bluuebunny/crossref_metadata_2025 huggingface dataset:
Signals, Educational Decision-Making, and Inequality
Authors: Holm Anders , Hjorth-Trolle Anders , Jæger Mads Meier
Published: February 2019

We propose a model of educational decision-making based on rational choice theory in which students use signals about academic ability to make inference about the costs and benefits of different educational options. Our model is simple, extends ideas from previous models, and has testable implications. We test our model using data on Danish monozygotic twins and find that (i) students who receive a positive signal about their academic ability have a higher likelihood of enrolling in and completing a college-bound track compared with those who do not; (ii) the effect of the signal is stronger for students from low socio-economic status (SES) backgrounds than for those from high-SES ones; and (iii) for low-SES students the effect is stronger on enrolment than on completion. Our results suggest that signals about academic ability affect educational decisions in general; they are more important for students who do not have a family ‘push’ to avoid downward social mobility; and they affect educational inequality by making low-SES students too optimistic about their likelihood of completing the college-bound track.
Dimension-Free L
p-Maximal Inequalities for Spherical Means in ℤm+1N
Authors: Greenblatt Jordan , Kolla Alexandra , Krause Ben
Published: February 2019

We extend the main result of Krause—the existence of dimension-free $L^p$-bounds, $p > 1$, for the spherical maximal function in the hypercube, $\{0,1\}^N$—to all cyclic groups, $\mathbb{Z}_{m+1}^N, \ m \geq 1$. Our approach follows that of Krause, which grew out of the arguments of Harrow, Kolla, and Schulman, which were in turn motivated by the spectral technique developed by Nevo and Stein, and by Stein, in the context of pointwise ergodic theorems on general groups.
Semi-Uniform Domains and the A∞ Property for Harmonic Measure
Authors: Azzam Jonas
Published: February 2019

We study the properties of harmonic measure in semi-uniform domains. Aikawa and Hirata showed in [ 5] that, for John domains satisfying the capacity density condition (CDC), the doubling property for harmonic measure is equivalent to the domain being semi-uniform. Our 1st result removes the John condition by showing that any domain satisfying the CDC whose harmonic measure is doubling is semi-uniform. Next, we develop a substitute for some classical estimates on harmonic measure in nontangentially accessible domains that works in semi-uniform domains. We also show that semi-uniform domains with uniformly rectifiable boundary have big pieces of chord-arc subdomains. We cannot hope for big pieces of Lipschitz subdomains (as was shown for chord-arc domains by David and Jerison [ 19]) due to an example of Hrycak, which we review in the appendix. Finally, we combine these tools to study the $A_{\infty }$-property of harmonic measure. For a domain with Ahlfors–David regular boundary, it was shown by Hofmann and Martell that the $A_{\infty }$ property of harmonic measure implies uniform rectifiability of the boundary [ 25, 27]. Since $A_{\infty }$-weights are doubling, this also implies the domain is semi-uniform. Our final result shows that these two properties, semi-uniformity and uniformly rectifiable boundary, also imply the $A_{\infty }$ property for harmonic measure, thus classifying geometrically all domains for which this holds.
A high-fat diet aggravates osteonecrosis through a macrophage-derived IL-6 pathway
Authors: Zhou Zubin , Pan Chenhao , Wang Nan , Zhou Lihui , Shan Haojie , Gao Youshui , Yu Xiaowei
Published: February 2019

Inflammation plays an important role in osteonecrosis. Obesity, a risk factor for osteonecrosis, leads to a chronic inflammatory status. We hypothesized that inflammation mediated the effects of obesity on osteonecrosis and tested our hypothesis in a mouse model of osteonecrosis. We fed mice with a high-fat diet (HFD) for 12 weeks before osteonecrosis induction by methylprednisolone and examined bone structure and IL-6 expression. Then we investigated the effects of IL-6 deletion in mice with osteonecrosis on the HFD. Next, we isolated bone marrow cells and determined the cell types responsible for HFD-induced IL-6 secretion. Finally, we investigated the roles of macrophages and macrophage-driven IL-6 in HFD-mediated effects on osteonecrosis and osteogenesis of bone marrow stromal cells (BMSCs). The HFD lead to exacerbated destruction of the femoral head in mice with osteonecrosis and increased IL-6 expression in macrophages. Il-6 knockout or macrophage depletion suppressed the effects of the HFD on bone damage. When co-cultured with macrophages isolated from HFD-fed mice with osteonecrosis, BMSCs showed reduced viability and suppressed osteogenic differentiation. Our results suggest that macrophage-driven IL-6 bridges obesity and osteonecrosis and inhibition of IL-6 or depletion of macrophage may represent a therapeutic strategy for obesity-associated osteonecrosis.
VLA-2 blockade in vivo by vatelizumab induces CD4+FoxP3+ regulatory T cells
Authors: Breuer Johanna , Schneider-Hohendorf Tilman , Ostkamp Patrick , Herich Sebastian , Rakhade Sanjay , Antonijevic Irina , Klotz Luisa , Wiendl Heinz , Schwab Nicholas
Published: February 2019

