bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut microbiome transition across a lifestyle gradient in Himalaya
Authors: Jha Aashish R , Davenport Emily R , Gautam Yoshina , Bhandari Dinesh , Tandukar Sarmila , Ng Katharine , Holmes Susan , Gautam Guru Prasad , Sherchand Jeevan Bahadur , Bustamante Carlos , Sonnenburg Justin
Published: January 2018

The composition of the gut microbiome in industrialized populations differs from those living traditional lifestyles. However, it has been difficult to separate the contributions of human genetic and geographic factors from lifestyle/modernization. Here, we characterize the stool bacterial composition of four Himalayan populations to investigate how the gut community changes in response to shifts in human lifestyles. These groups led seminomadic hunting-gathering lifestyles until transitioning to varying dependence upon farming. The Tharu began farming 250-300 years ago, the Raute and Raji transitioned 30-40 years ago, and the Chepang retain many aspects of a foraging lifestyle. We assess the contributions of dietary and environmental factors on their gut microbiota and find that the gut microbiome composition is significantly associated with lifestyle. The Chepang foragers harbor elevated abundance of taxa associated with foragers around the world. Conversely, the gut microbiomes of populations that have transitioned to farming are more similar to those of Americans, with agricultural dependence and several associated lifestyle and environmental factors correlating with the extent of microbiome divergence from the foraging population. For example, our results show that drinking water source and solid cooking fuel are significantly associated with the gut microbiome. Despite the pronounced differences in gut bacterial composition across populations, we found little differences in alpha diversity across populations. These findings in genetically similar populations living in the same geographical region establish the key role of lifestyle in determining human gut microbiome composition and point to the next challenging steps of isolating dietary effects from other factors that change during modernization.
Temporal evolution of immunity distributions in a population with waning and boosting
Authors: Barbarossa M. V. , Polner M. , Röst G.
Published: January 2018

We investigate the temporal evolution of the distribution of immunities in a population, which is determined by various epidemiological, immunological and demographical phenomena: after a disease outbreak, recovered individuals constitute a large immune population, however their immunity is waning in the long term and they may become susceptible again. Meanwhile, their immunity can be boosted by repeated exposure to the pathogen, which is linked to the density of infected individuals present in the population. This prolongs the length of their immunity.

We consider a mathematical model formulated as a coupled system of ordinary and partial differential equations, that connects all these processes, and systematically compare a number of boosting assumptions proposed in the literature, showing that different boosting mechanisms lead to very different stationary distributions of the immunity at the endemic steady state. In the situation of periodic disease outbreaks, the waveforms of immunity distributions are studied and visualized. Our results show that there is a possibility to infer the boosting mechanism from the population level immune-dynamics.

AMS Classification

92D30, 34K60, 34K34, 37M05
Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants
Authors: Farnaes Lauge , Hildreth Amber , Sweeney Nathaly M. , Clark Michelle M. , Chowdhury Shimul , Nahas Shareef , Cakici Julie A. , Benson Wendy , Kaplan Robert H. , Kronick Richard , Bainbridge Matthew N. , Friedman Jennifer , Gold Jeffrey J. , Ding Yan , Veeraraghavan Narayanan , Dimmock David , kingsmore Stephen F. ,   on behalf of the RCIGM Investigators
Published: January 2018

BACKGROUND

Genetic disorders are a leading cause of morbidity and mortality in infants. Rapid Whole Genome Sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants.

METHODS

Retrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016–March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points.

FINDINGS

The diagnostic sensitivity was 43% (eighteen of 42 infants) for rWGS and 10% (four of 42 infants) for standard of care (P=.0005). The rate of clinical utility for rWGS (31%, thirteen of 42 infants) was significantly greater than for standard of care (2%, one of 42; P=.0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800, 000 to $2,000,000.

DISCUSSION

These findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.
Validation of known risk factors associated with carpal tunnel syndrome: A retrospective nationwide 11-year population-based cohort study in South Korea
Authors: Lee Hong-Jae , Lim Hyun Sun , Kim Hyoung Seop
Published: January 2018

Key Points

Question

What is the relationship between the previously known risk factors and occurrence of carpal tunnel syndrome (CTS)?

Findings

In this retrospective population-based cohort study that included 512,942 participants sampled from the Korean National Health Insurance System database, we determined the following known risk factors were related to the occurrence of CTS: the age of 40s, female, being overweight, diabetes, rheumatoid arthritis, gout, and Raynaud’s syndrome. However, ESRD, hypothyroidism and smoking were not correlated with CTS occurrence.

Implications

We identified the age of 40s, female, overweight, diabetes, rheumatoid arthritis, gout, and Raynaud’s syndrome as risk factors for the occurrence of CTS.

Importance

There have been few large-scale studies that have included a risk factor analysis for CTS. No prior study has investigated and validated the relationship between the occurrence of CTS and known risk factors using nationwide health care database.

