bluuebunny/crossref_metadata_2025 huggingface dataset:
Endogenous amdoparvovirus-related elements reveal insights into the biology and evolution of vertebrate parvoviruses
Authors: Pénzes Judit J , Marsile-Medun Soledad , Agbandje-McKenna Mavis , Gifford Robert James
Published: December 2017

Amdoparvoviruses (familyParvoviridae:genusAmdoparvovirus) infect carnivores, and are a major cause of morbidity and mortality in farmed animals. In this study, we systematically screened animal genomes to identify PVe disclosing a high degree of similarity to amdoparvoviruses, and investigated their genomic, phylogenetic and protein structural features. We report the first examples of full-length, amdoparvovirus-derived PVe in the genome of the Transcaucasian mole vole (Ellobius lutescens). Furthermore, we identify four further PVe in mammal and reptile genomes that are intermediate between amdoparvoviruses and their sister genus (Protoparvovirus) in terms of their phylogenetic placement and genomic features. In particular, we identify a genome-length PVe in the genome of a pit viper (Protobothrops mucrosquamatus) that is more like a protoparvovirus than an amdoparvovirus in terms of its phylogenetic placement and the structural features of its capsid protein (as revealed by homology modeling), yet exhibits characteristically amdoparvovirus-like genome features including: (i) a putative middle ORF gene; (ii) a capsid gene that lacks a phospholipase A2 (PLA2) domain; (iii) a genome structure consistent with an amdoparvovirus-like mechanism of capsid gene expression. Our findings indicate that amdoparvovirus host range has extended to rodents in the past, and that parvovirus lineages possessing a mixture of proto- and amdoparvovirus-like characteristics have circulated in the past. In addition, we show that PVe in the mole vole and pit viper encode intact, expressible replicase genes that have potentially been co-opted or exapted in these host species.
High-efficiency optogenetic silencing with soma-targeted anion-conducting channelrhodopsins
Authors: Mahn Mathias , Gibor Lihi , Cohen-Kashi Malina Katayun , Patil Pritish , Printz Yoav , Oring Shir , Levy Rivka , Lampl Ilan , Yizhar Ofer
Published: December 2017

Optogenetic silencing allows time-resolved functional interrogation of defined neuronal populations. However, the limitations of inhibitory optogenetic tools impose stringent constraints on experimental paradigms. The high light power requirement of light-driven ion pumps and their effects on intracellular ion homeostasis pose unique challenges, particularly in experiments that demand inhibition of a widespread neuronal population in vivo. Guillardia theta anion-conducting channelrhodopsins (GtACRs) are promising in this regard, due to their high single-channel conductance and favorable photon-ion stoichiometry. However, GtACRs show poor membrane targeting in mammalian cells, and the activity of such channels can cause transient excitation in the axon due to an excitatory chloride reversal potential in this compartment. Here we address both problems by enhancing membrane targeting and subcellular compartmentalization of GtACRs. The resulting GtACR-based optogenetic tools show improved photocurrents, greatly reduced axonal excitation, high light sensitivity and rapid kinetics, allowing highly efficient inhibition of neuronal activity in the mammalian brain.
Cross-reactive immunity drives global oscillation and opposed alternation patterns of seasonal influenza A viruses
Authors: Gatti Lorenzo , Zhang Jitao David , Anisimova Maria , Schutten Martin , Osterhaus Ab , van der Vries Erhard
Published: December 2017

Several human pathogens exhibit distinct patterns of seasonality and circulate as pairs of discrete strains. For instance, the activity of the two co-circulating influenza A virus subtypes oscillates and peaks during winter seasons of the world’s temperate climate zones. These periods of increased activity are usually caused by a single dominant subtype. Alternation of dominant strains in successive influenza seasons makes epidemic forecasting a major challenge. From the start of the 2009 influenza pandemic we enrolled influenza A virus infected patients (n = 2,980) in a global prospective clinical study. Complete hemagglutinin (HA) sequences were obtained from 1,078 A/H1N1 and 1,033 A/H3N2 viruses and were linked to patient data. We then used phylodynamics to construct high resolution spatio-temporal phylogenetic HA trees and estimated global influenza A effective reproductive numbers (R) over time (2009-2013). We demonstrate that R, a parameter to define host immunity, oscillates around R = 1 with a clear opposed alternation pattern between phases of the A/H1N1 and A/H3N2 subtypes. Moreover, we find a similar alternation pattern for the number of global virus migration events between the sampled geographical locations. Both observations suggest a between-strain competition for susceptible hosts on a global level. Extrinsic factors that affect person-to-person transmission are a major driver of influenza seasonality, which forces influenza epidemics to coincide with winter seasons. The data presented here indicate that also cross-reactive host immunity is a key intrinsic driver of global influenza seasonality, which determines the outcome of competition between influenza A virus strains at the onset of each epidemic season.