Integrin α2β1, also known as very late antigen (VLA)-2, is a collagen-binding molecule expressed constitutively on platelets. Vatelizumab, a monoclonal antibody targeting the α2 subunit (CD49b) of VLA-2, was recently investigated for its safety and efficacy during a Phase 2 clinical study in multiple sclerosis patients, as integrin-mediated collagen binding at the site of inflammation is central to a number of downstream pro-inflammatory events. In the course of this study, we could show that VLA-2 is expressed ex vivo on platelets, platelet–T-cell aggregates, as well as a small population of highly activated memory T cells. Even though the clinical trial did not meet its primary clinical end-point (reduction in the cumulative number of new contrast-enhancing lesions on magnetic resonance imaging (MRI)), we observed enhanced frequencies of regulatory T cells (TREG) following vatelizumab treatment. Elevated TREG frequencies might be explained by the inhibition of p38 mitogen-activated protein kinase (MAPK) signaling, which is critically involved in the polarization of T helper 17 (TH17) cells and is activated by the α2 integrin cytoplasmic domain. Our findings suggest that blockade of VLA-2 might be a way to safely shift the TH17/TREG balance by inducing TREGin vivo.
Effect of PlzD, a YcgR homologue of c-di-GMP-binding protein, on polar flagellar motility in Vibrio alginolyticus
Authors: Kojima Seiji , Yoneda Takuro , Morimoto Wakako , Homma Michio
Published: February 2019

YcgR, a cyclic diguanylate (c-di-GMP)-binding protein expressed in Escherichia coli, brakes flagellar rotation by binding to the motor in a c-di-GMP dependent manner and has been implicated in triggering biofilm formation. Vibrio alginolyticus has a single polar flagellum and encodes YcgR homologue, PlzD. When PlzD or PlzD-GFP was highly over-produced in nutrient-poor condition, the polar flagellar motility of V. alginolyticus was reduced. This inhibitory effect is c-di-GMP independent as mutants substituting putative c-di-GMP-binding residues retain the effect. Moderate over-expression of PlzD-GFP allowed its localization at the flagellated cell pole. Truncation of the N-terminal 12 or 35 residues of PlzD abolished the inhibitory effect and polar localization, and no inhibitory effect was observed by deleting plzD or expressing an endogenous level of PlzD-GFP. Subcellular fractionation showed that PlzD, but not its N-terminally truncated variants, was precipitated when over-produced. Moreover, immunoblotting and N-terminal sequencing revealed that endogenous PlzD is synthesized from Met33. These results suggest that an N-terminal extension allows PlzD to localize at the cell pole but causes aggregation and leads to inhibition of motility. In V. alginolyticus, PlzD has a potential property to associate with the polar flagellar motor but this interaction is too weak to inhibit rotation.
Collecting French art in the late 1800s at the Art Gallery of New South Wales
Authors: O’Reilly Chiara
Published: February 2019

From the nineteenth century, Sydney’s Art Gallery of New South Wales has been a marker of cultural ambition in Australia. This paper critically considers five large French paintings purchased at the end of the nineteenth century at significant expense by the gallery. Feted by contemporaries as examples of the French academic style, they formed part of plans to develop a representative collection to further understanding of art in the colony and, over time, they have taken on a rich role in the collective cultural memory. Through close examination of these paintings, their historical reception, criticism, reproduction and traces in the gallery’s archives this article reveals a history of taste, class and the formation of the cultural value of art. Using an object-based approach, it positions these works as evidence of changing cultural ideas within the context of a state collection to offer new insight into their status, the gallery itself, and the multiple roles of public art collections.
Adults are more efficient in creating and transmitting novel signalling systems than children
Authors: Kempe Vera , Gauvrit Nicolas , Gibson Alison , Jamieson Margaret
Published: February 2019

Iterated language learning experiments have shown that meaningful and structured signalling systems emerge when there is pressure for signals to be both learnable and expressive. Yet, such experiments have mainly been conducted with adults using language-like signals. Here we explore whether structured signalling systems can also emerge when signalling domains are unfamiliar and when the learners are children with their well-attested cognitive and pragmatic limitations. In Experiment 1, we compared iterated learning of binary auditory sequences denoting small sets of meanings in chains of adults and 5- to 7-year-old children. Signalling systems became more learnable even though iconicity and structure did not emerge despite applying a homonymy filter designed to keep the systems expressive. When the same types of signals were used in referential communication by adult and child dyads in Experiment 2, only the adults, but not the children, were able to negotiate shared iconic and structured signals. Referential communication using their native language by 4- to 5-year-old children in Experiment 3 showed that only interaction with adults, but not with peers resulted in informative expressions. These findings suggest that emergence and transmission of communication systems are unlikely to be driven by children, and point to the importance of cognitive maturity and pragmatic expertise of learners as well as feedback-based scaffolding of communicative effectiveness by experts during language evolution.
Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease
Authors: Patel Deepa , Popple Sarah , Claydon Alison , Modha Deborah E , Gaillard Erol A
Published: February 2019

There is emerging evidence for the role of posaconazole in the management of Aspergillus-related cystic fibrosis (CF) lung disease. The tolerability and efficacy of posaconazole in paediatric CF is not well established. We report a prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3–17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels >1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy. Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.
Examining inequality of opportunity in the use of maternal and reproductive health interventions in Sierra Leone
Authors: Tsawe Mluleki , Susuman A Sathiya
Published: February 2019

Background

Poor countries, such as Sierra Leone, often have poor health outcomes, whereby the majority of the population cannot access lifesaving health services. Access to, and use of, maternal and reproductive health services is crucial for human development, especially in developing regions. However, inequality remains a persistent problem for many developing countries. Moreover, we have not found empirical studies, which have examined inequalities in maternal and reproductive health in Sierra Leone.