Objective

To confirm the actual risk factors for CTS out of various known risk factors

Design

We conducted this study using a retrospective cohort model based on the combined two databases of the Korean National Health Insurance System; the national periodic health screening program database from 2002–2003 and health insurance database of reimbursement claims from 2003 through 2013.

Setting

A population-based retrospective cohort study.

Participants

First, we randomly sampled 514,795 patients who represented 10% of the 5,147,950 people who took part in periodic health screenings in 2002–2003. Existing CTS patients were excluded from this group. Therefore, this study finally included 512,942 participants and followed up their medical records from 2003–2013.

Main Outcomes and Measures

Desired outcomes were the incidence rate of CTS in patients with various risk factors and the hazard ratios of risk factors affecting the disease’s occurrence.

Results

The incidence of CTS was highest in patients in the age of 40s, in the moderate obesity group, in females, and in patients with diabetes mellitus (DM). The hazard ratio analysis revealed that the following risk factors were strongly related to the occurrence of CTS: age of 40s, female, obesity, DM, rheumatoid arthritis, gout, and Raynaud’s syndrome. However, ESRD, hypothyroidism and smoking were not correlated with CTS occurrence.

Conclusions and Relevance

In our large-scale cohort study, risk factors such as being in one’s 40s, obesity, being female, suffering from DM, and rheumatoid arthritis were reaffirmed as those of CTS occurrence.
10 Year Epidemiologic data of Parkinson’s Disease: A Nationwide Population-based Retrospective Cohort of South Korea
Authors: Kim Hyoung Seop , Kwon Joon-Byum , Lim Hyun-Sun , Cha Jiook , Kim Hye Won
Published: January 2018

Objectives

The aims of this study were to determine the prevalence, incidence, and P/I ratio of Parkinson’s disease (PD) in South Korea and to present basic epidemiological information on PD patients for making effective health policies.

Methods

We used National Health Insurance Service-National Sample Cohort (KNHIS-NSC) data to analyze the prevalence, incidence, and P/I ratio of PD from 2003 to 2013 and then followed up using the NHID in 2008 to obtain the hazard ratio (HR) of death in PD itself and other comorbidities from 2008 to 2013.

Results

The prevalence and incidence of PD increased rapidly from 72.9 and 32.8 in 2003 to 213.4 and 58.0 in 2013, and the P/I ratio increased from 2.22 in 2003 to 3.62 in 2013. The prevalence, incidence, and P/I ratio of PD were all higher in women than in men. The hazard ratio for death was significantly higher in PD patients (15.36) compared to subjects without the disease. Stroke was the most frequent cause of death in the PD patient population followed by cancer and pneumonia.

Conclusion

The prevalence, incidence, and P/I ratio of PD rapidly increased as the years progressed. This indirectly proves that the health insurance system in Korea is efficient and has allowed patients with PD to access medical facilities more easily. However, a newer public healthy strategy should be established for patients with PD because PD itself has a high HR for death, and patients with PD have a high mortality rate when stroke and pneumonia are also involved.

Disclosure

All authors have reported no biomedical interests and potential conflicts of interests.
Risk factors associated with Parkinson’s disease: An 11-year population-based South Korean study
Authors: Kim Hyoung Seop , Lee Hong-Jae , Cha Jiook , Kwon Junbeom , Lim Hyunsun
Published: January 2018

Objective

To validate various known risk factors of Parkinsonism and to establish basic information to formulate public health policy by using a 10-year follow-up cohort model.

Methods

This population based nation-wide study was performed using the National Health Insurance Database of reimbursement claims of the Health Insurance Review and Assessment Service of South Korea data on regular health check-ups in 2003 and 2004, with 10 years’ follow-up.

Results

We identified 7,746 patients with Parkinsonism. Old age, hypertension, diabetes, depression, anxiety, taking statin medication, high body mass index, non-smoking, non-alcohol drinking, and low socioeconomic status were each associated with an increase in the risk of Parkinsonism (fully adjusted Cox proportional hazards model: hazard ratio (HR) 1.259, 95% confidence interval (CI) 1.194–1.328 for hypertension, HR 1.255, 95% CI 1.186–1.329 for diabetes, HR 1.554, 95% CI 1.664–1.965 for depression, HR 1.808, 95% CI 1.462–1.652 for anxiety, and HR 1.157, 95% CI 1.072–1.250 for taking statin medication).

