bluuebunny/crossref_metadata_2025 huggingface dataset:
The frailty index is a predictor of cause-specific mortality independent of familial effects from midlife onwards
Authors: Li Xia , Ploner Alexander , Karlsson Ida K , Liu Xingrong , Magnusson Patrik KE , Pedersen Nancy L , Hägg Sara , Jylhävä Juulia
Published: December 2018

Background

Frailty index (FI) is a well-established predictor of all-cause mortality, but less is known for cause-specific mortality and whether familial effects influence the associations. Furthermore, the population mortality impact of frailty remains understudied.

Objectives

To estimate the predictive value of frailty for all-cause and cause-specific mortality, and to test whether the associations are time-dependent. We also assessed the proportion of deaths that are attributable to increased levels of frailty.

Methods

We analyzed 42,953 participants from the Screening Across the Lifespan Twin Study (aged 41-95 years at baseline) with up to 20-years’ mortality follow-up. The FI was constructed using 44 health-related items. Deaths due to cardiovascular disease (CVD), respiratory-related causes and cancer were considered in the cause-specific analysis. Generalized survival models were used in the analysis.

Results

Increased FI was associated with higher risks of all-cause, CVD, and respiratory-related mortality. No significant associations were observed for cancer mortality. No attenuation of the mortality associations was found in unrelated individuals when adjusting for familial effects in twin pairs. The associations were time-dependent with relatively greater effects observed in younger ages. The proportion of deaths attributable to FI levels >0.10 were 13.0% of all-cause deaths, 14.7% of CVD deaths and 12.5% of respiratory-related deaths in men, and 12.2% of all-cause deaths, 9.9% of CVD deaths and 21.9% of respiratory-related deaths in women.

Conclusions

Increased FI predicts higher risks of all-cause, CVD, and respiratory-related mortality independent of familial effects. Increased FI levels have a significant population mortality impact in both men and women.
CRK2 enhances salt tolerance in Arabidopsis thaliana by regulating endocytosis and callose deposition in connection with PLDα1
Authors: Hunter Kerri , Kimura Sachie , Rokka Anne , Tran Cuong , Toyota Masatsugu , Kukkonen Jyrki P. , Wrzaczek Michael
Published: December 2018

High salinity has become an increasingly prevalent source of stress to which plants need to adapt. The receptor-like protein kinases (RLKs), including the cysteine-rich receptor-like kinase (CRK) subfamily, are a highly expanded family of transmembrane proteins in plants and are largely responsible for communication between cells and the extracellular environment. Various CRKs have been implicated in biotic and abiotic stress responses, however their functions on a cellular level remain largely uncharacterized. Here we have shown that CRK2 enhances salt tolerance at the germination stage in Arabidopsis thaliana. We identified CRK2 as a negative regulator of endocytosis, under both normal growth conditions and salt stress. We also established that functional CRK2 is required for salt-induced callose deposition. In doing so, we revealed a novel role for callose deposition, in response to increased salinity, and demonstrated its importance for salt tolerance during germination. Using fluorescently tagged proteins we observed specific changes in CRK2’s subcellular localization in response to various stress treatments. Many of CRK2’s cellular functions were dependent on phospholipase D (PLD) activity, as were the subcellular localization changes. Thus we propose that CRK2 acts downstream of PLD during salt stress to regulate endocytosis and promote callose deposition, and that CRK2 adopts specific stress-dependent subcellular localization patterns in order to carry out its functions.

One sentence summary

The receptor-like kinase CRK2 acts in connection with PLDα1 to regulate endocytosis and callose deposition at plasmodesmata, enhancing salt tolerance in Arabidopsis thaliana.
Intake of dietary fiber, fruits, and vegetables, and risk of diverticulitis
Authors: Ma Wenjie , Nguyen Long H. , Song Mingyang , Jovani Manol , Liu Po-Hong , Cao Yin , Tam Idy , Wu Kana , Giovannucci Edward L. , Strate Lisa L. , Chan Andrew T.
Published: December 2018

Background & Aims

Although low fiber intake has been considered a risk factor for diverticulitis, prospective evidence is limited and conflicting, with little known about variation in the protective effects according to food sources. We assessed the associations of intakes of fiber and major food sources of fiber including fruits and vegetables with risk of diverticulitis.

Methods

We followed 50,019 women in the Nurses’ Health Study (1990-2014) and 48,292 men in the Health Professionals Follow-up Study (1986-2014) who were free of diverticulitis, cancer, and inflammatory bowel disease at baseline. Incident diverticulitis was identified through self-report with validity confirmed by review of medical records.

