bluuebunny/crossref_metadata_2025 huggingface dataset:
Prodiginine Production inStreptomyces coelicolorCorrelates Temporally and Spatially to Programmed Cell Death
Authors: Tenconi Elodie , Traxler Matthew F. , Hoebreck Charline , Van Wezel Gilles P. , Rigali Sébastien
Published: January 2018

Programmed cell death (PCD) is a common feature of multicellularity and morphogenesis in bacteria. While cell death has been well documented whenStreptomycesspecies switch from vegetative (nutrition) to aerial (reproduction) growth, lethal determinants are yet to be discovered to unveil the genetic basis of PCD in mycelial bacteria. In this work we used prodiginines ofStreptomyces coelicoloras model to test the hypothesis that a bacterium uses ‘self-made’ antiproliferative DNA-damaging agents as toxins of their PCD process. Spatio-temporal visualisation of the autofluorescence of prodiginines reveals that their biosynthesis is triggered in the dying zone of the colony prior to morphological differentiation of the mycelium. A prodiginine nonproducer showed hyper-accumulation of viable filaments, with increased RNA and proteins synthesis when most of the mycelium of the wild-type strain was dead when prodiginine accumulated. Addition of a prodiginine synthesis inhibitor also strongly favoured viable over dead filaments. As self-toxicity has also been reported for other producers of DNA-damaging agents we propose that cytotoxic metabolites synthetized during the morphological transition of filamentous bacteria may be used to execute PCD.

Significance Statement

Actinobacteria are prolific producers of compounds with antiproliferative activity, but why these bacteria synthetize metabolites with this bioactivity has so far remained a mystery. Using prodiginines (PdGs) as model system, we revealed that the spatio-temporal synthesis of these molecules correlates to cell death of the producerStreptomyces coelicolorand that inhibition of their synthesis results in hyper-accumulation of viable filaments. Since PdGs potentiate death ofS. coelicolorrecurrently prior to morphological differentiation, this is a form of programmed cell death (PCD). Hence, next to weapons in competition between organisms or signals in inter- and intra-species communications, we propose a third role for secondary metabolites i.e., elements required for self-toxicity in PCD processes.
Intracranial fluid dynamics changes in idiopathic intracranial hypertension: pre and post therapy
Authors: Agarwal N. , Contarino C. , Bertazzi L. , Limbucci N. , Toro E. F.
Published: January 2018

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology frequently associated with dural sinus stenosis. There is emerging evidence that venous sinus stenting is an effective treatment. We use phase contrast cine MRI to observe changes in flow dynamics of multiple intracranial fluids and their response to different treatments in a patient with IIH. We quantified the following parameters at the level of the aqueduct of Sylvius and the cervical C2C3: cerebrospinal fluid (CSF), arterial and venous flow; CSF velocity amplitude; artero-venous delay (AVD); artero-CSF delay and percentage of venous outflow normalized to total arterial inflow (tIJV/tA). Analyses were run before lumbar puncture (LP) (A), after LP (B), after medical therapy (C) and after venous stent placements deployed at two separate times (D and E). AVD and tIJV/tA improved only after CSF removal and after stent placements. CSF velocity amplitude remained elevated. Arterial flow profile showed a dramatic reduction after LP with improvement in mean venous flow. This report is the first to demonstrate interactive changes in intracranial fluid dynamics that occur before and after different therapeutic interventions in IIH. We discuss how increased intracranial venous blood could be “tumoral” in IIH and facilitating its outflow could be therapeutic.
Neonatal gut and respiratory microbiota: coordinated development through time and space
Authors: Grier Alex , McDavid Andrew , Wang Bokai , Qiu Xing , Java James , Bandyopadhyay Sanjukta , Yang Hongmei , Holden-Wiltse Jeanne , Kessler Haeja A. , Gill Ann L. , Huyck Heidie , Falsey Ann R. , Topham David J. , Scheible Kristin M. , Caserta Mary T. , Pryhuber Gloria S. , Gill Steven R.
Published: January 2018

Background:Postnatal development of the microbiota in early life influences immunity, metabolism, neurodevelopment and long-term infant health. Microbiome development occurs at multiple body sites, each with distinct community compositions and functions. Associations between microbiota at multiple sites represent an unexplored influence on the infant microbiome. Here, we examined co-occurrence patterns of gut and respiratory microbiota in pre- and full-term infants over the first year of life, a period critical to neonatal development and risk of respiratory diseases.