Method

We used data collected from the Sierra Leone Demographic and Health Surveys (DHS) conducted in 2008 and 2013. Five maternal and reproductive health indicators were selected for this study, including four or more antenatal care visits, skilled antenatal care provider, births delivered in a facility, births assisted by a skilled birth attendant, and any method of contraception. To measure inequalities, we adopted the Human Opportunity Index (HOI). Using this measure, we measured differentials over the two periods, and decomposed it to measure the contribution of the selected circumstance variables to inequality.

Results

Inequalities declined over time, as shown by the decrease in the dissimilarity index. Due to the drop in the dissimilarity index, the HOI increased for all the selected maternal and reproductive health indicators. Moreover, antenatal services were closer to equality compared to the other selected services. Overall, we found that household wealth status, maternal education and place of residence, are the most important factors contributing to the inequality in the use of maternal and reproductive health services.

Conclusions

Even though there are improvements in inequalities over time, there are variations in the way in which inequality within the different indicators has improved. In order to improve the use of maternal and reproductive health services, and to reduce inequalities in these services, the government will have to invest in: (i) increasing the educational levels of women, (ii) improving the standard of living, as well as (iii) bringing maternal and reproductive health services closer to rural populations.
Clinical practices: Epilepsy at the National Hospital for the Paralysed and Epileptic, London, from 1860 to 1870
Authors: Vieyra Alejandra , Barahona Ana
Published: February 2019

In the nineteenth century, epilepsy was established as a curable and treatable condition at the National Hospital for the Paralysed and Epileptic, in London, England. Since its inception, the National Hospital (NH) hosted the work of many physicians who tried to characterise and define epilepsy as a nosological entity. During the first decade of this Institution, different medical traditions, clinical practices, staff, physicians (among them, John Hughlings Jackson, Charles-Édouard Brown-Séquard, Jabez Spence Ramskill, and Charles Bland Radcliffe), patients, remedies, devices and publications, began to grant the National Hospital a place in London society as a special medical community. The delimitation of epilepsy at the National Hospital would have an impact on the study and description of the human nervous system at the end of the nineteenth century.
Nutritional Treatment of a Young Infant with Cystic Fibrosis Presenting with Severe Kwashiorkor Dermatosis
Authors: Sandy Natascha Silva , Nogueira Roberto José Negrão
Published: February 2019

Kwashiorkor in infancy is typically associated to an underlying disease. Edema, a striking feature of this type of malnutrition, can be difficult to assess in this age group. The typical dermatosis of Kwashiorkor is not fully explained the deficiency of one isolated vitamin or micronutrient. This article presents an infant with cystic fibrosis, who developed Kwashiorkor in the third month of life with extensive cutaneous manifestations. An early, individualized and aggressive nutritional intervention with optimized supplementationof sulfur amino acids, vitamins and micronutrients was established, with impressively recovery of overall nutrition and skin manifestations in a relatively short period of time.
Big data: the end of the scientific method?
Authors: Succi Sauro , Coveney Peter V.
Published: February 2019

For it is not the abundance of knowledge, but the interior feeling and taste of things, which is accustomed to satisfy the desire of the soul.
(Saint Ignatius of Loyola).

We argue that the boldest claims of big data (BD) are in need of revision and toning-down, in view of a few basic lessons learned from the science of complex systems. We point out that, once the most extravagant claims of BD are properly discarded, a synergistic merging of BD with big theory offers considerable potential to spawn a new scientific paradigm capable of overcoming some of the major barriers confronted by the modern scientific method originating with Galileo. These obstacles are due to the presence of nonlinearity, non-locality and hyperdimensions which one encounters frequently in multi-scale modelling of complex systems.

This article is part of the theme issue ‘Multiscale modelling, simulation and computing: from the desktop to the exascale’.
Search for early pancreatic cancer blood biomarkers in five European prospective population biobanks using metabolomics
Authors: Fest Jesse , Vijfhuizen Lisanne S. , Goeman Jelle J. , Veth Olga , Joensuu Anni , Perola Markus , Männistö Satu , Ness-Jensen Eivind , Hveem Kristian , Haller Toomas , Tonisson Neeme , Mikkel Kairit , Metspalu Andres , van Duijn Cornelia M. , Ikram Arfan , Stricker Bruno H. , Ruiter Rikje , van Eijck Casper H.J. , van Ommen Gertjan B. , ’t Hoen Peter A.C.
Published: February 2019

Background and aim

Most patients with pancreatic cancer present with advanced disease and die within the first year after diagnosis. Predictive biomarkers that signal the presence of pancreatic cancer in an early stage are desperately needed. We aimed to identify new and validate previously found plasma metabolomic biomarkers associated with early stages of pancreatic cancer.

