bluuebunny/crossref_metadata_2025 huggingface dataset:
George IV and William IV in their Relations with the Church of England
Authors: Dixon Nicholas
Published: November 2019

George IV and William IV have long been represented as fundamentally pleasure-seeking monarchs who had little or no interest in religion. However, this assumption has never been sustained by detailed evidence. This article comprehensively challenges the stereotype by presenting the regency and reign of George IV together with William IV’s reign as a distinct and significant period in the relationship between the British monarchy and the Church of England. Three main aspects of this relationship are considered: George IV and William IV’s private commitments as manifested in court religion, the political actions of these monarchs in relation to the established church and their encouragement of Anglican church building and educational projects. The article draws upon a wide range of neglected sources, and especially the private correspondence and memoirs of those closest to George IV and William IV. Most notably, it introduces into the discussion the extensive and revealing autobiography of George IV’s chaplain Hugh Pearson, which has received scant attention from historians until now. From such sources, there emerges a picture of royal interaction with Anglicanism that almost entirely overturns the conventional view. Not only were the two last Hanoverian kings interested in religion; their Anglican beliefs directed much of their public and private conduct. This reinterpretation has important implications for our understanding of monarchy, religion and political culture in pre-Victorian England.
Health promotion and primary prevention in 21 European countries
Authors: Barnfield A , Savolainen N
Published: November 2019

It has been estimated that chronic diseases cost EU economies €115 billion or 0.8% of GDP annually. Approximately 70% to 80% of health care budgets are spent on treating chronic diseases. There is a wealth of knowledge within EU Member States on effective ways to prevent chronic diseases and promote health and wellbeing. There is great potential to reduce the burden by making better use of this knowledge as we know that the majority of chronic diseases can be prevented, or their onset delayed.

In order to unlock this knowledge we have compiled health promotion landscape reports from twenty-one European countries involved in the Joint Action CHRODIS PLUS. This paper will present the current actions, policies, and programmes that European countries are currently undertaking in health promotion. It is based on responses to a specially designed questionnaire that asked countries to assess their good practices, identify their gaps and needs, and outline their policy contexts and capacity in relation to health promotion. This paper makes four key conclusions: (1) health promotion across Europe receives limited attention from policy makers; (2) there is a division between medical and social approaches to health and health in all policies needs to be fully implemented more widely in more countries in Europe; (3) there is not enough funding for health promotion; (4) health promotion needs further operationalisation to facilitate easier monitoring and value assessment.

The need to develop mechanisms to share information, examples of good practice, and support for capacity development in health promotion and primary prevention is a shared goal across European countries. The Joint Action CHRODIS PLUS will lead the effort in implementing good practices, exploring inter- and intra-sectoral collaboration, and encouraging resilient and better informed investment in health promotion and primary prevention. The country reviews and this paper are a first step in that direction.
Nurse Aide Retention in Nursing Homes
Authors: Castle Nicholas G , Hyer Kathryn , Harris John A , Engberg John
Published: November 2019

Background and Objectives

The association of nurse aide retention with three quality indicators is examined. Retention is defined as the proportion of staff continuously employed in the same facility for a defined period of time.

Research Design and Methods

Data used in this investigation came from survey responses from 3,550 nursing facilities, Certification and Survey Provider Enhanced Reporting data, and the Area Resource File. Staffing characteristics, quality indicators, facility, and market information from these data sources were all measured in 2016. Nurse aide retention was measured at 1, 2, and 3 years of employment. The quality indicators examined were a count of all deficiency citations, quality of care deficiency citations, and J, K, L deficiency citations. Negative binomial regression analyses were used to study the associations between the three different retention measures and these three quality indicators.

Results

The 1-, 2-, and 3-year nurse aide retention measures were 53.2%, 41.4%, and 36.1%, respectively. The regression analyses show low levels of retention to be generally associated with poor performance on the three deficiency citation quality indicators examined.

Discussion and Implications

The research presented starts to provide information on nurse aide retention as an important workforce challenge and its potential impact on quality. Retention may be an additional staffing characteristic of nursing facilities with substantial policy and practice relevance.
Two New Species of Taygetina With a Possible Case of ‘Juxta Loss’ in Butterflies (Lepidoptera: Nymphalidae: Satyrinae)
Authors: Nakahara Shinichi , Matos-Maraví Pável , Barbosa Eduardo P , Willmott Keith R , Lamas Gerardo , Freitas André V L
Published: November 2019

The male genitalic characters of Hexapoda are well known for their great taxonomic and systematic value. Despite insect male genitalia displaying large diversity, variation, and modification across orders, some structures are consistently present, and such characters can serve as the basis for discussion regarding homology. In the order Lepidoptera, a male genitalic structure widely known as the ‘juxta’ is present in many taxa and absence or modification of this character can be phylogenetically informative at the generic or higher level. We here focus on the systematics of the so-called ‘Taygetis clade’ within the nymphalid subtribe Euptychiina, and report an unusual case of ‘juxta loss’ in a single species, Taygetina accacioi Nakahara & Freitas, n. sp., a new species from Brazil named and described herein. Additionally, we describe another west Amazonian Taygetina Forster, 1964 species, namely Taygetina brocki Lamas & Nakahara, n. sp., in order to better document the species diversity of Taygetina. Our most up-to-date comprehensive molecular phylogeny regarding ‘Taygetis clade’ recovered these two species as members of a monophyletic Taygetina, reinforcing the absence of juxta being a character state change occurring in a single lineage, resulting in an apomorphic condition, which we report here as a rare case in butterflies (Papilionoidea).
Gene Duplication Accelerates the Pace of Protein Gain and Loss from Plant Organelles
Authors: Costello Rona , Emms David M , Kelly Steven
Published: November 2019