Results:Gut and respiratory microbiota collected as longitudinal rectal, throat and nasal samples from 38 pre-term and 44 full-term infants were first clustered into community state types (CSTs) on the basis of their composition. Multiple methods were used to relate the occurrence of CSTs to several measures of infant maturity, including gestational age (GA) at birth, week of life (WOL), and post menstrual age (PMA: equal to GA plus WOL). Manifestation of CSTs followed one of three patterns with respect to infant maturity. First,chronological: independent of infant maturity (GA) at birth, and strongly associated with post-natal age (WOL). Second,idiosyncratic: primarily dependent on maturity (GA) at birth, with persistent differences in CST occurrence between pre- and full-term infants through the first year of life. Third,convergent: CSTs appear earlier in infants with greater maturity (GA) at birth, but after a sufficient post-natal interval their occurrence in pre-term infants reaches parity with full-term infants. The composition of CSTs was highly dissimilar between different body sites, but the CST of any one body site was highly predictive of the CSTs at other body sites. There were significant associations between the abundance of individual taxa at each body site and the CSTs of the other body sites, which persisted after stringent control for the non-linear effects of infant maturity. Significant canonical correlations exist between the microbiota composition at each pair of body sites, with the strongest correlations between more proximal locations.

Conclusion:Cross-body site associations of developing infant microbiota suggest the importance of research and clinical practices that focus on dynamic interactions between multiple microbial communities to elucidate and promote systemic microbiota development.
Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death
Authors: Rodriguez Steven , Schrank Benjamin R. , Sahin Asli , Al-Lawati Hawra , Costantino Isabel , Benz Eric , Fard Darian , Albers Alefiya D. , Cao Luxiang , Gomez Alexis C. , Ratti Elena , Cudkowicz Merit , Frosch Matthew P. , Talkowski Michael , Sorger Peter K. , Hyman Bradley T. , Albers Mark W.
Published: January 2018

Innate immune signaling activation and DNA damage are pathological hallmarks of aging that may herald multiple adult-onset neurodegenerative diseases. Here, we report that both cell autonomous and non-autonomous neuronal death are triggered by the production of cytoplasmic double-stranded RNA (cdsRNA) from a regulated, disarticulated transgene in the setting of type I interferon (IFN-I) signaling. CdsRNA is a pathogen associated molecular pattern that induces IFN-I in many cell types. Transfection of a dsRNA mimetic into cultured human neurons also induces IFN-I signaling and cell death in a dose-dependent manner. Direct relevance to human disease is found in neurons of ALS-FTD patients carrying C9ORF72 intronic hexanucleotide expansions; cdsRNA isolated from these tissues is comprised of repeat sequences. Together, these findings implicate cdsRNA generated from genomic sequences in neurons as a trigger for sterile, viral-mimetic IFN-I induction and propagated neuronal death within in a neural circuit in the aging nervous system.
Treemmer: a tool to reduce large phylogenetic datasets with minimal loss of diversity
Authors: Menardo Fabrizio , Loiseau Chloé , Brites Daniela , Coscolla Mireia , Gygli Sebastian M. , Rutaihwa Liliana K. , Trauner Andrej , Beisel Christian , Borrell Sonia , Gagneux Sebastien
Published: January 2018

Large sequence datasets are difficult to visualize and handle. Additionally, they are often not an adequate representation of the natural diversity, but the result of uncoordinated and convenience sampling. Consequently, they can suffer from redundancy and sampling biases. Here we present Treemmer, a simple tool to evaluate the redundancy of phylogenetic trees and reduce their complexity by eliminating leaves that contribute the least to the tree diversity.

Treemmer can reduce the size of datasets with different phylogenetic structures and levels of redundancy while maintaining a sub-sample that is representative of the original diversity.
The effect of education on adult mortality, health, and income: triangulating across genetic and policy reforms
Authors: Davies Neil M , Dickson Matt , Davey Smith George , Windmeijer Frank , van den Berg Gerard J
Published: January 2018

1

On average, educated people are healthier, wealthier and have higher life expectancy than those with less education. Numerous studies have attempted to determine whether these differences are caused by education, or are merely correlated with it and are ultimately caused by another factor. Previous studies have used a range of natural experiments to provide causal evidence. Here we exploit two natural experiments, perturbation of germline genetic variation associated with education which occurs at conception, known as Mendelian randomization, and a policy reform, the raising of the school leaving age in the UK in 1972. Previous studies have suggested that the differences in outcomes associated with education may be due to confounding. However, the two independent sources of variation we exploit largely imply consistent causal effects of education on outcomes much later in life.
The Healthy Nevada Project: rapid recruitment for population health study
Authors: Grzymski Joseph J , Coppes Max J , Metcalf Jim , Galanopoulos Christos , Rowan Chris , Henderson Michele , Read Robert , Reed Harry , Lipp Bruce , Miceli Dave , Rybarski Susan , Slonim Anthony
Published: January 2018

Background

Nevada ranks in the bottom half of overall health rankings in the United States. The majority of residents of Northern Nevada live in Washoe County, which is confounded with high age-adjusted death rates for heart disease, cancer and chronic lower respiratory disease.