Methods

The low incidence rate complicates prospective biomarker studies. Here, we took advantage of the availability of biobanked samples from five large population cohorts (HUNT2, HUNT3, FINRISK, Estonian biobank, Rotterdam Study) and identified prediagnostic blood samples from individuals who were to receive a diagnosis of pancreatic cancer between one month and seventeen years after blood sampling, and compared these with age- and gender-matched controls from the same cohorts. We applied1H-NMR-based metabolomics on the Nightingale platform on these samples and applied logistic regression to assess the predictive value of individual metabolite concentrations, with gender, age, body mass index, smoking status, type 2 diabetes mellitus status, fasting status, and cohort as covariates.

Results

After quality assessment, we retained 356 cases and 887 controls. We identified two interesting hits, glutamine (p=0.011) and histidine (p=0.012), and obtained Westfall-Young family-wise error rate adjusted p-values of 0.43 for both. Stratification in quintiles showed a 1.5x elevated risk for the lowest 20% of glutamine and a 2.2x increased risk for the lowest 20% of histidine. Stratification by time to diagnosis (<2 years, 2-5 years, >5 years) suggested glutamine to be involved in an earlier process, tapering out closer to onset, and histidine in a process closer to the actual onset. Lasso-penalized logistic regression showed a slight improvement of the area under the Receiver Operator Curves when including glutamine and histidine in the model. Finally, our data did not support the earlier identified branched-chain amino acids as potential biomarkers for pancreatic cancer in several American cohorts.

Conclusion

While identifying glutamine and histidine as early biomarkers of potential biological interest, our results imply that a study at this scale does not yield metabolomic biomarkers with sufficient predictive value to be clinically usefulper seas prognostic biomarkers.
Glutathionylation primes soluble GAPDH for late collapse into insoluble aggregates
Authors: Zaffagnini M. , Marchand C.H. , Malferrari M. , Murail S. , Bonacchi S. , Genovese D. , Montalti M. , Venturoli G. , Falini G. , Baaden M. , Lemaire S.D. , Fermani S. , Trost P.
Published: February 2019

Protein aggregation is a complex physiological process, primarily determined by stress-related factors revealing the hidden aggregation propensity of proteins that otherwise are fully soluble. Here we report a mechanism by which glycolytic glyceraldehyde-3-phosphate dehydrogenase of Arabidopsis thaliana (AtGAPC1) is primed to form insoluble aggregates by the glutathionylation of its catalytic cysteine (Cys149). Following a lag phase, glutathionylated AtGAPC1 initiates a self-aggregation process resulting in the formation of branched chains of globular particles made of partially misfolded and totally inactive proteins. GSH molecules within AtGAPC1 active sites are suggested to provide the initial destabilizing signal. The following removal of glutathione by the formation of an alternative disulfide bond between Cys149 and Cys153 reinforces the aggregation process. Besides acting as a protective mechanism against overoxidation, S-glutathionylation of AtGAPC1 triggers an unexpected aggregation pathway with completely different and still unexplored physiological implications.
Mapping of long-term impact of conventional and organic soil management on resident and active fractions of rhizosphere communities of barley
Authors: Harkes Paula , Suleiman Afnan K.A. , van den Elsen Sven J.J. , Haan Janjo J. de , Holterman Martijn , Kuramae Eiko E. , Helder Johannes
Published: February 2019

Soil biota plays an essential role in ecosystem services such as carbon fixation, nitrogen and phosphorous cycling, and disease suppressiveness. Conventional soil management with large inputs of mineral fertilizers and pesticides have a significant impact on primary decomposer communities (bacteria and fungi), as well as on protists and metazoa, representatives of the next trophic level. Organic soil management is thought to contribute to a more diverse and stable soil food web. However, information to pinpoint this supposed beneficial effect is sparse and fragmented. Keeping in mind that a substantial fraction of the soil biota is dormant, we set out to map both the resident and the active the bacterial, fungal, protozoan and metazoan communities under various soil management regimes in two distinct soil types with barley as main crop. For all four organismal groups, the contrast between resident (rDNA-based) and active (rRNA-based) was the most important explanatory variable explaining 22%, 14%, 21% and 25% of the variance among bacterial, fungal, protozoan, and metazoan communities. Less prominent were the effects of soil management and soil type, however significant as well for all four organismal groups. LEfSe was used to identify indicator taxa for both the contrasts between resident and active communities, and the effects of soil management. Our results suggest that - next to DNA-based community characterisation - mapping of the active microbial community could provide essential insights in the effects of variables such as crop and soil management on the soil living community.
Treatment utilization and medical problems in a community sample of adult women with anorexia nervosa
Authors: Brodrick Brooks , Harper Jessica A. , Van Enkevort Erin , McAdams Carrie J.
Published: February 2019

