bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonality and pathogen transmission in pastoral cattle contact networks
Authors: VanderWaal Kimberly , Gilbertson Marie , Okanga Sharon , Allan Brian F. , Craft Meggan E.
Published: December 2017

Capturing heterogeneity in contact patterns in animal populations is essential for understanding the spread of infectious diseases. In contrast to other regions of the world in which livestock movement networks are integral to pathogen prevention and control policies, contact networks are understudied in pastoral regions of Africa due to the challenge of measuring contact among mobile herds of cattle whose movements are driven by access to resources. Furthermore, the extent to which seasonal changes in the distribution of water and resources impacts the structure of contact networks in cattle is uncertain. Contact networks may be more conducive to pathogen spread in the dry season due to congregation at limited water sources. Alternatively, less abundant forage may result in decreased pathogen transmission due to competitive avoidance among herds, as measured by reduced contact rates. Here, we use GPS technology to concurrently track 49 free-roaming cattle herds within a semi-arid region of Kenya, and use these data to characterize seasonal contact networks and model the spread of a highly infectious pathogen. This work provides the first empirical data on the local contact network structure of mobile herds based on quantifiable contact events. The contact network demonstrated high levels of interconnectivity. An increase in contacts near to water resources in the dry season resulted in networks with both higher contact rates and higher potential for pathogen spread than in the wet season. Simulated disease outbreaks were also larger in the dry season. Results support the hypothesis that limited water resources enhance connectivity and transmission within contact networks, as opposed to reducing connectivity as a result of competitive avoidance. These results cast light on the impact of seasonal heterogeneity in resource availability on predicting pathogen transmission dynamics, which has implications for other free-ranging wild and domestic populations.
The adsorption features between insecticidal crystal protein and nano-Mg(OH)
2
Authors: Pan Xiaohong , Xu Zhangyan , Zheng Yilin , Huang Tengzhou , Li Lan , Chen Zhi , Rao Wenhua , Chen Saili , Hong Xianxian , Guan Xiong
Published: December 2017

Nano-Mg(OH)
2
, with low biological toxicity, is an ideal nano-carrier for insecticidal protein to improve the bioactivity. In this work, the adsorption features of insecticidal protein by nano-Mg(OH)
2
have been studied. The adsorption capacity could reach as high as 136 mg g
−1
, and the adsorption isotherm had been fitted with Langmuir and Freundlich models. Moreover, the adsorption kinetics followed a pseudo-first or -second order rate model, and the adsorption was spontaneous and an exothermic process. However, high temperatures are not suitable for adsorption, which implies that the temperature would be a critical factor during the adsorption process. In addition, FT-IR confirmed that the protein was adsorbed on the nano-Mg(OH)
2
, zeta potential analysis suggested that insecticidal protein was loaded onto the nano-Mg(OH)
2
not by electrostatic adsorption but maybe by intermolecular forces, and circular dichroism spectroscopy of Cry11Aa protein before and after loading with nano-Mg(OH)
2
was changed. The study applied the adsorption information between Cry11Aa and nano-Mg(OH)
2
, which would be useful in the practical application of nano-Mg(OH)
2
as a nano-carrier.
Complex interplay of interatomic bonding in a multi-component pyrophosphate crystal: K2Mg (H2P2O7)2·2H2O
Authors: Adhikari Puja , Khaoulaf Redouane , Ez-Zahraouy Hamid , Ching Wai-Yim
Published: December 2017

The electronic structure and interatomic bonding of pyrophosphate crystal K2Mg (H2P2O7)2·2H2O are investigated for the first time showing complex interplay of different types of bindings. The existing structure from single-crystal X-ray diffraction is not sufficiently refined, resulting in unrealistic short O─H bonds which is rectified by high-precision density functional theory (DFT) calculation. K2Mg (H2P2O7)2·2H2O has a direct gap of 5.22 eV and a small electron effective mass of 0.14me. Detailed bond analysis between every pair of atoms reveals the complexity of various covalent, ionic, hydrogen bonding and bridging bonding and their sensitive dependence on structural differences. The K--O bonds are much weaker than Mg--O bonds and contributions from the hydrogen bonds are non-negligible. Quantitative analysis of internal cohesion in terms of total bond order density and partial bond order density divulges the relative importance of different types of bonding. The calculated optical absorptions show multiple peaks and a sharp Plasmon peak at 23 eV and a refractive index of 1.44. The elastic and mechanical properties show features unique to this low-symmetry crystal. Phonon calculation gives vibrational frequencies in agreement with reported Raman spectrum. These results provide new insights indicating that acidic pyrophosphates could have a variety of unrealized applications in advanced technology.
Investigating the geometrical preferences of a flexible benzimidazolone-based linker in the synthesis of coordination polymers
Authors: Jones Corey L. , Marsden Elizabeth A. , Nevin Adam C. , Kariuki Benson M. , Bhadbhade Mohan M. , Martin Adam D. , Easun Timothy L.
Published: December 2017