Methods

Saliva as a source of DNA was collected from adults in Northern Nevada as the first phase of a much larger (100,000 participants) effort to contribute to comprehensive population health studies in Nevada. The personal genetics company 23andMe was used to genotype the first 10,250 participants and deliver their custom ancestry, traits, wellness, and carrier status reports.

Results

The study was announced by Governor Brian Sandoval on September 15, 2016 and within two days the registration of 9,700 volunteers for an appointment was complete. Processing of 9,344 participants was achieved in 3 months, with a no-show rate of just over 11%. The participant population was skewed to female and was less racially diverse than the population.

Conclusion

DNA genotyping was administered free-of-charge and the patient population was representative of the socio-economic diversity in northern Nevada – indicating that free genetic testing is of interest to a broad swath of the population and a powerful motivator for comprehensive population health study research.
Near Perfect Neural Critic from Motor Cortical Activity Toward an Autonomously Updating Brain Machine Interface
Authors: An Junmo , Yadav Taruna , Ahmadi Mohammad Badri , Tarigoppula Venkata S Aditya , Francis Joseph Thachil
Published: January 2018

We are developing an autonomously updating brain machine interface (BMI) utilizing reinforcement learning principles. One aspect of this system is a neural critic that determines reward expectations from neural activity. This critic is then used to update a BMI decoder towards an improved performance from the user’s perspective. Here we demonstrate the ability of a neural critic to classify trial reward value given activity from the primary motor cortex (M1), using neural features from single/multi units (SU/MU), and local field potentials (LFPs) with prediction accuracies up to 97% correct. A nonhuman primate subject conducted a cued center out reaching task, either manually, or observationally. The cue indicated the reward value of a trial. Features such as power spectral density (PSD) of the LFPs and spike-field coherence (SFC) between SU/MU and corresponding LFPs were calculated and used as inputs to several classifiers. We conclude that hybrid features of PSD and SFC show higher classification performance than PSD or SFC alone (accuracy was 92% for manual tasks, and 97% for observational). In the future, we will employ these hybrid features towards our autonomously updating BMI.
Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors
Authors: Rohde Jason M. , Brimacombe Kyle R. , Liu Li , Pacold Michael E. , Yasgar Adam , Cheff Dorian M. , Lee Tobie D. , Rai Ganesha , Baljinnyam Bolormaa , Li Zhuyin , Simeonov Anton , Hall Matthew D. , Shen Min , Sabatini David M. , Boxer Matthew B.
Published: January 2018

Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhibitors of human PHGDH. Feedback inhibition was minimized by coupling PHGDH activity to two downstream enzymes (PSAT1 and PSPH), providing a significant improvement in enzymatic turnover. Further coupling of NADH to a diaphorase/resazurin system enabled a red-shifted detection readout, minimizing interference due to compound autofluorescence. With this protocol, over 400,000 small molecules were screened for PHGDH inhibition, and following hit validation and triage work, a piperazine-1-thiourea was identified. Following rounds of medicinal chemistry and SAR exploration, two probes (NCT-502 and NCT-503) were identified. These molecules demonstrated improved target activity and encouraging ADME properties, enabling both in vitro and in vivo assessment of the biological importance of PHGDH, and its role in the fate of serine in PHGDH-dependent cancer cells.
Size-dependent segregation controls macrophage phagocytosis of antibody-opsonized targets
Authors: Bakalar Matthew H. , Joffe Aaron M. , Schmid Eva M. , Son Sungmin , Podolski Marija , Fletcher Daniel A.
Published: January 2018

Macrophages protect the body from damage and disease by targeting antibody-opsonized cells for phagocytosis. Though antibodies can be raised against antigens with diverse structures, shapes, and sizes, it is unclear why some are more effective at triggering antibody-dependent phagocytosis than others. Here we quantitatively define an antigen height threshold that regulates phagocytosis of both engineered and cancer-specific antigens by macrophages. Using a reconstituted model of antibody-opsonized target cells, we find that phagocytosis is dramatically impaired for antigens that position antibodies >10 nm from the target surface. Increasing antigen height allows for co-localization of Fc receptors and the inhibitory phosphatase CD45 at the cell-cell interface, which reduces Fc receptor phosphorylation, and inhibits phagocytosis. Our work shows that close contact between macrophage and target cell is a requirement for efficient phagocytosis, suggesting that therapeutic antibodies should target short antigens in order to trigger Fc receptor activation through size-dependent physical segregation.
Assessment of the CTCF Binding Sites and Repeat-Positions Upstream the Human H19 Gene
Authors: Bina Minou
Published: January 2018

