bluuebunny/crossref_metadata_2025 huggingface dataset:
Prescribing of different antibiotics, rates of bacteremia/septicemia and associated mortality in the US and England, and the utility of antibiotic replacement vs. reduction in prescribing
Authors: Goldstein Edward
Published: January 2019

Background

Antibiotic use contributes to the rates of bacteremia, sepsis and associated mortality, particularly through lack of clearance of resistant infections following antibiotic treatment. At the same time, there is limited information on the effects of prescribing of some antibiotics vs. others, of antibiotic replacement and of reduction in prescribing on the rates of severe outcomes associated with bacterial infections.

Methods

For each of several antibiotic types/classes, we looked at associations (univariate, and multivariable for the US data) between the proportions (state-specific in the US, Clinical Commissioning Group (CCG)-specific in England) of a given antibiotic type/class among all prescribed antibiotics in the outpatient setting, and rates of outcomes (mortality with septicemia, ICD-10 codes A40-41 present on the death certificate in different age groups of adults in the US, andE. colior MSSA bacteremia in England) per unit of antibiotic prescribing (defined as the rate of outcome divided by the rate of prescribing of all antibiotics).

Results

In the US, prescribing of penicillins was positively associated with rates of mortality with septicemia for persons aged 75-84y and 85+y between 2014-2015, while multivariable analyses also suggest an association between the percent of individuals aged 50-64y lacking health insurance, as well as the percent of individuals aged 65-84y who are African-American and rates of mortality with septicemia. In England, prescribing of penicillins other than amoxicillin/co-amoxiclav was positively associated with rates of both MSSA andE. colibacteremia for the period between financial years 2014/15 through 2017/18. Additionally, as time progressed, correlations between prescribing for both trimethoprim and co-amoxiclav and rates of bacteremia in England decreased, while correlations between amoxicillin prescribing and rates of bacteremia increased.

Conclusions

Our results suggest that prescribing of penicillins is associated with rates ofE. coliand MSSA bacteremia in England, and rates of mortality with septicemia in older US adults, which agrees with our earlier findings. Those results, as well as the related epidemiological data suggest that antibiotic replacement rather than reduction in prescribing may be the more effective mechanism for reducing the rates of severe bacterial infections.
Dietary intake and diet quality of Swiss adult survivors of childhood cancer compared to the general population
Authors: Belle Fabiën N. , Chatelan Angeline , Kasteler Rahel , Guessous Idris , Beck Popovic Maja , Ansari Marc , Kuehni Claudia E. , Bochud Murielle ,   for the Swiss Pediatric Oncology Group (SPOG)
Published: January 2019

Background

Childhood cancer survivors (CCSs) are at increased risk of developing chronic health conditions, which may be reduced by following a healthy lifestyle including a good diet.

Objectives

This study compared the dietary intake and quality of CCSs and the general population.

Design

As part of the Swiss Childhood Cancer Survivor Study, we sent a food frequency questionnaire (FFQ) to CCSs who had a median age of 34 years (IQR: 29-40 years) and a median of 26 years (20-31 years) postdiagnosis at the time of survey. We compared dietary intake and quality of CCSs and three comparison groups representing the general adult population using FFQ and 24h recall data (24HDR). We evaluated whether mean individual intake met national dietary recommendations and used the Alternative Healthy Eating Index (AHEI) to estimate diet quality.

Results

The 774 CCSs in our study were compared to 8964 participants in the Bus Santé study, 1276 participants in the CoLaus study, and 1134 participants in the Swiss National Nutrition Survey. Dietary intake was equally poor in CCSs and the general Swiss population. CCSs consumed inadequate amounts of vitamin D, fiber, carbohydrates, iron, vitamin A, and calcium (12%, 41%, 72%, 72%, 79%, and 89% of the recommended intakes, respectively), and excessive amounts of saturated fat, protein, cholesterol, and total fat (137%, 126%, 114%, and 107% of the recommended intakes). The mean AHEI score in CCSs was low at 48.0 (men: 45.0, women: 50.9) out of a maximum score of 100. The general population, assessed by 24HDR, scored lower overall than CCSs (41.5; men: 38.7, women: 43.8). Clinical characteristics were not associated with diet quality in CCSs.

Conclusion

Long-term CCSs and the general adult population have similarly poor dietary intake and quality in Switzerland, which suggests population-based interventions for everyone.
Elevated serum aspartate aminotransferase levels concomitant with normal alanine aminotransferase levels in older low body weight people: Preliminary findings from a community-based epidemiological study
Authors: Shibata Michi , Nakajima Kei
Published: January 2019

Background

Serum enzyme levels, including hepatic transaminase, are unknown in older people with low body weight (LBW), who can easily experience sarcopenia. Therefore, we addressed preliminarily this issue in a cross-sectional study of an apparently healthy population.

Methods

We investigated the relationship of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and total bilirubin levels with body mass index (BMI) and age in 79,623 subjects aged 20–80 years who underwent an annual checkup.

