bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of H3K9me3 and DNA methylation by tethered heterochromatin factors in
Neurospora crassa
Authors: Gessaman Jordan D. , Selker Eric U.
Published: October 2017

Significance

Chemical modifications to histones and DNA are critical for the establishment of distinct chromatin states and the regulation of the underlying DNA sequence. Aberrant heterochromatin, often with hyper- or hypomethylated DNA, is associated with many human disease states, including cancers, but the mechanisms controlling heterochromatin establishment are not fully understood. We developed in vivo protein tethering in
Neurospora crassa
, a filamentous fungus harboring many aspects of heterochromatin found in higher eukaryotes, and used it to direct heterochromatin to normally active, euchromatic loci. Testing tethered heterochromatin factors in various mutant backgrounds revealed interrelationships among the classic hallmarks of heterochromatin: DNA methylation, histone deacetylation, and H3K9me3. We also found evidence of complex regulation of the DIM-2 DNA methyltransferase.
Similarity between soybean and
Arabidopsis
seed methylomes and loss of non-CG methylation does not affect seed development
Authors: Lin Jer-Young , Le Brandon H. , Chen Min , Henry Kelli F. , Hur Jungim , Hsieh Tzung-Fu , Chen Pao-Yang , Pelletier Julie M. , Pellegrini Matteo , Fischer Robert L. , Harada John J. , Goldberg Robert B.
Published: October 2017

Significance

We describe the spatial and temporal profiles of soybean and
Arabidopsis
seed methylomes during development. CHH methylation increases globally from fertilization through dormancy in all seed parts, decreases following germination, and targets primarily transposons. By contrast, CG- and CHG-context methylation remains constant throughout seed development. Mutant seeds lacking non-CG methylation develop normally, but have a set of up-regulated transposon RNAs suggesting that the CHH methylation increase may be a failsafe mechanism to reinforce transposon silencing. Major classes of seed genes have similar methylation profiles, whether they are active or not. Our results suggest that soybean and
Arabidopsis
seed methylomes are similar, and that DNA methylation does not play a significant role in regulating many genes important for seed development.
Indigenous Toponyms in the Antipodes: A Gazetteer-Based Study
Authors: Tent Jan
Published: October 2017

During the centuries of Britain’s colonial expansion, English was transplanted to the four corners of the globe, and became an extensive and prolific borrower of general lexical items and toponyms from indigenous languages. The Englishes of Australia, New Zealand, and Fiji are three typical examples. Indigenous loanwords and toponyms comprise one of the most distinctive features of these Englishes, and are regularly used to express national identity. Although these nations share a common colonial language, they differ markedly in their indigenous cultures and languages, the way they were occupied, and the colonizers’ attitudes towards indigenous peoples. These factors significantly influenced relationships between the two groups, and resulted in distinct patterns and degrees of indigenous borrowings into the three regional varieties of English. This gazetteer-based study provides evidence of these patterns and degrees of borrowing through an analysis of the number and distribution of indigenous toponyms in the three jurisdictions. It also considers the various linguistic, sociocultural, attitudinal, and historical factors that shaped place naming.
A new lead to NLRP3 inhibition
Authors: Lamkanfi Mohamed , Dixit Vishva M.
Published: October 2017

The discovery of a small molecule inhibitor that targets the inflammasome sensor NLRP3 offers a new path for the development of selective inflammasome blockers with potential therapeutic benefit in a wide range of human diseases (in this issue, see Jiang et al., https://doi.org/10.1084/jem.20171419).
Subtle mutation, far-reaching effects
Authors: Apell Hans-Jürgen
Published: October 2017

Insufficient sodium-ion extrusion by mutated Na+,K+-ATPases causes hyperaldosteronism.
Optoelectronic and photoacoustic studies of an organic dye synthesized through green route
Authors: Vijayakumar S , Sreelatha S , Hatamimoslehabadi M , Yelleswarappu C S
Published: October 2017

An azo dye was prepared through an environmentally benign and economically feasible synthesis route with cardanol as a starting material. Cardanol is a cost-effective and renewable natural source obtained from Cashew Nut Shell Liquid, a by-product of the cashew industry. The dye was spectrally characterized by IR, UV-Vis, NMR and fluorescence studies. UV-Vis absorption showed a bathochromic shift between solvents of lower and higher polarities. Nonlinear optical and photoacoustic properties were studied using a frequency doubled Nd:YAG laser producing 532 nm laser pulses of 3 ns pulse width. Results show that the nonlinear absorption coefficient decreases with the increase of on-axis intensity, suggesting excited state absorption as the principal mechanism. The observed nonlinearity has applications in optoelectronics.
Global Economic Growth and Agricultural Land Conversion under Uncertain Productivity Improvements in Agriculture
Authors: Lanz Bruno , Dietz Simon , Swanson Tim
Published: October 2017

We study how stochasticity in the evolution of agricultural productivity interacts with economic and population growth at the global level. We use a two‐sector Schumpeterian model of growth, in which a manufacturing sector produces the traditional consumption good and an agricultural sector produces food to sustain contemporaneous population. Agriculture demands land as an input, itself treated as a scarce form of capital. In our model both population and sectoral technological progress are endogenously determined, and key technological parameters of the model are structurally estimated using 1960‐2010 data on world GDP, population, cropland and technological progress. Introducing random shocks to the evolution of total factor productivity in agriculture, we show that uncertainty optimally requires more land to be converted into agricultural use as a hedge against production shortages, and that it significantly affects both optimal consumption and population trajectories.
Benzodiazepine Consumption Is Associated With Lower Blood Pressure in Ambulatory Blood Pressure Monitoring (ABPM): Retrospective Analysis of 4938 ABPMs
Authors: Mendelson Nitsan , Gontmacher Bella , Vodonos Allina , Novack Victor , Abu-AjAj Muhammad , Wolak Arik , Shalev Haddar , Wolak Talya
Published: October 2017

BACKGROUND

The effect of chronic benzodiazepine use on blood pressure has not been documented. We aimed to evaluate whether regular benzodiazepine use can be associated to the results of ambulatory blood pressure monitoring (ABPM).