Conclusions

In our study, old age, depression, anxiety, and a non-smoker status were found to be risk factors of Parkinsonism, in agreement with previous studies. However, sex, hypertension, diabetes, taking statin medication, non-drinking of Alcohol, and lower socioeconomic status have not been described as risk factors in previous studies and need further verification in future studies.
A comprehensive manually-curated Compendium of Bovine Transcription Factors
Authors: de Souza Marcela M , Vaquerizas Juan M , Zerlotini Adhemar , Geistlinger Ludwig , Hernández-Rodríguez Benjamín , Tizioto Polyana C , Taylor Jeremy F , Rocha Marina IP , Diniz Wellison JS , Coutinho Luiz L , Regitano Luciana CA
Published: January 2018

Transcription factors (TFs) are pivotal regulatory proteins that control gene expression in a context-dependent and tissue-specific manner. In contrast to human, where comprehensive curated TF collections exist, bovine TFs are only rudimentary recorded and characterized. In this article, we present a manually-curated compendium of 865 sequence-specific DNA-binding bovines TFs, which we analyzed for domain family distribution, evolutionary conservation, and tissue-specific expression. In addition, we provide a list of putative transcription cofactors derived from known interactions with the identified TFs. Since there is a general lack of knowledge concerning the regulation of gene expression in cattle, the curated list of TF should provide a basis for an improved comprehension of regulatory mechanisms that are specific to the species.
A comprehensive model of DNA fragmentation for the preservation of High Molecular Weight DNA
Authors: Klingström Tomas , Bongcam-Rudloff Erik , Pettersson Olga Vinnere
Published: January 2018

For long-read sequencing applications, shearing of DNA is a significant issue as it limits the read-lengths generated by sequencing. During extraction and storage of DNA the DNA polymers are susceptible to physical and chemical shearing. In particular, the mechanisms of physical shearing are poorly understood in most laboratories as they are of little relevance to commonly used short-read sequencing technologies. This study draws upon lessons learned in a diverse set of research fields to create a comprehensive theoretical framework for obtaining high molecular weight DNA (HMW-DNA) to support improved quality management in laboratories and biobanks for long-read sequencing applications.

Under common laboratory conditions physical and chemical shearing yields DNA fragments of 5-35 kilobases (kb) in length. This fragment length is sufficient for DNA sequencing using short-read technologies but for Nanopore sequencing, linked reads and single molecular real time sequencing (SMRT) poorly preserved DNA will limit the length of the reads generated.

The shearing process can be divided into physical and chemical shearing which generates different patterns of fragmentation. Exposure to physical shearing creates a characteristic fragment length where the main cause of shearing is shear stress induced by turbulence. The characteristic fragment length is several thousand base pairs longer than the reads produced by short-read sequencing as the shear stress imposed on short DNA fragments is insufficient to shear the DNA. This characteristic length can be measured using gel electrophoresis or instruments for DNA fragment analysis,. Chemical shearing generates randomly distributed fragment lengths visible as a smear of DNA below the peak fragment length. By measuring the peak of the DNA fragment length distribution and the proportion of very short DNA fragments, both sources of shearing can be measured using commonly used laboratory techniques, providing a suitable quantification of DNA integrity of DNA for sequencing with long-read technologies.
Signaling pathway screening platforms are an efficient approach to identify therapeutic targets in precision-medicine oriented early phase clinical trials
Authors:   Pedro Torres-Ayuso, Sahoo Sudhakar , Galvin Melanie , Leong Hui Sun , Frese Kristopher K , Hughes Andrew , Marais Richard , Dive Caroline , Krebs Matthew G , Brognard John
Published: January 2018

Precision medicine aims to tailor cancer therapies to target specific tumorpromoting aberrations. For tumors that lack actionable drivers, extensive molecular characterization and pre-clinical drug efficacy studies will be required to match patients with the appropriate targeted therapy. A cell line maintained at low passage and a patient-derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention. No actionable mutations were identified after whole exome sequencing of the patient’s DNA; however, whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, that include the PIK3CA and RICTOR genes, respectively. Consistent with amplification of these genes, pathway analysis revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated in the tumor biopsy-derived cell culture and PDX, and response to the AKT inhibitor AZD5363 was observed both in vitro and in vivo indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. In conclusion, our study demonstrates that high throughput signaling pathway analysis complements next-generation sequencing approaches for detection of actionable alterations and will aid in patient stratification into early-phase clinical trials.
Exploring morphological motifs for a single neuron based on multiple 3D reconstructions
Authors: Yang Jian , He Yishan , Zhou Zhi , Zhong Ning , Peng Hanchuan
Published: January 2018

The morphology of individual neurons is useful to study structures and functions of nervous system. Researchers have invented many semi or fully automatic tracing methods to efficiently generate a reconstruction from a single neuron. Different tracing methods have different design principles, and could produce different reconstructions. However, the “common substructures” of various reconstructions, called morphological motifs, should be highly reliable. In this work, we propose a Vaa3D based framework to explore morphological motifs of 3D reconstructions from a single neuron. The framework contains four steps: (1) resampling and sorting each reconstruction according to a standard reconstruction, such as a gold standard reconstruction, consensus reconstruction or a certain reliable reconstruction; (2) applying local alignment algorithm for each pair of the standard reconstruction and a reconstruction, or each pair of two reconstructions; (3) constructing overlaps based on selected points in local alignment pairs; (4) obtaining morphological motifs by post-processing these overlaps. Under the proposed framework, three methods were implemented and tested on a dataset of 73 fruitfly neurons released by the BigNeuron project (http://bigneuron.org), which contains a gold standard reconstruction, a consensus reconstruction and about 40 automatic reconstructions for each neuron. We quantitatively evaluated these three methods to choose reliable morphological motifs.
Gradual repression of selenoprotein W ensures physiological bone remodelling
Authors: Kim Hyunsoo , Lee Kyunghee , Kim Jin Man , Kim Jae-Ryong , Lee Han-Woong , Chung Youn Wook , Shin Hong-In , Park Eui-Soon , Rho Jaerang , Lee Seoung Hoon , Kim Nacksung , Lee Soo Young , Choi Yongwon , Jeong Daewon
Published: January 2018