Results

Serum levels of AST, ALP, and LDH levels were significantly higher in older (≥50 years) non-obese subjects compared with younger (< 50 years) corresponding subjects. Serum AST levels were significantly higher in older LBW subjects (BMI≤18.9 kg/m2) than in those with a reference BMI of 20.9–22.9 kg/m2. Serum AST levels showed a J-shaped curve against BMI, whereas ALT and GGT levels showed a linear relationship, regardless of age.

Conclusion

Elevated serum AST levels concomitant with normal ALT levels, which might reflect systemic damage of skeletal muscle, may be prevalent in older LBW people. Further studies need to determine whether such a condition is equivalent to the etiology of sarcopenia.
Novel Structural Features of Human Norovirus Capsid
Authors: Devant Jessica , Hofhaus Götz , Hansman Grant S.
Published: January 2019

Human noroviruses are a major cause of gastroenteritis, yet there are still no vaccines or antivirals available. Nevertheless, a number of vaccine candidates that are currently in clinical trials are composed of norovirus virus-like particles (VLPs). These VLPs are recognized as morphologically and antigenically similar to norovirus virions. An X-ray crystal structure of the prototype (GI.1) VLPs showed that the norovirus capsid has a T=3 icosahedral symmetry and is composed of 180 copies of the major capsid protein (VP1) that folds into three quasi-equivalent subunits (A, B, and C). In this study, we determined the cryo-EM structure of VLPs for two GII.4 noroviruses that were detected in 1974 and 2012. We showed that these VLPs had a T=4 symmetry and were composed of 240 copies of VP1. The VP1 on the T=4 VLPs adapted four quasi-equivalent subunits (termed A, B, C, and D), which formed two distinct dimers (A/B and C/D). We found that the T=4 protruding domain was elevated ~21 Å off the capsid shell, which was ~7 Å more than the previously determined for the T=3 GII.10 norovirus. Another interesting feature of the T=4 VLPs was a small cavity and flaplike structure located at the twofold axis. This structural feature was associated with the shell domain (D subunit) and disrupted the contiguous shell. Altogether, we showed that the T=4 VLPs had a number of structural similarities and differences with other noroviruses, but how these structural changes associate with norovirus virions could be important for vaccine studies.

IMPORTANCE

The discovery that the GII.4 VLPs (identified in 1974 and 2012, termed CHDC-1974 and NSW-2012, respectively) have a T=4 symmetry is of major significance, since the NSW-2012 is clinically important and previous structural and biochemical studies assumed noroviruses have a T=3 symmetry and are composed of 180 copies of VP1. More importantly, NSW-2012 norovirus shared 96% amino acid identity with a GII.4 vaccine candidate and our data suggests that this vaccine might also have a T=4 symmetry. Although it is not clear if the T=4 VLPs were an artifact of the insect cell expression system, the T=4 VLP vaccines might not recognize equivalent epitopes on T=3 virions, which will be important for future neutralization studies. Finally, further studies with other norovirus genotypes and virions are clearly needed in order to determine the level of this structural diversity.
Cassava planting material movement and grower behaviour in Zambia: implications for disease management
Authors: Szyniszewska Anna Maria , Chiza Chikoti Patrick , Tembo Mathias , Mulenga Rabson , van den Bosch Frank , Finn McQuaid Christopher
Published: January 2019

Cassava is an important food crop for most small-holder growers across sub-Saharan Africa, where production is largely limited by the presence of two viral diseases: cassava mosaic disease (CMD) and cassava brown streak disease (CBSD), both propagated by a vector whitefly and via human-mediated movement of infected cassava stems. Despite its importance, there is limited knowledge of growers’ behaviour related to planting material movement, as well as growers’ perception and knowledge of cassava diseases, which have major implications for disease spread and control. This study was conducted to address this knowledge gap by surveying small-holder growers in Zambia. A total of 96 subsistence cassava growers across five provinces were surveyed between 2015 and 2017. Most growers interviewed used planting materials from their own fields (94%) or those of nearby (<10 km) family and friends, although some large transactions with markets, middlemen, and NGOs occurred over longer distances. At the same time, information related to cassava diseases and uninfected planting material only reached 48% of growers, where those with access to information were more concerned about the disease. These data provide a basis for future planning of cassava clean seed systems to control virus diseases, emphasising the critical role of grower knowledge, and consequently education, in success of these systems. In particular, we highlight the importance of extension workers in this education process, as well as farmer’s groups and the media.
An evaluation of the Air Quality Health Index Program on respiratory diseases in Hong Kong: an interrupted time series analysis
Authors: Mason Tonya G. , Schooling C. Mary , Chan King Pan , Tian Linwei
Published: January 2019

Background

On December 30th, 2013, the Hong Kong government implemented the Air Quality Health Index (AQHI) to reduce short-term impacts of air pollution on the population. However, whether air quality alert programs, such as the AQHI, reduce morbidity is still questionable. Using a quasi-experimental design, we conducted the first evaluation of the AQHI in Hong Kong focusing on respiratory morbidity.

Method

Interrupted time series with Poisson segmented regression from 2010 to 2016 were used to detect any sudden or gradual changes in emergency respiratory hospital admissions, adjusted for air pollutants (NO2, SO2, PM10, O3), temperature and humidity, when the AQHI policy was implemented. Findings were validated using three false policy periods. We also assessed changes by specific respiratory diseases (respiratory tract infections (RTI), asthma, chronic obstructive pulmonary disease and pneumonia) and by age.