Organelle biogenesis and function is dependent on the concerted action of both organellar-encoded (if present) and nuclear-encoded proteins. Differences between homologous organelles across the Plant Kingdom arise, in part, as a result of differences in the cohort of nuclear-encoded proteins that are targeted to them. However, neither the rate at which differences in protein targeting accumulate nor the evolutionary consequences of these changes are known. Using phylogenomic approaches coupled to ancestral state estimation, we show that the plant organellar proteome has diversified in proportion with molecular sequence evolution such that the proteomes of plant chloroplasts and mitochondria lose or gain on average 3.6 proteins per million years. We further demonstrate that changes in organellar protein targeting are associated with an increase in the rate of molecular sequence evolution and that such changes predominantly occur in genes with regulatory rather than metabolic functions. Finally, we show that gain and loss of protein target signals occurs at a higher rate following gene duplication, revealing that gene and genome duplication are a key facilitator of plant organelle evolution.
Objectively measured sleep and telomere length in a population-based cohort of children and midlife adults
Authors: Nguyen Minh Thien , Lycett Kate , Olds Timothy , Matricciani Lisa , Vryer Regan , Ranganathan Sarath , Burgner David , Saffery Richard , Wake Melissa
Published: November 2019

Study Objectives

Poor sleep patterns in older adults are associated with chromosomal telomere shortening, a marker of cellular senescence. However, studies have relied on self-reported sleep characteristics, with few data for younger individuals. We investigated whether sleep measured via actigraphy was cross-sectionally associated with telomere length in children and midlife adults.

Methods

A population-based sample of 1874 11–12 year olds and midlife adults (mean age 44 years, SD 5.1) had biological and physical assessments at centers across Australia in 2015–2016. Sleep characteristics, including duration, onset, offset, day-to-day variability, and efficiency, were derived from actigraphy. Relative telomere length (T/S ratio) was measured by quantitative polymerase chain reaction on genomic DNA from peripheral blood. Multivariable regression models estimated associations, adjusting for prespecified confounders.

Results

Both sleep and telomere data were available for 728 children and 1070 adults. Mean (SD) T/S ratio was 1.09 (0.55) in children and 0.81 (0.38) in adults. T/S ratio was not predicted by sleep duration (β 0.04, 95% confidence interval [CI] −0.02 to 0.09, p = .16, children; β −0.004, 95% CI −0.03 to 0.02, p = .70, adults) or most other sleep metrics. The only exception was a weak association between later sleep timing (the midpoint of sleep onset and offset) and longer telomeres in adults (β 0.03, 95% CI 0.01 to 0.06, p = .01).

Conclusions

Objective sleep characteristics show no convincing associations with telomere length in two largely healthy populations up to at least midlife. Sleep–telomere associations may be a late-life occurrence or may present only with a trigger such as presence of other morbidities.
Pragmatic measures for implementation research: development of the Psychometric and Pragmatic Evidence Rating Scale (PAPERS)
Authors: Stanick Cameo F , Halko Heather M , Nolen Elspeth A , Powell Byron J , Dorsey Caitlin N , Mettert Kayne D , Weiner Bryan J , Barwick Melanie , Wolfenden Luke , Damschroder Laura J , Lewis Cara C
Published: November 2019

The use of reliable, valid measures in implementation practice will remain limited without pragmatic measures. Previous research identified the need for pragmatic measures, though the characteristic identification used only expert opinion and literature review. Our team completed four studies to develop a stakeholder-driven pragmatic rating criteria for implementation measures. We published Studies 1 (identifying dimensions of the pragmatic construct) and 2 (clarifying the internal structure) that engaged stakeholders—participants in mental health provider and implementation settings—to identify 17 terms/phrases across four categories: Useful, Compatible, Acceptable, and Easy. This paper presents Studies 3 and 4: a Delphi to ascertain stakeholder-prioritized dimensions within a mental health context, and a pilot study applying the rating criteria. Stakeholders (N = 26) participated in a Delphi and rated the relevance of 17 terms/phrases to the pragmatic construct. The investigator team further defined and shortened the list, which were piloted with 60 implementation measures. The Delphi confirmed the importance of all pragmatic criteria, but provided little guidance on relative importance. The investigators removed or combined terms/phrases to obtain 11 criteria. The 6-point rating system assigned to each criterion demonstrated sufficient variability across items. The grey literature did not add critical information. This work produced the first stakeholder-driven rating criteria to assess whether measures are pragmatic. The Psychometric and Pragmatic Evidence Rating Scale (PAPERS) combines the pragmatic criteria with psychometric rating criteria, from previous work. Use of PAPERS can inform development of implementation measures and to assess the quality of existing measures.
How intensive longitudinal data can stimulate advances in health behavior maintenance theories and interventions
Authors: Dunton Genevieve F , Rothman Alexander J , Leventhal Adam M , Intille Stephen S
Published: November 2019