Selenoproteins containing selenium in the form of selenocysteine are critical for bone remodelling. However, their mechanism of action is not well understood. Here, we report the identification of selenoprotein W (SELENOW) through large-scale mRNA profiling of receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclast differentiation, as a protein that is downregulated via RANKL/RANK/tumour necrosis factor receptor-associated factor 6/p38 signalling. RNA sequencing analysis revealed that SELENOW regulates osteoclastogenic genes. SELENOW overexpression enhanced osteoclastogenesis in vitro via nuclear translocation of NF-κB and nuclear factor of activated T-cells cytoplasmic 1, whereas its loss suppressed osteoclast formation. SELENOW-deficient and SELENOW-overexpressing mice exhibited osteopetrosis and osteoporosis, respectively. Ectopic SELENOW expression stimulated cell-cell fusion critical for osteoclast maturation as well as bone resorption. Thus, RANKL-dependent repression of SELENOW maintains proper osteoclast differentiation and blocks osteoporosis caused by overactive osteoclasts. These findings demonstrate a biological link between selenium and bone metabolism.
A genetically encoded biosensor reveals location bias of opioid drug action
Authors: Stoeber Miriam , Jullie Damien , Laeremans Toon , Steyaert Jan , Schiller Peter W. , Manglik Aashish , von Zastrow Mark
Published: January 2018

Opioid receptors (ORs) precisely modulate behavior when activated by native peptide ligands but distort behaviors to produce pathology when activated by non-peptide drugs. A fundamental question is how drugs differ from peptides in their actions on target neurons. One way that drugs can differ is by imposing selective effects on the conformational equilibrium of individual ORs. We wondered if drugs can also impose selective effects on the location of OR activation in individual OR-expressing neurons. Here we develop a genetically encoded biosensor that directly localizes ligand-induced activation and deactivation of ORs in living cells, and use it to generate the first real-time map of the spatiotemporal organization of μ‐ and δ-OR activation in neurons. Peptide agonists produce a characteristic activation pattern initiated in the plasma membrane and propagating to endosomes after receptor internalization. Drugs produce a different activation pattern by uniquely driving OR activation in the somatic Golgi apparatus and extending throughout the dendritic arbor in Golgi outposts. These results demonstrate a new approach to probe the cellular basis of neuromodulation and reveal that drugs profoundly distort the spatiotemporal landscape of neuronal OR activation.
Base-pair resolution detection of transcription factor binding site by deep deconvolutional network
Authors: Salekin Sirajul , Zhang Jianqiu (Michelle) , Huang Yufei
Published: January 2018

Motivation

Transcription factor (TF) binds to the promoter region of a gene to control gene expression. Identifying precise transcription factor binding sites (TFBS) is essential for understanding the detailed mechanisms of TF mediated gene regulation. However, there is a shortage of computational approach that can deliver single base pair (bp) resolution prediction of TFBS.

Results

In this paper, we propose DeepSNR, a Deep Learning algorithm for predicting transcription factor binding location at Single Nucleotide Resolution de novo from DNA sequence. DeepSNR adopts a novel deconvolutional network (deconvNet) model and is inspired by the similarity to image segmentation by deconvNet. The proposed deconvNet architecture is constructed on top of ‘Deep-Bind’ and we trained the entire model using TF specific data from ChIP-exonuclease (ChIP-exo) experiments. DeepSNR has been shown to outperform motif search based methods for several evaluation metrics. We have also demonstrated the usefulness of DeepSNR in the regulatory analysis of TFBS as well as in improving the TFBS prediction specificity using ChIP-seq data.