The human H19 and IGF2 genes share an Imprinting Control Region (ICR) that regulates gene expression in a parent-of-origin dependent manner. Understanding of the ICR sequence organization is critical to accurate localization of disease-associated abnormalities including Beckwith-Wiedemann and Silver-Russell syndromes. Previous studies established that the ICR of the H19 - IGF2 imprinted domain included several repeated DNA segments. Using BLAST, BLAT, and Clustal Omega, I conducted detailed sequence comparisons to evaluate the annotation of the unique-repeats upstream of the H19 transcription start site (TSS) and to investigate the extent of similarities among the various repeats. Initial analyses confirmed the existence of two DNA segments consisting of two types of repeats (A and B). However, I find that one of the repeats (B7) is unlikely to be a partial repeat. I provide the genomic positions of the various repeats in the build hg19 of the human genome. I also evaluated the previously predicted CTCF sites (1 to 7) in the context of the ENCODE data: including the positions of DNase I HS clusters and results of ChIP assays. My evaluations did not support the existence of CTCF site 5. Furthermore, the ENCODE data revealed a previously unknown chromatin boundary (consisting of CTCF, RAD21, and SMC3), in a CpG island (CpG27) between the A1 repeat and the H19 TSS. Furthermore, a sequence within this boundary corresponds to a newly discovered CTCF site (I named it CTCF site 8). My discovery of this chromatin boundary in CpG27 entails mechanistic implications.
CSF biomarkers are differentially related to structural and functional changes in dementia of the Alzheimer’s type
Authors: Malpas Charles B , Saling Michael M , Velakoulis Dennis , Desmond Patricia , Hicks Rodney J , Zetterberg Henrik , Blennow Kaj , O’Brien Terence J.
Published: January 2018

The two cardinal pathologies of Alzheimer’s disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer’s type. Interrelationships were analysed between cerebrospinal fluid (CSF) biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks.
Improved prediction of fungal effector proteins from secretomes with EffectorP 2.0
Authors: Sperschneider Jana , Dodds Peter N. , Gardiner Donald M. , Singh Karam B. , Taylor Jennifer M.
Published: January 2018

Plant-pathogenic fungi secrete effector proteins to facilitate infection. We describe extensive improvements to EffectorP, the first machine learning classifier for fungal effector prediction. EffectorP 2.0 is now trained on a larger set of effectors and utilizes a different approach based on an ensemble of classifiers trained on different subsets of negative data, offering different views on classification. EffectorP 2.0 achieves accuracy of 89%, compared to 82% for EffectorP 1.0 and 59.8% for a small size classifier. Important features for effector prediction appear to be protein size, protein net charge as well as the amino acids serine and cysteine. EffectorP 2.0 decreases the number of predicted effectors in secretomes of fungal plant symbionts and saprophytes by 40% when compared to EffectorP 1.0. However, EffectorP 1.0 retains value and combining EffectorP 1.0 and 2.0 results in a stringent classifier with low false positive rate of 9%. EffectorP 2.0 predicts significant enrichments of effectors in 12 out of 13 sets of infection-induced proteins from diverse fungal pathogens, whereas a small cysteine-rich classifier detects enrichment only in 7 out of 13. EffectorP 2.0 will fast-track prioritization of high-confidence effector candidates for functional validation and aid in improving our understanding of effector biology. EffectorP 2.0 is available at http://effectorp.csiro.au.
FoodEstNet: Estimating True Food Consumption with Machine Learning
Authors: Akogo Darlington A. , Danquah Joseph B
Published: January 2018

We developed a Machine Learning/Artificial Intelligence model that estimates how much of a food type a person truly consumes. People tend to underestimate how much they consume which makes the work of nutritionists and dietitians difficult since they rely on food estimates for food portion size control and nutritional management of diseases. We trained an XGBoost model to estimate how much a patient truly consumes based on Age, Sex, BMI, socioeconomic status and perceived consumption.
Fatigue influences the recruitment, but not structure, of muscle synergies
Authors: Ortega-Auriol P.A. , Besier T.F. , Byblow W.D. , McMorland A.J.C.
Published: January 2018