A series of new group 2 coordination polymers,
MgL
 ={MgL(H
2
O)(DMF)
0.75
}
∞
,
CaL
 = {CaL(DMF)
2
}
∞
,
SrL
 = {SrL(H
2
O)
0.5
}
∞
and
BaL
 = {BaL(H
2
O)
0.5
}
∞
, were synthesized using a flexible benzimidazolone diacetic acid linker (
H
2
L
) in which the two carboxylic acid binding sites are connected to a planar core via {–CH
2
–} spacers that can freely rotate in solution. In a ‘curiosity-led' diversion from group 2 metals, the first row transition metal salts Mn
2+
, Cu
2+
and Zn
2+
were also reacted with
L
to yield crystals of
MnL =
{MnL(DMF)(H
2
O)
3.33
}
∞
,

Cu
3
L
2

 = {Cu
3
L
2
(DMF)
2
(CHO
2
)
2
}
∞
and
ZnL
 = {ZnL(DMF)}
∞
. Crystal structures were obtained for all seven materials. All structures form as two-dimensional sheets and contain six-coordinate centres, with the exception of
ZnL,
which displays tetrahedrally coordinated metal centres, and

Cu
3
L
2

, which contains square planar coordinated metal centres and Cu paddle-wheels. In each structure, the linker adopts one of two distinct conformations, with the carboxylate groups either
cis
or
trans
with respect to the planar core. All materials were also characterized by powder X-ray diffraction and thermogravimetric analysis.
Effect of vitamin D supplementation on biomarkers of inflammation and immune function: functional genomics analysis of the BEST-D trial
Authors: Berlanga-Taylor Antonio J. , Plant Katherine , Dahl Andrew , Lau Evelyn , Hill Michael , Sims David , Heger Andreas , Emberson Jonathan , Armitage Jane , Clarke Robert , Knight Julian C.
Published: December 2017

Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomised trials may afford an opportunity to systematically assess molecular responses to treatments. In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D34000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline, and transcriptome and plasma levels of cytokines (IFN-γ, IL-10, IL-8, IL-6 and TNF-α) at baseline and after 12 months, were measured. The trial had >90% power to detect a 2-fold change in gene expression. Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D), but had no significant effect on whole-blood gene expression (FDR <5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose but not on the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose), but had no significant effect on cis-eQTLs specific to vitamin D supplementation. The trial demonstrates the feasibility of application of functional genomics approaches in randomised trials to assess the effects of vitamin D on immune function.

One sentence summary

Supplementation with high-dose vitamin D in older people for 12 months in a randomised, placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of cytokines.

Trial registration

SRCTN registry (Number 07034656) and the European Clinical Trials Database (EudraCT Number 2011-005763-24).

Funding

Medical Research Council, British Heart Foundation, Wellcome Trust, European Research Council and Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom

Copyright

Open access article under the terms of CC BY.
K-nearest neighbor smoothing for high-throughput single-cell RNA-Seq data
Authors: Wagner Florian , Yan Yun , Yanai Itai
Published: December 2017

High-throughput single-cell RNA-Seq (scRNA-Seq) is a powerful approach for studying heterogeneous tissues and dynamic cellular processes. However, compared to bulk RNA-Seq, single-cell expression profiles are extremely noisy, as they only capture a fraction of the transcripts present in the cell. Here, we propose the k-nearest neighbor smoothing (kNN-smoothing) algorithm, designed to reduce noise by aggregating information from similar cells (neighbors) in a computationally efficient and statistically tractable manner. The algorithm is based on the observation that across protocols, the technical noise exhibited by UMI-filtered scRNA-Seq data closely follows Poisson statistics. Smoothing is performed by first identifying the nearest neighbors of each cell in a step-wise fashion, based on partially smoothed and variance-stabilized expression profiles, and then aggregating their transcript counts. We show that kNN-smoothing greatly improves the detection of clusters of cells and co-expressed genes, and clearly outperforms other smoothing methods on simulated data. To accurately perform smoothing for datasets containing highly similar cell populations, we propose the kNN-smoothing 2 algorithm, in which neighbors are determined after projecting the partially smoothed data onto the first few principal components. We show that unlike its predecessor, kNN-smoothing 2 can accurately distinguish between cells from different T cell subsets, and enables their identification in peripheral blood using unsupervised methods. Our work facilitates the analysis of scRNA-Seq data across a broad range of applications, including the identification of cell populations in heterogeneous tissues and the characterization of dynamic processes such as cellular differentiation. Reference implementations of our algorithms can be found at https://github.com/yanailab/knn-smoothing.
Stability in the genetic structure of a Zymoseptoria tritici population from epidemic to interepidemic stages at a small spatial scale
Authors: Morais D. , Duplaix C. , Sache I. , Laval V. , Suffert F. , Walker A-S.
Published: December 2017