METHODS

A retrospective analysis of the ABPM database between 2009 and 2015 was performed. The study groups were divided according to benzodiazepine treatment at least 3 months before ABPM. Generalized estimating equation (GEE) model analysis was conducted to estimate the association between benzodiazepine treatment and ABPM test measurements. Multivariable COX regression survival analysis model for mortality and cardiovascular (CV) events was performed.

RESULTS

A total of 4,938 ABPM studies were included in final analysis, 670 ABPMs of benzodiazepine-treated patients, and 4,268 of untreated patients. The benzodiazepine-treated group was significantly older, with a predominance of female patients, comprised more diabetic patients and consumed more antihypertensive medications. Adjustment for age, gender, diabetes mellitus, and number of antihypertensive medications, showed an association between benzodiazepine treatment and significantly lower ABPM measurements. When the analysis was split into those ≥60 years old and the other <60 years old, regular benzodiazepine consumption was associated with lower ABPM measurements only among ≥60 years old. Multivariable Cox regression survival analysis showed that regular benzodiazepine consumption was not associated with increased mortality or CV events (mean follow-up period of 42.4 ± 19.8 and 42.1 ± 20.0 months, respectively).

CONCLUSIONS

Long-term use of benzodiazepines by ≥60 years old was independently associated with lower diastolic and systolic blood pressure in all parameters of ABPM, but not among younger patients.
MEBS, a software platform to evaluate large (meta)genomic collections according to their metabolic machinery: unraveling the sulfur cycle
Authors: De Anda Valerie , Zapata-Peñasco Icoquih , Poot-Hernandez Augusto Cesar , Eguiarte Luis E , Contreras-Moreira Bruno , Souza Valeria
Published: October 2017

The increasing number of metagenomic and genomic sequences has dramatically improved our understanding of microbial diversity, yet our ability to infer metabolic capabilities in such datasets remains challenging. We describe the Multigenomic Entropy Based Score pipeline (MEBS), a software platform designed to evaluate, compare, and infer complex metabolic pathways in large “omic” datasets, including entire biogeochemical cycles. MEBS is open source and available through https://github.com/eead-csic-compbio/metagenome_Pfam_score. To demonstrate its use, we modeled the sulfur cycle by exhaustively curating the molecular and ecological elements involved (compounds, genes, metabolic pathways, and microbial taxa). This information was reduced to a collection of 112 characteristic Pfam protein domains and a list of complete-sequenced sulfur genomes. Using the mathematical framework of relative entropy (H΄), we quantitatively measured the enrichment of these domains among sulfur genomes. The entropy of each domain was used both to build up a final score that indicates whether a (meta)genomic sample contains the metabolic machinery of interest and to propose marker domains in metagenomic sequences such as DsrC (PF04358). MEBS was benchmarked with a dataset of 2107 non-redundant microbial genomes from RefSeq and 935 metagenomes from MG-RAST. Its performance, reproducibility, and robustness were evaluated using several approaches, including random sampling, linear regression models, receiver operator characteristic plots, and the area under the curve metric (AUC). Our results support the broad applicability of this algorithm to accurately classify (AUC = 0.985) hard-to-culture genomes (e.g., Candidatus Desulforudis audaxviator), previously characterized ones, and metagenomic environments such as hydrothermal vents, or deep-sea sediment. Our benchmark indicates that an entropy-based score can capture the metabolic machinery of interest and can be used to efficiently classify large genomic and metagenomic datasets, including uncultivated/unexplored taxa.
A 15-Year Old Burmese Girl With Hemoptysis: A Case Report
Authors: McLeod Charlie , Yeoh Daniel , Truarn Cameron , Blyth Christopher C , Bowen Asha C , Snelling Tom L , Wadia Ushma , Hazelton Briony , Porter Michelle
Published: October 2017

We report the case of a 15-year-old Burmese girl who presented with hemoptysis 3 years after immigrating to Australia with a background of previously treated pulmonary tuberculosis at 6 years of age. Cavitation in the right upper lobe had originally been identified on her baseline chest radiograph following arrival to Australia; extensive investigations were conducted thereafter to exclude causes of cavitary lung disease; these were negative. Paragonimus westermani was finally diagnosed on serological grounds 3 years after this child’s original presentation, with subsequent identification of P. westermani ova in sputum and in stool. Clinicians should be alert to the possibility of Paragonimiasis in children who have traveled to or originate from endemic countries who present with a clinically compatible illness. Treatment is simple and effective. Failure to consider this pathogen early may result in unnecessary investigative workup and delayed diagnosis.
Isolation and Characterization of Novel Pantoea stewartii subsp. indologenes Strains Exhibiting Center Rot in Onion
Authors: Stumpf Spencer , Kvitko Brian , Gitaitis Ron , Dutta Bhabesh
Published: October 2017