Anorexia nervosa has a prolonged course of illness, making both defining recovery and determining optimal outpatient treatments difficult. Here, we report the types of treatments utilized in a naturalistic sample of adult women with anorexia nervosa in Texas. Participants were recruited from earlier studies of women with anorexia nervosa (AN-C, n = 28) and in weight recovery following anorexia nervosa (AN-WR, n = 18). Participants provided information about both their illness and treatments during their most severe period (severe period) as well as during the two to six years following original assessments (follow-up period). New follow-up groups were defined based on current clinical status (continued eating disorder, AN-CC; newly in recovery, AN-CR; sustained weight-recovery, AN-WS), and clinical utilization was compared across groups. There were no differences in groups related to symptoms or treatments utilized during the severe-period. During the follow-up period, intensive outpatient programs were utilized significantly more by the AN-CC group than the other groups, and dietitians were seen significantly less by the AN-WS group. Medical complications related to the ED were significantly more common in the AN-CC group. All groups maintained similar levels of contact with outpatient psychiatrists, therapists, and primary care physicians.
Trends of Hospitalization in Acute Pancreatitis in Patients in the United States from 2001-2014
Authors: Casey Kevin , Argo Roberto , Bianco Albert
Published: February 2019

Background & Purpose

The prevalence of acute pancreatitis(AP) has increased over time and is one of the most important gastrointestinal causes of frequent admissions to hospital in the United States. The cost burden of AP has been steadily increasing. The primary objective of our study was to analyze patient demographics, cost burden, mortality and length of stay associated with AP hospital admissions.

Methods

Nationwide inpatient sample (NIS) database was used to identify AP admissions in all patients from ≥18 years of age from 2001 to 2014 using ICD-9-CM code 577.0 as the principal discharge diagnosis

Results

The number of hospitalizations increased from 215,238 in 2001 to 279,145 in 2014. Inhospital mortality decreased from 1.74% in 2001 to 0.66% in 2014. Mean length of hospital stay has decreased from 6.1 days to 4.6 days during the same period, but the mean hospital charges increased from $19,303 in 2001 to $35,728 in 2014. The proportion of males to females with acute pancreatitis is slowly trending up from 2001 to 2014.

Conclusion

The number of hospitalizations due to acute pancreatitis has been steadily increasing, and further research needs to be done on finding out the reasons for increased causes of hospitalization and ways to decrease the cost burden on patients and hospitals.
Spatial distribution ofSalmonella entericain poultry shed environments observed by intensive longitudinal environmental sampling
Authors: Crabb Helen K , Allen Joanne Lee , Devlin Joanne Maree , Wilks Colin Reginald , Gilkerson James Rudkin
Published: February 2019

During a series of epidemiological studies to investigate the transmission of salmonellae within poultry environments, intensive longitudinal sampling within caged sheds revealed that both the number and location of sample collection within this environment were important to ensure the best chance of detectingSalmonellaspp. Multiple serovars ofSalmonella entericasubspeciesentericawere detected in each shed; 5% of all samples contained more than one serovar. Samples collected on the north side of the shed (OR = 1.77, 95% CI [1.17, 2.68]), on the sheltered side of the shed (OR = 1.90, 95% CI [1.26, 2.89]) and during winter (OR = 48.41, 95%CI [23.56, 104.19]) were more likely to be positive for salmonellae. The distribution of salmonellae within a shed was not homogenous, as differences were identified in the within-shed distribution ofSalmonella entericasubspeciesentericaserovar Typhimurium (χ2(27, 1,538) = 54.4, P < 0.001), andSalmonella entericasubspeciesentericaserovar Infantis (χ2(27, 1,538) = 79.8, P < 0.0001). The difference in sample prevalence by serovar and spatial location within a shed indicates that there are important shed micro-environmental factors that influence survival and/or distribution of salmonellae. These factors should be taken into consideration when undertaking environmental surveillance for salmonellae in flocks housed in caged sheds.

IMPORTANCE

Routine epidemiological surveillance for salmonellae in poultry relies initially on environmental sampling. Our study confirmed that the sampling methodology conducted within a poultry environment is a non-trivial part of sampling design. The spatial locations of sample collection within a shed revealed differences in both the sample prevalence and serovar of salmonellae detected.
Cryptic inoviruses are pervasive in bacteria and archaea across Earth’s biomes
Authors: Roux Simon , Krupovic Mart , Daly Rebecca A. , Borges Adair L. , Nayfach Stephen , Schulz Frederik , Cheng Jan-Fang , Ivanova Natalia N. , Bondy-Denomy Joseph , Wrighton Kelly C. , Woyke Tanja , Visel Axel , Kyrpides Nikos C. , Eloe-Fadrosh Emiley A.
Published: February 2019