Subpopulations of the wheat pathogen Zymoseptoria tritici (26 sample groups composed of 794 strains) were collected in two nearby wheat fields in the Paris basin, during both epidemic and inter-epidemic periods of three successive years (2009-2013). In addition to the type of inoculum (ascospores vs. pycnidiospores), the alternative presence of wheat debris allowed taking into account its putative origin (local vs. distant). We used a molecular epidemiology approach, based on population genetic indices derived from SSR marker analysis, to describe putative changes in the structure and genotypic diversity of these subpopulations over three years, at a spatiotemporal scale consistent with epidemiological observations. Genetic structure was stable over time (within and between years) and between fields. All subpopulations displayed very high levels of gene and genotypic diversity. The low levels of linkage disequilibrium and the very low clonal fraction at all stages were consistent with the regular occurrence of sexual reproduction in the two fields. A significant increase of the MAT1-1/MAT1-2 ratio was observed over the course of the epidemics, suggesting a competitive advantage of MAT1-1 strains consistently with their greater pathogenicity reported in the literature. Finally, we found that the period, the type of inoculum and its putative origin had little effect on the short term evolution of the local population of Z. tritici. Fungal population size and diversity are apparently large enough to prevent genetic drift at this fine spatiotemporal scale, and more likely short distance migration contributes strongly to the stabilization of genetic diversity among and within plots.
Testing the parasite mass burden effect on host behaviour alteration in the Schistocephalus-stickleback system
Authors: Grécias Lucie , Valentin Julie , Aubin-Horth Nadia
Published: December 2017

Many parasites with complex life cycles modify their intermediate host’s behaviour, which has been proposed to increase transmission to their definitive host. This behavioural change could result from the parasite actively manipulating its host, but could also be explained by a mechanical effect, where the parasite’s physical presence affects host behaviour. We created an artificial internal parasite using silicone injections in the body cavity to test this mechanical effect hypothesis. We used the Schistocephalus solidus - threespine stickleback (Gasterosteus aculeatus) system, as this cestode can reach up to 92% of its fish host mass. Our results suggest that the mass burden brought by this macroparasite alone is not sufficient to cause behavioural changes in its host. Furthermore, our results show that wall-hugging (thigmotaxis), a measure of anxiety in vertebrates, is significantly reduced in Schistocephalus-infected sticklebacks, unveiling a new altered component of behaviour that may result from manipulation by this macroparasite.
Predictability and persistence of prebiotic dietary supplementation in a healthy human cohort
Authors: Gurry Thomas ,   HST Microbiome Consortium, Gibbons Sean M , Nguyen Le Thanh Tu , Kearney Sean M , Ananthakrishnan Ashwin , Jiang Xiaofang , Kassam Zain , Alm Eric J
Published: December 2017

Dietary interventions to manipulate the human gut microbiome for improved health have received increasing attention. However, their design has been limited by a lack of understanding of the quantitative impact of diet on a host’s microbiota. We present a highly controlled diet perturbation experiment in a healthy, human cohort in which individual micronutrients are spiked in against a standardized background. We identify strong and predictable responses of specific microbes across participants consuming prebiotic spike-ins, at the level of both strains and functional genes, suggesting fine-scale resource partitioning in the human gut. No predictable responses to non-prebiotic micronutrients were found. Surprisingly, we did not observe decreases in day-to-day variability of the microbiota compared to a complex, varying diet, and instead found evidence of diet-induced stress and an associated loss of biodiversity. Our data offer insights into the effect of a low complexity diet on the gut microbiome, and suggest that effective personalized dietary interventions will rely on functional, strain-level characterization of a patient’s microbiota.
Abundance of Enterovirus C in RD-L20B cell culture negative stool samples from Acute Flaccid Paralysis cases in Nigeria is geographically defined
Authors: Donbraye E , Olasunkanmi O.I. , Opabode B.A. , Ishola T.R. , Faleye T.O.C. , Adewumi M.O. , Adeniji J.A.
Published: December 2017

We recently showed that Enteroviruses (EVs); majorly species Cs (EV-Cs) were present in about 46.7% of faecal samples from children <15 years old diagnosed with Acute Flaccid Paralysis (AFP) in Nigeria but declared to be EV free by the RD-L20B cell culture based algorithm. In this study, we investigated whether this observed preponderance of EVs (and EV-Cs) in such samples vary by geographical region.

In all, 108 samples (i.e. 54 paired stool suspensions from 54 AFP cases) previously confirmed negative for EVs by the WHO recommended RD-L20B cell culture based algorithm were analyzed in this study. The 108 samples were made into 54 pools (27 each from Northwest [NW] and Southsouth [SS] Nigeria). All samples were subjected to RNA extraction, cDNA synthesis and the WHO recommended seminestedPCR (snPCR) assay and its modifications. All amplicons were sequenced, and enteroviruses identified using the enterovirus genotyping tool and phylogenetic analysis.

Altogether, EVs were detected in 16 (29.63%) of the 54 samples screened but successfully identified in 14 (25.93%): 10 from NW- and 4 from SS-Nigeria. Precisely, one (7.14%), two (14.29%) and 11 (78.57%) of the strains detected were EV-A, EV-B and EV-C respectively. The 10 strains from NW-Nigeria are 7 EV types and include CV-A10, E29, CV-A13, CV-A17, CV-A19, CV-A24 and EV-C99. The four EV types recovered from SS-Nigeria include E31, CV-A1, EV-C99 and EV-C116. EV-C99 is the only EV type that was detected in both NW- and SS-Nigeria.