Results

During a mean follow-up time of 22 years, we documented 4,343 incident cases of diverticulitis in women and 1,142 cases in men. Compared to participants in the lowest quintile, the multivariable HRs (95% CIs) of diverticulitis in the highest quintile of total fiber intake were 0.86 (0.78-0.95;P-trend=0.002) among women and 0.63 (0.51-0.79;P-trend<0.001) among men. Fiber from different food sources, except for vegetable fiber in women, was associated with a decreased risk of diverticulitis. Furthermore, total whole fruit intake was associated with reduced risk of diverticulitis in both cohorts with a multivariable HR for diverticulitis of 0.95 (0.92-0.98;P-trend<0.001) in women and 0.91 (0.86-0.96;P-trend<0.001) in men for every serving increase of total whole fruit intake per day.

Conclusions

Higher intake of dietary fiber and fiber from different food sources are associated with a lower risk of diverticulitis. A greater intake of whole fruit is also associated with reduced risk.
CCN4 shifts melanoma cells from a fragile proliferative state to a resilient metastatic state
Authors: Deng Wentao , Fernandez Audry , McLaughlin Sarah L. , Klinke David J.
Published: December 2018

While deregulated intracellular signaling initiates melanoma, intercellular crosstalk within the tumor microenvironment, often coordinated by soluble factors, is essential for melanoma progression and metastasis. One such secreted matricellular protein, cellular communication network factor 4 (CCN4), stimulates metastasis in other malignancies. Here, we report that CCN4 expression is associated progressively with reduced overall survival in patients with primary melanomas. To reveal the roles of CCN4 in melanoma progression, we used mouse melanoma models and knocked outCcn4using a homology-directed repair CRISPR/CAS9 system to generate pools ofCcn4-knockout cells.In vitroassays supported previous findings using clones generated using a double nickase-based CRISPR/CAS9 system that CCN4 promoted an epithelial – mesenchymal-like transition in melanoma cells and stimulated invasion and metastasis. We also found that, whileCcn4knockout enhanced cell growth in optimal 2D culture conditions, the knockout suppressed certain cell survival signaling pathways and rendered cells less resistant to stress conditions. Tumor cell growth assays at sub-optimal conditionsin vitro, quantitative analysis of tumor growth assaysin vivo,and transcriptomics analysis of human melanoma cell lines suggested that CCN4 repressed cell growth and simultaneously enhanced cell survival. The collective role of CCN4 suggests a potential therapeutic target for limiting metastatic invasion in melanoma and a biomarker for metastatic potential.
The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility
Authors: Ma Yiqin , McKay Daniel J , Buttitta Laura
Published: December 2018

During terminal differentiation most cells will exit the cell cycle and enter into a prolonged or permanent G0. Cell cycle exit is usually initiated through the repression of cell cycle gene expression by formation of a transcriptional repressor complex called DREAM. However when DREAM repressive function is compromised during terminal differentiation, additional unknown mechanisms act to stably repress cycling and ensure robust cell cycle exit. Here we provide evidence that developmentally programmed, temporal changes in chromatin accessibility at a subset of critical cell cycle genes acts to enforce cell cycle exit during terminal differentiation in the Drosophila melanogaster wing. We show that during terminal differentiation, chromatin closes at a set of pupal wing enhancers for the key rate-limiting cell cycle regulators cycE, e2f1 and stg. This closing coincides with wing cells entering a robust postmitotic state that is strongly refractory to cell cycle re-activation. When cell cycle exit is genetically disrupted, chromatin accessibility at cell cycle genes remains largely unaffected and the closing of enhancers at cycE, e2f1 and stg proceeds independent of the cell cycling status. Instead, disruption of cell cycle exit leads to changes in accessibility and expression of a subset of hormone-induced transcription factors involved in the progression of terminal differentiation. Our results uncover a mechanism that acts as a cell cycle-independent timer to limit aberrant cycling in terminally differentiating tissues. In addition, we provide a new molecular description of the cross-talk between cell cycle exit and terminal differentiation during metamorphosis.
Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction
Authors: Tiosano Dov , Feldman Hagit Baris , Chen Anlu , Hitzert Marrit M. , Schueler Markus , Gulluni Federico , Wiesener Antje , Bergua Antonio , Mory Adi , Copeland Brett , Gleeson Joseph G. , Rump Patrick , van Meer Hester , Sival Deborah A. , Haucke Volker , Kriwinsky Josh , Knaup Karl X. , Reis André , Hauer Nadine N. , Hirsch Emilio , Roepman Ronald , Pfundt Rolph , Thiel Christian T. , Wiesener Michael S. , Aslanyan Mariam G. , Buchner David A.
Published: December 2018

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.
The consensus molecular classification of muscle-invasive bladder cancer
Authors: Kamoun Aurélie , de Reyniès Aurélien , Allory Yves , Sjödahl Gottfrid , Robertson A. Gordon , Seiler Roland , Hoadley Katherine A. , Al-Ahmadie Hikmat , Choi Woonyoung , Groeneveld Clarice S. , Castro Mauro A. A. , Fontugne Jacqueline , Eriksson Pontus , Mo Qianxing , Kardos Jordan , Zlotta Alexandre , Hartmann Arndt , Dinney Colin P. , Bellmunt Joaquim , Powles Thomas , Malats Núria , Chan Keith S. , Kim William Y. , McConkey David J. , Black Peter C. , Dyrskjøt Lars , Höglund Mattias , Lerner Seth P. , Real Francisco X. , Radvanyi François ,   The Bladder Cancer Molecular Taxonomy Group
Published: December 2018

Muscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes, which hampers the clinical implications of such knowledge. Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes: Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), Basal/Squamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.
Destabilizing evolutionary and eco-evolutionary feedbacks drive empirical eco-evolutionary cycles
Authors: Cortez Michael H. , Patel Swati , Schreiber Sebastian J.
Published: December 2018

We develop a method to identify how ecological, evolutionary, and eco-evolutionary feedbacks influence system stability. We apply our method to nine empirically-parameterized eco-evolutionary models of exploiter-victim systems from the literature and identify which particular feedbacks cause some systems to converge to a steady state or to exhibit sustained oscillations. We find that ecological feedbacks involving the interactions between all species and evolutionary and eco-evolutionary feedbacks involving only the interactions between exploiter species (predators or pathogens) are typically stabilizing. In contrast, evolutionary and eco-evolutionary feedbacks involving the interactions between victim species (prey or hosts) are destabilizing more often than not. We also find that while eco-evolutionary feedbacks rarely altered system stability from what would be predicted from just ecological and evolutionary feedbacks, eco-evolutionary feedbacks have the potential to alter system stability at faster or slower speeds of evolution. As the number of empirical studies demonstrating eco-evolutionary feedbacks increases, we can continue to apply these methods to determine whether the patterns we observe are common in other empirical communities.
Engineering of chimeric polyketide synthases using SYNZIP docking domains
Authors: Klaus Maja , D’Souza Alicia D. , Nivina Aleksandra , Khosla Chaitan , Grininger Martin
Published: December 2018

Engineering of assembly line polyketide synthases (PKSs) to produce novel bioactive compounds has been a goal for over twenty years. The apparent modularity of PKSs has inspired many engineering attempts in which entire modules or single domains were exchanged. In recent years, it has become evident that certain domain-domain interactions are evolutionarily optimized, and if disrupted, cause a decrease of the overall turnover rate of the chimeric PKS. In this study, we compared different types of chimeric PKSs in order to define the least invasive interface and to expand the toolbox for PKS engineering. We generated bimodular chimeric PKSs in which entire modules were exchanged, while either retaining a covalent linker between heterologous modules or introducing a non-covalent docking domain- or SYNZIP domain-mediated interface. These chimeric systems exhibited non-native domain-domain interactions during intermodular polyketide chain translocation. They were compared to otherwise equivalent bimodular PKSs in which a non-covalent interface was introduced between the condensing and processing parts of a module, resulting in non-native domain interactions during the extender unit acylation and polyketide chain elongation steps of their catalytic cycles. We show that the natural PKS docking domains can be efficiently substituted with SYNZIP domains and that the newly introduced non-covalent interface between the condensing and processing parts of a module can be harnessed for PKS engineering. Additionally, we established SYNZIP domains as a new tool for engineering PKSs by efficiently bridging non-native interfaces without perturbing PKS activity.
Tick-borne pathogen detection in midgut and salivary glands of adult Ixodes ricinus
Authors: Lejal Emilie , Moutailler Sara , Simo Ladislav , Vayssier-Taussat Muriel , Pollet Thomas
Published: December 2018

Background: Tick midgut and salivary glands represent the primary organs for pathogen acquisition and transmission, respectively. Specifically, the midgut is the first organ to have contact with pathogens during the blood meal uptake, while salivary glands along with their secretions play a crucial role in pathogen transmission to the host. Currently there is little data about pathogen composition and prevalences in I. ricinus midgut and salivary glands. The present study investigated the presence of 32 pathogen species in the midgut and salivary glands of unfed I. ricinus males and females using high-throughput microfluidic real-time PCR. Such an approach is important for enriching the knowledge about pathogen distribution in distinct tick organs which should lead to a better understanding I. ricinus-borne disease epidemiology.
Results: Borrelia lusitaniae, Borrelia spielmanii, and Borrelia garinii, were detected in both midgut and salivary glands suggesting that the migration of these pathogens between these two organs might not be triggered by the blood meal. In contrast, Borrelia afzelii was detected only in the tick midgut. Anaplasma phagocytophilum and Rickettsia helvetica were the most frequently detected in ticks and were found in both males and females in the midgut and salivary glands. In contrast, Rickettsia felis was only detected in salivary glands. Finally Borrelia miyamotoi and Babesia venatorum were detected only in males in both midgut and salivary glands. Among all collected ticks, between 10 and 21% of organs were co-infected. The most common bacterial co-infections in male and female midgut and salivary glands was R. helvetica/A. phagocytophilum and R. helvetica/B. lusitaniae respectively.
Conclusions: Analysing tick-borne pathogen (TBP) presence in specific tick organs enabled us to (i) highlight contrasting results with well-established transmission mechanism postulates, (ii) venture new hypotheses concerning pathogen location and migration from midgut to salivary glands, and (iii) suggest other potential associations between pathogens not previously detected at the scale of the whole tick. This work highlights the importance of considering all tick scales (i.e. whole ticks vs organs) to study TBP ecology and represents another step towards improved understanding of TBP transmission.
Interpenetration between a polymer brush and a polymer star at thermal equilibrium: A theoretical approach
Authors: Edwards Mike
Published: December 2018