The development of fatigue elicits multiple adaptations from the neuromuscular system. Muscle synergies are common patterns of neuromuscular activation that have been proposed as the building blocks of human movement. We wanted to identify possible adaptations of muscle synergies to the development of fatigue in the upper limb. Recent studies have reported that synergy structure remains invariant during the development of fatigue, but these studies did not examine isolated synergies. We propose a novel approach to characterize synergy adaptations to fatigue by taking advantage of the spatial tuning of synergies. This approach allows improved identification of changes to individual synergies that might otherwise be confounded by changing contributions of overlapping synergies. To analyse upper limb synergies we applied non-negative matrix factorization to 14 EMG signals from muscles of 11 participants performing isometric contractions. A preliminary multidirectional task was used to identify synergy directional tuning. A subsequent fatiguing task was designed to fatigue the participants in their synergies’ preferred directions. Both tasks provided virtual reality feedback of the applied force direction and magnitude, and were performed at 40% of each participant’s maximal voluntary force. Five epochs were analysed throughout the fatiguing task to identify progressive changes of EMG amplitude, median frequency, synergy structure, and activation coefficients. Three to four synergies were sufficient to account for the variability contained in the original data. Synergy structure was conserved with fatigue, but interestingly synergy activation coefficients decreased on average by 24.5% with fatigue development. EMG amplitude did not change systematically with fatigue, whereas EMG median frequency consistently decreased across all muscles. These results support the notion of a neuromuscular modular organization as the building blocks of human movement, with adaptations to synergy recruitment occurring with fatigue. When synergy tuning properties are considered, the reduction of activation of muscle synergies may be a reliable marker to identify fatigue.
Analysis of mycobacterial infection-induced changes to host lipid metabolism in a zebrafish infection model reveals a conserved role for LDLR in infection susceptibility
Authors: Johansen Matt D. , Hortle Elinor , Kasparian Joshua A. , Romero Alejandro , Novoa Beatriz , Figueras Antonio , Britton Warwick J. , de Silva Kumudika , Purdie Auriol C. , Oehlers Stefan H.
Published: January 2018

Changes to lipid metabolism are well-characterised consequences of human tuberculosis infection but their functional relevance are not clearly elucidated in these or other host-mycobacterial systems. The zebrafish-Mycobacterium marinum infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of infection-induced lipid metabolism. We find mammalian mycobacterial infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-mycobacterial species pairings.

Funding

This work was supported by the Australian National Health and Medical Research Council (APP1099912 and APP1053407 to S.H.O.); Meat and Livestock Australia (P.PSH. 0813 to A.C.P. and K. dS); the Marie Bashir Institute for Infectious Diseases and Biosecurity (grant to S.H.O., A.C.P. and K. dS); the Kenyon Family Foundation Inflammation Award (grant to S.H.O.); the University of Sydney (fellowship to S.H.O.); Consellería de Economía, Emprego e Industria (GAIN), Xunta de Galicia (grant IN607B 2016/12 to Institute of Marine Research (IIM-CSIC)).
Genetic Signatures of Lipid Metabolism Evolution in Cetacea
Authors: Endo Yoshinori , Kamei Ken-ichiro , Inoue-Murayama Miho
Published: January 2018

In mammalian evolutionary history, Cetacea (whales, dolphins, and porpoises) achieved astonishing success by adapting to an aquatic environment. One unique characteristic of cetaceans, contributing to this adaptive success, is efficient lipid utilization. Here we report comparative genetic analysis of aquatic and terrestrial Cetartiodactyla using 144 genes associated with lipid metabolism. We analyzed mutation rate, amino acid substitution, and metabolic pathways using genetic data publicly available. Our test detected 18 positively selected genes in Cetacea compared to 13 in Bovidae with little overlap between the lineages. We identified lineage-specific patterns of amino acid substitutions and functional domain that were mutually exclusive between cetaceans and bovids, supporting divergent evolution of lipid metabolism since the divergence of these taxa from a common ancestor. Moreover, a pathway analysis showed that the identified genes in cetaceans were associated with lipid digestion, lipid storage, and energy producing pathways. This study emphasizes the evolutionary context of lipid metabolism modification of cetaceans and provides a foundation for future studies of elucidating the adapted biological mechanisms of cetacean lipid metabolism and a framework for incorporating ecological context into studies aimed at investigating adaptive evolution.
5-hydroxy-4′-nitro-7-propionyloxy-genistein inhibited invasion and metastasis via inactivating wnt/β-catenin signal pathway in human endometrial carcinoma JEC cells
Authors: Bai Jun , Yang Binjian , Luo Xin
Published: January 2018