The results of this study showed that the preponderance of EVs and consequently EV-Cs in AFP samples declared to be EV free by the RD-L20B cell culture based algorithm vary by geographical region in Nigeria. It further confirmed the EV-B bias of the RD-L20B cell culture based algorithm.
Fe2+/H2O2-mediated oxidation of homogentisic acid indicates the production of ochronotic and non-ochronotic pigments. Implications in Alkaptonuria and beyond
Authors: Vercruysse Koen P. , Taylor Adam M. , Knight Juan
Published: December 2017

Homogentisic acid (HGA) can be oxidized by a combination of Fe2+and H2O2into a darkly colored high molecular mass pigment. Increasing the concentration of H2O2can lead to the formation of a high molecular mass material that exhibits less absorbance in the visible range of the electromagnetic spectrum, while maintaining a strong absorbance in the UV range of the electromagnetic spectrum. FT-IR spectroscopy did indicate the presence of a chemical feature in the pigments generated through H2O2-mediated oxidation that is absent in pigments generated through air-mediated oxidation. Our observations could have implications in the pathophysiology of alkaptonuria. In alkaptonuria, patients suffer from homogentisic aciduria from birth, but develop ochronosis (darkening) of collagenous tissues much later in life due to the formation of a melanin-like pigment. Three major questions regarding ochronosis remain to be answered: 1) how is the pigment formed, 2) why does it appear by the third decade of life and 3) why is it sporadic in appearance? Our results suggest that ochronotic or non-ochronotic pigments can be generated from HGA depending on the oxidation reaction conditions. Thus, the absence of any visible pigment, as for younger alkaptonuria patients, could not necessarily mean the absence of HGA-derived melanin-like molecules. We compare our results and their potential implications for ochronosis to the changes in pigmentation observed in vitiligo or aging (greying) hair.
Trends in Escherichia coli bloodstream infection, urinary tract infections and antibiotic susceptibilities in Oxfordshire, 1998-2016: an observational study
Authors: Vihta Karina-Doris , Stoesser Nicole , Llewelyn Martin J , Quan Phuong T , Davies Timothy , Fawcett Nicola , Dunn Laura , Jeffery Katie , Butler Christopher , Hayward Gail , Andersson Monique , Morgan Marcus , Oakley Sarah , Mason Amy , Wyllie David H , Crook Derrick , Wilcox Mark , Johnson Alan P , Peto Tim , Walker Sarah A
Published: December 2017

Background:
The incidence of Escherichia coli bloodstream infections (EC-BSIs), particularly those caused by antibiotic-resistant strains, is increasing in the UK and internationally. This is a major public health concern but the evidence base to guide interventions is limited.

Methods:
Incidence of EC-BSIs and E. coli urinary tract infections (EC-UTIs) in one UK region (Oxfordshire) were estimated from anonymised linked microbiological and hospital electronic health records, and modelled using negative binomial regression based on microbiological, clinical and healthcare exposure risk factors. Infection severity, 30-day all-cause mortality, and community and hospital co-amoxiclav use were also investigated.

Findings:
From 1998-2016, 5706 EC-BSIs occurred in 5215 patients, and 228376 EC-UTIs in 137075 patients. 1365(24%) EC-BSIs were nosocomial (onset >48h post-admission), 1863(33%) were community (>365 days post-discharge), 1346(24%) were quasi-community (31-365 days post-discharge), and 1132(20%) were quasi-nosocomial (<=30 days post-discharge). 1413(20%) EC-BSIs and 36270(13%) EC-UTIs were co-amoxiclav-resistant (41% and 30%, respectively, in 2016). Increases in EC-BSIs were driven by increases in community (10%/year (95% CI:7%-13%)) and quasi-community (8%/year (95% CI:7%-10%)) cases. Changes in EC-BSI-associated 30-day mortality were at most modest (p>0.03), and mortality was substantial (14-25% across groups). By contrast, co-amoxiclav-resistant EC-BSIs increased in all groups (by 11%-19%/year, significantly faster than susceptible EC-BSIs, pheterogeneity<0.001), as did co-amoxiclav-resistant EC-UTIs (by 13%-29%/year, pheterogeneity<0.001). Co-amoxiclav use in primary-care facilities was associated with subsequent co-amoxiclav-resistant EC-UTIs (p=0.03) and all EC-UTIs (p=0.002).

Interpretation:
Current increases in EC-BSIs in Oxfordshire are primarily community-associated, with high rates of co-amoxiclav resistance, nevertheless not impacting mortality. Interventions should target primary-care facilities with high co-amoxiclav usage.