Availability

DeepSNR is available open source in the GitHub repository (https://github.com/sirajulsalekin/DeepSNR)

Contact

yufei.huang@utsa.edu
Genetic contribution to ‘theory of mind’ in adolescence
Authors: Warrier Varun , Baron-Cohen Simon
Published: January 2018

Difficulties in ‘theory of mind’ (the ability to attribute mental states to oneself or others, and to make predictions about another’s behaviour based on these attributions) have been observed in several psychiatric conditions. We investigate the genetic architecture of theory of mind in 4,577 13-year-olds who completed the Emotional Triangles Task (Triangles Task), a first-order test of theory of mind. We observe a small but significant female-advantage on the Triangles Task (Cohen’s d = 0.19, P < 0.01), in keeping with previous work using other tests of theory of mind. Genome-wide association analyses did not identify any significant loci, and SNP heritability was small and non-significant. Polygenic scores for six psychiatric conditions (ADHD, anorexia, autism, bipolar disorder, depression, and schizophrenia), and empathy were not associated with scores on the Triangles Task. However, polygenic scores of cognitive aptitude, and cognitive empathy, a term synonymous with theory of mind and measured using the “Reading the Mind in the Eyes” Test, were significantly associated with scores on the Triangles Task at multiple P-value thresholds, suggesting shared genetics between different measures of theory of mind and cognition.
Heat shock factor 5 is conserved in vertebrates and essential for spermatogenesis in zebrafish
Authors: Saju Jolly M. , Hossain Mohammad Sorowar , Liew Woei Chang , Pradhan Ajay , Thevasagayam Natascha May , Anand Amit , Olsson Per-Erik , Orbán László
Published: January 2018

Heat shock factors (Hsfs) are transcription factors that regulate response to heat shock and to variety of other environmental and physiological stimuli. Four HSFs (HSF1-4) known in vertebrates till date, perform a wide variety of functions from mediating heat shock response to development and gametogenesis. Here, we describe a new yet conserved member of HSF family, Hsf5, which likely exclusively functions for spermatogenesis. Thehsf5is predominantly expressed in developing testicular tissues, in comparison to wider expression reported for other HSFs. HSF5 loss causes male sterility due to drastically reduced sperm count, and severe abnormalities in remaining few spermatozoa. While hsf5 mutant female did not show any abnormality. We show that Hsf5 is required for progression through meiotic prophase 1 during spermatogenesis. Thehsf5mutants indeed show misregulation of a substantial number of genes regulating cell cycle, DNA-damage repair, apoptosis and cytoskeleton proteins. We also show that Hsf5 physically binds to majority of these differentially expressed genes, suggesting its direct role in regulating the expression of many genes important for spermatogenesis.
A role for a conserved kinase in the transcriptional control of methionine biosynthesis inEscherichia coliexperiencing sustained nitrogen starvation
Authors: Switzer Amy , Evangelopoulos Dimitrios , Figueira Rita , de Carvalho Luiz Pedro S. , Brown Daniel R. , Wigneshweraraj Sivaramesh
Published: January 2018

The initial adaptive transcriptional response to nitrogen (N) starvation inEscherichia coliinvolves large-scale alterations to the transcriptome mediated by the transcription activator, NtrC. One of the NtrC-activated genes isyeaG, which encodes a conserved bacterial kinase. Although it is known that YeaG is required for optimal survival under sustained N starvation, the molecular basis by which YeaG benefits N starvedE. coliremains elusive. By combining transcriptomics with targeted metabolomics analyses, we demonstrate that the methionine biosynthesis pathway becomes transcriptionally dysregulated inΔyeaGbacteria experiencing sustained N starvation. This results in the aberrant and energetically costly biosynthesis of methionine and associated metabolites under sustained N starvation with detrimental consequences to cell viability. It appears the activity of the master transcriptional repressor of methionine biosynthesis genes, MetJ, is compromised inΔyeaGbacteria under sustained N starvation, resulting in transcriptional derepression of MetJ-regulated genes. The results suggest that YeaG is a novel regulatory factor and functions as a molecular brake in the transcriptional control of both the NtrC-regulon and methionine biosynthesis genes inE. coliexperiencing sustained N starvation.
Experimental analysis of exome-scale mutational signature of glycidamide, the reactive metabolite of acrylamide
Authors: Zhivagui Maria , Ardin Maude , Ng Alvin W.T. , Churchwell Mona I. , Pandey Manuraj , Villar Stephanie , Cahais Vincent , Robitaille Alexis , Bouaoun Liacine , Heguy Adriana , Guyton Kathryn , Stampfer Martha R. , McKay James , Hollstein Monica , Olivier Magali , Rozen Steven G. , Beland Frederick A. , Korenjak Michael , Zavadil Jiri
Published: January 2018