Center rot of onion is an economically important disease caused by three Pantoea spp.: Pantoea ananatis, P. agglomerans, and P. allii. Symptoms caused by these three species are similar and include white streaking and necrosis of foliage; and, in some cases, the bacterium may enter the bulb, causing liquefaction and rot of bulb scales. Two bacterial strains were isolated from onion expressing symptoms indicative of center rot from two different outbreaks in Toombs County, GA in 2003 (PNA 03-3) and 2014 (PNA 14-12). These strains were initially identified as P. ananatis based on physiological and specific polymerase chain reaction (PCR) assays; however, further 16S ribosomal RNA (rRNA) and multilocus sequence analysis showed that the strains were more closely related to P. stewartii subsp. stewartii and P. stewartii subsp. indologenes. Further characterization using phylogenetic analysis, a P. stewartii subsp. indologenes-specific PCR assay, indole test, and pathogenicity on onion and pearl millet were conducted. Phylogenetic analyses (16S rRNA and atpD, gyB, infB, and rpoB genes) revealed that these strains formed a distinct cluster with the type strains of P. stewartii subsp. indologenes LMG 2632T and P. stewartii subsp. stewartii LMG 2715T separate from P. ananatis, P. agglomerans, and P. allii. Furthermore, onion strains were amplified with the P. stewartii subsp. indologenes-specific PCR assay. The pathogenicity assays with onion strains showed that they were pathogenic on onion and pearl millet, a known host of P. stewartii subsp. indologenes. However, the type strain of P. stewartii subsp. indologenes LMG 2632T was pathogenic only on pearl millet but not on onion. These results suggest that the onion strains PNA 03-3 and PNA 14-12 can potentially be novel P. stewartii subsp. indologenes strains capable of producing symptoms on onion. Hence, we recommend the inclusion of P. stewartii subsp. indologenes as the fourth member in the center rot complex of onion, along with P. ananatis, P. agglomerans, and P. allii.
Comparative genomics ofMycobacterium africanumLineage 5 and Lineage 6 from Ghana suggests different ecological niches
Authors: Otchere Isaac Darko , Coscollá Mireia , Sánchez-Busó Leonor , Asante-Poku Adwoa , Brites Daniela , Loiseau Chloe , Meehan Conor , Osei-Wusu Stephen , Forson Audrey , Laryea Clement , Yahayah Abdallah Iddrisu , Baddoo Akosua , Ansa Gloria Akosua , Aboagye Samuel Yaw , Asare Prince , Borrell Sonia , Gehre Florian , Beckert Patrick , Kohl Thomas A , N'dira Sanoussi , Beisel Christian , Antonio Martin , Niemann Stefan , de Jong Bouke C , Parkhill Julian , Harris Simon R , Gagneux Sebastien , Yeboah-Manu Dorothy
Published: October 2017

Mycobacterium africanum(Maf) causes up to half of human tuberculosis in West Africa, but little is known on this pathogen. We compared the genomes of 253Mafclinical isolates from Ghana, including both L5 and L6. We found that the genomic diversity of L6 was higher than in L5, and the selection pressures differed between both groups. Regulatory proteins appeared to evolve neutrally in L5 but under purifying selection in L6. Conversely, human T cell epitopes were under purifying selection in L5, but under positive selection in L6. Although only 10% of the T cell epitopes were variable, mutations were mostly lineage-specific. Our findings indicate thatMafL5 and L6 are genomically distinct, possibly reflecting different ecological niches.
Deep profiling of mouse splenic architecture with CODEX multiplexed imaging
Authors: Goltsev Yury , Samusik Nikolay , Kennedy-Darling Julia , Bhate Salil , Hale Matthew , Vazquez Gustavo , Black Sarah , Nolan Garry P.
Published: October 2017

A highly multiplexed cytometric imaging approach, termed CO-Detection by indEXing (CODEX), is used here to create multiplexed datasets of normal and lupus (MRL/lpr) murine spleens. CODEX iteratively visualizes antibody binding events using DNA barcodes, fluorescent dNTP analogs, and an insitu polymerization-based indexing procedure. An algorithmic pipeline for single-cell antigen quantification in tightly packed tissues was developed and used to overlay well-known morphological features with de novo characterization of lymphoid tissue architecture at a single-cell and cellular neighborhood levels. We observed an unexpected, profound impact of the cellular neighborhood on the expression of protein receptors on immune cells. By comparing normal murine spleen to spleens from animals with systemic autoimmune disease (MRL/lpr), extensive and previously uncharacterized splenic cell interaction dynamics in the healthy versus diseased state was observed. The fidelity of multiplexed spatial cytometry demonstrated here allows for quantitative systemic characterization of tissue architecture in normal and clinically aberrant samples.
Analysis of LRRC45 indicates cooperative functions of distal appendages at early steps of ciliogenesis
Authors: Kurtulmus Bahtiyar , Yuan Cheng , Schuy Jakob , Neuner Annett , Hata Shoji , Kalamakis Georgios , Martin-Villalba Ana , Pereira G.
Published: October 2017