Funding:
National Institute for Health Research.
High Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance
Authors: Vanoye Carlos G. , Desai Reshma R. , Fabre Katarina L. , Potet Franck , DeKeyser Jean-Marc , Macaya Daniela , Meiler Jens , Sanders Charles R. , George Alfred L.
Published: December 2017

Background

The explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that impact diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels, such as congenital long-QT syndrome (LQTS), in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost-, time- and labor-intensive.

Methods and Results

We implemented a strategy for performing high throughput, functional evaluations of ion channel variants that repurposed an automated electrophysiology platform developed previously for drug discovery. We demonstrated success of this approach by evaluating 78 variants in KCNQ1, a major LQTS gene. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. Our results provided functional data useful for classifying ~70% of previously unstudied KCNQ1 variants annotated with uninformative descriptions in the public database ClinVar. Further, we show that rare and ultra-rare KCNQ1 variants in the general population exhibit functional properties ranging from normal to severe loss-of-function indicating that allele frequency is not a reliable predictor of channel function.

Conclusions

Our results illustrate an efficient and high throughput paradigm linking genotype to function for a human cardiac channelopathy that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.
Modular assembly of the nucleolar large subunit processome
Authors: Sanghai Zahra Assur , Miller Linamarie , Molloy Kelly R. , Barandun Jonas , Hunziker Mirjam , Chaker-Margot Malik , Wang Junjie , Chait Brian T. , Klinge Sebastian
Published: December 2017

Early co-transcriptional events of eukaryotic ribosome assembly result in the formation of the small and large subunit processomes. We have determined cryo-EM reconstructions of the nucleolar large subunit processome in different conformational states at resolutions up to 3.4 Ångstroms. These structures reveal how steric hindrance and molecular mimicry are used to prevent premature folding states and binding of later factors. This is accomplished by the concerted activity of 21 ribosome assembly factors that stabilize and remodel pre-ribosomal RNA and ribosomal proteins. Mutually exclusive conformations of these particles suggest that the formation of the polypeptide exit tunnel is achieved through different folding pathways during subsequent stages of ribosome assembly.
Mutations in RPL3L and MYZAP increase risk of atrial fibrillation
Authors: Thorolfsdottir Rosa B. , Sveinbjornsson Gardar , Sulem Patrick , Jonsson Stefan , Halldorsson Gisli H. , Melsted Pall , Ivarsdottir Erna V. , Davidsson Olafur B. , Kristjansson Ragnar P. , Thorleifsson Gudmar , Helgadottir Anna , Gretarsdottir Solveig , Norddahl Gudmundur , Rajamani Sridharan , Torfason Bjarni , Valgardsson Atli S. , Sverrisson Jon T. , Tragante Vinicius , Asselbergs Folkert W. , Roden Dan M. , Darbar Dawood , Pedersen Terje R. , Sabatine Marc S. , Løchen Maja-Lisa , Halldorsson Bjarni V. , Jonsdottir Ingileif , Arnar David O. , Thorsteinsdottir Unnur , Gudbjartsson Daniel F. , Holm Hilma , Stefansson Kari
Published: December 2017

We performed a meta-analysis of genome-wide association studies on atrial fibrillation (AF) among 14,710 cases and 373,897 controls from Iceland and 14,792 cases and 393,863 controls from the UK Biobank, focusing on low frequency coding and splice mutations, with follow-up in samples from Norway and the US. We observed associations with two missense (OR=1.19 for both) and one splice-donor mutation (OR=1.52) in RPL3L, encoding a ribosomal protein primarily expressed in skeletal muscle and heart. Analysis of 167 RNA samples from the right atrium revealed that the splice donor mutation in RPL3L results in exon skipping. AF is the first disease associated with RPL3L and RPL3L is the first ribosomal gene implicated in AF. This finding is consistent with tissue specialization of ribosomal function. We also found an association with a missense variant in MYZAP (OR=1.37), encoding a component of the intercalated discs of cardiomyocytes, the organelle harbouring most of the mutated proteins involved in arrhythmogenic right ventricular cardiomyopathy. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
Quantifying antimicrobial access and practices for paediatric diarrheal disease in an urban community setting in Southeast Asia
Authors: Nhi Le Thi Quynh , de Alwis Ruklanthi , Lam Phung Khanh , Hoa Nguyen Nhon , Nhan Nguyen Minh , Oanh Le Thi Tu , Nam Dang Thanh , Han Bui Nguyen Ngoc , Huyen Hoang Thi , Duong Vu Thuy , Vi Lu Lan , Tien Bui Thi Thuy , Tuyet Hoang Thi Diem , Nha Le Hoang , Thwaites Guy , Dung Do Van , Baker Stephen
Published: December 2017