Interventions that promote long-term maintenance of behaviors such as exercise, healthy eating, and avoidance of tobacco and excessive alcohol are critical to reduce noncommunicable disease burden. Theories of health behavior maintenance tend to address reactive (i.e., automatic) or reflective (i.e., deliberative) decision-making processes, but rarely both. Progress in this area has been stalled by theories that say little about when, why, where, and how reactive and reflective systems interact to promote or derail a positive health behavior change. In this commentary, we discuss factors influencing the timing and circumstances under which an individual may shift between the two systems such as (a) limited availability of psychological assets, (b) interruption in exposure to established contextual cues, and (c) lack of intrinsic or appetitive motives. To understand the putative factors that regulate the interface between these systems, research methods are needed that are able to capture properties such as (a) fluctuation over short periods of time, (b) change as a function of time, (c) context dependency, (d) implicit and physiological channels, and (e) idiographic phenomenology. These properties are difficult to assess with static, cross-sectional, laboratory-based, or retrospective research methods. We contend that intensive longitudinal data (ILD) collection and analytic strategies such as smartphone and sensor-based real-time activity and location monitoring, ecological momentary assessment (EMA), machine learning, and systems modeling are well-positioned to capture and interpret within-person shifts between reactive and reflective systems underlying behavior maintenance. We conclude with examples of how ILD can accelerate the development of theories and interventions to sustain health behavior over the long term.
The Impact of Information Sharing on the Use of Collateral versus Guarantees
Authors: De Haas Ralph , Millone Matteo
Published: November 2019

This study exploits contract-level data from Bosnia and Herzegovina to assess the impact of a new credit registry on the use of borrower collateral versus third-party guarantees. Among first-time borrowers, the introduction of mandatory information sharing leads to a shift from collateral to guarantees, in particular for riskier borrowers. Among repeat borrowers, both collateral and guarantee requirements decline in proportion to the length of the lending relationship. These results suggest that information sharing can both reduce adverse selection among new borrowers and hold-up problems among repeat borrowers.
The effects of anthropogenic noise on animals: a meta-analysis
Authors: Kunc Hansjoerg P. , Schmidt Rouven
Published: November 2019

Anthropogenic noise has become a major global pollutant and studies have shown that noise can affect animals. However, such single studies cannot provide holistic quantitative assessments on the potential effects of noise across species. Using a multi-level phylogenetically controlled meta-analysis, we provide the first holistic quantitative analysis on the effects of anthropogenic noise. We found that noise affects many species of amphibians, arthropods, birds, fish mammals, molluscs and reptilians. Interestingly, phylogeny contributes only little to the variation in response to noise. Thus, the effects of anthropogenic noise can be explained by the majority of species responding to noise rather than a few species being particularly sensitive to noise. Consequently, anthropogenic noise must be considered as a serious form of environmental change and pollution as it affects both aquatic and terrestrial species. Our analyses provide the quantitative evidence necessary for legislative bodies to regulate this environmental stressor more effectively.
Species diversity and composition drive the aesthetic value of coral reef fish assemblages
Authors: Tribot Anne-Sophie , Deter Julie , Claverie Thomas , Guillhaumon François , Villéger Sébastien , Mouquet Nicolas
Published: November 2019

Cultural and recreational values of biodiversity are considered as important dimensions of nature's contribution to people. Among these values, the aesthetics can be of major importance as the appreciation of beauty is one of the simplest forms of human emotional response. Using an online survey, we disentangled the effects of different facets of biodiversity on aesthetic preferences of coral reef fish assemblages that are among the most emblematic assemblages on Earth. While we found a positive saturating effect of species' richness on human preference, we found a net negative effect of species abundance, no effect of species functional diversity and contrasting effects of species composition depending on species' attractiveness. Our results suggest that the biodiversity–human interest relationship is more complex than has been previously stated. By integrating several scales of organization, our study is a step forward in better evaluating the aesthetic value of biodiversity.
Time-scales Herglotz type Noether theorem for delta derivatives of Birkhoffian systems
Authors: Tian Xue , Zhang Yi
Published: November 2019

The time-scales theory provides a powerful theoretical tool for studying differential and difference equations simultaneously. With regard to Herglotz type variational principle, this generalized variational principle can deal with non-conservative or dissipative problems. Combining the two tools, this paper aims to study time-scales Herglotz type Noether theorem for delta derivatives of Birkhoffian systems. We introduce the time-scales Herglotz type variational problem of Birkhoffian systems firstly and give the form of time-scales Pfaff–Herglotz action for delta derivatives. Then, time-scales Herglotz type Birkhoff’s equations for delta derivatives are derived by calculating the variation of the action. Furthermore, time-scales Herglotz type Noether symmetry for delta derivatives of Birkhoffian systems are defined. According to this definition, time-scales Herglotz type Noether identity and Noether theorem for delta derivatives of Birkhoffian systems are proposed and proved, which can become the ones for delta derivatives of Hamiltonian systems or Lagrangian systems in some special cases. Therefore, it is shown that the results of Birkhoffian formalism are more universal than Hamiltonian or Lagrangian formalism. Finally, the time-scales damped oscillator and a non-Hamiltonian Birkhoffian system are given to exemplify the superiority of the results.
Now or never: noticing occurs early in sustained inattentional blindness
Authors: Wood Katherine , Simons Daniel J.
Published: November 2019