Bacteriophages from the Inoviridae family (inoviruses) are characterized by their unique morphology, genome content, and infection cycle. To date, a relatively small number of inovirus isolates have been extensively studied, either for biotechnological applications such as phage display, or because of their impact on the toxicity of known bacterial pathogens including Vibrio cholerae and Neisseria meningitidis. Here we show that the current 56 members of the Inoviridae family represent a minute fraction of a highly diverse group of inoviruses. Using a new machine learning approach leveraging a combination of marker gene and genome features, we identified 10,295 inovirus-like genomes from microbial genomes and metagenomes. Collectively, these represent six distinct proposed inovirus families infecting nearly all bacterial phyla across virtually every ecosystem. Putative inoviruses were also detected in several archaeal genomes, suggesting that these viruses may have occasionally transferred from bacterial to archaeal hosts. Finally, we identified an expansive diversity of inovirus-encoded toxin-antitoxin and gene expression modulation systems, alongside evidence of both synergistic (CRISPR evasion) and antagonistic (superinfection exclusion) interactions with co-infecting viruses which we experimentally validated in a Pseudomonas model. Capturing this previously obscured component of the global virosphere sparks new avenues for microbial manipulation approaches and innovative biotechnological applications.
Model ensembles with different response variables for base and meta models: malaria disaggregation regression combining prevalence and incidence data
Authors: Lucas Tim C. D. , Nandi Anita , Nguyen Michele , Rumisha Susan , E. Battle Katherine , E. Howes Rosalind , Hendriks Chantal , Python Andre , Hancock Penny , Cameron Ewan , Gething Pete , Weiss Daniel J.
Published: February 2019

Maps of infection risk are a vital tool for the elimination of malaria. Routine surveillance data of malaria case counts, often aggregated over administrative regions, is becoming more widely available and can better measure low malaria risk than prevalence surveys. However, aggregation of case counts over large, heterogeneous areas means that these data are often underpowered for learning relationships between the environment and malaria risk. A model that combines point surveys and aggregated surveillance data could have the benefits of both but must be able to account for the fact that these two data types are different malariometric units. Here, we train multiple machine learning models on point surveys and then combine the predictions from these with a geostatistical disaggregation model that uses routine surveillance data. We find that, in tests using data from Colombia and Madagascar, using a disaggregation regression model to combine predictions from machine learning models trained on point surveys improves model accuracy relative to using the environmental covariates directly.
Competitive Inhibitors of Ras Effector Binding
Authors: Wiechmann Svenja , Maisonneuve Pierre , Grebbin Britta M. , Hoffmeister Meike , Kaulich Manuel , Clevers Hans , Rajalingam Krishnaraj , Kurinov Igor , Farin Henner F. , Sicheri Frank , Ernst Andreas
Published: February 2019

The small GTPases H, K and NRas are molecular switches that are indispensable for the correct regulation of cellular proliferation and growth. Mutations in Ras are associated with cancer and result in unwanted activation of signaling processes caused by aberrant recruitment of downstream effector proteins. In this study, we have engineered variants of the Ras-binding domain (RBD) of CRAF kinase that bind with highly improved affinity the effector binding site of Ras. Structural characterization demonstrates how the engineered RBD variants outcompete effector binding and inhibit Ras signaling in cells leading to apoptosis, growth arrest and senescence. The optimized RBD variants provide new insights in Ras biology and enabled the functional stratification of Ras dependency in patient-derived colorectal cancer organoids.

One sentence summary

Inhibition of effector kinase binding to Ras induces senescence in non-tumorigenic cells and reveals Ras dependency in patient-derived cancer organoids.
Global patterns of seed germination after ingestion by mammals
Authors: Torres Diego A. , Castaño John H. , Carranza-Quiceno Jaime A.
Published: February 2019

Seed germination is the first step in seedling recruitment. Understanding what factors determine germination success allows some predictions of the effect of climate change or defaunation on the dynamics of plant communities. Mammals play an important role on seed germination through the ingestion of fruit and seeds. However, the populations of many mammal species have been reduced throughout the world, affecting in many ways the dynamics of plant communities. To understand how the loss of mammal populations might impact the dynamics of plant communities first requires us to collect and synthetize all the available evidence on the effects of mammals on seedling recruitment. Here, we used meta-analytical methods to describe the global patterns of the ingestion of seeds by mammals and their effect on seed germination. Our results showed a positive cumulative effect of mammals on seed germination. However, this effect was not the same for all the mammal orders; it varied depending on the plant family and the bioregion. Additionally, increased seed germination was related to rapid germination. These data highlight the important role that some mammals such as Primates and Elephants have on seed germination, and this poses many questions about the mechanisms behind seed germination patterns that will help to guide future research efforts.
Abstracted functions for engineering the autonomous growth and formation of patterns
Authors: Choksi Atri , Endy Drew
Published: February 2019

Natural biological patterns arise via the growth, differentiation, death, differential adhesion, communication, and movement of or among cells. Synthetic biologists typically impose explicit genetic control of cell-cell communication and programmable cell state to realize engineered biological patterns. Such engineering approaches do not usually consider the underlying physical properties of individual cells that inevitably contribute to pattern development. To better integrate synthetic genetic systems engineering with natural growth and patterning we derived abstract functions that relate how changes in basic cell properties such as growth rate, length, and radius of curvature result in differences in the curvature, end-point reliability, and texture of borders that define boundaries among growing cell lineages. Each abstracted border function is derived holistically as an emergent consequence of underlying cell physical properties. We experimentally demonstrate control of border curvature to angles of 60° from initial trajectories, control of end-point variability to within 15° of desired target endpoints, and control of border texture between 10 to 60 unit cell lengths. In combination with synthetic genetic control systems, we grow arbitrary two-dimensional patterns including phases of the moon, PacMen, and a yinyang-like pattern. Differences between the idealized and observed behavior of abstracted border functions highlight opportunities for realizing more precise control of growth and form, including better integration of synthetic genetic systems with native cellular properties and processes.
Comparison Between UMAP and t-SNE for Multiplex-Immunofluorescence Derived Single-Cell Data from Tissue Sections
Authors: Wu Duoduo , Poh Sheng Joe Yeong , Su-En Grace Tan , Chevrier Marion , Jie Hua Josh Loh , Kiat Hon Tony Lim , Chen Jinmiao
Published: February 2019