By means of the density functional theory framework I tackle the long-standing problem of a polymer star interpenetrating with a polymer brush at thermal equilibrium. Remarkably, the star is repelled to the outside of the brush once it sucks into the brush. It turns out that there could be a highly fluctuating region at the brush edge. The highly fluctuating region would be responsible for discontinuous absorption transitions by brushes. However, up to an small interpenetration length, below which asphericity of the star is maintained, the star gets collapsed by sucking more and more into the brush.
Computational exploration of molecular receptive fields in the olfactory bulb reveals a glomerulus-centric chemical map
Authors: Soelter Jan , Schumacher Jan , Spors Hartwig , Schmuker Michael
Published: December 2018

Progress in olfactory research is currently hampered by incomplete knowledge about chemical receptive ranges of primary receptors. Moreover, the chemical logic underlying the arrangement of computational units in the olfactory bulb has still not been resolved. We undertook a large-scale approach at characterising molecular receptive ranges (MRRs) of glomeruli innervated by the MOR18-2 olfactory receptor in the dorsal olfactory bulb (dOB). Guided by an iterative approach that combined biological screening and machine learning, we selected 214 odorants to characterise the response of MOR18-2 and its neighbouring glomeruli. We discovered several previously unknown odorants activating MOR18-2 glomeruli, and we obtained detailed MRRs of MOR18-2 glomeruli and their neighbours. Physico-chemical MRR descriptions revealed that the spatial layout of glomeruli followed a chemical logic. Our results confirm earlier findings that demonstrate a partial chemical map underlying glomerular arrangement in the dOB. Moreover, our novel methodology that combines machine learning and physiological measurements lights the way towards future high-throughput studies to deorphanise and characterise structure-activity relationships in olfaction.
Fission Yeast Cells Grow Approximately Exponentially
Authors: Pickering Mary , Hollis Lauren Nicole , D’Souza Edridge , Rhind Nicholas
Published: December 2018

How the rate of cell growth is influenced by cell size is a fundamental question of cell biology. The simple model that cell growth is proportional to cell size, based on the proposition that larger cells have proportionally greater synthetic capacity than smaller cells, leads to the predication that the rate of cell growth increases exponentially with cell size. However, other modes of cell growth, including bilinear growth, have been reported. The distinction between exponential and bilinear growth has been explored in particular detail in the fission yeastSchizosaccharomyces pombe. We have revisited the mode of fission yeast cell growth using high-resolution time-lapse microscopy and find, as previously reported, that these two growth models are difficult to distinguish both because of the similarity in shapes between exponential and bilinear curves over the two-fold change in length of a normal cell cycle and because of the substantial biological and experimental noise inherent to these experiments. Therefore, we contrived to have cells grow more than two fold, by holding them in G2 for up to eight hours. Over this extended growth period, in which cells grow up to 5.5-fold, the two growth models diverge to the point that we can confidently exclude bilinear growth as a general model for fission yeast growth. Although the growth we observe is clearly more complicated than predicted by simple exponential growth, we find that exponential growth is a robust approximation of fission yeast growth, both during an unperturbed cell cycle and during extended periods of growth.
Exercise restores chloride homeostasis and decreases spasticity through the BDNF-KCC2 pathway after chronic SCI
Authors: Schulze Henrike , Choyke Samantha , Klaszky Michael , Cote Marie-Pascale
Published: December 2018