People can show sustained inattentional blindness for unexpected objects visible for seconds or even minutes. Would such objects eventually be noticed given enough time, with the likelihood of noticing accumulating while the unexpected object is visible? Or, is there a narrow window around onset or offset when an object is most likely to be detected, with the chances of noticing dropping outside of that window? Across three experiments (total
n
's = 283, 756, 488) exploring the temporal dynamics of noticing in sustained inattentional blindness, subjects who noticed the unexpected object did so soon after it onset. Doubling or even tripling the time when the unexpected object was visible barely affected the likelihood of noticing it and had no impact on how accurately subjects reported its features. When people notice an unexpected object in these sustained inattentional blindness tasks, they do so soon after the unexpected object onsets.
Saccharomycopsis oxydans sp. nov., a new non-fermentative member in the genus Saccharomycopsis isolated from a traditional dairy product of Iran
Authors: Hajihosseinali Mehrdad , Nasr Shaghayegh , Amoozegar Mohammad Ali , Yurkov Andrey
Published: November 2019

A total of 21 yeast isolates were recovered as part of a research project on biodiversity of yeasts in traditional dairy products in Alborz province, Iran. Standard protocols were used to carry out phenotypic, biochemical, physiological characterization and the phylogenetic analysis of combined the D1/D2 domain of the large ribosomal subunit (26S or LSU) and ITS region sequences. Five strains represented a potential new ascomycetous yeast species. Ascospore formation was not observed in these strains, and they did not ferment the examined carbon sources. Phylogenetic analysis placed these isolates in a well-supported sub-clade in the genus Saccharomycopsis. Here, we describe this novel yeast as Saccharomycopsis oxydans sp. nov.
Creatine Kinase is Associated with Bleeding after Myocardial Infarction
Authors: Brewster Lizzy M. , Fernand Jim D.
Published: November 2019

Background

Highly elevated plasma activity of the ADP scavenging enzyme creatine kinase (CK) might reduce ADP and ADP-dependent platelet activation. Therefore, we studied, whether high CK after myocardial infarction (MI) is associated with bleeding.

Methods

Data of the Thrombolysis In Myocardial Infarction Study Group phase II trial on the efficacy of angioplasty following intravenous recombinant tissue-type plasminogen activator (rt-PA), are used to assess whether peak plasma CK (CKmax) is independently associated with adjudicated fatal or non-fatal bleeding (primary) and combined bleeding/all-cause mortality (secondary) in multivariable binomial logistic regression analysis, adjusting for baseline and treatment allocation covariates.

Results

The included patients (N=3339, 82% men, 88% white, mean age 57 y, SE 0.2), had a history of angina pectoris (55%), hypertension (38%), and/or diabetes mellitus (13%). CKmax ranged between 16 and 55 890 IU/L (mean 2389 IU/L; SE 41), reached within 8 h in 51% of the patients (93% within 24 h). Adjudicated fatal/non-fatal bleeding occurred in 30% of the patients (respectively 26% in the low vs 34% in the high CK tertile), and bleeding/all-cause mortality in 35% (29% in the low, vs 40% in the high CK tertile). The adjusted odds ratio for fatal/non-fatal bleeding (vs not bleeding and survival) was 2.6 [95% CI, 1.8 to 3.7]/log CKmax increase, and 3.1 [2.2 to 4.4] for bleeding/all-cause mortality).

Conclusion

Highly elevated plasma CK after MI might be a hitherto overlooked independent indicator of bleeding and hemorrhagic death. This biologically plausible association warrants prospective study of the potential role of CK in hemorrhagic diathesis, and the risk of severe, potentially fatal bleeding with antithrombotic or thrombolytic therapy in the presence of high plasma CK.

ClinicalTrials.gov identifier (NCT number)

NCT00000505
DNA origami nanostructures as a tool for the targeted destruction of bacteria
Authors: Mela Ioanna , Vallejo-Ramirez Pedro P. , Makarchuk Stanislaw , Christie Graham , Bailey David , Henderson Robert. M. , Sugiyama Hiroshi , Endo Masayuki , Kaminski Clemens F.
Published: November 2019

Antibiotic resistance is a growing worldwide human health issue that is now rendering us vulnerable once again to infections that have been treatable for decades. Various approaches have been proposed in an effort to overcome this threat and effectively treat bacterial infections. We use a DNA origami nanostructure, functionalized with aptamers, as a vehicle for delivering the antibacterial peptide lysozyme in a specific and efficient manner, in order to destroy bacterial targets. We test the system against Gram-positive (Bacillus subtilis) and Gram - negative (Escherichia coli) targets. We use direct stochastic optical reconstruction microscopy (dSTORM) and atomic force microscopy (AFM) to characterize the DNA origami nanostructures and structured illumination microscopy (SIM) to assess the binding of origami to the bacteria. We show that treatment with lysozyme-functionalized origami slows bacterial growth more effectively than treatment with free lysozyme. Our study introduces DNA origami as a tool in the fight against antibiotic resistance, and our results demonstrate the specificity and efficiency of the nanostructure as a drug delivery vehicle.