Results

From January 1st, 2010-December 31st, 2016, 10576.98 deseasonalized, age- and sex-standardized hospital admissions for respiratory diseases occurred in Hong Kong. On implementation of the AQHI, RTI admissions immediately dropped by 14% (relative risk (RR) 0.86 95% confidence interval (CI) 0.76-0.98). In age specific analysis, immediate reductions in hospital admissions, were only apparent in children for RTI (RR 0.84, 95% CI 0.74-0.96) and pneumonia (RR 0.88, 95% CI 0.60-0.96).

Conclusion

Hong Kong’s AQHI helped reduced hospital admissions in children, particularly for RTI and pneumonia. To maximize the health benefits of the policy, at risk groups need to be able to follow the behavioral changes recommended by the AQHI index.
A multidisciplinary approach to a unique Palaeolithic human ichnological record from Italy (Bàsura Cave)
Authors: Romano Marco , Citton Paolo , Salvador Isabella , Arobba Daniele , Rellini Ivano , Firpo Marco , Negrino Fabio , Zunino Marta , Starnini Elisabetta , Avanzini Marco
Published: January 2019

Based on the integration of laser scan, sedimentology, geochemistry, archeobotany, geometric morphometries and photogrammetry, here we present evidence testifying a Palaeolithic group that explored a deep cave in northern Italy about 14 ky cal. BP. Ichnological data enable us to shed light on individual and group level behavior, social relationship and mode of exploration of the highly uneven environment. Five individuals, two adults, an adolescent and two children, entered the cave barefoot and with a set of wood chips to illuminate the way. Traces of crawling locomotion are documented for the first time in the global human ichnological record. The anatomic details recognizable in the crawling traces show that no garment was interposed between the limb and the trampled sediments. Our study demonstrate that very young children (the youngest less than three years old) were active members in the Upper Palaeolithic populations, even in seemingly dangerous activities and social ones.
Do clinical investigations predict long-term outcome? A follow-up of paediatric respiratory outpatients
Authors: de Jong Carmen CM. , Pedersen Eva SL. , Goutaki Myrofora , Trachsel Daniel , Barben Juerg , Kuehni Claudia E.
Published: January 2019

Introduction

The contribution of clinical investigations to prediction of long-term outcomes of children investigated for asthma is unclear.

Aim

We performed a broad range of clinical tests and investigated whether they helped to predict long-term wheeze among children referred for evaluation of possible asthma.

Methods

We studied children aged 6-16 years referred to two Swiss pulmonary outpatient clinics with a history of wheeze, dyspnoea, or cough in 2007. The initial assessment included spirometry, body plethysmography, fractional exhaled nitric oxide, skin prick tests, and bronchial provocation tests (BPT) by exercise, methacholine, and mannitol. Respiratory symptoms were assessed with questionnaires at baseline and at follow-up seven years later. Associations between baseline factors and wheeze at follow-up were investigated by logistic regression.

Results

At baseline, 111 children were examined in 2007. Seven years after baseline, 85 (77%) completed the follow-up questionnaire, among whom 61 (72%) had wheeze at baseline, while at follow-up 39 (46%) reported wheeze. Adjusting for age and sex, the following characteristics predicted wheeze at adolescence: wheeze triggered by pets (odds ratio 4.2, 95% CI 1.2-14.8), pollen (2.8, 1.1-7.0), and exercise (3.1, 1.2-8.0). Of the clinical tests, only a positive exercise test (3.2, 1.1-9.7) predicted wheeze at adolescence.

Conclusion

Reported exercise-induced wheeze and wheeze triggered by pets or pollen were important predictors of wheeze persistence into adolescence. None of the clinical tests predicted wheeze more strongly than reported symptoms. Clinical tests might be important for asthma diagnosis but medical history is more helpful in predicting prognosis in children referred for asthma.
Ncl1 mediated metabolic rewiring critical during metabolic stress
Authors: Bhat Ajay , Chakraborty Rahul , Adlakha Khushboo , Agam Ganesh , Chakraborty Kausik , Sengupta Shantanu
Published: January 2019

Nutritional limitation has been vastly studied, however, there is limited knowledge of how cells maintain homeostasis in excess nutrients. In this study, using yeast as a model system, we show that some amino acids are toxic at higher concentrations. With cysteine as a physiologically relevant example, we delineated the pathways/processes that are altered and those that are involved in survival in presence of elevated levels of this amino acid. Using proteomics and metabolomics approach, we found that cysteine upregulates proteins involved in amino acid metabolism, alters amino acid levels, and inhibits protein translation, events that are rescued by leucine supplementation. Through a comprehensive genetic screen we show that leucine mediated effect depends on a tRNA methyltransferase (Ncl1), absence of which decouples cell’s transcription and translation, inhibits the conversation of leucine to ketoisocaproate and leads to TCA cycle block. We therefore, propose a role of Ncl1 in regulating metabolic homeostasis through translational control.
Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development
Authors: Krieger Teresa G , Moran Carla M , Frangini Alberto , Visser W Edward , Schoenmakers Erik , Muntoni Francesco , Clark Chris , Gadian David , Chong Wui K , Kuczynski Adam , Dattani Mehul , Lyons Greta , Efthymiadou Alexandra , Varga-Khadem Faraneh , Simons Benjamin D , Chatterjee Krishna , Livesey Frederick J
Published: January 2019