Acrylamide, a probable human carcinogen, is ubiquitously present in the human environment, with sources including heated starchy foods, coffee and cigarette smoke. Humans are also exposed to acrylamide occupationally. Acrylamide is genotoxic, inducing gene mutations and chromosomal aberrations in various experimental settings. Covalent haemoglobin adducts were reported in acrylamide-exposed humans and DNA adducts in experimental systems. The carcinogenicity of acrylamide has been attributed to the effects of glycidamide, its reactive and mutagenic metabolite capable of inducing rodent tumors at various anatomical sites. In order to characterize the pre-mutagenic DNA lesions and global mutation spectra induced by acrylamide and glycidamide, we combined DNA-adduct and whole-exome sequencing analyses in an established exposure-clonal immortalization system based on mouse embryonic fibroblasts. Sequencing and computational analysis revealed a unique mutational signature of glycidamide, characterized by predominant T:A>A:T transversions, followed by T:A>C:G and C:G>A:T mutations exhibiting specific trinucleotide contexts and significant transcription strand bias. Computational interrogation of human cancer genome sequencing data indicated that a combination of the glycidamide signature and an experimental benzo[a]pyrene signature are nearly equivalent to the COSMIC tobacco-smoking related signature 4 in lung adenocarcinomas and squamous cell carcinomas. We found a more variable relationship between the glycidamide‐ and benzo[a]pyrene-signatures and COSMIC signature 4 in liver cancer, indicating more complex exposures in the liver. Our study demonstrates that the controlled experimental characterization of specific genetic damage associated with glycidamide exposure facilitates identifying corresponding patterns in cancer genome data, thereby underscoring how mutation signature laboratory experimentation contributes to the elucidation of cancer causation.

A 40-word summary

Innovative experimental approaches identify a novel mutational signature of glycidamide, a metabolite of the probable human carcinogen acrylamide. The results may elucidate the cancer risks associated with exposure to acrylamide, commonly found in tobacco smoke, thermally processed foods and beverages.
Mechanical evolution of DNA double-strand breaks in the nucleosome
Authors: Cleri Fabrizio , Landuzzi Fabio , Blossey Ralf
Published: January 2018

Double strand breaks in the DNA backbone are the most lethal type of defect that can be induced in the cell nucleus by chemical and radiation treatments of cancer. However, little is known about the potentially large differences in the outcomes of damage between free and nucleosomal DNA, leading to corresponding differences in damage repair capability. We performed microsecond-length molecular dynamics computer simulations of nucleosomes including double-strand breaks (DSB) at various sites, to characterize the early stages of the evolution of this important DNA lesion right after its formation. We find that all DSB configurations tend to remain compact, with only the terminal bases interacting with histone proteins; the interacting molecular structures are studied by looking at the essential dynamics of the relevant DNA and histone fragments, and compared to the intact nucleosome, thus exposing key features of the interactions. Moreover, we show that the broken DNA ends at the DSB must overcome a free-energy barrier to detach from the nucleosome core, as measured by means of umbrella sampling of the potential of mean force. Finally, by using state-of-the-art calculation of the covariant mechanical stress at the molecular scale, we demonstrate that, depending on the DNA-core separation distance, the coupled bending and torsional stress stored in the detached DNA can force the free end to either stick back to the nucleosome core surface, or to open up straight, thus making it accessible to damage signalization proteins.
Genetic factors and age are the strongest predictors of humoral immune responses to common pathogens and vaccines
Authors: Scepanovic Petar , Alanio Cécile , Hammer Christian , Hodel Flavia , Bergstedt Jacob , Patin Etienne , Thorball Christian W. , Chaturvedi Nimisha , Charbit Bruno , Abel Laurent , Quintana-Murci Lluis , Duffy Darragh , Albert Matthew L. , Fellay Jacques ,   The Milieu Intérieur Consortium
Published: January 2018

Introduction

Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluate the impact of intrinsic (age and sex), environmental and genetic factors on the variability of humoral response to common pathogens and vaccines.

Methods

We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age‐ and sex-stratified cohort of 1,000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests.

Results and discussion

We identified age and sex as important determinants of humoral response, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leucocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.

Conclusions

Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrate that age, sex and specific human genetic variants contribute to inter-individual variability in humoral response. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.
Exposure of zebra mussels to extracorporeal shock waves demonstrates formation of new mineralized tissue inside and outside the focus zone
Authors: Sternecker Katharina , Geist Juergen , Beggel Sebastian , Dietz-Laursonn Kristin , de la Fuente Matias , Frank Hans-Georg , Furia John P. , Milz Stefan , Schmitz Christoph
Published: January 2018

A substantial body of evidence supports the use of extracorporeal shock wave therapy (ESWT) for fracture nonunions in human medicine. However, the success rate (i.e., radiographic union at six months after ESWT) is only approximately 75%. Detailed knowledge regarding the underlying mechanisms that induce bio-calcification after ESWT is limited. The aim of the present study was to analyze the biological response within mineralized tissue of a new invertebrate model organism, the zebra mussel Dreissena polymorpha, after exposure with extracorporeal shock waves (ESWs). Mussels were exposed to ESWs with positive energy density of 0.4 mJ/mm2 or were sham exposed. Detection of newly calcified tissue was performed by concomitantly exposing the mussels to fluorescent markers. Two weeks later, the fluorescence signal intensity of the valves was measured. Mussels exposed to ESWs showed a statistically significantly higher mean fluorescence signal intensity within the shell zone than mussels that were sham exposed. Additional acoustic measurements revealed that the increased mean fluorescence signal intensity within the shell of those mussels that were exposed to ESWs was independent of the size and position of the focal point of the ESWs. These data demonstrate that induction of bio-calcification after ESWT may not be restricted to the region of direct energy transfer of ESWs into calcified tissue. The results of the present study are of relevance for better understanding of the molecular and cellular mechanisms that induce formation of new mineralized tissue after ESWT. Specifically, bio-calcification following ESWT may extend beyond the direct area of treatment.