Activity-based therapies are routinely integrated in rehabilitation programs to induce repetitive activation of the neuromuscular system and facilitate functional recovery after spinal cord injury (SCI). Among the beneficial effects of physical therapy is a reduction of hyperreflexia and spasticity in SCI individuals, but the precise mechanism by which exercise regulates spinal networks and facilitate recovery remains elusive. Spasticity is a debilitating condition that affects ~ 75% of the SCI population and interferes with residual motor function. Current pharmacological treatments not only have serious side effects but also actively depress spinal excitability and interferes with motor recovery. Understanding how activity-based therapies contribute to decrease spasticity will help identify critical pharmacological targets and optimize rehabilitation programs. KCC2, a neuron-specific Cl- extruder, is critical to the maintenance of [Cl-]i and its downregulation after SCI leads to a shift in chloride homeostasis that contributes to develop spasticity. We have shown in earlier studies that not only exercise promotes reflex modulation but also restores KCC2 expression in motoneurons. KCC2 is dynamically modulated by several signaling pathways, the most prevalent being BDNF-TrkB. Interestingly, activity-dependent processes triggered by exercise include an increase in the expression of BDNF in the lumbar spinal cord. However, whether the increase in KCC2 contributes to functional recovery and rely on BDNF activity have not been established. Our objective was to determine 1) whether the activity-dependent upregulation of KCC2 contributes to decrease spasticity after SCI; 2) if BDNF regulates KCC2 expression in an activity-dependent manner. Using a model of complete SCI, we investigated this possible causal effect by intrathecally delivering VU0240551, a specific KCC2 blocker, or TrkB-IgG, a BDNF scavenger. Drugs were specifically delivered during the daily rehabilitation sessions to transiently prevent KCC2/BDNF activity. We provide evidence that the beneficial effect of exercise on functional recovery relies on a BDNF-dependent increase in KCC2 expression on motoneurons and the restoration of endogenous inhibition to a mature state. We identify, for the first time, that the increase in KCC2 activity with activity-based therapies functionally contributes to H-reflex recovery and critically depends on BDNF activity. This provides a new perspective on our understanding of how exercise impact hyperreflexia by identifying the biological basis of recovery of function. Acting directly on chloride homeostasis through BDNF to restore endogenous inhibition rather than actively depress excitability can diminish the reduction in motor output associated with the current pharmacological management of SCI and improve the outcome of rehabilitation programs.
Scale invariance of BMP signaling gradients in zebrafish
Authors: Huang Yan , Umulis David
Published: December 2018

In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both vertebrates and invertebrates, however the mechanisms that regulate gradient scaling remain controversial. To obtain quantitative data that can be used to address core questions of scaling, we introduce a method to tune the size of zebrafish embryos by reducing varying amounts of vegetal yolk. We quantified the BMP signaling gradient in wild-type and perturbed embryos and found that the system scales for reductions in cross-sectional perimeter of up to 30%. Furthermore, we found that the degree of scaling for intraspecies scaling within zebrafish is greater than that between Danioninae species.
High-resolution structure determination of sub-100 kilodalton complexes using conventional cryo-EM
Authors: Herzik Mark A. , Wu Mengyu , Lander Gabriel C.
Published: December 2018

Determining high-resolution structures of biological macromolecules with masses of less than 100 kilodaltons (kDa) has long been a goal of the cryo-electron microscopy (cryo-EM) community. While the Volta Phase Plate has enabled cryo-EM structure determination of biological specimens of this size range, use of this instrumentation is not yet fully automated and can present technical challenges. Here, we show that conventional defocus-based cryo-EM methodologies can be used to determine the high-resolution structures of specimens amassing less than 100 kDa using a transmission electron microscope operating at 200 keV coupled with a direct electron detector. Our ~2.9 Å structure of alcohol dehydrogenase (82 kDa) proves that bound ligands can be resolved with high fidelity, indicating that these methodologies can be used to investigate the molecular details of drug-target interactions. Our ~2.8 Å and ~3.2 Å resolution structures of methemoglobin demonstrate that distinct conformational states can be identified within a dataset for proteins as small as 64 kDa. Furthermore, we provide the first sub-nanometer cryo-EM structure of a protein smaller than 50 kDa.
Targeted genomic integration of EGFP under tubulin beta 3 class III promoter and mEos2 under tryptophan hydroxylase 2 promoter does not produce sufficient levels of reporter gene expression
Authors: Menzorov Aleksei G. , Orishchenko Konstantin E. , Fishman Veniamin S. , Shevtsova Anastasia A. , Mungalov Roman V. , Pristyazhnyuk Inna E. , Kizilova Elena A. , Matveeva Natalia M. , Alenina Natalia , Bader Michael , Rubtsov Nikolai B. , Serov Oleg L.
Published: December 2018

Neuronal tracing is a modern technology that is based on the expression of fluorescent proteins under the control of cell type-specific promoters. However, random genomic integration of the reporter construct often leads to incorrect spatial and temporal expression of the marker protein. Targeted integration (or knock-in) of the reporter coding sequence is supposed to provide better expression control by exploiting endogenous regulatory elements. Here we describe the generation of two fluorescent reporter systems: EGFP under pan-neural marker class III β-tubulin (Tubb3) promoter and mEos2 under serotonergic neuron specific tryptophan hydroxylase 2 (Tph2) promoter. Differentiation of Tubb3-EGFP ES cells into neurons revealed that though Tubb3-positive cells express EGFP, its expression level is not sufficient for the neuronal tracing by routine fluorescent microscopy. Similarly, the expression levels of mEos2-TPH2 in differentiated ES cells was very low and could be detected only on mRNA level using PCR-based methods. Our data shows that the use of endogenous regulatory elements to control transgene expression is not always beneficial compared to random genomic integration.
Age Grading An. Gambiae and An. Arabiensis Using Near Infrared Spectra and Artificial Neural Networks
Authors: Milali Masabho P. , Sikulu-Lord Maggy T. , Kiware Samson S. , Dowell Floyd E. , Corliss George F. , Povinelli Richard J.
Published: December 2018

