite material at the mesoscopic level. The number and position of the aggregates are modeled by the Walraven formula and Monte–Carlo stochastic method, respectively. The RAC specimen is divided by the finite-element mesh to establish the dynamic base force element model. In this model, the element mechanical parameters of each material phase satisfy Weibull distribution. To simulate and analyze the dynamic mechanical behavior of RAC under axial tension, flexural tension and shear tension, the dynamic tensile modes of the double-notched specimens, the simply supported beam and the L specimens are modeled, respectively. In addition, the different concrete samples are numerically investigated under different loading rates.

Findings

The failure strength and failure pattern of RAC have strong rate-dependent characteristics because of the inhomogeneity and the inertial effect of the material.

Originality/value

The dynamic base force element method has been successfully applied to the study of recycled concrete.
An efficient and accurate method for transient heat conduction in a periodic structure with moving heat sources
Authors: Cui Haichao , Gao Qiang , Li Xiaolan , Ouyang Huajiang
Published: February 2020

Purpose

This paper aims to propose an efficient and accurate method to analyse the transient heat conduction in a periodic structure with moving heat sources.

Design/methodology/approach

The moving heat source is modelled as a localised Gaussian distribution in space. Based on the spatial distribution, the physical feature of transient heat conduction and the periodic property of structure, a special feature of temperature responses caused by the moving heat source is illustrated. Then, combined with the superposition principle of linear system, within a small time-step, computation of results corresponding to the whole structure excited by the Gaussian heat source is transformed into that of some small-scale structures. Lastly, the precise integration method (PIM) is used to solve the temperature responses of each small-scale structure efficiently and accurately.

Findings

Within a reasonable time-step, the heat source applied on a unit cell can only cause the temperature responses of a limited number of adjacent unit cells. According to the above feature and the periodic property of a structure, the contributions caused by the moving heat source for the most of time-steps are repeatable, and the temperature responses of the entire periodic structure can be obtained by some small-scale structures.

Originality/value

A novel numerical method is proposed for analysing moving heat source problems, and the numerical examples demonstrate that the proposed method is much more efficient than the traditional methods, even for larger-scale problems and multiple moving heat source problems.
An asymptotic-numerical comparative study for axisymmetric free surface liquid jet near and far from exit at high Reynolds number
Authors: Wang Yunpeng , Khayat Roger E.
Published: February 2020

Purpose

The purpose of this study is to examine theoretically the axisymmetric flow of a steady free-surface jet emerging from a tube for high inertia flow and moderate surface tension effect.

Design/methodology/approach

The method of matched asymptotic expansion is used to explore the rich dynamics near the exit where a stress singularity occurs. A boundary layer approach is also proposed to capture the flow further downstream where the free surface layer has grown significantly.

Findings

The jet is found to always contract near the tube exit. In contrast to existing numerical studies, the author explores the strength of upstream influence and the flow in the wall layer, resulting from jet contraction. This influence becomes particularly evident from the nonlinear pressure dependence on the upstream distance, as well as the pressure undershoot and overshoot at the exit for weak and strong gravity levels, respectively. The approach is validated against existing experimental and numerical data for the jet profile and centerline velocity where good agreement is obtained. Far from the exit, the author shows how the solution in the diffusive region can be matched to the inviscid far solution, providing the desired appropriate initial condition for the inviscid far flow solution. The location, at which the velocity becomes uniform across the jet, depends strongly on the gravity level and exhibits a non-monotonic behavior with respect to gravity and applied pressure gradient. The author finds that under weak gravity, surface tension has little influence on the final jet radius. The work is a crucial supplement to the existing numerical literature.

Originality/value

Given the presence of the stress singularity at the exit, the work constitutes a superior alternative to a computational approach where the singularity is typically and inaccurately smoothed over. In contrast, in the present study, the singularity is entirely circumvented. Moreover, the flow details are better elucidated, and the various scales involved in different regions are better identified.
Mobile users’ information privacy concerns instrument and IoT
Authors: Foltz C. Bryan , Foltz Laura
Published: February 2020

Purpose

Internet of Things (IoT) presents new privacy dilemmas. While IoT is becoming more common, a model to understand privacy concerns has not been established. The purpose of this paper is to examine an existing privacy model, the mobile users’ information privacy concerns (MUIPC), in the context of IoT.