Summary statement

The use of zebra mussels in research on extracorporeal shock wave (ESW) therapy for fracture nonunions allows new insights into the complex process of induction of biomineralization by ESWs.
Optimizing CRISPR/Cas9 System to Precisely Model Plasminogen Activator Inhibitor-1 Point Mutations in Mice
Authors: Liu Yang , Saunders Thomas L. , Sisson Thomas , Blackburn Robert , Ginsberg David S. , Day Duane
Published: January 2018

CRISPR/Cas9 has become a powerful genome editing tool in recent years. CRISPR/Cas9 can be utilized to not only efficiently generate knock out models in various organisms, but also to precisely model human disease or variants to study gene function and develop therapies. However, the latter remains challenging because of low knock-in (KI) efficiency. In this study, precise gene editing modeling plasminogen activator inhibitor-1 (PAI-1) ‐tissue plasminogen activator (tPA) binding deficiency and PAI-1-vitronectin binding deficiency were generated respectively in mice. Optimization of single guide RNAs (sgRNA) and repair templates, and utilization of restriction fragment length polymorphism (RFLP) to detect KI events are described. Injection of sgRNA/Cas9/single-stranded oligodeoxynucleotide (ssODN) into mouse zygotes resulted in homozygous changes of two silent mutations and changed Arg369>Ala, which abolishes PAI-1 inhibitory activity against tPA. Targeting Arg124 and Gln146 simultaneously involved in vitronectin binding proved to be challenging. However, we successfully generated these relatively distant mutations (23 amino acids apart) seamlessly. Generation of the Arg124 mutation alone was achieved with over 60% efficiency along with the integration of a restriction site, compared to the relatively low double mutation frequency. In summary, our data indicates that the distance between desired mutations and CRISPR-induced double-stranded break (DSB) site is the most critical factor for achieving high efficiency in precise gene modification.
To jump or not to jump: The Bereitschaftspotential required to jump into 192-meter abyss
Authors: Nann M. , Cohen L.G. , Deecke L. , Soekadar S.R.
Published: January 2018

Self-initiated voluntary acts, such as pressing a button, are preceded by a negative electrical brain potential, the Bereitschaftspotential (BP), that can be recorded over the human scalp using electroencephalography (EEG). Up to now, the BP required to initiate voluntary acts has only been recorded under well-controlled laboratory conditions.

It is thus not known if this form of brain activity also underlies motor initiation in possible life-threatening decision making, such as jumping into a 192-meter abyss, an act requiring extraordinary willpower. Here, we report BP before self-initiated 192-meter extreme bungee jumping across two semi-professional cliff divers (both male, mean age 19.3 years). We found that the spatiotemporal dynamics of the BP is comparable to that recorded under laboratory conditions. These results, possible through recent advancements in wireless and portable EEG technology, document for the first time pre-movement brain activity preceding possible life-threatening decision making.
Genomic dissection of Systemic Lupus Erythematosus: Distinct Susceptibility, Activity and Severity Signatures
Authors: Panousis Nikolaos I. , Bertsias George , Ongen Halit , Gergianaki Irini , Tektonidou Maria , Trachana Maria , Romano-Palumbo Luciana , Bielser Deborah , Howald Cedric , Pamfil Cristina , Fanouriakis Antonis , Kosmara Despoina , Repa Argyro , Sidiropoulos Prodromos , Dermitzakis Emmanouil T. , Boumpas Dimitrios T.
Published: January 2018

Recent genetic and genomics approaches have yielded novel insights in the pathogenesis of Systemic Lupus Erythematosus (SLE) but the diagnosis, monitoring and treatment still remain largely empirical1,2. We reasoned that molecular characterization of SLE by whole blood transcriptomics may facilitate early diagnosis and personalized therapy. To this end, we analyzed genotypes and RNA-seq in 142 patients and 58 matched healthy individuals to define the global transcriptional signature of SLE. By controlling for the estimated proportions of circulating immune cell types, we show that the Interferon (IFN) and p53 pathways are robustly expressed. We also report cell-specific, disease-dependent regulation of gene expression and define a core/susceptibility and a flare/activity disease expression signature, with oxidative phosphorylation, ribosome regulation and cell cycle pathways being enriched in lupus flares. Using these data, we define a novel index of disease activity/severity by combining the validated Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)1with a new variable derived from principal component analysis (PCA) of RNA-seq data. We also delineate unique signatures across disease endo-phenotypes whereby active nephritis exhibits the most extensive changes in transcriptome, including prominent drugable signatures such as granulocyte and plasmablast/plasma cell activation. The substantial differences in gene expression between SLE and healthy individuals enables the classification of disease versus healthy status with median sensitivity and specificity of 83% and 100%, respectively. We explored the genetic regulation of blood transcriptome in SLE and found 3142cis-expression quantitative trait loci (eQTLs). By integration of SLE genome-wide association study (GWAS) signals and eQTLs from 44 tissues from the Genotype-Tissue Expression (GTEx) consortium, we demonstrate that the genetic causality of SLE arises from multiple tissues with the top causal tissue being the liver, followed by brain basal ganglia, adrenal gland and whole blood. Collectively, our study defines distinct susceptibility and activity/severity signatures in SLE that may facilitate diagnosis, monitoring, and personalized therapy.
Effects of inhibitors on Hsp90’s conformational dynamics, cochaperone and client interactions
Authors: Schmid Sonja , Götz Markus , Hugel Thorsten
Published: January 2018