Significance statement

Annual influenza epidemics coincide with winter seasons in many parts of the world. Environmental factors, such as air humidity variation or temperature change, are commonly believed to drive these seasonality patterns. Interestingly, three out of the four latest pandemics (1918, 1968 and 2009) did not spread in winter initially, but during summer. This questions to what extent other factors could also impact virus spread among humans. We demonstrate that cross-reactive host immunity is a key factor. It drives the well-known seasonal patterns of virus activity oscillation and alternation of the dominant influenza virus subtype in successive seasons. Furthermore, this factor may also explain the efficient spread of pandemic viruses during summer when cross-reactive host immunity is relatively low.
Excess deaths associated with the chikungunya epidemic of 2014 in Jamaica were higher among children under 5 and over 40 years of age, an analysis based on official data
Authors: Freitas André Ricardo Ribas , Donalisio Maria Rita
Published: December 2017

We assessed the excess of all causes of mortality by age groups during the chikungunya epidemics in Jamaica, 2014. Excess mortality was estimated by subtracting deaths observed in 2014 from that expected based on the average mortality rate of 2012-2013, with confidence interval of 99%.

Overall mortality 91.9 / 100,000 population, 2,499 additional deaths than expected coincided with the peak of the epidemic, there was a strong correlation between the monthly incidence and the excess of deaths (Spearman Rho = 0.939; p <0.005). No other significant epidemiological phenomenon occurred on that island that could explain this increase in mortality. Thus, we suggest that mortality associated with chikungunya is underestimated in Jamaica, as in other countries.

The excess of deaths could be a strategic tool for the epidemiological surveillance of chikungunya as it has already been used in influenza and respiratory syncytial.
Excess mortality in Guadeloupe and Martinique, islands of the French West Indies, during the chikungunya epidemic of 2014
Authors: Freitas A. R. R. , Alarcon-Elbal P. M. , Donalisio M. R.
Published: December 2017

In some chikugunya epidemics, deaths are not fully captured by the traditional surveillance system, based on case reports and death reports. This is a time series study to evaluate the excess of mortality associated with epidemic of chikungunya virus (CHIKV) in Guadeloupe and Martinique, Antilles, 2014. The population (total 784,097 inhabitants) and mortality data estimated by sex and age were accessed at the Institut National de la Statistique et des Etudes Economiques - France. Age adjusted mortality rates were calculated also in Reunion, Indian Ocean for comparison. Epidemiological data on CHIKV (cases, hospitalizations, and deaths) were obtained in the official epidemiological reports of the Cellule de Institut de Veille Sanitaire - France. The excess of deaths for each month in 2014 and 2015 was the difference between the expected and observed deaths for all age groups, considering the 99% confidence interval threshold. Pearson coefficient of correlation between monthly excess of deaths and reported cases of chikungunya show a strong correlation (R = 0.81, p <0.005), also with a 1-month lag (R = 0.87, p <0.001), and between monthly rates of hospitalization for CHIKV and the excess of deaths with a delay of 1 month (R = 0.87, p <0.0005).The peak of the epidemic occurred in the month with the highest mortality, returning to normal soon after the end of the CHIKV epidemic. The overall mortality estimated by this method (639 deaths) was about 4 times greater than that obtained through death declarations (160 deaths). Excess mortality increased with age. Although etiological diagnosis of all deaths associated with CHIKV infection is not possible, already well-known statistical tools can contribute to an evaluation of the impact of this virus on the mortality and morbidity in the different age groups.
Behavior Variability of a Conditional Gene Knockout Mouse as a Measure of Subtle Phenotypic Trait Expression. The Case of Mouse Executive Function Distortion
Authors: Prosselkov Pavel , Zhang Qi , Goto Hiromichi , Polygalov Denis , McHugh Thomas J. , Itohara Shigeyoshi
Published: December 2017