Abstract Figure
Nanocomposite bioink exploits dynamic covalent bonds between nanoparticles and polysaccharides for precision bioprinting
Authors: Lee Mihyun , Bae Kraun , Levinson Clara , Zenobi-Wong Marcy
Published: November 2019

The field of bioprinting has made significant recent progress towards engineering tissues with increasing complexity and functionality. It remains challenging, however, to develop bioinks with optimal biocompatibility and good printing fidelity. Here, we demonstrate enhanced printability of a polymer-based bioink based on dynamic covalent linkages between nanoparticles (NPs) and polymers, which retains good biocompatibility. Amine-presenting silica NPs (ca. 45 nm) were added to a polymeric ink containing oxidized alginate (OxA). The formation of reversible imine bonds between amines on the NPs and aldehydes of OxA lead to significantly improved rheological properties and high printing fidelity. In particular, the yield stress increased with increasing amounts of NPs (14.5 Pa without NPs, 79 Pa with 2 wt% NPs). In addition, the presence of dynamic covalent linkages in the gel provided improved mechanical stability over 7 days compared to ionically crosslinked gels. The nanocomposite ink retained high printability and mechanical strength, resulting in generation of centimetre-scale porous constructs and an ear structure with overhangs and high structural fidelity. Furthermore, the nanocomposite ink supported both in vitro and in vivo maturation of bioprinted gels containing chondrocytes. This approach based on simple oxidation can be applied to any polysaccharide, thus the widely applicability of the method is expected to advance the field towards the goal of precision bioprinting.
Lipid-mediated insertion of Toll-like receptor (TLR) ligands for facile immune cell engineering
Authors: Zhang Michael H. , Slaby Emily M. , Stephanie Georgina , Yu Chunsong , Watts Darcy M. , Liu Haipeng , Szeto Gregory L.
Published: November 2019

Cell-based immunotherapies have tremendous potential to treat many diseases, such as activating immunity in cancer or suppressing it in autoimmune diseases. Most cell-based cancer immunotherapies in the clinic provide adjuvant signals through genetic engineering to enhance T cell functions. However, genetically encoded signals have minimal control over dosing and persist for the life of a cell lineage. These properties make it difficult to balance increasing therapeutic efficacy with reducing toxicities. Here, we demonstrated the potential of phospholipid-coupled ligands as a non-genetic system for immune cell engineering. This system provides simple, controlled, non-genetic adjuvant delivery to immune cells via lipid-mediated insertion into plasma membranes. Lipid-mediated insertion (depoting) successfully delivered Toll-like receptor (TLR) ligands intracellularly and onto cell surfaces of diverse immune cells. These ligands depoted into immune cells in a dose-controlled fashion and did not compete during multiplex pairwise loading. Immune cell activation could be enhanced by autocrine and paracrine mechanisms depending on the biology of the TLR ligand tested. We determined that depoted ligands can functionally persist on plasma membranes for up to four days in naïve and activated T cells, enhancing their activation, proliferation, and skewing cytokine secretion. Depoted ligands provide a persistent yet non-permanent adjuvant signal to immune cells that may minimize the intensity and duration of toxicities compared to permanent genetic delivery. Altogether, these findings demonstrate potential for lipid-mediated insertion (depoting) as a universal cell engineering approach with unique, complementary advantages to other cell engineering methods.
Domoic acid disruption of neurodevelopment and behavior involves altered myelination in the spinal cord
Authors: Panlilio Jennifer M. , Aluru Neelakanteswar , Hahn Mark E.
Published: November 2019

Harmful algal blooms (HABs) produce potent neurotoxins that threaten human health. Early life exposure to low levels of the HAB toxin domoic acid (DomA) produces long-lasting behavioral deficits, but the mechanisms involved are unknown. Using zebrafish, we investigated the developmental window of susceptibility to low doses of DomA and examined cellular and molecular targets. Larvae exposed to DomA at 2 days post-fertilization (dpf), but not at 1 or 4 dpf, showed consistent deficits in startle behavior including reduced responsiveness and altered kinematics. Similarly, myelination in the spinal cord was disorganized after exposure only at 2 dpf. Time-lapse imaging revealed disruption of the initial stages of myelination. DomA down-regulated genes required for maintaining myelin structure and the axonal cytoskeleton. These results identify a developmental window of susceptibility to DomA-induced behavioral deficits involving altered gene expression and disrupted myelin structure, and establish a zebrafish model for investigating the underlying mechanisms.