Background
Near infrared spectroscopy (NIRS) is currently complementing techniques to age-grade mosquitoes. NIRS classifies lab-reared and semi-field raised mosquitoes into < or ≥ 7 days old with an average accuracy of 80%, achieved by training a regression model using partial least squares (PLS) and interpreted as a binary classifier.
Methods and findings
We explore whether using an artificial neural network (ANN) analysis instead of PLS regression improves the current accuracy of NIRS models for age-grading malaria transmitting mosquitoes. We also explore if directly training a binary classifier instead of training a regression model and interpreting it as a binary classifier improves the accuracy.
A total of 786 and 870 NIR spectra collected from laboratory reared An. gambiae and An. arabiensis, respectively, were used and pre-processed according to previously published protocols.
Based on ten-fold Monte Carlo cross-validation, an ANN regression model scored root mean squared error (RMSE) of 1.6 ± 0.2 for An. gambiae and 2.8 ± 0.2 for An. arabiensis; whereas the PLS regression model scored RMSE of 3.7 ± 0.2 for An. gambiae, and 4.5 ± 0.1 for An. arabiensis. When we interpreted regression models as binary classifiers, the accuracy of the ANN regression model was 93.7 ± 1.0 % for An. gambiae, and 90.2 ± 1.7 % for An. arabiensis; while PLS regression model scored the accuracy of 83.9 ± 2.3% for An. gambiae, and 80.3 ± 2.1% for An. arabiensis. We also find that a directly trained binary classifier yields higher age estimation accuracy than a regression model interpreted as a binary classifier. A directly trained ANN binary classifier scored an accuracy of 99.4 ± 1.0 for An. gambiae, and 99.0 ± 0.6% for An. arabiensis; while a directly trained PLS binary classifier scored 93.6 ± 1.2% for An. gambiae, and 88.7 ± 1.1% for An. arabiensis.
Conclusion
Training both regression and binary classification age models using ANNs yields models with higher estimation accuracies than when the same age models are trained using PLS. Regardless of the model architecture, directly trained binary classifiers score higher accuracy on classifying age of mosquitoes than a regression model translated as binary classifier. Therefore, we recommend training models to estimate age of An. gambiae and An. arabiensis using ANN model architectures and direct training of binary classifier instead of training a regression model and interpret it as a binary classifier.
Seeing emotions, reading emotions: behavioral and ERPs evidence of the effect of strategy and of regulation for pictures and words.
Authors: Grecucci Alessandro , Sulpizio Simone , Tommasello Elisa , Vespignani Francesco , Job Remo
Published: December 2018

Background: Whilst there has been extensive study of the mechanisms underlying the effect of regulation for the emotions elicited by pictures, the ability and the mechanisms beyond the regulation of words remains to be clarified. Similarly, the effect of strategy when applying a regulatory process is still poorly explored. The present study seeks to elucidate these issues comparing the effect of regulation and of strategy to both neutral and emotional words and pictures.
Methodology/Principal Findings: Thirty young adults observed and took the distance from unpleasant and neutral pictures and words while their subjective ratings and ERPs were recorded. At a behavioral level, participants successfully regulated the arousal and the valence of both pictures and words. At a neural level, unpleasant pictures produced an increase in the late positive potential modulated during the regulate condition. Unpleasant linguistic stimuli elicited a posterior negativity as compared to neutral stimuli, but no effect of regulation on ERP was detectable. More importantly, the effect of strategy independently of stimulus type, produced a significant larger Stimulus Preceding Negativity. Dipole reconstruction localized this effect in the middle frontal areas of the brain.
Conclusions: As such, these new psychophysiological findings might help to understand how pictures and words can be regulated by distancing in daily life and clinical contexts, and the neural bases of the effect of strategy for which we suggest an integrative model.
Subset selection of markers for genome-enabled prediction of genetic val-ues using radial basis function neural networks
Authors: Sant' Anna Isabela de Castro , Silva Gabi Nunes , Nascimento Moysés , Cruz Cosme Damiao
Published: December 2018