Cilia perform essential signalling functions during development and tissue homeostasis. Ciliary malfunction causes a variety of diseases, named ciliopathies. The key role that the mother centriole plays in cilia formation can be attributed to appendage proteins that associate exclusively with the mother centriole. The distal appendages form a platform that docks early ciliary vesicles and removes CP110/Cep97 inhibitory complexes from the mother centriole. Here, we analysed the role played by LRRC45 in appendage formation and ciliogenesis. We show that the core appendage proteins Cep83 and SCLT1 recruit LRRC45 to the mother centriole. Once there LRRC45 recruits FBF1. The association of LRRC45 with the basal body of primary and motile cilia in differentiated and stem cells reveals a broad function in ciliogenesis. In contrast to the appendage components Cep164 and Cep123, LRRC45 was neither essential for docking of early ciliary vesicles nor for removal of CP110. Rather, LRRC45 promotes cilia biogenesis in CP110-uncapped centrioles by organising centriolar satellites and promoting the docking of Rab8 GTPase-positive vesicles. We propose that, instead of acting solely as a platform to recruit early vesicles, centriole appendages form discrete scaffolds of cooperating proteins that execute specific functions that promote the initial steps of ciliogenesis.
Two distinct mechanisms silencechinmoinDrosophilaneuroblasts and neuroepithelial cells to limit their self-renewal
Authors: Dillard Caroline , Narbonne-Reveau Karine , Foppolo Sophie , Lanet Elodie , Maurange Cédric
Published: October 2017

Whether common principles regulate the self-renewing potential of neural stem cells (NSCs) throughout the developing central nervous system is still unclear. In theDrosophilaventral nerve cord and central brain, asymmetrically dividing NSCs, called neuroblasts (NBs), progress through a series of sequentially expressed transcription factors that limits self-renewal by silencing a genetic module involving the transcription factor Chinmo. Here, we find that Chinmo also promotes neuroepithelium growth in the optic lobe during early larval stages by boosting symmetric self-renewing divisions while preventing differentiation. Neuroepithelium differentiation in late larvae requires the transcriptional silencing ofchinmoby ecdysone, the main steroid hormone, therefore allowing coordination of NSC self-renewal with organismal growth. In contrast,chinmosilencing in NBs is post-transcriptional and does not require ecdysone. Thus, duringDrosophiladevelopment, humoral cues or tissue-intrinsic temporal specification programs respectively limit self-renewal in different types of neural progenitors through the transcriptional and post-transcriptional regulation of the same transcription factor.

SUMMARY STATEMENT

Here, we demonstrate that the transcription factorchinmoacts as a master gene of NSC self-renewal in the different regions of the developingDrosophilabrain where it is controlled by distinct regulatory strategies.
Clearing the FoG: Antifungal tolerance is a subpopulation effect that is distinct from resistance and is associated with persistent candidemia
Authors: Rosenberg Alexander , Ene Iuliana V. , Bibi Maayan , Zakin Shiri , Segal Ella Shtifman , Ziv Naomi , Dahan Alon M. , Colombo Arnaldo L. , Bennett Richard J. , Berman Judith
Published: October 2017

Drug susceptibility, defined by the minimal inhibitory concentration (MIC), often does not predict whether fungal infections will respond to therapy in the clinic. Tolerance at supra-MIC antifungal drug concentrations is rarely quantified and current clinical recommendations suggest it be ignored. Here, we measured and characterized drug-response variables that could influence the outcomes of fungal infections and be generalizable across major clades ofCandida albicans, one of the most frequently isolated human fungal pathogens. We quantified antifungal tolerance as the fraction of growth (FoG) above the MIC and found that it is clearly distinct from susceptibility/resistance measured as MIC. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with the accumulation of intracellular drug. Importantly, many adjuvant drugs used together with fluconazole, a fungistatic drug, reduce tolerance without affecting resistance. These include inhibitors of major stress response hubs such as Hsp90, calcineurin, PKC1 and TOR. Accordingly, in an invertebrate infection model, adjuvant combination therapy was significantly more effective than fluconazole alone in treating highly tolerant isolates and did not improve the treatment of isolates with low tolerance levels. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia displayed significantly higher tolerance than isolates that were readily cleared by fluconazole. Thus, tolerance correlates with the response to fluconazole therapy in patients and may help predict whether infections will respond to fluconazole alone. Similarly, measuring tolerance may provide a useful clinical parameter for choosing appropriate therapeutic strategies to overcome persistent clinical candidemia.
Simulation of visual perception and learning with a retinal prosthesis
Authors: Golden James R. , Erickson-Davis Cordelia , Cottaris Nicolas P. , Parthasarathy Nikhil , Rieke Fred , Brainard David H. , Wandell Brian A. , Chichilnisky E.J.
Published: October 2017