Using human hepatocellular carcinoma (HCC) tissue samples stained with seven immune markers including one nuclear counterstain, we compared and evaluated the use of a new dimensionality reduction technique called Uniform Manifold Approximation and Projection (UMAP), as an alternative to t-Distributed Stochastic Neighbor Embedding (t-SNE) in analysing multiplex-immunofluorescence (mIF) derived single-cell data. We adopted an unsupervised clustering algorithm called FlowSOM to identify eight major cell types present in human HCC tissues. UMAP and t-SNE were ran independently on the dataset to qualitatively compare the distribution of clustered cell types in both reduced dimensions. Our comparison shows that UMAP is superior in runtime. Both techniques provide similar arrangements of cell clusters, with the key difference being UMAP’s extensive characteristic branching. Most interestingly, UMAP’s branching was able to highlight biological lineages, especially in identifying potential hybrid tumour cells (HTC). Survival analysis shows patients with higher proportion of HTC have a worse prognosis (p-value = 0.019). We conclude that both techniques are similar in their visualisation capabilities, but UMAP has a clear advantage over t-SNE in runtime, making it highly plausible to employ UMAP as an alternative to t-SNE in mIF data analysis.
PhotorhabdusVirulence Cassettes: extracellular multi-protein needle complexes for delivery of small protein effectors into host cells
Authors: Vlisidou Isabella , Hapeshi Alexia , Healey Joseph R. J. , Smart Katie , Yang Guowei , Waterfield Nicholas R.
Published: February 2019

Photorhabdusis a highly effective insect pathogen and symbiont of insecticidal nematodes. To exert its potent insecticidal effects, it elaborates a myriad of toxins and small molecule effectors. Among these, thePhotorhabdusVirulence Cassettes (PVCs) represent an elegant self-contained delivery mechanism for diverse protein toxins. Importantly, these self-contained nanosyringes overcome host cell membrane barriers, and act independently, at a distance from the bacteria itself. In this study, we demonstrate that Pnf, a PVC needle complex associated toxin, is a Rho-GTPase, which acts via deamidation and transglutamination to disrupt the cytoskeleton. TEM and Western blots have shown a physical association between Pnf and its cognate PVC delivery mechanism. We demonstrate that for Pnf to exert its effect, translocation across the cell membrane is absolutely essential.

SIGNIFICANCE STATEMENT

Here we provide an up to date analysis of the nano-scale syringe-like molecular devices thatPhotorhabdususe to manipulate invertebrate hosts, the PVC system. They are related to theSerratiaAnti-Feeding Prophage and the Psuedoalteromonas MAC system. All these systems are in turn more distantly related to the well characterized Type VI secretion system currently receiving a great deal of attention. We demonstrate for the first time that the PVC nanosyringes are physically “loaded” with an effector protein payload before being freely released. The PVCs therefore represent bacterial molecular machines that are used as “long-range” protein delivery systems. This widespread class of toxin delivery system will likely prove of great significance in understanding many diverse bacteria/host interactions in future.
An Exclusively Skewed Distribution of Pediatric Immune Reconstitution Inflammatory Syndrome Towards the Female Sex is Associated with Advanced Acquired Immune Deficiency Syndrome
Authors: de Souza Campos Fernandes Regina Célia , Louvain de Souza Thaís , da Silva Barcellos Thiago , Medina-Acosta Enrique
Published: February 2019

In human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) patients with very low CD4 cell counts, there is a temporal relationship between administration of antiretroviral therapy (ART) and an increased inflammatory response state known as the immune reconstitution inflammatory syndrome (IRIS). The predominant clinical presentation of IRIS is an infectious disease that can be life-threatening. IRIS-related infectious events are distributed similarly between adult males and females, albeit a few studies have shown a skewing towards the male sex in pediatric IRIS. Here, we assessed sex-specific differences in the causes and extent of IRIS infectious events in HIV-infected pediatric patients on ART. We carried out a prospective clinical analysis (from 2000 to 2018) of IRIS-related infectious events after ART in a cohort of 82 Brazilian children and adolescents infected with HIV-1 through mother-to-child transmission as well as a comprehensive cross-referencing with public records on IRIS-related infectious causes in pediatric HIV/AIDS. Twelve events fulfilling the criteria of IRIS occurred exclusively in eleven females in our cohort. The median age at IRIS events was 3.6 years. The infectious causes included Mycobacterium bovis, varicella-zoster virus, molluscum contagiosum virus, human papillomavirus, cytomegalovirus, and Mycobacterium tuberculosis. In one female, there was regional bacillus Calmette-Guérin dissemination and cytomegalovirus esophagitis. There was complete health recovery after ten IRIS events without the use of corticosteroids or ART interruption. One case of IRIS-associated miliary tuberculosis was fatal. The biological female sex was a significant risk factor for IRIS events (odds ratio: 23.67; 95% confidence interval 95%: 1.341 – 417.7; P = 0.0016). We observed an effect of the advanced HIV/AIDS variable in IRIS females as compared with non-IRIS females (mean CD4+ T cell percentage 13.36% versus 18.63%; P = 0.0489), underpinning the exclusively skewed distribution towards the female sex of this cohort. Moreover, the IRIS females in our cohort had higher mean CD4+ T cell percentages before (13.36%) and after IRIS (26.56%) than those of the IRIS females (before IRIS, 4.978%; after IRIS, 13.81%) in previous studies conducted worldwide. We concluded that the exclusively skewed distribution of pediatric IRIS towards females is associated with more advanced AIDS.
Robust 3D Bloch-Siegert based B1+ mapping using Multi-Echo General Linear Modelling
Authors: Corbin Nadège , Acosta-Cabronero Julio , Malik Shaihan J. , Callaghan Martina F.
Published: February 2019