This paper aimed to evaluate the efficiency of subset selection of markers for genome-enabled prediction of genetic values using radial basis function neural networks (RBFNN). For this purpose, an F1 population from hybridization of divergent parents with 500 individuals geno-typed with 1,000 SNP-type markers was simulated. Phenotypic traits were determined by adopting three different gene action models – additive, additive-dominant, and epistasic , com-plying with two dominance situations: partial and complete with quantitative traits admitting heritability (h2) equal to 30 and 60%, each one controlled by 50 loci, considering two alleles per locus, totaling 12 different scenarios. To evaluate the predictive ability of RR_BLUP and the neural networks, a cross-validation procedure with five replicates were trained using 80% of the individuals of the population. Two methods were used: dimensionality reduction and stepwise regression. The square of the correlation between the predicted genomic estimated breeding val-ue (GEBV) and the phenotype value was used to measure predictive reliability. For h2 = 0.3 in the additive scenario, the R2 values were 59% for neural network (RBFNN) and 57% for RR-BLUP, and in the epistatic scenario, R2 values were 50% and 41%, respectively. Additionally, when analyzing the mean-squared error root, the difference in performance between the tech-niques is even greater. For the additive scenario, the estimates were 91 for RR-BLUP and 5 for neural networks and, in the most critical scenario, they were 427 for RR-BLUP and 20 for neu-ral network. The results showed that the use of neural networks and variable selection tech-niques allows capturing epistasis interactions, leading to an improvement in the accuracy of pre-diction of the genetic value and, mainly, to a large reduction of the mean square error, which indicates greater genomic value.
Closing Target Trimming: a Perl Package for Discovering Hidden Superfamily Loci in Genomes
Authors: Hua Zhihua , Early Matthew J
Published: December 2018

The contemporary capacity of genome sequence analysis significantly lags behind the rapidly evolving sequencing technologies. Retrieving biological meaningful information from an ever-increasing amount of genome data would be significantly beneficial for functional genomic studies. For example, the duplication, organization, evolution, and function of superfamily genes are arguably important in many aspects of life. However, the incompleteness of annotations in many sequenced genomes often results in biased conclusions in comparative genomic studies of superfamilies. Here, we present a Perl software, called Closing Target Trimming, for automatically identifying most, if not all, members of a gene family in any sequenced genomes. Our test data on the F-box gene superfamily showed 78.2 and 79% gene finding accuracies in two well annotated plant genomes, Arabidopsis thaliana and rice, respectively. This annotation performance is clearly higher than the best ab initio methods that are currently available. To further demonstrate the effectiveness of this program, we ran it through 18 plant genomes and five non-plant genomes to compare the expansion of the F-box and the BTB superfamilies. The program discovered that on average 12.7 and 9.3% of the total F-box and BTB members, respectively, are new loci in plant genomes while it only found a small number of new members in vertebrate genomes. Therefore, different evolutionary and regulatory mechanisms of cullin-RING ubiquitin ligases may be present in the plant and the animal kingdoms. Further studies may shed light on new discoveries in the ubiquitin-26S proteasome system-mediated regulatory pathways in eukaryotic organisms. With a detailed compiling instruction and a simple running operation, we expect that this software will assist many biological scientists with little programming experience to smoothly obtain a comprehensive dataset of a gene superfamily in any sequenced eukaryotic genomes.
Projected expansion in climatic suitability for Trypanosoma cruzi, the etiological agent of Chagas Disease, and five widespread Triatoma species by 2070: the role of climate change on infectious diseases
Authors: Nichols Matthew , Butler Chris J , Lord Wayne D , Haynie Michelle L
Published: December 2018

The vector-borne parasite Trypanosoma cruzi infects seven million individuals globally and causes chronic cardiomyopathy and gastrointestinal diseases. Recently, T. cruzi has emerged in the southern United States. It is crucial for disease surveillance efforts to detail regions that present favorable climatic conditions for T. cruzi and vector establishment. We used MaxEnt to develop an ecological niche model for T. cruzi and five widespread Triatoma vectors based on 546 published localities within the United States. We modeled regions of current potential T. cruzi and Triatoma distribution and then regions projected to have suitable climatic conditions by 2070. Regions with suitable climatic conditions for the study organisms are predicted to increase within the United States. Our findings agree with the hypothesis that climate change will facilitate the expansion of tropical diseases throughout temperate regions and suggest climate change will influence the expansion of T. cruzi and Triatoma vectors in the United States.
A Strategy Study on Risk Communication of Pandemic Influenza ——A Mental Model Study of College Students in Beijing
Authors: Yang HongLin , Wang Linxian , Wang Yadong , Zheng Bo , Du Shuai , Lu Xinyi
Published: December 2018

Understanding the risk perception of pandemic influenza can improve the risk communication efficiency of the government and ultimately reduce losses caused by the disaster. A mental model interview of 28 individuals who discussed pandemic influenza was analyzed in this paper. The interviewees were college students in Beijing, China who were evaluated to understand their views on the risk perception of pandemic influenza. Referring to the mental model theory, the researchers using Delphi method to identify the key risk factors and concepts to examine the public understanding of these contents; then, the researchers identify the deviations in their understanding so that suggestions and countermeasures have been put forward to enhance the effectiveness of risk communication. Most of the conceptual content was mentioned by most interviewees. However, some interviewees showed misunderstanding including excessive optimism about the consequences of pandemic influenza, a lack of detailed mitigation measures, and negative attitudes toward health education and vaccination. Once faced with threats, this may lead to the failure of risk communication. In Beijing City, the center of domestic and international education, the historical SARS epidemic and this year's seasonal flu peak are all hints of the potential risk of a pandemic outbreak. Beijing’s college students' one-sided understanding and misunderstanding of the relevant risk information may increase the risk during an influenza pandemic. The results highlight the necessity for the government to clearly focus on the communication content of the student group, provide an official reference plan for the public and update health education on this topic.
Roles and responsibilities in integrated care for dementia
Authors: Robertshaw David , Cross Ainslea
Published: December 2018

Purpose

Effective integrated healthcare systems require capable, trained workforces with leadership, shared governance and co-ordination. The purpose of this paper is to characterise roles and responsibilities in relation to integrated care from the perspective of massive open online course (MOOC) participants.