The nature of artificial vision with a retinal prosthesis, and the degree to which the brain can adapt to the unnatural input from such a device, are poorly understood. Therefore, the development of current and future devices may be aided by theory and simulations that help to infer and understand what prosthesis patients see. A biologically-informed, extensible computational framework is presented here to predict visual perception and the potential effect of learning with a subretinal prosthesis. The framework relies on optimal linear reconstruction of the stimulus from retinal responses to infer the visual information available to the patient. A simulation of the physiological optics of the eye and light responses of the major retinal neurons was used to calculate the optimal linear transformation for reconstructing natural images from retinal activity. The result was then used to reconstruct the visual stimulus during the artificial activation expected from a subretinal prosthesis in a degenerated retina, as a proxy for inferred visual perception. Several simple observations reveal the potential utility of such a simulation framework. The inferred perception obtained with prosthesis activation was substantially degraded compared to the inferred perception obtained with normal retinal responses, as expected given the limited resolution and lack of cell type specificity of the prosthesis. Consistent with clinical findings and the importance of cell type specificity, reconstruction using only ON cells, and not OFF cells, was substantially more accurate. Finally, when reconstruction was re-optimized for prosthesis stimulation, simulating the greatest potential for learning by the patient, the accuracy of inferred perception was much closer to that of healthy vision. The reconstruction approach thus provides a more complete method for exploring the potential for treating blindness with retinal prostheses than has been available previously. It may also be useful for interpreting patient data in clinical trials, and for improving prosthesis design.
Explainable machine learning predictions to help anesthesiologists prevent hypoxemia during surgery
Authors: Lundberg Scott M. , Nair Bala , Vavilala Monica S. , Horibe Mayumi , Eisses Michael J. , Adams Trevor , Liston David E. , Low Daniel King-Wai , Newman Shu-Fang , Kim Jerry , Lee Su-In
Published: October 2017

Hypoxemia causes serious patient harm, and while anesthesiologists strive to avoid hypoxemia during surgery, anesthesiologists are not reliably able to predict which patients will have intraoperative hypoxemia. Using minute by minute EMR data from fifty thousand surgeries we developed and tested a machine learning based system called Prescience that predicts real-time hypoxemia risk and presents an explanation of factors contributing to that risk during general anesthesia. Prescience improved anesthesiologists’ performance when providing interpretable hypoxemia risks with contributing factors. The results suggest that if anesthesiologists currently anticipate 15% of events, then with Prescience assistance they could anticipate 30% of events or an estimated additional 2.4 million annually in the US, a large portion of which may be preventable because they are attributable to modifiable factors. The prediction explanations are broadly consistent with the literature and anesthesiologists’ prior knowledge. Prescience can also improve clinical understanding of hypoxemia risk during anesthesia by providing general insights into the exact changes in risk induced by certain patient or procedure characteristics. Making predictions of complex medical machine learning models (such as Prescience) interpretable has broad applicability to other data-driven prediction tasks in medicine.
Controlled iris radiance in a diurnal fish looking at prey
Authors: Michiels Nico K. , Seeburger Victoria C. , Kalb Nadine , Meadows Melissa G. , Anthes Nils , Mailli Amalia A. , Jack Colin B.
Published: October 2017

1.

Active sensing using light, or active photolocation, is only known from deep sea and nocturnal fish with chemiluminescent “search” lights. Bright irides in diurnal fish species have recently been proposed as a potential analogue. Here, we contribute to this discussion by testing whether iris radiance is actively modulated. The focus is on behaviourally controlled iris reflections, called “ocular sparks”. The triplefinTripterygion delaisican alternate between red and blue ocular sparks, allowing us to test the prediction that spark frequency and hue depend on background hue and prey presence. In a first experiment, we found that blue ocular sparks were significantly more often “on” against red backgrounds, and red ocular sparks against blue backgrounds, particularly when copepods were present. A second experiment tested whether hungry fish showed more ocular sparks, which was not the case. Again, background hue resulted in differential use of ocular spark types. We conclude that iris radiance through ocular sparks inT. delaisiis not a side effect of eye movement, but adaptively modulated in response to the context under which prey are detected. We discuss the possible alternative functions of ocular sparks, including an as yet speculative role in active photolocation.
Enumerating the Economic Cost of Antimicrobial Resistance Per Antibiotic Consumed to Inform the Evaluation of Interventions Affecting their Use
Authors: Shrestha Poojan , Cooper Ben S , Coast Joanna , Oppong Raymond , Do Nga T. T. , Podha Tuangrat , Celhay Olivier , Guerin Philippe J. , Wertheim Heiman , Lubell Yoel
Published: October 2017

Background

– Antimicrobial resistance (AMR) poses a colossal threat to global health and incurs high economic costs to society. Economic evaluations of antimicrobials and interventions such as diagnostics and vaccines that affect their consumption rarely include the costs of AMR, resulting in sub-optimal policy recommendations. We estimate the economic cost of AMR per antibiotic consumed, stratified by drug class and national income level.

Methods

– The model is comprised of three components: correlation coefficients between human antibiotic consumption and subsequent resistance; the economic costs of AMR for five key pathogens; and consumption data for antibiotic classes driving resistance in these organisms. These were used to calculate the economic cost of AMR per antibiotic consumed for different drug classes, using data from Thailand and the United States (US) to represent low/middle and high-income countries.

Results

– The correlation coefficients between consumption of antibiotics that drive resistance in S. aureus, E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa and resistance rates were 0.37, 0.27, 0.35, 0.45, and 0.52, respectively. The total economic cost of AMR due to resistance in these five pathogens was $0.5 billion and $2.8 billion in Thailand and the US, respectively. The cost of AMR associated with the consumption of one standard unit (SU) of antibiotics ranged from $0.1 for macrolides to $0.7 for quinolones, cephalosporins and broad-spectrum penicillins in the Thai context. In the US context, the cost of AMR per SU of antibiotic consumed ranged from $0.1 for carbapenems to $0.6 for quinolones, cephalosporins and broad spectrum penicillins.