Antimicrobial-resistant infections are increasing across Asia. Aiming to evaluate antimicrobial access and practices in Ho Chi Minh City (HCMC) of Vietnam, we mapped pharmacy locations and used a simulated client method to calculate antimicrobial sales for paediatric diarrheal disease. We additionally evaluated healthcare choices for parents and caregivers when their children experienced diarrhoea. District 8 (population 396,175) of HCMC had 301 pharmacies (one for every 1,316 people), with a density of 15.8 pharmacies/km2. A wide range of different treatments (n=57) were sold for paediatric diarrheal disease, with 8% (3/37) and 22% (8/37) of the sampled pharmacies selling antimicrobials for watery and mucoid diarrhoea, respectively. Despite the apparent abundance of pharmacies, the majority of caregivers chose to take their child to a specialized hospital, with 81% (319/396) and 88% (347/396) of responders selecting this as their first, second, or third choice for watery and mucoid diarrhoea, respectively. Lastly, by combining denominators derived from caregiver interviews and diarrheal incidence figures, we calculated that 16% (2,359/14,427) of watery or mucoid diarrhoea episodes of the District 8 population aged 1 to <5 years would receive an antimicrobial for diarrhoea annually, but antimicrobial prescribing was almost ten times greater in hospitals than in the community. Our novel mixed-methods approach found that, whilst antimicrobials are commonly available for paediatric diarrhoea in the community of HCMC, usage is greater in hospitals. The observed non-standardized approach to diarrheal treatments is indicative of poor recommendations. We advocate better guidelines, training and dissemination of information regarding antimicrobials and their use in this location.
Engineering Human CNS Morphogenesis: Controlled Induction of Singular Neural Rosette Emergence
Authors: Knight Gavin T. , Lundin Brady F. , Iyer Nisha , Ashton Lydia M.T. , Sethares William A. , Willett Rebecca L. , Ashton Randolph S.
Published: December 2017

Human pluripotent stem cell (hPSC)-derived neural organoids have revolutionized in vitro modelling of human neurological disorders. Cell-intrinsic morphogenesis processes displayed within these tissues could serve as the basis for ex vivo manufacture of brain and spinal cord tissues with biomimetic anatomy and physiology. However, we must first understand how to control their emergent properties starting at the genesis of neural organoid formation, i.e. emergence of polarized neuroepithelium. In vivo, all CNS tissues develop from a singular neuroepithelial tube. Yet, current protocols yield organoids with multiple neuroepithelial rings, a.k.a. neural rosettes, each acting as independent centers of morphogenesis and thereby impeding coordinate tissue development. We discovered that the morphology of hPSC-derived neural tissues is a critical biophysical parameter for inducing singular neural rosette emergence. Tissue morphology screens conducted using micropatterned array substrates and an automated image analysis determined that circular morphologies of 200-250 and 150μm diameter are optimal for inducing singular neural rosette emergence within 80-85% forebrain and 73.5% spinal tissues, respectively. The discrepancy in optimal circular morphology for Pax6+/N-cadherin+neuroepithelial forebrain versus spinal tissues was due to previously unknown differences in ROCK-mediated cell contractility. The singular neuroepithelium induced within geometrically confined tissues persisted as the tissues morphed from a 2-D monolayer to multilayered 3-D hemispherical aggregate. Upon confinement release using clickable micropatterned substrates, the tissue displayed radial outgrowth with maintenance of a singular neuroepithelium and peripheral neuronal differentiation. Thus, we have quantitatively defined a pertinent biophysical parameter for effectively inducing a singular neuroepithelium emergence within morphing hPSC-derived neural tissues.

Significance Statement

Human pluripotent stem cell (hPSC)-derived neural organoids display emergent properties that, if harnessed, could serve as the basis for ex vivo manufacture of brain and spinal cord tissues with biomimetic macroscale anatomy and physiology. Their chaotic terminal structure arises from uncontrolled morphogenesis at their genesis, resulting in spontaneous induction of multiple neuroepithelial morphogenesis centers,a.k.a. neural rosettes. Here, we determined that neural tissue morphology is a pertinent biophysical parameter for controlling subsequent morphogenesis, and identified discrete circular tissue morphologies as optimal and effective at inducing singular neural rosette emergence within forebrain and spinal neural tissues. Thus, we developed an approach to reproducibly control the initial stage of hPSC-derived neural tissue morphogenesis enabling their manufacture with a biomimetic nascent CNS anatomy.
Molecular Identification and Characterization of Two Rubber Dandelion Amalgaviruses
Authors: Debat Humberto , Luo Zinan , Iaffaldano Brian J. , Zhuang Xiaofeng , Cornish Katrina
Published: December 2017

The Amalgaviridae family comprise persistent viruses that share the genome architecture of Totiviridae and gene evolutionary resemblance to Partitiviridae. Two genera have been assigned to this family, including genus Amalgavirus consisting in nine recognized species, corresponding to plant infecting viruses with dsRNA monosegmented genomes of ca. 3.4 kb. Here, we present the molecular characterization of two novel viruses detected in rubber dandelion (Taraxacum kok-saghyz). The sequenced viruses are 3,409 and 3,413 nt long, including two partially overlapping ORFs encoding a putative coat protein and an RNA-dependent RNA polymerase (RdRP). Phylogenetic insights based on the RdRP suggest them to be members of two new species within the Amalgavirus genus. Multiple independent RNAseq data suggest that the identified viruses have a dynamic distribution and low relative RNA levels in infected plants. Virus presence was not associated with any apparent symptoms on the plant hosts. We propose the names rubber dandelion latent virus 1 & 2 to the detected amalgaviruses; the first viruses to be associated to this emergent and sustainable natural rubber crop.
Distinct chromatin signatures of DNA hypomethylation in aging and cancer
Authors: F. Pérez Raúl , Tejedor Juan Ramón , F. Bayón Gustavo , F. Fernández Agustín , F. Fraga Mario
Published: December 2017

Background

Cancer is an aging-associated disease but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, any similarities of the regions where this loss of DNA methylation occurs is currently not well characterized, nor is it known whether such regions also share a common chromatin signature in aging and cancer.