GRAPHICAL ABSTRACT
Gene expression profiles based flux balance model to predict the carbon source for Bacillus subtilis
Authors: Thanamit Kulwadee , Hoerhold Franziska , Oswald Marcus , Koenig Rainer
Published: November 2019

Finding drug targets for antimicrobial treatment is a central focus in biomedical research. To discover new drug targets, we developed a method to identify which nutrients are essential for microorganisms. Using 13C labeled metabolites to infer metabolic fluxes is the most informative way to infer metabolic fluxes to date. However, the data can get difficult to acquire in complicated environments, for example, if the pathogen homes in host cells. Although data from gene expression profiling is less informative compared to metabolic tracer derived data, its generation is less laborious, and may still provide the relevant information. Besides this, metabolic fluxes have been successfully predicted by flux balance analysis (FBA). We developed an FBA based approach using the stoichiometric knowledge of the metabolic reactions of a cell combining them with expression profiles of the coding genes. We aimed to identify essential drug targets for specific nutritional uptakes of microorganisms. As a case study, we predicted each single carbon source out of a pool of eight different carbon sources for B. subtilis based on gene expression profiles. The models were in good agreement to models basing on 13C metabolic flux data of the same conditions. We could well predict every carbon source. Later, we applied successfully the model to unseen data from a study in which the carbon source was shifted from glucose to malate and vice versa. Technically, we present a new and fast method to reduce thermodynamically infeasible loops, which is a necessary preprocessing step for such model-building algorithms.

SIGNIFICANCE

Identifying metabolic fluxes using 13C labeled tracers is the most informative way to gain insight into metabolic fluxes. However, obtaining the data can be laborious and challenging in a complex environment. Though transcriptional data is an indirect mean to estimate the fluxes, it can help to identify this. Here, we developed a new method employing constraint-based modeling to predict metabolic fluxes embedding gene expression profiles in a linear regression model. As a case study, we used the data from Bacillus subtilis grown under different carbon sources. We could well predict the correct carbon source. Additionally, we established a novel and fast method to remove thermodynamically infeasible loops.
Global reprogramming of virulence and antibiotic resistance inPseudomonas aeruginosaby a single nucleotide polymorphism in the elongation factor-encoding gene,fusA1
Authors: Maunders Eve A. , Triniman Rory C. , Rahman Taufiq , Welch Martin
Published: November 2019

Pseudomonas aeruginosais a common opportunistic pathogen. The organism displays elevated intrinsic antibiotic resistance and can cause life-threatening infections. The gene encoding an elongation factor, FusA1, is frequently mutated in clinical isolates ofP. aeruginosafrom patients with cystic fibrosis (CF). Recent work has shown thatfusA1mutants often display elevated aminoglycoside resistance due to increased expression of the aminoglycoside efflux pump, MexXY. In the current work, we isolated a spontaneous gentamicin-resistantfusA1mutant (FusA1P443L) in whichmexXYexpression was increased. Through a combination of proteomic and transcriptomic analyses, we found that thefusA1mutant also exhibited large-scale but discrete changes in the expression of key pathogenicity-associated genes. Most notably, thefusA1mutant displayed greatly increased expression of the Type III Secretion system (T3SS), widely considered to be the most potent virulence factor in theP. aeruginosaarsenal, and also elevated expression of the Type VI Secretion (T6S) machinery. This was unexpected because expression of the T3SS is usually reciprocally coordinated with T6S system expression. ThefusA1mutant also displayed elevated exopolysaccharide production, dysregulated siderophore production, elevated ribosomal protein synthesis, and transcriptomic signatures indicative of translational stress. Each of these phenotypes (and almost all of the transcriptomic and proteomic changes associated with thefusA1mutation) were restored to levels comparable to that in the PAO1-derived progenitor strain by expression of the wild-typefusA1genein trans, indicating that the mutant gene is recessive. Our data show that in addition to elevating antibiotic resistance throughmexXYexpression (although we also identify additional contributory resistance mechanisms), mutations infusA1can lead to highly-selective dysregulation of virulence gene expression.
Spatially heterogeneous dynamics of cells in a growing tumor spheroid: Comparison between Theory and Experiments
Authors: Sinha Sumit , Kakkada Abdul N-Malmi , Li Xin , Samanta Himadri , Thirumalai D.
Published: November 2019

Collective cell movement, characterized by multiple cells that are in contact for substantial periods of time and undergo correlated motion, plays a central role in cancer and embryogenesis. Recent imaging experiments have provided time-dependent traces of individual cells, thus providing an unprecedented picture of tumor spheroid growth. By using simulations of a minimal cell model, we analyze the experimental data that map the movement of cells in fibrosarcoma tumor spheroid embedded in a collagen matrix. Both simulations and experiments show that cells in the core of the spheroid exhibit subdiffusive glassy dynamics (mean square displacement, Δ(t) ≈tαwithα< 1), whereas cells in the periphery exhibit superdiffusive motion, Δ(t) ≈tαwithα> 1). The motion of most of the cells near the periphery undergo highly persistent and correlated directional motion, thus explaining the observed superdiffusive behavior. Theαvalues for cells in the core and periphery, extracted from simulations and experiments are in near quantitative agreement with each other, which is surprising given that no parameter in the model was used to fit the measurements. The qualitatively different dynamics of cells in the core and periphery is captured by the fourth order susceptibility, introduced to characterize metastable states in glass forming systems. Analyses of the velocity autocorrelation of individual cells show remarkable spatial heterogeneity with no two cells exhibiting similar behavior. The prediction thatαshould depend on the location of the cells in the tumor is amenable to experimental test. The highly heterogeneous dynamics of cells in the tumor spheroid provides a plausible mechanism for the origin of intratumor heterogeneity.
Neural correlates of goal-directed and non-goal-directed movements
Authors: Sendhilnathan Naveen , Basu Debaleena , Goldberg Michael E. , Schall Jeffrey D. , Murthy Aditya
Published: November 2019