Conclusion

– The economic costs of AMR per antibiotic consumed were considerable, often exceeding their purchase cost. Differences between Thailand and the US were apparent, corresponding with variation in the overall burden of AMR and relative prevalence of different pathogens. Notwithstanding their limitations, use of these estimates in economic evaluations can make better-informed policy recommendations regarding interventions that affect antimicrobial consumption and those aimed specifically at reducing the burden of AMR.
The molecular genetics of participation in the Avon Longitudinal Study of Parents and Children
Authors: Taylor Amy E. , Jones Hannah J. , Sallis Hannah , Euesden Jack , Stergiakouli Evie , Davies Neil M. , Zammit Stanley , Lawlor Debbie A. , Munafò Marcus R. , Davey Smith George , Tilling Kate
Published: October 2017

Background

It is often assumed that selection (including participation and dropout) does not represent an important source of bias in genetic studies. However, there is little evidence to date on the effect of genetic factors on participation.

Methods

Using data on mothers (N=7,486) and children (N=7,508) from the Avon Longitudinal Study of Parents and Children, we 1) examined the association of polygenic risk scores for a range of socio-demographic, lifestyle characteristics and health conditions related to continued participation, 2) investigated whether associations of polygenic scores with body mass index (BMI; derived from self-reported weight and height) and self-reported smoking differed in the largest sample with genetic data and a sub-sample who participated in a recent follow-up and 3) determined the proportion of variation in participation explained by common genetic variants using genome-wide data.

Results

We found evidence that polygenic scores for higher education, agreeableness and openness were associated with higher participation and polygenic scores for smoking initiation, higher BMI, neuroticism, schizophrenia, ADHD and depression were associated with lower participation. Associations between the polygenic score for education and self-reported smoking differed between the largest sample with genetic data (OR for ever smoking per SD increase in polygenic score:0.85, 95% CI:0.81,0.89) and sub-sample (OR:0.95, 95% CI:0.88,1.02). In genome-wide analysis, single nucleotide polymorphism based heritability explained 17-31% of variability in participation.

Conclusions

Genetic association studies, including Mendelian randomization, can be biased by selection, including loss to follow-up. Genetic risk for dropout should be considered in all analyses of studies with selective participation.
Strong positive biodiversity–productivity relationships in a subtropical forest experiment
Authors: Huang Yuanyuan , Chen Yuxin , Castro-Izaguirre Nadia , Baruffol Martin , Brezzi Matteo , Lang Anne , Li Ying , Härdtle Werner , von Oheimb Goddert , Yang Xuefei , Pei Kequan , Both Sabine , Liu Xiaojuan , Yang Bo , Eichenberg David , Assmann Thorsten , Bauhus Jürgen , Behrens Thorsten , Busçot Francois , Chen Xiao-Yong , Chesters Douglas , Ding Bing-Yang , Durka Walter , Erfmeier Alexandra , Fang Jingyun , Fischer Markus , Guo Liang-Dong , Guo Dali , Gutknecht Jessica L.M. , He Jin-Sheng , He Chun-Ling , Hector Andy , Hönig Lydia , Hu Ren-Yong , Klein Alexandra-Maria , Kuehn Peter , Liang Yu , Michalski Stefan , Scherer-Lorenzen Michael , Schmidt Karsten , Scholten Thomas , Schuldt Andreas , Shi Xuezheng , Tan Man-Zhi , Tang Zhiyao , Trogisch Stefan , Wang Zhengwen , Welk Erik , Wirth Christian , Wubet Tesfaye , Xiang Wenhua , Yan Jiye , Yu Mingjian , Yu Xiao-Dong , Zhang Jiayong , Zhang Shouren , Zhang Naili , Zhou Hong-Zhang , Zhu Chao-Dong , Zhu Li , Bruelheide Helge , Ma Keping , Niklaus Pascal A. , Schmid Bernhard
Published: October 2017

Forest ecosystems contribute substantially to global terrestrial primary productivity and climate regulation, but, in contrast to grasslands, experimental evidence for a positive biodiversity-productivity relationship in highly diverse forests is still lacking1. Here, we provide such evidence from a large forest biodiversity experiment with a novel design2 in subtropical China. Productivity (stand-level tree basal area, aboveground volume and carbon and their annual increment) increased linearly with the logarithm of tree species richness. Additive partitioning3 showed that increasing positive complementarity effects combined with weakening negative selection effects caused a strengthening of the relationship over time. In 2-species mixed stands, complementary effects increased with functional distance and selection effects with vertical crown dissimilarity between species. Understorey shrubs reduced stand-level tree productivity, but this effect of competition was attenuated by shrub species richness, indicating that a diverse understorey may facilitate overall ecosystem functioning. Identical biodiversity-productivity relationships were found in plots of different size, suggesting that extrapolation to larger scales is possible. Our results highlight the potential of multi-species afforestation strategies to simultaneously contribute to mitigation of climate change and biodiversity restoration.
Overnight memory consolidation facilitates rather than interferes with new learning of similar materials - a study probing NMDA-receptors
Authors: Alizadeh Asfestani M , Braganza E , Schwidetzky J , Santiago J , Soekadar S , Born J , Feld GB
Published: October 2017