Results

To address this issue we analysed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain and lung tumors and healthy blood, and integrated the results with histone, chromatin state and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging, and 286,746 in cancer. Hyper- and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue-independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, whilst in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark.

Conclusions

Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.
Barley Long Non-Coding RNAs and Their Tissue-Specific Co-expression Pattern with Coding-Transcripts
Authors: Karakülah Gökhan , Unver Turgay
Published: December 2017

Long non-coding RNAs (lncRNA) with non-protein or small peptide-coding potential transcripts are emerging regulatory molecules. With the advent of next-generation sequencing technologies and novel bioinformatics tools, a tremendous number of lncRNAs has been identified in several plant species. Recent reports demonstrated roles of plant lncRNAs such as development and environmental response. Here, we reported a genome-wide discovery of ~8,000 barley lncRNAs and measured their expression pattern upon excessive boron (B) treatment. According to the tissue-based comparison, leaves have a greater number of B-responsive differentially expressed lncRNAs than the root. Functional annotation of the coding transcripts, which were co-expressed with lncRNAs, revealed that molecular function of the ion transport, establishment of localization, and response to stimulus significantly enriched only in the leaf. On the other hand, 32 barley endogenous target mimics (eTM) as lncRNAs, which potentially decoy the transcriptional suppression activity of 18 miRNAs, were obtained. Presented data including identification, expression measurement, and functional characterization of barley lncRNAs suggest that B-stress response might also be regulated by lncRNA expression via cooperative interaction of miRNA-eTM-coding target transcript modules.
Brain networks, dimensionality, and global signal averaging in resting-state fMRI: Hierarchical network structure results in low-dimensional spatiotemporal dynamics
Authors: Gotts Stephen J , Gilmore Adrian W. , Martin Alex
Published: December 2017

One of the most controversial practices in resting-state fMRI functional connectivity studies is whether or not to regress out the global average brain signal (GS) during artifact removal. Some groups have argued that it is absolutely essential to regress out the GS in order to fully remove head motion, respiration, and other global imaging artifacts. Others have argued that removing the GS distorts the resulting correlation matrices, qualitatively alters the results of group comparisons, and impairs relationships to behavior. At the core of this argument is the assessment of dimensionality in terms of the number of brain networks with uncorrelated time series. If the dimensionality is high, then the distortions due to GS removal could be effectively negligible. In the current paper, we examine the dimensionality of resting-state fMRI data using principal component analyses (PCA) and network clustering analyses. In two independent datasets (Set 1: N=62, Set 2: N=32), scree plots of the eigenvalues level off at or prior to 10 principal components, with prominent elbows at 3 and 7 components. While network clustering analyses have previously demonstrated that numerous networks can be distinguished with high thresholding of the voxel-wise correlation matrices, lower thresholding reveals a lower-dimensional hierarchical structure, with the first prominent branch at 2 networks (corresponding to the previously described “task-positive”/“task-negative” distinction) and further stable subdivisions at 4, 7 and 17. Since inter-correlated time series within these larger branches do not cancel to zero when averaged, the hierarchical nature of the correlation structure results in much lower effective dimensionality. Consistent with this, partial correlation analyses revealed that network-specific variance remains present in the GS at each level of the hierarchy, accounting for at least 18-20% of the overall GS variance in each dataset. These results demonstrate that GS regression is expected to remove substantial portions of neurogenic brain signals along with artifacts. We highlight alternative means of controlling for residual global artifacts when not removing the GS.
Multi-SKAT: General framework to test multiple phenotype associations of rare variants
Authors: Dutta Diptavo , Scott Laura , Boehnke Michael , Lee Seunggeun
Published: December 2017

In genetic association analysis, a joint test of multiple distinct phenotypes can increase power to identify sets of trait-associated variants within genes or regions of interest. Existing multi-phenotype tests for rare variants make specific assumptions about the patterns of association of underlying causal variants, and the violation of these assumptions can reduce power to detect association. Here we develop a general framework for testing pleiotropic effects of rare variants based on multivariate kernel regression (Multi-SKAT). Multi-SKAT models effect sizes of variants on the phenotypes through a kernel matrix and performs a variance component test of association. We show that many existing tests are equivalent to specific choices of kernel matrices with the Multi-SKAT framework. To increase power to detect association across tests with different kernel matrices, we developed a fast and accurate approximation of the significance of the minimum observed p-value across tests. To account for related individuals, our framework uses a random effects for the kinship matrix. Using simulated data and amino acid and exome-array data from the METSIM study, we show that Multi-SKAT can improve power over single-phenotype SKAT-O test and existing multiple phenotype tests, while maintaining type I error rate.
Harnessing informal education for community resilience
Authors: Feng Shihui , Hossain Liaquat , Paton Douglas
Published: December 2017