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a novel micropatterned chip assay, we find that spatial self-organisation of mutation-containing progenitor cells is impaired, consistent with downregulated expression of cell-cell adhesion genes. These results reveal for the first time that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation and organisation in human cerebral cortical development. They also exemplify novel quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.
Neural Coding of Gustatory Information in the Nucleus of the Solitary Tract in Lean and Obese Awake Freely-licking Rats
Authors: Weiss Michael S , Hajnal Andras , Czaja Krzysztof , Di Lorenzo Patricia M
Published: January 2019

Taste perception changes with obesity but the underlying neural changes remain poorly understood. To address this issue, we recorded taste responses from single cells in the nucleus tractus solitarius (NTS, the fist central synapse in the gustatory circuit) in awake, diet-induced obese [(DIO; ≥8wks on a high-energy diet (HED)] and lean rats. Rats were implanted with a bundle of microelectrodes in the NTS and allowed to recover. Water-deprived rats were allowed to freely lick various tastants in an experimental chamber. Taste stimuli included an array of sapid stimuli dissolved in artificial saliva (AS). Each taste trial consisted of 5 consecutive licks followed by 5 AS licks presented on a VR5 schedule. Results showed that taste responses in NTS cells in DIO rats (n=49) were smaller in magnitude, shorter in duration and longer in latency that those in lean rats (n=74). However, there were proportionately more taste-responsive cells in DIO than in lean rats. Lick coherence in DIO rats was significantly lower than in lean rats, both in taste-responsive and lick-related cells (n=172 in lean; n=65 in DIO). Analyses of temporal coding showed that taste cells in DIO rats conveyed less information about taste quality than cells in lean rats. Collectively, results suggest that a HED produces blunted, but more prevalent, responses to taste in the NTS and a weakened association of taste responses with ingestive behavior. These neural adaptations may represent both negative effects and compensatory mechanisms of a HED that may underlie deficits in taste-related behavior associated with obesity.
Rice bran supplementation modulates growth, microbiome and metabolome in weaning infants: a clinical trial in Nicaragua and Mali
Authors: Zambrana Luis E. , McKeen Starin , Ibrahim Hend , Zarei Iman , Borresen Erica C. , Doumbia Lassina , Bore Abdoulaye , Cissoko Alima , Douyon Seydou , Kone Karim , Perez Johann , Perez Claudia , Hess Ann , Abdo Zaid , Sangare Lansana , Maiga Ababacar , Becker-Dreps Sylvia , Yuan Lijuan , Koita Ousmane , Vilchez Samuel , Ryan Elizabeth P.
Published: January 2019

Rice bran supplementation provides nutrients, prebiotics and phytochemicals that enhance gut immunity, reduce enteric pathogens in mice and diarrhea in neonatal pigs, and warranted attention for improvement of environmental enteric dysfunction (EED) in children at risk. EED is a condition that drives childhood stunting via intestinal dysbiosis and impaired nutrient metabolism. This study investigated effects of rice bran supplementation on growth, EED biomarkers, gut microbiome and metabolome in weaning infants from 6 to 12 months old in Nicaragua and Mali. Healthy infants were randomized to a control group or rice bran group that received daily supplementation at increasing doses each month. Stool microbiomes were characterized using 16S rDNA amplicon sequencing. Stool metabolomes were analyzed using ultra-high-performance liquid-chromatography tandem mass-spectrometry. Statistical comparisons were completed at 6, 8, and 12 months of age. Daily consumption of rice bran was safe and feasible for infant growth, decreasing alpha-1 antitrypsin levels, and modulating gut microbiome and metabolome when compared to control. Rice bran merits investigation as a practical intervention strategy that could decrease EED prevalence and risk for children from low- and middle-income countries where rice is grown as a staple food, and bran is used as animal feed or wasted.

One Sentence Summary

Dietary rice bran supplementation during infant weaning from 6-12 months of age improved growth outcomes, modulated environmental enteric dysfunction biomarkers, and supported metabolism by the gut microbiome.

The authors declare no competing financial or non financial interests to disclose as defined by Nature Research. There are also no other interests that might be perceived to influence the results and/or discussion reported in this paper.