Design/methodology/approach

A survey was distributed via email to 1,257 undergraduate students enrolled in a Carnegie Master’s level university in the mid-south; 192 students completed the survey, a response rate of 15.3%. SmartPLS, a structural equation modeling software, was used to evaluate the measurement model and to examine the relationships.

Findings

All relationships were significant at the 0.05 level indicating that the MUIPC model does appear to apply to IoT.

Research limitations/implications

A convenience sample was used and the response rate was low and, therefore, may not be generalizable to another population.

Originality/value

This research demonstrates the MUIPC is indeed applicable to privacy research within IoT, thus opening another avenue for future research and confirms the influence of information privacy upon intention within the IoT realm.
Managing project complexity: how to cope with multiple dimensions of complex systems
Authors: Mamédio Diórgenes Falcão , Meyer Victor
Published: February 2020

Purpose

This study aimed to contribute to the field of project management (PM) by exploring the elements of project complexity and how individuals respond to such complexity. Multiple dimensions were examined, including technical, human and political dimensions, with a significant impact on project implementation.

Design/methodology/approach

An in-depth case study was conducted, focusing on the implementation of a Brazilian hospital. Data were collected through semi-structured interviews, participant observation and document analysis. Bridging the research gap involved unraveling the project complexity elements and how to manage them, more specifically in the hospital context.

Findings

The findings revealed that project complexity challenges managers to deal with uncertainties, emergencies and unexpected situations. It implies coping with multiple factors of technical, human and political dimensions. Divergent interests contributed to the formation of coalitions, triggering relevant individual and group learning. Strategic improvisation had a potentially significant response from managers regarding project complexity to make adjustments and changes, focusing on project effectiveness and performance.

Practical implications

The challenge of managing project complexity is to deal with the balance between structure and improvisation in response to complexity. Flexibility, adaptability, self-organisation and strategic improvisation are key elements in managerial practices that address complexity, especially in hospital projects.

Originality/value

The differentiated approach lies in the proposed model of project complexity, with elements that make up the technical, human and political dimensions, with significant results for complex projects.
Protection offered by leaf fungal endophytes to an invasive species against native herbivores depends on soil nutrients
Authors: Graff Pamela , Gundel Pedro E. , Salvat Adriana , Cristos Diego , Chaneton Enrique J.
Published: February 2020

Natural grassland ecosystems are increasingly threatened by excessive loadings of nutrients and by the presence of species bred for high productivity. By manipulating grazing regimes and nutrient availability, agricultural practices facilitate the establishment and spread of certain forage plant species outside managed landscapes, challenging local biodiversity. The ecological success of some species in the invaded range sometimes seems to be associated with the symbiosis with foliar fungal endophytes. Symbiotic fungi may increase the competitiveness of host species, but also the resistance to herbivory through the production of toxic secondary compounds such as alkaloids. While progress has been made in understanding how soil nutrients modulate other benefits offered by fungal endophytes to plants (e.g. stress tolerance, competitive ability, etc), the consequences for a higher trophic level (i.e. herbivores) and the potential feedbacks on plant invasion have not been explored yet.

We explored the relative and interactive importance of soil nitrogen (N) and phosphorus (P) in modulating the interaction of the invasive grass tall fescue—associated with fungal endophytes—and native herbivores in a natural grassland. We hypothesized that N and P nutrients modulate differentially leaf quality traits, namely nutritional value and fungal alkaloid contents, determining the level of damage by native insect herbivores on the exotic tall fescue.

We found that only the addition of P significantly increased native caterpillar density in the field, which corresponded to a concomitant increase in leaf damage. In contrast to expectations, the concentration of the alkaloid ergovaline in leaves was not strongly related to N. It was the level of soil P which dictated the concentration of the element (P) in the leaves and reduced the level of defence against herbivores in this endophyte‐symbiotic species. Then, herbivore performance increased, and plants were more prone to be attacked.

Synthesis. Our study indicates a strong control of soil P fertility on the triple interaction among plants, fungal endophytes and native herbivores. This highlights the potential role of increased soil nutrients on the invasion spread of endophyte‐symbiotic forage plants in natural grasslands.