Purpose

Disaster education is considered as a newly emerging area of research and practice, which promotes community-based educational approaches for building resilience. Given the atypical nature of these disturbances, people and communities need to develop the knowledge required to anticipate and understand what they could have to contend with and proactively develop strategies that can minimize their risk and afford ways to cope with and adapt to adverse situations in an effective manner. The purpose of this paper is to suggest that informal education resulting from daily activities related to work, family life, or leisure can be harnessed to develop disaster resilience within community settings.

Design/methodology/approach

This conceptual paper provides the discussion and synthesis of literature covering community resilience, disaster risk reduction (DRR) and informal education. In doing so, this study proposes a conceptual framework and implementation strategies for harnessing informal education in building community resilience.

Findings

To harness informal disaster education for community resilience, the authors suggest a conceptual framework and four implementation strategies with the corresponding implications: cultivate social environment for conversations, discussions, reflections and learning; design social activities for promoting and encouraging informal learning; appropriate interventions by informal educators in social activities; and transparent resources and channels for information and social supports. A compilation of a number of community-based DRR practices involving civil society organizations has been incorporated in the proposed framework for exemplifying informal disaster education for community resilience.

Originality/value

Promoting informal education in community settings is aimed at building community resilience in a collective way, which is especially important in disaster-prone areas. Informal education for community resilience not only educates individuals how to deal with disasters, but also connects individuals together to be more resilient in their ability to cope or bounce back from adverse events in their life.
University context matter
Authors: Oftedal Elin Merethe , Iakovleva Tatiana A. , Foss Lene
Published: December 2017

Purpose

How university context (UC) enhances students’ entrepreneurial intentions and opportunity recognition is an emerging topic. It is known that students learn, not only from educational programmes, but also from the context in which they are embedded. The purpose of this paper is to investigate the effect of such context on student’s entrepreneurial intentions and opportunity recognition.

Design/methodology/approach

The authors use a three-dimensional institutional framework to describe UC including regulative, normative and cognitive structures. Regulative structures refer to rules and regulations, support initiatives in relation to entrepreneurship; normative structures include shared values and norms; while cognitive structures apply to knowledge among students and faculty. A heterogeneous sample of 196 respondents from five countries was used to create reliable measures of UC and to test the hypotheses with the help of regression analysis.

Findings

The findings indicate that two dimensions of UC in particular (regulative and normative) were shown to be of great importance in increasing entrepreneurial intentions and opportunity recognition among students.

Originality/value

The study contributes to this further by suggesting a reliable and theory-grounded scale of UC. Furthermore, this study adds to the discussion on entrepreneurship education by proving evidence of the importance of UC on entrepreneurial intentions. The important contribution is acknowledgement of the fact that social systems both constrain and enable entrepreneurs in their discovery, evaluation and exploitation of opportunities. The authors have established that “would-be student entrepreneurs” do not exist separately from their structural context. Attempts to understand them outside of this context cannot, therefore, fully capture their nature.
“Yes, sir”: Leadership and blind obedience in hierarchal organisations
Authors: Drummond-Smith Ian
Published: December 2017

Purpose

The purpose of this paper is to explore human issues within subordinate and leader interaction and guide police leaders in how they can achieve success. Although focussed on uniformed services, leaders from all areas will find the arguments presented here useful.

Design/methodology/approach

The paper draws on a number of catastrophic case studies, including the collision of two war ships, two Jumbo Jets, the defeat of the Spanish Armarda and the failure of Hitler’s military to respond effectively to the D-Day landings. It will examine work by Rittel and Webber (1973) and Grint (2005), who propose different styles of leadership for different problems.

Findings

The paper will find that humans are inherently obedient and reluctant obedient, reluctant to challenge authority and introduces the concept of blind obedience into police leadership. A distinction will be drawn between commanding in critical situations, which are rare, and leading in routine situations; the paper will conclude that to lead the police service through the turbulent times ahead, police leaders must be on guard against blind obedience and create an environment where subordinates have a voice and will be heard. The paper also finds that “micro-management” from a remote location is ineffective and that staff must be afforded time and space to undertake tasks and that strategic leaders must allow their subordinates, at the tactical and operational levels, freedom to act with the overall strategy; the paper recommends leaders adopt a mission command approach.

Originality/value

The paper will contribute to understanding how subordinates and leaders interact and will be of value to all who lead, particularly in structured organisations like the police, where rank plays a factor in establishing a strict hierarchy. It introduces the concept of blind obedience into police leadership and warns that police leaders, and indeed leaders in all hierarchal organisations, must be on constant guard against it.