Whereas sleep-dependent consolidation and its neurochemical underpinnings have been strongly researched, less is known about how consolidation during sleep affects subsequent learning. Since sleep enhances memory, it can be expected to pro-actively interfere with learning after sleep, in particular of similar materials. This pro-active interference should be enhanced by substances that benefit consolidation during sleep, such as D-cycloserine. We tested this hypothesis in two groups (Sleep, Wake) of young healthy participants receiving on one occasion D-cycloserine (175 mg) and on another occasion placebo, according to a double-blind balanced cross-over design. Treatment was administered after participants had learned a set of word-pairs (A-B list) and before nocturnal retention periods of sleep vs. wakefulness. After D-cycloserine blood plasma levels had dropped to negligible amounts, i.e., the next day in the evening, participants learned, in three sequential runs, new sets of word-pairs. One list – to enhance interference – consisted of the same cue words as the original set paired with a new target word (A-C list) and the other of completely new cue words (D-E set). Unexpectedly, during post-retention learning the A-C interference list was generally better learned than the completely new D-E list, which suggests that consolidation of previously encoded similar material enhances memory integration rather than pro-active interference. Consistent with this view, new learning of word-pairs was better after sleep than wakefulness. Similarly, D-cycloserine generally enhanced learning of new word-pairs, compared to placebo. This effect being independent of sleep or wakefulness, leads us to speculate that D-cycloserine, in addition to enhancing sleep-dependent consolidation, might mediate a time-dependent process of active forgetting.
Transcriptional control and exploitation of an immune-responsive family of plant retrotransposons
Authors: Zervudacki Jérôme , Yu Agnès , Amesefe Delase , Wang Jingyu , Drouaud Jan , Navarro Lionel , Deleris Angélique
Published: October 2017

Mobilization of transposable elements (TEs) in plants has been recognized as a driving force of evolution and adaptation, in particular by providing genes with regulatory modules that impact their transcription. In this study, we employed anATCOPIA93Long terminal repeats (LTR) promoter-GUSfusion to show that this retrotransposon behaves like an immune-responsive gene during plant defense in Arabidopsis. We also showed that the reactivation of the endogenousATCOPIA93copy“EVD”, in the presence of bacterial stress, is not only negatively regulated by DNA methylation but also by Polycomb-mediated silencing—a mode of repression typically found at protein-coding and microRNA genes. Interestingly, one of theATCOPIA93-derived soloLTRs is located upstream of the disease resistance geneRPP4and is devoid of either DNA methylation or H3K27m3 marks. Through loss-of-function experiments, we demonstrated that this soloLTR is required for proper expression ofRPP4during plant defense, thus linking the responsiveness ofATCOPIA93to biotic stress and the co-option of its LTR for plant immunity.
The Wisconsin Registry for Alzheimer’s Prevention: A Review of findings and current directions
Authors: Johnson Sterling C. , Koscik Rebecca L. , Jonaitis Erin M. , Clark Lindsay R. , Mueller Kimberly D. , Berman Sara E. , Bendlin Barbara B. , Engelman Corinne D. , Okonkwo Ozioma C. , Hogan Kirk J. , Asthana Sanjay , Carlsson Cynthia M. , Hermann Bruce P. , Sager Mark A.
Published: October 2017

The Wisconsin Registry for Alzheimer’s Prevention (WRAP) is a longitudinal observational cohort study enriched with persons with a parental history (PH) of probable Alzheimer’s Disease (AD) dementia. Since late 2001, WRAP has enrolled 1,561 people at a mean baseline age of 54. Participants return for a second visit four years after baseline and subsequent visits occur every two years. Eighty-one percent (1270) of participants remain active in the study at a current mean age of 64 and 9 years of follow-up. Serially assessed cognition, self-reported medical and lifestyle histories (e.g. diet, physical and cognitive activity, sleep, and mood), laboratory tests, genetics, and linked studies comprising molecular imaging, structural imaging and cerebrospinal fluid data, have yielded many important findings. In this cohort, PH of probable AD is associated with 46%APOEε4 positivity, more than twice the rate of 22% among persons without PH. Subclinical or worse cognitive decline relative to internal normative data has been observed in 17.6% of the cohort. Twenty-eight percent exhibit amyloid and/or tau positivity. Biomarker elevations, but notAPOEor PH status, are associated with cognitive decline. Salutary health and lifestyle factors are associated with better cognition and brain structure, and lower AD pathophysiologic burden. Of paramount importance is establishing the amyloid and tau AD endophenotypes to which cognitive outcomes can be linked. Such data will provide new knowledge on the early temporal course of AD pathophysiology and inform the design of secondary prevention clinical trials.
Life history effects on neutral diversity levels of autosomes and sex chromosomes
Authors: Amster Guy , Sella Guy
Published: October 2017

All else being equal, the ratio of genetic diversity levels on X and autosomes at selectively neutral sites should mirror the ratio of their numbers in the population and thus equal ¾. Because X chromosomes spend twice as many generations in females as in males, however, the ratio of diversity levels is also affected by sex differences in life history. The effects of life history on diversity levels, notably those of sex-specific age structures and reproductive variances, have been studied for decades, yet existing theory relies on many parameters that are difficult to measure and lacks generality in ways that limit their applicability. We derive general yet simple expressions for these effects and show that life history effects on X-to-autosome (X:A) ratios of diversity levels depend only on sex-ratios of mutation rates, generation times, and reproductive variances. These results reveal that changing the sex-ratio of generation times has opposite effects on X:A ratios of polymorphism and divergence. They also explain how sex-specific life histories modulate the response of X:A polymorphism ratios to changes in population size. More generally, they clarify that sex-specific life history—generation times in particular—should have a marked effect on X:A polymorphism ratios in many taxa and enable the investigation of these effects.