Purpose

Quantitative MRI applications, such as mapping the T1 time of tissue, puts high demands on the accuracy and precision of transmit field (B1+) estimation. A candidate approach to satisfy these requirements exploits the difference in phase induced by the Bloch-Siegert Shift (BSS) of two acquisitions with opposite off-resonance frequency RF pulses. Interleaving these RF pulses ensures robustness to motion and scanner drifts, however, here we demonstrate that doing so also introduces a bias in the B1+ estimates.

Methods

We show via simulation and experiments that the amplitude of the error depends on MR pulse sequence parameters, such as TR and RF spoiling increment, but more problematically, on the intrinsic properties, T1 and T2, of the investigated tissue. To solve these problems, we present a new approach to BSS-based B1+ estimation that uses a multi-echo acquisition and a general linear model (GLM) to estimate the correct BSS-induced phase.

Results

In line with simulations, phantom and in-vivo experiments confirmed that the GLM-based method removed the dependency on tissue properties and pulse sequence settings. It also showed greater robustness to hardware imperfections.

Conclusion

The GLM-based method is recommended as a more accurate approach to BSS-based B1+ mapping.
Attacked from above and below, new observations of cooperative and solitary predators on roosting cave bats
Authors: Tanalgo Krizler Cejuela. , Waldien Dave L. , Monfort Norma , Hughes Alice Catherine
Published: February 2019

Predation of bats in their roosts has previously only been attributed to a limited number of species such as various raptors, owls, and snakes. However, in situations where due to over-crowding and limited roost space, some individuals may be forced to roost in suboptimal conditions, such as around the entrances of caves and may thus be vulnerable to predation by species which would normally be unlikely to predate bats whilst roosting inside caves. Here, we describe the first documented cooperative hunting of the Large-billed Crow, Corvus macrorhynchos Wagler, 1827 (Passeriformes: Corvidae) and opportunistic predation by the Yellow-headed water monitor, Varanus cumingi Martin, 1839 (Squamata: Varanidae) in the world’s largest colony of Geoffroy’s Rousette, Rousettus amplexicaudatus (É. Geoffroy Saint-Hilaire, 1810) (Chiroptera: Pteropidae) in the Island of Samal, Mindanao, Philippines.
LatentToxoplasma gondiiinfection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease
Authors: Donley David W. , Jenkins Teal , Deiter Cailin , Campbell Reed , Realing Marley , Chopra Vanita , Hersch Stephen , Gigley Jason P. , Fox Jonathan H.
Published: February 2019

Toxoplasma gondiicauses a prevalent neuroinvasive protozoal pathogen that in immune competent individuals results in latent infection characterized by intra-cellular parasite cysts in brain. Despite life-long infection, the role of latent toxoplasmosis on chronic neurodegenerative processes is poorly understood. Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a dominant CAG repeat expansion in the huntingtin gene (HTT) that results in the expression and accumulation of mutant huntingtin protein (mHTT). The mutant HD gene is fully penetrant. However, there is significant variability in disease progression that is in part explained by as yet unidentified environmental factors. The kynurenine pathway of tryptophan metabolism (KP) is an inflammatory pathway and its activation is implicated in HD pathogenesis. KP upregulation also occurs in response to infection withToxoplasma gondiisuggesting that the latent infection may promote HD. We discovered that mice on the FVB/NJ background develop latent toxoplasmosis following infection with the ME49 strain ofT. gondii. This finding enabled us to address the hypothesis that latent toxoplasmosis potentiates disease in the YAC128 mouse model of HD, as these mice are maintained on the FVB/NJ background. Wild-type and HD mice were infected at 2-months of age. During the 10-month follow-up, infection had adverse effects on mice of both genotypes. However, YAC128 HD mice demonstrated specific vulnerability to latent toxoplasmosis, as demonstrated by the presence of increased striatal degeneration, high levels of the blood neurodegeneration marker neurofilament light protein, and elevated brain soluble mHTT. Our studies have uncovered a novel HD-infection interaction in mice that provides insights into the large variability of the human HD phenotype.