The molecular chaperone and heat-shock protein Hsp90 has become a central target in anti-cancer therapy. Nevertheless, the effect of Hsp90 inhibition is still not understood at the molecular level, preventing a truly rational drug design. Here we report on the effect of the most prominent drug candidates, namely radicicol, geldanamycin, derivatives of purine and novobiocin, on Hsp90’s characteristic conformational dynamics and the binding of three interaction partners. Unexpectedly, the global opening and closing transitions are hardly affected by Hsp90 inhibitors. Instead, the conformational equilibrium, as well as the associated kinetic rate constants remain almost untouched. Moreover, we find no significant changes in the binding of the cochaperones Aha1 and p23 nor of the model substrate Δ131Δ. This holds true for both, competitive and allosteric inhibitors. Therefore, direct inhibition mechanisms, affecting only one molecular interaction, are unlikely. Based on our results, we speculate that the inhibitory action observed in vivo is caused by a combination of subtle effects, which can be used in the search for novel Hsp90 inhibition mechanisms.
Missionary, Reformer, and Old Believer in Revolutionary Russia: Bishop Andrei (Ukhtomskii) (1872–1937)
Authors: White James M.
Published: January 2018

This article examines the life and thought of Andrei (Ukhtomskii), a prominent Orthodox churchman in late imperial and early Soviet Russia. A proponent of ecclesiastical reform, Andrei believed that the Church was unable to instil piety because of an overly close relationship with the state. Basing his opinions on Slavophile philosophy, Andrei campaigned for the restoration of the Russian patriarchate and parish reform that would grant the laity increased autonomy. As a missionary among non‐Russian populations, he rejected linguistic Russification. After 1905, these beliefs led him to clash with the right and Rasputin. After the February Revolution of 1917, the Provisional Government appointed Andrei to a leading position in the Holy Synod. However, during the collapse of the Church's hierarchy in the 1920s, he grew weary of the prevalent inertia and in 1925 attempted to single‐handedly resolve the centuries‐old Old Believer schism. This was rejected by the Moscow Patriarchate, leading Andrei to create his own catacomb church. This article concludes that Andrei should be seen as a church politician undone by the contradictions inherent both in his own position and that of the Church.
Parishes under Pressure ‐ The Church of England in South Buckinghamshire 1913–1939
Authors: Masom Grant
Published: January 2018

Secularisation, or the reducing social significance of religion in the twentieth century, has been widely researched in terms of “demand” factors, but less so on the “supply‐side,” considering the contributory effects of the strategies and actions of religious organisations themselves. This article explores these strategies in a group of Anglican churches in South Buckinghamshire in the period leading up to the Second World War, as industrial and population development shifted proportionally to the southeast. This rapid growth and accompanying demographic change posed major challenges to the Church of England, subjecting the parish system to severe pressure. The availability, allocation, and suitability of clergy were a constant concern. The very basis of the Church of England's “offer” to the average citizen — of being the established, national church, there for everyone — seemed under threat: in some places, there was simply no church to “belong” to. Money was in short supply — perhaps both a cause and a symptom of other problems. A general issue was how to reach young people, but a specific concern was the funding of church schools. More widely, the church seemed to be losing touch with the changing cultural and moral landscape in which it operated.
Using multivariate time series methods to estimate location and climate change effects on temperature readings employed in electricity demand simulation
Authors: Bowden Ross S. , Clarke Brenton R.
Published: January 2018

Long‐term historical daily temperatures are used in electricity forecasting to simulate the probability distribution of future demand but can be affected by changes in recording site and climate. This paper presents a method of adjusting for the effect of these changes on daily maximum and minimum temperatures. The adjustment technique accommodates the autocorrelated and bivariate nature of the temperature data which has not previously been taken into account. The data are from Perth, Western Australia, the main electricity demand centre for the South‐West of Western Australia. The statistical modelling involves a multivariate extension of the univariate time series ‘interleaving method’, which allows fully efficient simultaneous estimation of the parameters of replicated Vector Autoregressive Moving Average processes. Temperatures at the most recent weather recording location in Perth are shown to be significantly lower compared to previous sites. There is also evidence of long‐term heating due to climate change especially for minimum temperatures.