Correspondence and requests for materials should be addressed to Dr. Elizabeth Ryan (e.p.ryan@colostate.edu).
On the innovation and evolution of predatory tactics
Authors: Gokhale Chaitanya S. , Wignall Anne E.
Published: January 2019

Predator-prey systems are ubiquitous across ecological systems. Typical ecological models focus on the dynamics of predator-prey populations. Eco-evolutionary models integrate arms race or Red-Queen like dynamics. The roles of the predator and prey species are always assumed to be static. Nevertheless, sometimes predators can bite off more than they can chew. For example, predators that encounter multiple or dangerous prey types may need to develop new predatory tactics to capture prey. We explore the dynamics of predator-prey dynamics when the prey can injure or kill the predator. This common ecological scenario places pressure on the predator to develop novel predatory tactics to both capture prey and avoid counter-attack from prey. Taking a bottom-up approach, we develop the Holling function mechanistically and then implement it in a model of innovationselection dynamics inspired by economic theory. We show how an interdisciplinary approach can be used to explain the emergence of complex predatory behaviours. Notably, our study shows why predators may hunt dangerous prey even when safe prey are available. In a broader context, we demonstrate how a multidisciplinary approach combining ecology, evolution and economics improves our understanding of a complex behavioural trait.
Sex and Estrous Cycle Effects on Anxiety- and Depression-related Phenotypes in Two-hit Developmental Stress Model
Authors: Jaric Ivana , Rocks Devin , Cham Heining , Herchek Alice , Kundakovic Marija
Published: January 2019

Stress during sensitive developmental periods can adversely affect physical and psychological development and contribute to later-life mental disorders. In particular, adverse experiences during childhood dramatically increase the risk for the development of depression and anxiety disorders. Although women of reproductive age are twice as likely to develop anxiety and depression than men of the corresponding age, little is known about sex-specific factors that promote or protect against the development of psychopathology. To examine potential developmental mechanisms driving sex disparity in risk for anxiety and depression, we established a two-hit developmental stress model including maternal separation in early life followed by social isolation in adolescence. Our study shows complex interactions between early-life and adolescent stress, between stress and sex, and between stress and female estrogen status in shaping behavioral phenotypes of adult animals. In general, increased locomotor activity and body weight reduction were the only two phenotypes where two stressors showed synergistic activity. In terms of anxiety- and depression-related phenotypes, single exposure to early-life stress had the most significant impact and was female-specific. We show that early-life stress disrupts the protective role of estrogen in females, and promotes female vulnerability to anxiety- and depression-related phenotypes associated with the low-estrogenic state. We found plausible transcriptional and epigenetic alterations in psychiatric risk genes, Nr3c1 and Cacna1c, that likely contributed to the stress-induced behavioral effects. In addition, two general transcriptional regulators, Egr1 and Dnmt1, were found to be dysregulated in maternally-separated females and in animals exposed to both stressors, respectively, providing insights into possible transcriptional mechanisms that underlie behavioral phenotypes. Our findings provide a novel insight into developmental risk factors and biological mechanisms driving sex differences in depression and anxiety disorders, facilitating the search for more effective, sex-specific treatments for these disorders.
Thunor: Visualization and Analysis of High-Throughput Dose-response Datasets
Authors: Lubbock Alexander L. R. , Harris Leonard A. , Quaranta Vito , Tyson Darren R. , Lopez Carlos F.
Published: January 2019

High-throughput cell proliferation assays to quantify drug-response are becoming increasingly common and powerful with the emergence of improved automation and multi-time point analysis methods. However, pipelines for analysis of these datasets that provide reproducible, efficient, and interactive visualization and interpretation are sorely lacking. To address this need, we introduce Thunor, an open-source software platform to manage, analyze, and visualize large, dose-dependent cell proliferation datasets. Thunor supports both end-point and time-based proliferation assays as input. It provides a simple, user-friendly interface with interactive plots and publication-quality images of cell proliferation time courses, dose–response curves, and derived dose–response metrics, e.g. IC50, including across datasets or grouped by tags. Tags are categorical labels for cell lines and drugs, used for aggregation, visualization, and statistical analysis, e.g. cell line mutation or drug class/target pathway. A graphical plate map tool is included to facilitate plate annotation with cell lines, drugs, and concentrations upon data upload. Datasets can be shared with other users via point-and-click access control. We demonstrate the utility of Thunor to examine and gain insight from two large drug response datasets: a large, publicly available cell viability database and an in-house, high-throughput proliferation rate dataset. Thunor is available from www.thunor.net.
Codon clusters with biased synonymous codon usage represent hidden functional domains in protein-coding DNA sequences
Authors: Peng Zhen , Ben-Shahar Yehuda
Published: January 2019

1.

Protein-coding DNA sequences are thought to primarily affect phenotypes via the peptides they encode. Yet, emerging data suggest that, although they do not affect protein sequences, synonymous mutations can cause phenotypic changes. Previously, we have shown that signatures of selection on gene-specific codons usage bias are common in genomes of diverse eukaryotic species. Thus, synonymous codon usage, just as amino acid usage pattern, is likely a regular target of natural selection. Consequently, here we propose the hypothesis that at least for some protein-coding genes, codon clusters with biased synonymous codon usage patterns might represent “hidden” nucleic-acid-level functional domains that affect the action of the corresponding proteins via diverse hypothetical mechanisms. To test our hypothesis, we used computational approaches to identify over 3,000 putatively functional codon clusters (PFCCs) with biased usage patterns in about 1,500 protein-coding genes in theDrosophila melanogastergenome. Specifically, our data suggest that these PFCCs are likely associated with specific categories of gene function, including enrichment in genes that encode membrane-bound and secreted proteins. Yet, the majority of the PFCCs that we have identified are not associated with previously annotated functional protein domains. Although the specific functional significance of the majority of the PFCCs we have identified remains unknown, we show that in the highly conserved family of voltage-gated sodium channels, the existence of rare-codon cluster(s) in the nucleic-acid region that encodes the cytoplasmic loop that constitutes inactivation gate is conserved across paralogs as well as orthologs across distant animal species. Together, our findings suggest that codon clusters with biased usage patterns likely represent “hidden” nucleic-acid-level functional domains that cannot be simply predicted from the amino acid sequences they encode. Therefore, it is likely that on the evolutionary timescale, protein-coding DNA sequences are shaped by both amino-acid-dependent and codon-usage-dependent selective forces.
Classifying Non-Small Cell Lung Cancer Histopathology Types and Transcriptomic Subtypes using Convolutional Neural Networks
Authors: Yu Kun-Hsing , Wang Feiran , Berry Gerald J. , Ré Christopher , Altman Russ B. , Snyder Michael , Kohane Isaac S.
Published: January 2019