What are the neural correlates that distinguish goal-directed (G) from non-goal-directed movements (nG)? We investigated this question in the monkey frontal eye field, which is implicated in voluntary control of saccades. We found that only for G-saccades, the variability in spike rate across trials decreased, the regularity of spike timings within trials increased, the neural activity increased earlier from baseline and had a concurrent reduction of LFP beta band power.
Elevated CO2effects on morphology and survival rate in intertidal benthic foraminifera
Authors: Kannan Gunasekaran , Ayyappan Saravanakumar , Perumal Karthikeyan
Published: November 2019

Oceans are absorbing about one-third of the anthropogenic CO2from the atmosphere, and the excess CO2leads to reduce the seawater pH, carbonate ion concentrations and saturation states of biologically important calcium carbonate minerals. The ocean acidification affects many calcifying organisms such as foraminifera. The present study assessed experimentally modified ocean pH impacts on survival rate and shell morphology variation in three species of intertidal benthic foraminifera. Foraminifera was collected from Parangipettai coastal waters, Tamilnadu, India. Foraminiferal specimens were cultured for a period of five weeks at three different pH treatments that replicated future scenarios of a high CO2and low pH. The experimental results revealed that reduction of seawater pH significantly affected foraminiferal survival and morphology. Scanning Electron Microscopic observations revealed significant changes in foraminiferal morphology with clear evidence of dissolution and cracking processes on the test surface, and reduction in teeth structure in treatments with decreasing pH. Hence, altering the seawater chemistry might have extensive impacts on benthic foraminifera.
Phenotypic heterogeneity in particle size is a viral mechanism of persistence
Authors: Li Tian , Li Zhenyu , Deans Erin E. , Mittler Eva , Liu Meisui , Chandran Kartik , Ivanovic Tijana
Published: November 2019

Assembly of many enveloped animal viruses yields a mixture of particle morphologies, from small, essentially isometric forms to vastly longer, filamentous forms. Selective advantage of pleomorphic virus structure is apparent onlyin vivo, hindering functional characterization of distinct particle shapes. Here we sought to mimic thein vivopressures on virus entry in cultured cells and in single-particle experiments of membrane fusion for influenza virus preparations enriched in spherical or filamentous particles. We show that filamentous shape confers functional advantage in the presence of neutralizing antibodies or fusion inhibitors and in cases of only limited fusion-protein activation. For very long particles, inactivation of >95% of associated fusion proteins still permits enough active-protein cooperation to induce membrane merger. Experiments with Ebola virus-like particles show that resistance to antibody pressure is a conserved feature of filamentous particles. Our results offer a strategy for averting drug resistance or immune evasion by targeting filamentous virus particles.
IRIS: Big data-informed discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
Authors: Pan Yang , Lee Alexander H. , Yang Harry T. , Wang Yuanyuan , Xu Yang , Kadash-Edmondson Kathryn E. , Phillips John , Champhekar Ameya , Puig Cristina , Ribas Antoni , Witte Owen N. , Prins Robert M. , Xing Yi
Published: November 2019

Aberrant alternative splicing (AS) is widespread in cancer, leading to an extensive but largely unexploited repertoire of potential immunotherapy targets. Here we describe IRIS, a computational platform leveraging large-scale cancer and normal transcriptomics data to discover AS-derived tumor antigens for T-cell receptor (TCR) and chimeric antigen receptor T-cell (CAR-T) therapies. Applying IRIS to RNA-Seq data from 22 glioblastomas resected from patients, we identified candidate epitopes and validated their recognition by patient T cells, demonstrating IRIS’s utility for expanding targeted cancer immunotherapy.
A unique predator in a unique ecosystem: modelling the apex predator from the late cretaceous crocodyliform-dominated fauna in brazil
Authors: Montefeltro Felipe C. , Lautenschlager Stephan , Godoy Pedro L. , Ferreira Gabriel S. , Butler Richard J.
Published: November 2019