Chemotherapy has been demonstrating more important roles in the treatment of carcinoma, but drug resistance and side effects restrict its usage in clinic, so developing new type of drug with low side effects and low-drug resistance has become a hot researching spot. The present study aimed to investigate the anticancer effects of 5-hydroxy-4’-nitro-7-propionyloxy-genistein (HNPG) and elucidate its underlying molecular mechanism. The inhibitory effects of cell viability of HNPG were detected using MTT assay, flat plate clone formation method and Transwell assay. The distribution of cell cycle was analyzed using FCM method. The morphological alteration, root-mean-squared roughness (Rq), average roughness (Ra), Young's modulus and adhesive force were measured by AFM. qRT-PCR and western blotting analysis were used to explore the possible molecular mechanism. It was found that HNPG presented with dramatic activity against JEC cellsin vitro, inhibited the proliferation and colony formation, attenuated invasion and migration ability, arrested cell cycle in G1 phase in dose-dependent manner. Simultaneously, cell body shrunk and pseudopod structure retracted, Rq and Ra reduced, Young's modulus and adhesive force increased, accompanied by β-catenin, C-myc, Cyclin D1, MMP-2, MMP-7 and MMP-9 down-regulated. In summary, HNPG may be a novel candidate for chemotherapeutic drug.
Differential antiviral activities of RSV inhibitors in human airway epithelium
Authors: Mirabelli Carmen , Jaspers Martine , Boon Mieke , Jorissen Mark , Koukni Mohamed , Bardiot Dorothee , Chaltin Patrick , Marchand Arnaud , Neyts Johan , Jochmans Dirk
Published: January 2018

We report the use of reconstituted 3D-human airway epithelium cells of bronchial origin (HuAEC) in an air-liquid interface to study respiratory syncytial virus (RSV) infection and to assess the efficacy of RSV inhibitors in (pre-)clinical development. RSV-A replicates efficiently in HuAEC and viral RNA is shed for weeks after infection. RSV infection reduces the ciliary beat frequency of the ciliated cells as of 4 days post infection, with complete ciliary dyskinesia observed by day 10. Treatment with RSV fusion inhibitors resulted in an antiviral effect only when added at the time of infection. In contrast, the use of replication inhibitors (both nucleoside and non-nucleosides) elicited a marked antiviral effect even when start of treatment was delayed until one or even three days after infection. Levels of the inflammation marker RANTES (mRNA) increased ∼200-fold in infected-untreated cultures (at three weeks post infection), but levels were comparable to those of uninfected cultures in the presence of PC-876, a RSV-replication inhibitor, demonstrating that an efficient antiviral treatment inhibits virus induced inflammation in this model. Overall, HuAEC offer a robust and physiologically relevant model to study RSV replication and to assess the efficacy of antiviral compounds.
TNscope: Accurate Detection of Somatic Mutations with Haplotype-based Variant Candidate Detection and Machine Learning Filtering
Authors: Freed Donald , Pan Renke , Aldana Rafael
Published: January 2018

Detection of somatic mutations in tumor samples is important in the clinic, where treatment decisions are increasingly based upon molecular diagnostics. However, accurate detection of these mutations is difficult, due in part to intra-tumor heterogeneity, contamination of the tumor sample with normal tissue and pervasive structural variation. Here, we describe Sentieon TNscope, a haplotype-based somatic variant caller with increased accuracy relative to existing methods. An early engineering version of TNscope was used in our submission to the most recent ICGC-DREAM Somatic Mutation calling challenge. In that challenge, TNscope is the leader in accuracy for SNVs, indels and SVs. To further improve variant calling accuracy, we combined the improvements in the variant caller with machine learning. We benchmarked TNscope using in-silico mixtures of well-characterized Genome in a Bottle (GIAB) samples. TNscope displays higher accuracy than the other benchmarked tools and the accuracy is substantially improved by the machine learning model.
Data-driven models of dominantly-inherited Alzheimer’s disease progression
Authors: Oxtoby Neil P. , Young Alexandra L. , Cash David M. , Benzinger Tammie L. S. , Fagan Anne M. , Morris John C. , Bateman Randall J. , Fox Nick C. , Schott Jonathan M. , Alexander Daniel C.
Published: January 2018

Dominantly-inherited Alzheimer’s disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer’s disease. We use emerging techniques in generative data-driven disease-progression modelling to characterise dominantly-inherited Alzheimer’s disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset (EYO). We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers: 163PSEN1; 17PSEN2; and 31APP) and a baseline visit (age 19–66; up to four visits each, 1·1 ± 1·9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential-equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then sub-cortical regions (approximately 24±11 years before onset); CSF p-tau (17±8 years), tau and Aβ42 changes; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than EYO: root-mean-squared error of 1·35 years versus 5·54 years. The models reveal hidden detail on dominantly-inherited Alzheimer’s disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.
Molecular crypsis by pathogenic fungi using human factor H. A numerical model
Authors: Lang Stefan , Germerodt Sebastian , Glock Christina , Skerka Christine , Zipfel Peter F. , Schuster Stefan
Published: January 2018