Non-small cell lung cancer is a leading cause of cancer death worldwide, and histopathological evaluation plays the primary role in its diagnosis. However, the morphological patterns associated with the molecular subtypes have not been systematically studied. To bridge this gap, we developed a quantitative histopathology analytic framework to identify the gene expression subtypes of non-small cell lung cancer objectively. We processed whole-slide histopathology images of lung adenocarcinoma (n=427) and lung squamous cell carcinoma patients (n=457) in The Cancer Genome Atlas. To establish neural networks for quantitative image analyses, we first build convolutional neural network models to identify tumor regions from adjacent dense benign tissues (areas under the receiver operating characteristic curves (AUC) > 0.935) and recapitulated expert pathologists’ diagnosis (AUC > 0.88), with the results validated in an independent cohort (n=125; AUC > 0.85). We further demonstrated that quantitative histopathology morphology features identified the major transcriptomic subtypes of both adenocarcinoma and squamous cell carcinoma (P < 0.01). Our study is the first to classify the transcriptomic subtypes of non-small cell lung cancer using fully-automated machine learning methods. Our approach does not rely on prior pathology knowledge and can discover novel clinically-relevant histopathology patterns objectively. The developed procedure is generalizable to other tumor types or diseases.
BalticMethanosarcinaandClostridiumcompete for electrons from metallic iron
Authors: Jaramillo Paola Andrea Palacios , Snoeyenbos-West Oona , Löscher Carolin Regina , Thamdrup Bo , Rotaru Amelia-Elena
Published: January 2019

Microbial induced corrosion of steel structures, used for transport or storage of fuels, chemical weapons or waste radionuclides, is an environmental and economic threat. In non-sulfidic environments, the exact role of methanogens in steel corrosion is poorly understood. From the non-sulfidic, methanogenic sediments of the Baltic Sea corrosive communities were enriched using exclusively Fe0as electron donor and CO2as electron acceptor. Methane and acetate production were persistent for three years of successive transfers.MethanosarcinaandClostridiumwere attached to the Fe0, and dominated metagenome libraries. Since prior reports indicatedMethanosarcinawere merely commensals, consuming the acetate produced by acetogens, we investigated whether these methanogens were capable of Fe0corrosion without bacterial partners (inhibited by an antibiotic cocktail). Unassisted, methanogens corroded Fe0to Fe2+at similar rates to the mixed community. Surprisingly, in the absence of competitive bacteria, Baltic-Methanosarcinaproduced six times more methane than they did in the mixed community. This signifies that Baltic-Methanosarcinaachieved better corrosion alone, exclusive of an operative bacterial partner. Our results also show that together with acetogens,Methanosarcinainteract competitively to retrieve electrons from Fe0rather than as commensals as previously assumed.
Prospective hippocampus and putamen activations support conditional memory-guided behavior
Authors: Hamm A. G. , Mattfeld Aaron T.
Published: January 2019

Memory of past events, in addition to contextual cues, influence conditional behavior. The hippocampus (HPC), medial prefrontal cortex (mPFC), and striatum are important contributors to this process. The mechanisms by which these regions facilitate conditional memory-guided behavior remains unclear. We developed a conditional-associative task in which the correct conditional choice was dependent on the preceding stimulus. We examined activations related to successful conditional behavior and the timing of their contributions. Two distinct networks emerged: (1) a prospective system consisting of the HPC, putamen, mPFC, and other cortical regions, which exhibited increased activation preceding successful conditional decisions; and (2) a concurrent system supported by the caudate, dlPFC, and additional cortical structures that engaged during execution of correct conditional choices. Our findings demonstrate two distinct neurobiological circuits through which memory prospectively biases conditional memory-guided decisions, as well as influence the execution of current choices.
Precision Brain Morphometry: Feasibility and Opportunities of Extreme Rapid Scans
Authors: Nielsen Jared A. , Mair Ross W. , Baker Justin T. , Buckner Randy L.
Published: January 2019