Theropod dinosaurs were relatively scarce in the Late Cretaceous ecosystems of southeast Brazil. Instead, hypercarnivorous crocodyliforms known as baurusuchids were abundant and probably occupied the ecological role of apex predators. Baurusuchids exhibited a series of morphological adaptations hypothesised to be associated with this ecological role, but quantitative biomechanical analyses of their morphology have so far been lacking. Here, we employ a biomechanical modelling approach, applying finite element analysis (FEA) to models of the skull and mandibles of a baurusuchid specimen. This allowed us to characterise the craniomandibular apparatus of baurusuchids, as well as to compare the functional morphology of the group to that of other archosaurian carnivores, such as theropods and crocodylians. Our results support the ecological role of baurusuchids as specialised apex predators in the continental Late Cretaceous ecosystems of South America. With a relatively weak bite force (∼600 N), baurusuchids’ predation strategies likely relied on other morphological specializations, such as ziphodont dentition and strong cervical musculature. Comparative assessments of the stress distribution and magnitude of scaled models of other predators (the theropod Allosaurus fragilis and the living crocodylian Alligator mississippiensis) consistently show different responses to loadings under the same functional scenarios, suggesting distinct predatory behaviours for these animals. The unique selective pressures in the arid to semi-arid Late Cretaceous ecosystems of southeast Brazil, which were dominated by crocodyliforms, possibly drove the emergence and evolution of the biomechanical features seen in baurusuchids, which are distinct from those previously reported for other predatory taxa.
Recently formed context fear memories can be retrieved without the hippocampus
Authors: Krueger Jamie N. , Wilmot Jacob H. , Teratani-Ota Yusuke , Puhger Kyle R. , Nemes Sonya E. , Lafreniere Marrisa , Wiltgen Brian J.
Published: November 2019

The current study determined if inactivation of the dorsal hippocampus impairs the retrieval of newly formed context fear memories. This region was silencing by activating inhibitory neurons or by hyperpolarizing pyramidal cells directly. When inhibitory neurons were stimulated with ChR2, memory retrieval was significantly impaired. In contrast, when the same neurons were activated with the excitatory DREADD hM3Dq, retrieval was not affected. This dissociation was not due to differences in inhibition, as both manipulations activated interneurons and reduced excitation throughout the dorsal hippocampus. Therefore, we hypothesize that the retrieval deficit caused by ChR2 stimulation is due to an immediate reduction in hippocampal activity that does not provide enough time for other brain regions to compensate. Stimulation of DREADDs, on the other hand, produces a gradual loss of excitation that takes several minutes to reach asymptote. This appears to be a sufficient amount of time for extra-hippocampal structures to become engaged and express context fear. Implications for theories of hippocampal function, systems consolidation and memory retrieval are discussed.
Atypical Protein Kinase C iota (PKCλ/ι) Ensures Mammalian Development by Establishing the Maternal-Fetal Exchange Interface
Authors: Bhattacharya Bhaswati , Home Pratik , Ganguly Avishek , Ray Soma , Ghosh Ananya , Islam Rashedul , French Valerie , Marsh Courtney , Gunewardena Sumedha , Okae Hiroaki , Arima Takahiro , Paul Soumen
Published: November 2019

In utero mammalian development relies on the establishment of the maternal–fetal exchange interface, which ensures transportation of nutrients and gases between the mother and the fetus. This exchange interface is established via development of multinucleated syncytiotrophoblast cells (SynTs) during placentation. In mouse, SynTs develop via differentiation of the trophoblast progenitor cells (TSPCs) of the placenta primordium and in human, SynTs are developed via differentiation of villous cytotrophoblast (CTB) progenitors. Despite the critical need in pregnancy progression, conserved signaling mechanisms that ensure SynT development are poorly understood. Herein, we show that Atypical Protein Kinase C iota (PKCλ/I) plays an essential role in establishing the SynT differentiation program in trophoblast progenitors. Loss of PKCλ/I in the mouse TSPCs abrogates SynT development leading to embryonic death at ~E9.0. We also show that PKCλ/I-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. PKCλ/I is selectively expressed in the first-trimester CTBs of a developing human placenta. Furthermore, loss of PKCλ/I in CTB-derived human trophoblast stem cells (Human TSCs) impairs their SynT differentiation potential both in vitro and after transplantation in immunocompromised mice. Our mechanistic analyses indicate that PKCλ/I signaling maintains expression of GCM1, GATA2, and PPARγ, which are key transcription factors to instigate SynT differentiation programs in both mouse and human trophoblast progenitors. Our study uncovers a conserved molecular mechanism, in which PKCλ/I signaling regulates establishment of the maternal-fetal exchange surface by promoting trophoblast progenitor to SynT transition during placentation.
Ubiquitination modulates a protein energy landscape site-specifically with consequences for proteasomal degradation
Authors: Carroll Emma C , Greene Eric R , Martin Andreas , Marqusee Susan
Published: November 2019

Cellular environments modulate protein energy landscapes to drive important biology, where small perturbations are consequential for biological signaling, allostery, and other vital processes. The energetic effects of ubiquitination are interesting due to its potential influence on degradation by the 26S proteasome, which requires intrinsically flexible or unstructured initiation regions that many known proteasome substrates lack. We generated proteins with natively attached, isopeptide-linked ubiquitin in structured domains to assess the energetic changes contributed by ubiquitin and how such changes manifest at the proteasome. Ubiquitination at sensitive sites destabilizes the native structure, and thereby increases the rate of degradation for substrates containing unstructured initiation regions. Importantly, this ubiquitination can even induce those requisite regions in well-folded proteins for proteasomal engagement. Our results indicate a biophysical role of site-specific ubiquitination as a potential regulatory mechanism for energy-dependent substrate degradation.