Significance Statement

Understanding the determinants of neutral diversity patterns on autosomes and sex chromosomes provides a bedrock for our interpretation of population genetic data. Sex-specific age-structure and variation in reproductive success have long been thought to affect neutral diversity, but theoretical descriptions of these effects were complicated and/or lacked in generality, stymying attempts to relate diversity patterns of species with their life history. We derive general yet simple expressions for these effects, which clarify how they impact neutral diversity and should enable studies of relative diversity levels on the autosomes and sex chromosomes in many taxa.
In vivocross-linking and transmembrane helix dynamics support a bidirectional non-piston model of signaling withinE. coliEnvZ
Authors: Yusuf Rahmi , Nguyễn Tuyết Linh , Heininger Annika , Lawrence Robert J. , Hall Benjamin A. , Draheim Roger R.
Published: October 2017

In Gram-negative bacteria, porins span the outer membrane and control the influx of several prominent groups of antibiotics. Thus, it should not be surprising that expression of these porins is often altered in clinical isolates exhibiting multidrug resistance (MDR). The major regulator of porin expression inEscherichia coliis EnvZ, a canonical sensor histidine kinase (SHK). It allosterically processes periplasmic interactions with MzrA and cytoplasmic osmosensing into a single unified change in the ratio of its kinase and phosphatase activities. Unfortunately, the role of the EnvZ transmembrane domain (TMD) in bidirectional communication of these signals remains not well understood. Here, we employedin vivosulfhydryl-reactivity to probe the dynamics of the TM2 helices and demonstrate that upon stimulus perception, only the region proximal to the periplasm undergoes conformational rearrangement. Furthermore,in silicocoarse-grained molecular dynamics (CG-MD) simulations with aromatically tuned variants of EnvZ TM2 demonstrate the existence of both tilting and azimuthal rotational components to transmembrane communication while ruling out piston-type repositioning of TM2. Finally, in contrast to a similar analysis of TM1, we identified position-specific mutants possessing a “flipped” phenotype by dual-color fluorescent reporter analysis suggesting that both the periplasmic and cytoplasmic ends of TM2 are critical for maintenance of EnvZ signal output. Taken together, these data strongly support that EnvZ employs a non-piston-type mechanism during transmembrane communication. We conclude by discussing these results within the context of allosteric processing by EnvZ and propose that these results can be used to predict and classify transmembrane communication by various SHKs.

Importance

The EnvZ sensor histidine kinase serves as the major regulator of porin expression withinEscherichia coli. A long-standing question is how stimulus perception by a bacterial receptor on one side of a biological membrane is transmitted to the opposite side of the membrane. To address this question, we monitored the dynamics of the transmembrane domain of EnvZin vivoand coupled these results within silicosimulations of membrane-embedded EnvZ transmembrane domains. Taken together, these results demonstrate that detection of osmotic stress by the cytoplasmic domain of EnvZ results in non-piston communication across the inner membrane ofE. coli.Thus, in addition to understanding how EnvZ regulates porin balance and antibiotic influx, these results contribute to answering the long-standing question of how transmembrane communication is performed by bacterial receptors. Our work concludes with a framework that correlates receptor domain composition and signal transduction mechanisms that could be employed by other research groups on their particular receptors of interest.
Free energy landscape for the entire transport cycle of triose-phosphate/phosphate translocator
Authors: Takemoto Mizuki , Lee Yongchan , Ishitani Ryuichiro , Nureki Osamu
Published: October 2017

Secondary active transporters translocate their substrates using the electrochemical potentials of other chemicals, undergoing large-scale conformational changes. Despite extensive structural studies, the atomic details of the transport mechanism still remain elusive. Here we performed a series of all-atom molecular dynamics simulations of the triose-phosphate/phosphate translocator (TPT), which exports organic phosphates in the chloroplast stroma in strict counter exchange with inorganic phosphate (Pi). Biased sampling methods, including string method and umbrella sampling, successfully reproduced the conformational changes between the inward– and outward-facing states, along with the substrate binding. The free energy landscape of this entire TPT transition pathway demonstrated the alternating access and substrate translocation mechanisms, which revealed Piis relayed by positively charged residues along the transition pathway. Furthermore, the conserved Glu207 functions as a “molecular switch”, linking the local substrate binding and the global conformational transition. Our results provide atomic-detailed insights into the energy coupling mechanism of antiporter.
Complex versus simple models: ion-channel cardiac toxicity prediction
Authors: Mistry Hitesh. B.
Published: October 2017

There is growing interest in applying detailed mathematical models of the heart for ion-channel related cardiac toxicity prediction. However, a debate as to whether such complex models are required exists. Here an assessment in the predictive performance between two established cardiac models, gold-standard and cardiac safety simulator, and a simple linear model Bnet was conducted. Three ion-channel data-sets were extracted from literature. Each compound was designated a cardiac risk category based on information within CredibleMeds. The predictive performance of each model within each data-set was assessed via a leave-one-out cross validation. In two of the data-sets Bnet performed equally as well as the leading cardiac model, cardiac safety simulator, both of these outperformed the gold-standard model. In the 3rd data-set, which contained the most detailed ion-channel pharmacology, Bnet outperformed both cardiac models. These results highlight the importance of benchmarking models but also encourage the development of simple models.