Task learning relies on brain executive function (EF), the construct of controlling and coordinating behavior under the everlasting flow of environmental changes. We have previously shown, that a complete knockout of a vertebrate brain-specific pair of gene paralogs (Ntng1/2) distorts the mouse EF, making behavior less predictable (more variable) via the affected working memory and attention (1). In the current study, conditionally targeting either serotonin transporter (5-HTT) or Emx1-expressing neurons, we show that the cell type-specific ablation of Ntng1 within the excitatory circuits of either cortex or thalamus does not have a profound impact on the EF but rather affects its certain modalities, i.e. impulsivity and/or selective attention, modulated by cognitive demand. Several mice of both conditional genotypes simultaneously occupy either top or bottom parameter-specific behavioral ranks, indicative of a subject-unique antagonistic either proficit or deficit of function within the same behavior. Employing genotype-attributable behavior variability as a phenotypic trait, we deduce, that Ntng1-parsed excitatory pathways contribute but do not fully reconstitute the attention-impulsivity phenotypes, associated with the mouse EF deficit. However, complete knockdown of Ntng1/2, and associated with it behavior variability, explains the deficit of executive function and task learning.
Decoding the chromatin proteome of a single genomic locus by DNA sequencing
Authors: Korthout Tessy , Poramba-Liyanage Deepani W. , Verzijlbergen Kitty F. , van Welsem Tibor , van Leeuwen Fred
Published: December 2017

Transcription, replication and repair involve interactions of specific genomic loci with many different proteins. How these interactions are orchestrated at any given location and under changing cellular conditions is largely unknown because systematically measuring protein-DNA interactions at a specific locus in the genome is challenging. To address this problem, we developed Epi-Decoder, a Tag-ChIP-Barcode-Seq technology in budding yeast to identify and quantify in an unbiased and systematic manner the proteome of an individual genomic locus. Epi-Decoder is orthogonal to proteomics approaches because it does not rely on mass spectrometry but instead takes advantage of DNA sequencing. Analysis of the proteome of a transcribed locus proximal to an origin of replication revealed more than 400 proteins. Moreover, replication stress induced changes in local chromatin-proteome composition prior to local origin firing, affecting replication proteins as well as transcription proteins. Epi-Decoder will enable the delineation of complex and dynamic protein-DNA interactions across many regions of the genome.
Farm productive realities and the dynamics of bovine viral diarrhea (BVD) transmission
Authors: Iotti Bryan , Valdano Eugenio , Savini Lara , Candeloro Luca , Giovannini Armando , Rosati Sergio , Colizza Vittoria , Giacobini Mario
Published: December 2017

Bovine Viral Diarrhea (BVD) is a viral disease that affects cattle and that is endemic to many European countries. It has a markedly negative impact on the economy, through reduced milk production, abortions, and a shorter lifespan of the infected animals. Cows becoming infected during gestation may give birth to Persistently Infected (PI) calves, which remain highly infective throughout their life, due to the lack of immune response to the virus. As a result, they are the key driver of the persistence of the disease both at herd scale, and at the national level. In the latter case, the trade-driven movements of PIs, or gestating cows carrying PIs, are responsible for the spatial dispersion of BVD. Past modeling approaches to BVD transmission have either focused on within-herd or between-herd transmission. A comprehensive portrayal, however, targeting both the generation of PIs within a herd, and their displacement throughout the Country due to trade transactions, is still missing. We overcome this by designing a multiscale metapopulation model of the spatial transmission of BVD, accounting for both within-herd infection dynamics, and its spatial dispersion. We focus on Italy, a country where BVD is endemic and seroprevalence is very high. By integrating simple within-herd dynamics of PI generation, and the highly-resolved cattle movement dataset available, our model requires minimal arbitrary assumptions on its parameterization. Notwithstanding, it accurately captures the dynamics of the BVD epidemic, as demonstrated by the comparison with available prevalence data. We use our model to study the role of the different productive realities of the Italian market, and test possible intervention strategies aimed at prevalence reduction. We find that dairy farms are the main drivers of BVD persistence in Italy, and any control strategy targeting these farms would lead to significantly higher prevalence reduction, with respect to targeting other production compartments. Our multiscale metapopulation model is a simple yet effective tool for studying BVD dispersion and persistence at country level, and is a good instrument for testing targeted strategies aimed at the containment or elimination of this disease. Furthermore, it can readily be applied to any national market for which cattle movement data is available.
Spotiton: New Features and Applications
Authors: Dandey Venkata P. , Wei Hui , Zhang Zhening , Tan Yong Zi , Acharya Priyamvada , Eng Edward T. , Rice William J. , Kahn Peter A. , Potter Clinton S. , Carragher Bridget
Published: December 2017