Design/methodology/approach

MOOC discussion board posts were analysed using framework analysis consisting of transcription, familiarisation, coding, developing an analytical framework and application of the framework.

Findings

Boundaries and key issues surrounding roles and responsibilities were highlighted and participants suggested a number of enablers which could enhance integrated care in addition to barriers to consider and overcome.

Originality/value

Enablers included introduction of shared communication and IT systems to support continuity of care. Awareness and understanding of dementia was seen as crucial to promote person-centred care and care planning. The roles of education and experience were highlighted. Barriers preventing effective roles and suitable responsibility include funding, role conflicts, time constraints and time-consuming paperwork.
Arguing about Indigenous administrative participation in the Whitlam era: A representation theory analysis
Authors: Ganter Elizabeth
Published: December 2018

In 1974 Prime Minister Gough Whitlam established the Royal Commission on Australian Government Administration (‘the Commission’), appointing HC Coombs as chair. The Commission's brief was ‘to inquire into and report on the administrative organization and services of the Australian Government’ giving particular attention to, among other issues, public servants’ ‘participation in forming policy and making decisions’. From the outset the Commission aligned itself with the view that Aboriginal people were ‘less than proportionately represented in the administration’. The Commission asked CD Rowley to prepare a report on Aboriginal issues. Barrie Dexter, Secretary of the newly established Department of Aboriginal Affairs and Charles Perkins, Assistant Secretary and Arrernte man from Central Australia, both gave evidence to the Commission. The competing ideas on Indigenous administrative participation expressed by Coombs, Rowley, Dexter and Perkins in the course of the Commission will be considered through the lens of representation theory. While all four doubted the capacity of the bureaucracy to provide a meaningful channel for Indigenous representation internally, each argued from a different view of representation. Understanding their positions on how Indigenous people should be represented in public administration, including their assumption that there would also be external Indigenous representation, could shed light on tensions that are still present today.
Recalibrating the machinery of government for Indigenous affairs: Towards a new policy design for self‐determination
Authors: Perche Diana
Published: December 2018

Relations between First Nations and the Commonwealth government are in a parlous state in Australia, and the Commonwealth government's response to the Uluru Statement from the Heart has prompted much criticism from First Nations leaders. This paper examines the impact of one of the significant changes made by the Abbott government, the machinery of government change placing Indigenous Affairs into the Department of Prime Minister and Cabinet, with a Minister for Indigenous Affairs sitting in Cabinet. It considers the rationale for the move and explores the implications of the loss of a ‘shadow team’ function and the placement of a sensitive portfolio in the highly politicised environment of a central agency. Given that the current governance arrangements are not ‘fit for purpose’, the paper notes the call by First Nations organisations in the Redfern Statement for the establishment of a stand‐alone Department of Aboriginal and Torres Strait Islander Affairs, and recommends adoption of this as a partial government response to demands for First Nations self‐determination.
Orofacial neuralgia associated with a middle cerebral artery aneurysm
Authors: Mascarenhas RJ , Hapangama ND , Mews PJ , Burlakoti A , Ranjitkar S
Published: December 2018

Chronic orofacial pain of neuropathic origin can present diagnostic and management dilemmas to dental practitioners and also affects the patient's quality of life. Intracranial aneurysms are a potential cause of stroke (e.g. sub‐arachnoid haemorrhage) that is usually associated with, high rates of mortality and morbidity. A patient who had been previously managed for symptoms of temporomandibular joint disorder (TMD) presented with sharp, shooting pain of moderate intensity. It was precipitated by swallowing, and radiated to the right throat, posterior border of the mandible, ear and temporomandibular joint. Clinical and radiological investigations ruled out odontogenic pain, TMD and other more common types of facial pain. Magnetic resonance imaging revealed a 7 × 6 mm aneurysm in the right middle cerebral artery (MCA) which was subsequently surgically clipped. Interestingly, the facial pain resolved after this procedure. Compression of the insular region of the brain innervated by the trigeminal, glossopharyngeal and vagus nerves provides a plausible explanation for the pain reported. To our knowledge, this is the first case of facial neuralgia associated with an aneurysm in the MCA which emphasizes the importance of a multidisciplinary approach in the diagnosis and management of unusual cases of chronic orofacial pain.