Molecular mimicry is the formation of specific molecules by microbial pathogens to avoid recognition and attack by the immune system of the host. Several pathogenic Ascomycota and Zygomycota show such a behaviour by utilizing human complement factor H to hide in the blood stream. We call this type of mimicry molecular crypsis. Such a crypsis can reach a point where the immune system can no longer clearly distinguish between self and non-self cells. Thus, a trade-off between attacking disguised pathogens and erroneously attacking host cells has to be made, which can lead to autoreactivity. Based on signalling theory and protein-interaction modelling, we here present a mathematical model of molecular crypsis of pathogenic fungi using the example ofCandida albicans. We tackle the question whether perfect crypsis is feasible, which would imply that protection of human cells by complement factors would be useless. The model identifies pathogen abundance relative to host cell abundance as the predominant factor influencing successful or unsuccessful molecular crypsis. If pathogen cells gain a (locally) quantitative advantage over host cells, even autoreactivity may occur. Our new model enables insights into the mechanisms of candidiasis-induced sepsis and complement associated autoimmune diseases.
Mitogenomic data indicate admixture components of Asian Hun and Srubnaya origin in the Hungarian Conquerors
Authors: Neparáczki Endre , Maróti Zoltán , Kalmár Tibor , Kocsy Klaudia , Maár Kitti , Bihari Péter , Nagy István , Fóthi Erzsébet , Pap Ildikó , Kustár Ágnes , Pálfi György , Raskó István , Zink Albert , Török Tibor
Published: January 2018

It has been widely accepted that the Finno-Ugric Hungarian language, originated from proto Uralic people, was brought into the Carpathian Basin by the Hungarian Conquerors. From the middle of the 19thcentury this view prevailed against the deep-rooted Hungarian Hun tradition, maintained in folk memory as well as in Hungarian and foreign written medieval sources, which claimed that Hungarians were kinsfolk of the Huns. In order to shed light on the genetic origin of the Conquerors we sequenced 102 mitogenomes from early Conqueror cemeteries and compared them to sequences of all available databases. We applied novel population genetic algorithms, named Shared Haplogroup Distance and MITOMIX, to reveal past admixture of maternal lineages. Phylogenetic and population genetic analysis indicated that more than one third of the Conqueror maternal lineages were derived from Central-Inner Asia and their most probable ultimate sources were the Asian Huns. The rest of the lineages most likely originated from the Bronze Age Potapovka-Poltavka-Srubnaya cultures of the Pontic-Caspian steppe, which area was part of the later European Hun empire. Our data give support to the Hungarian Hun tradition and provides indirect evidence for the genetic connection between Asian and European Huns. Available data imply that the Conquerors did not have a major contribution to the gene pool of the Carpathian Basin, raising doubts about the Conqueror origin of Hungarian language.
Single-Cell Transcriptome Analysis of Lineage Diversity and Microenvironment in High-Grade Glioma
Authors: Yuan Jinzhou , Levitin Hanna Mendes , Frattini Veronique , Bush Erin C. , Boyett Deborah M. , Samanamud Jorge , Ceccarelli Michele , Dovas Athanassios , Zanazzi George , Canoll Peter , Bruce Jeffrey N. , Lasorella Anna , Iavarone Antonio , Sims Peter A.
Published: January 2018

Background

Despite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). We sampled the cellular milieu of HGGs with massively-parallel single-cell RNA-Seq.

Results

While HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors.

Conclusions

These studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.
Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention
Authors: Inouye Michael , Abraham Gad , Nelson Christopher P. , Wood Angela M. , Sweeting Michael J. , Dudbridge Frank , Lai Florence Y. , Kaptoge Stephen , Brozynska Marta , Wang Tingting , Ye Shu , Webb Thomas R , Rutter Martin K. , Tzoulaki Ioanna , Patel Riyaz S. , Loos Ruth J.F. , Keavney Bernard , Hemingway Harry , Thompson John , Watkins Hugh , Deloukas Panos , Angelantonio Emanuele Di , Butterworth Adam S. , Danesh John , Samani Nilesh J. ,   for The UK Biobank CardioMetabolic Consortium CHD Working Group
Published: January 2018

Background

Coronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention.

Methods

Using a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank.

Findings

In UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution.

Interpretation

Recent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification.