We present an update describing new features and applications of Spotiton, a novel instrument for vitrifying samples for cryoEM. We have used Spotiton to prepare several test specimens that can be reconstructed using routine single particle analysis to ~3 Å resolution, indicating that the process has no apparent deleterious effect on the sample integrity. The system is now in routine and continuous use in our lab and has been used to successfully vitrify a wide variety of samples.
Antiseptic Agents Elicit Short-Term, Personalized and Body Site-Specific Shifts in Resident Skin Bacterial Communities
Authors: SanMiguel Adam J. , Meisel Jacquelyn S. , Horwinski Joseph , Zheng Qi , Bradley Charles W. , Grice Elizabeth A.
Published: December 2017

Despite critical functions in cutaneous health and disease, it is unclear how resident skin microbial communities are altered by topical antimicrobial interventions commonly used in personal and clinical settings. Here we show that acute exposure to antiseptic treatments elicits rapid but short-term depletion of microbial community diversity and membership. Thirteen subjects were enrolled in a longitudinal treatment study to analyze the effects of topical treatments (ethanol, povidone-iodine, chlorhexidine, water) on the skin microbiome at two skin sites of disparate microenvironment: forearm and back. Treatment effects were highly dependent on personalized and body site-specific colonization signatures, which concealed community dynamics at the population level when not accounted for in this analysis. The magnitude of disruption was influenced by the identity and abundance of particular bacterial inhabitants. Lowly abundant members of the skin microbiota were more likely to be displaced, and subsequently replaced by the most abundant taxa prior to treatment. Members of the skin commensal family Propionibactericeae were particularly resilient to treatment, suggesting a distinct competitive advantage in the face of disturbance. These results provide insight into the stability and resilience of the skin microbiome, while establishing the impact of topical antiseptic treatment on skin bacterial dynamics and community ecology.
To be a Grid Cell: Shuffling procedures for determining “Gridness”
Authors: Barry C. , Burgess N.
Published: December 2017

Grid cells in freely behaving mammals are defined by the strikingly regular periodic spatial distribution of their firing. The standard method of identification calculates the “Gridness” of the spatial firing pattern, with significance being defined relative to the 95th percentile of a null distribution of the Gridness values found after randomly permuting spike times relative to behaviour. We determined the false-positive rate by applying the method to simulated firing with irregular spatially inhomogeneity (i.e. randomly distributed Gaussian patches). We found surprisingly high false positive rates (potentially approaching 20%), which were strongly dependent on the type of Gridness measure used and the number of spatial fields in the synthetic data. This likely reflects the spatial homogeneity of the distributions of spikes after shuffling compared to the inhomogeneous synthetic data. However, false positive rates were reduced (generally below 8%), and less dependent on other factors, when an alternative spatial field shuffling method was used to generate the null Gridness distribution. For comparison, we analysed single unit recordings made using tetrodes implanted into rat medial entorhinal cortex for the purpose of finding grid cells. We found 24% of active neurons were classified as grid cells via spike shuffling and 22% via field shuffling. These results, and the potentially high false-positive rate when classifying cells with patchy but irregular firing as grid cells, indicate that the proportion of cells with regular grid-like firing patterns can be over-estimated by standard methods.
Assembly-free and alignment-free sample identification using genome skims
Authors: Sarmashghi Shahab , Bohmann Kristine , P. Gilbert M. Thomas , Bafna Vineet , Mirarab Siavash
Published: December 2017