The traditional approach to achieve optimal structural brain morphometry is to increase spatial resolution and maintain a high signal-to-noise ratio within a single scanning session using long acquisitions. Here we explore alternative approaches that use multiple rapid structural scans and averaging to achieve stable morphometric estimates. Effects of sequence, resolution, acceleration, and number of scans within- and between-sessions were varied across six studies that included 1,025 scans. Single ~1-min magnetization-prepared rapid gradient echo (MP-RAGE) scans that use wave-controlled aliasing in parallel imaging (Wave-CAIPI) encoding yield morphometric estimates nearly as accurate as those obtained with traditional long scans. Averaging estimates from multiple rapid scans reduces error below traditional approaches using less total acquisition time. Test-retest reliability within- and between-sessions for ~2 min multi-echo MP-RAGE scans revealed that a source of error is the idiosyncratic positioning of the subject's head between sessions. Cluster scanning over multiple tightly-spaced sessions mitigates this effect and achieves cortical thickness estimates with less than 10μm global (30μm regional) error. Test-retest error for the hippocampus falls below 0.6%. Additional sources of error include coil heating when scans are acquired rapidly within the same session and change in console software between sessions. Rapid acquisitions allow novel experimental designs that can use cluster scanning to achieve precise longitudinal assessment within the individual, build in robustness by affording redundant acquisitions, and reduce the structural scanning burden to a minute when anatomical registration is the goal. The field should consider replacing long structural scans with fast alternatives.
Identification and characterization of a novelpicgene cluster responsible for picolinic acid degradation inAlcaligenes faecalisJQ135
Authors: Qiu Jiguo , Zhao Lingling , Xu Siqiong , Chen Qing , Chen Le , Liu Bin , Hong Qing , Lu Zhenmei , He Jian
Published: January 2019

Picolinic acid (PA) is a natural toxic pyridine derivative. Microorganisms can degrade and utilize PA for growth. However, the full metabolic pathway and its physiological and genetic foundation remain unknown. In this study, we identified thepicgene cluster responsible for the complete degradation of PA fromAlcaligenes faecalisJQ135. PA was initially 6-hydroxylated into 6-hydroxypicolinic acid (6HPA) by PA dehydrogenase (PicA). 6HPA was then 3-hydroxylated by a four-component 6HPA monooxygenase (PicB) to form 3,6-dihydroxypicolinic acid (3,6DHPA), which was then converted into 2,5-dihydroxypyridine (2,5DHP) by a decarboxylase (PicC). The 2,5DHP was further degraded into fumaric acid, through PicD (2,5DHP dioxygenase), PicE (N-formylmaleamic acid deformylase), PicF (maleamic acid amidohydrolase), and PicG (maleic acid isomerase). Homologouspicgene clusters with diverse organizations were found to be widely distributed inα-,β-, andγ-Proteobacteria. Our findings provide new insights into the microbial metabolism of environmental toxic pyridine derivatives.

Importance

Picolinic acid is a common metabolite of L-tryptophan and some aromatic compounds and is an important intermediate of industrial concern. Although the microbial degradation/detoxification of picolinic acid has been studied for over 50 years, the underlying molecular mechanisms are still unknown. Here, we show thepicgene cluster responsible for the complete degradation of picolinic acid into the tricarboxylic acid cycle. This gene cluster was found to be widespread in otherα-,β-, andγ-Proteobacteria. These findings provide new perspective for understanding the mechanisms of picolinic acid biodegradation in bacteria.
Hand-hygiene mitigation strategies against global disease spreading through the air transportation network
Authors: Nicolaides Christos , Avraam Demetris , Cueto-Felgueroso Luis , González Marta C. , Juanes Ruben
Published: January 2019

Hand hygiene is considered as an efficient and cost-effective way to limit the spread of diseases and, as such, it is recommended by both the World Health Organization (WHO) and the Centres for Disease Control and Prevention (CDC). While the effect of hand washing on individual transmissibility of a disease has been studied through medical and public-health research, its potential as a mitigation strategy against a global pandemic has not been fully explored yet. In this study, we investigate contagion dynamics through the world air transportation network and analyze the impact of hand-hygiene behavioural changes of airport population against the spread of infectious diseases worldwide. Using a granular dataset of the world air transportation traffic, we build a detailed individual mobility model that controls for the correlated and recurrent nature of human travel and the waiting-time distributions of individuals at different locations. We perform a Monte-Carlo simulation study to assess the impact of different hand-washing mitigation strategies at the early stages of a global epidemic. From the simulation results we find that increasing the hand cleanliness homogeneously at all airports in the world can inhibit the impact of a potential pandemic by 24 to 69%. By quantifying and ranking the contribution of the different airports to the mitigation of an epidemic outbreak, we identify ten key airports at the core of a cost-optimal deployment of the hand-washing strategy: increasing the engagement rate at those locations alone could potentially reduce a world pandemic by 8 to 37%. This research provides evidence of the effectiveness of hand hygiene in airports on the global spread of infectious diseases, and has important implications for the way public-health policymakers may design new effective strategies to enhance hand hygiene in airports through behavioral changes.
Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells
Authors: Lieb Simone , Blaha-Ostermann Silvia , Kamper Elisabeth , Ehrenhöfer-Wölfer Katharina , Schlattl Andreas , Wernitznig Andreas , Lipp Jesse J. , Nagasaka Kota , Bader Gerd , Neumüller Ralph A. , Kraut Norbert , Pearson Mark A. , Petronczki Mark , Wöhrle Simon
Published: January 2019

Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent large-scale genomic profiling and functional screening of cancer cell lines we identified Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair is frequently detected in human malignancies, in particular in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in the emergence of chromosome breaks, chromatin bridges and micronuclei highlighting defective genome integrity. WRN variants harboring mutations abrogating the ATPase function of WRN helicase fail to rescue the viability phenotype of WRN-depleted MSI-H colorectal cells. Our study suggests that pharmacological inhibition of WRN helicase function might represent a novel opportunity to develop a targeted therapy for MSI-H cancers.
Cross-reactivity of a rice NLR immune receptor to distinct effectors from the blast pathogen leads to partial disease resistance
Authors: Varden Freya A. , Saitoh Hiromasa , Yoshino Kae , Franceschetti Marina , Kamoun Sophien , Terauchi Ryohei , Banfield Mark J.
Published: January 2019

Unconventional integrated domains in plant intracellular immune receptors (NLRs) can directly bind translocated pathogen effector proteins to initiate an immune response. The rice immune receptor pairs Pik-1/Pik-2 and RGA5/RGA4 both use integrated heavy metal-associated (HMA) domains to bind the Magnaporthe oryzae effectors AVR-Pik and AVR-Pia, respectively. These effectors both belong to the MAX effector family and share a core structural fold, despite being divergent in sequence. How integrated domains maintain specificity of recognition, even for structurally similar effectors, has implications for understanding plant immune receptor evolution and function. Here we show that the rice NLR pair Pikp-1/Pikp-2 triggers an immune response leading to partial disease resistance towards the “mismatched” effector AVR-Pia in planta, and that the Pikp-HMA domain binds AVR-Pia in vitro. The HMA domain from another Pik-1 allele, Pikm, is unable to bind AVR-Pia, and does not trigger a response in plants. The crystal structure of Pikp-HMA bound to AVR-Pia reveals a different binding interface compared to AVR-Pik effectors, suggesting plasticity in integrated domain/effector interactions. This work shows how a single NLR can bait multiple pathogen effectors via an integrated domain, and may enable engineering immune receptors with extended disease resistance profiles.
Structural Determinants of Coiled Coil Mechanics
Authors: Lopez-Garcia Patricia , Goktas Melis , Bergues-Pupo Ana E. , Koksch Beate , Varon Silva Daniel , Blank Kerstin G.
Published: January 2019

The natural abundance of coiled coil (CC) motifs in the cytoskeleton and the extracellular matrix suggests that CCs play a crucial role in the bidirectional mechanobiochemical signaling between cells and the matrix. Their functional importance and structural simplicity has allowed the development of numerous applications, such as protein-origami structures, drug delivery systems and biomaterials. With the goal of establishing CCs as nanomechanical building blocks, we investigated the importance of helix propensity and hydrophobic core packing on the mechanical stability of 4-heptad CC heterodimers. Using single-molecule force spectroscopy, we show that both parameters determine the force-induced dissociation in shear loading geometry; however, with different effects on the energy landscape. Decreasing the helix propensity lowers the transition barrier height, leading to a concomitant decrease in the distance to the transition state. In contrast, a less tightly packed hydrophobic core increases the distance to the transition state. We propose that this sequence-structure-mechanics relationship is evolutionarily optimized in natural CCs and can be used for tuning their mechanical properties in applications.
Commonly used insect repellents hide human odors from Anopheles mosquitoes
Authors: Afify Ali , Betz Joshua F. , Riabinina Olena , Potter Christopher J.
Published: January 2019

The mode of action for most mosquito repellents is unknown. This is primarily due to the difficulty in monitoring how the mosquito olfactory system responds to repellent odors. Here, we used the Q-system of binary expression to enable activity-dependent Ca2+ imaging in olfactory neurons of the African malaria mosquito Anopheles coluzzii. This system allows neuronal responses to common insect repellents to be directly visualized in living mosquitoes from all olfactory organs including the antenna. The synthetic repellents DEET and IR3535 did not activate Odorant Receptor Co-Receptor (Orco) expressing olfactory receptor neurons (ORNs) at any concentration, while picaridin weakly activated ORNs only at high concentrations. In contrast, natural repellents (i.e. lemongrass oil and eugenol) strongly activated small numbers of ORNs in the mosquito antennae at low concentrations. We determined that DEET, IR3535, and picaridin decrease the response of Orco expressing ORNs when these repellents are physically mixed with activating human-derived odorants. We present evidence that synthetic repellents may primarily exert their olfactory mode of action by decreasing the amount of activating ligand reaching ORNs. These results suggest that synthetic repellents disruptively change the chemical profile of host scent signatures on the skin surface rendering humans invisible to mosquitoes.
Fast and accurate long-read assembly with wtdbg2
Authors: Ruan Jue , Li Heng
Published: January 2019

Existing long-read assemblers require tens of thousands of CPU hours to assemble a human genome and are being outpaced by sequencing technologies in terms of both throughput and cost. We developed a novel long-read assembler wtdbg2 that, for human data, is tens of times faster than published tools while achieving comparable contiguity and accuracy. It represents a significant algorithmic advance and paves the way for population-scale long-read assembly in future.