Funding

National Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.
Expression ofSULTR2;2in the Arabidopsis bundle sheath is mediated by a highly conserved positive regulator
Authors: Kirschner Sandra , Woodfield Helen , Prusko Katharina , Koczor Maria , Gowik Udo , Hibberd Julian M. , Westhoff Peter
Published: January 2018

The bundle sheath provides a conduit linking veins and mesophyll cells. In C3Arabidopsis thalianait also plays important roles in oxidative stress and sulphur metabolism. However, the mechanisms responsible for the patterns of gene expression that underpin these metabolic specialisations are poorly understood. Here we used theA. thaliana SULTR2;2gene as a model to better understand mechanisms that restrict expression to the bundle sheath. Deletion analysis indicated that theSULTR2;2promoter contains a short region necessary for expression in the bundle sheath. This sequence acts as a positive regulator and is tolerant to multiple consecutive deletions indicating considerable redundancy in thecis-elements involved. It is highly conserved inSULTR2;2genes of the Brassicaceae and is functional in the distantly related C4speciesFlaveria bidentisthat belongs to the Asteraceae. We conclude that expression ofSULTR2;2in the bundle sheath is underpinned by a highly redundant sequence that likely represents an ancient and conserved mechanism found in families as diverse as the Asteraceae and Brassicaceae.
Fine-tuning of substrate preferences of the Src-family kinase Lck revealed through a high-throughput specificity screen
Authors: Shah Neel H. , Löbel Mark , Weiss Arthur , Kuriyan John
Published: January 2018

To obtain a comprehensive map of the intrinsic specificities of tyrosine kinase domains, we developed a high-throughput method that uses bacterial surface-display and next-generation sequencing to analyze the specificity of any tyrosine kinase against a library of thousands of peptides derived from human tyrosine phosphorylation sites. Using this approach, we identified a difference in the electrostatic recognition of substrates between the cytoplasmic Src-family tyrosine kinases Lck and c-Src. This divergence likely reflects the specialization of Lck to act in concert with the tyrosine kinase ZAP-70 in T cell receptor signaling. The current understanding of substrate recognition by tyrosine kinases emphasizes the role of localization by non-catalytic domains, but our results point to the importance of direct recognition at the kinase active site in fine-tuning specificity. Our method provides a simple approach that leverages next-generation sequencing to readily map the specificity of any tyrosine kinase at the proteome level.
Conserved and ubiquitous expression of piRNAs and PIWI genes in mollusks antedates the origin of somatic PIWI/piRNA expression to the root of bilaterians
Authors: Jehn Julia , Gebert Daniel , Pipilescu Frank , Stern Sarah , Kiefer Julian Simon Thilo , Hewel Charlotte , Rosenkranz David
Published: January 2018

PIWI proteins and a specific class of small non-coding RNAs, termed Piwi interacting RNAs (piRNAs), suppress transposon activity in animals on the transcriptional and post-transcriptional level, thus protecting genomes from detrimental insertion mutagenesis. While in vertebrates the PIWI/piRNA system appears to be restricted to the germline, somatic expression of piRNAs directed against transposons is widespread in arthropods, likely representing the ancestral state for this phylum. Here, we show that somatic expression of PIWI genes and piRNAs directed against transposons is conserved in mollusks, suggesting that somatic PIWI/piRNA expression was already realized in an early bilaterian ancestor. We further describe lineage specific adaptations regarding transposon composition of piRNA clusters and show that different piRNA clusters are dynamically expressed during oyster development. Finally, bioinformatics analyses suggest that different populations of piRNAs participate in the ping-pong amplification loop in a tissue specific manner.
Identification of rare de novo epigenetic variations in congenital disorders
Authors: Barbosa Mafalda , Joshi Ricky S. , Garg Paras , Martin-Trujillo Alejandro , Patel Nihir , Jadhav Bharati , Watson Corey T. , Gibson William , Chetnik Kelsey , Tessereau Chloe , Mei Hui , Rubeis Silvia De , Reichert Jennifer , Lopes Fatima , Vissers Lisenka E.L.M. , Kleefstra Tjitske , Grice Dorothy E. , Edelmann Lisa , Soares Gabriela , Maciel Patricia , Brunner Han G. , Buxbaum Joseph D. , Gelb Bruce D. , Sharp Andrew J.
Published: January 2018

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. With recent dramatic advances in genomic technologies, genome-wide surveys of cohorts of patients with ND/CAs for point mutations and structural variations have greatly advanced our understanding of their genetic etiologies1,2. However, even after whole genome sequencing (WGS), a substantial fraction of such disorders remain unexplained3. In contrast, the possibility that constitutive epigenetic variations (epivariations) might underlie such traits has not been well explored. We hypothesized that some cases of ND/CA are caused by aberrations of DNA methylation that lead to a dysregulation of normal genome function. By comparing DNA methylation profiles from 489 individuals with ND/CAs against 1,534 population controls, we identified epivariations as a frequent occurrence in the human genome. De novo epivariations were significantly enriched in cases when compared to controls. RNAseq data from population studies showed that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detected and replicated an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations. Thus, some epivariations occur secondary to cis-linked mutations in regulatory regions, providing a rationale for interpreting non-coding genetic variation. We propose that epivariations likely represent the causative genomic defect in 5-10% of patients with unexplained ND/CAs. This constitutes a yield comparable to CNV microarrays, and as such has significant diagnostic relevance.