The ability to quickly and inexpensively describe taxonomic diversity is critical in this era of rapid climate and biodiversity changes. The currently preferred molecular technique, barcoding, has been very successful, but is based on short organelle markers. Recently, an alternative genome-skimming approach has been proposed: low-pass sequencing (100Mb – several Gb per sample) is applied to voucher and/or query samples, and marker genes and/or organelle genomes are recovered computationally. The current practice of genome-skimming discards the vast majority of the data because the low coverage of genome-skims prevents assembling the nuclear genomes. In contrast, we suggest using all unassembled reads directly, but existing methods poorly support this goal. We introduce a new alignment-free tool, Skmer, to estimate genomic distances between the query and each reference genome-skim using the k-mer decomposition of reads. We test Skmer on a large set of insect and bird genomes, sub-sampled to create genome-skims. Skmer shows great accuracy in estimating genomic distances, identifying the closest match in a reference dataset, and inferring the phylogeny. The software is publicly available on https://github.com/shahab-sarmashghi/Skmer.git
Is there association between APOE e4 genotype and structural brain ageing phenotypes, and does that association increase in older age in UK Biobank? (N = 8,395)
Authors: Lyall Donald M. , Cox Simon R. , Lyall Laura M. , Celis-Morales Carlos , Cullen Breda , Mackay Daniel F. , Ward Joey , Strawbridge Rona J. , McIntosh Andrew M. , Sattar Naveed , Smith Daniel J. , Cavanagh Jonathan , Deary Ian J. , Pell Jill P.
Published: December 2017

Apolipoprotein (APOE) e4 genotype is a purported risk factor for accelerated cognitive ageing and dementia, though its neurostructural substrates are unclear. The deleterious effects of this genotype on brain structure may increase in magnitude into older age. This study aimed to investigate in UK Biobank the association between APOE e4 allele presence vs. absence and brain imaging variables that have been associated with worse cognitive abilities; and whether this association varies by cross-sectional age. We used brain magnetic resonance imaging (MRI) and genetic data from a general-population cohort: the UK Biobank (N=8,395). We adjusted for the covariates of age in years, sex, Townsend social deprivation scores, smoking history and cardiometabolic diseases. There was a statistically significant association between APOE e4 genotype and increased (i.e. worse) white matter (WM) hyperintensity volumes (standardised beta = 0.088, 95 confidence intervals = 0.036 to 0.139, P = 0.001), a marker of poorer cerebrovascular health. There were no associations with left or right hippocampal, total grey matter (GM) or WM volumes, or WM tract integrity indexed by fractional anisotropy (FA) and mean diffusivity (MD). There were no statistically significant interactions with age. Future research in UK Biobank utilising intermediate phenotypes and longitudinal imaging hold significant promise for this area, particularly pertaining to APOE e4’s potential link with cerebrovascular contributions to cognitive ageing.
Complex multicellularity in fungi: evolutionary convergence, single origin, or both?
Authors: Nagy László G. , Krizsán Krisztina
Published: December 2017

Complex multicellularity comprises the most advanced level of organization evolved on Earth. It has evolved only a few times in metazoans, green plants, brown and red algae and fungi. Compared to other lineages, the evolution of multicellularity in fungi follows different principles; both simple and complex multicellularity evolved via unique mechanisms not seen in other lineages. In this article we review ecological, paleontological, developmental and genomic aspects of complex multicellularity in fungi and discuss the general principles of the evolution of complex multicellularity in light of its fungal manifestations. Fungi represent the only lineage in which complex multicellularity shows signatures of convergent evolution: it appears 8-12 distinct fungal lineages, which show a patchy phylogenetic distribution, yet share some of the genetic mechanisms underlying complex multicellular development. To mechanistically explain the patchy distribution of complex multicellularity across the fungal tree of life we identify four key observations that need to be considered: the large number of apparently independent complex multicellular clades; the lack of documented phenotypic homology between these; the universal conservation of gene circuits regulating the onset of complex multicellular development; and the existence of clades in which the evolution of complex multicellularity is coupled with limited gene family diversification. We discuss how these patterns and known genetic aspects of fungal development can be reconciled with the genetic theory of convergent evolution to explain its pervasive occurrence in across the fungal tree of life.
Terrestrial effects of moderately nearby supernovae
Authors: Melott Adrian L. , Thomas Brian C.
Published: December 2017

Recent data indicate one or more moderately nearby supernovae in the early Pleistocene, with additional events likely in the Miocene. This has motivated more detailed computations, using new information about the nature of supernovae and the distances of these events to describe in more detail the sorts of effects that are indicated at the Earth. This short communication/review is designed to describe some of these effects so that they may possibly be related to changes in the biota around these times.

It has been known for some time that moderately nearby supernovae may have substantial effects on the Earth. Events at ˜150 light years will happen on average every few Myr, but will tend to happen in groups, with long periods between with no events. The effects of cosmic rays from such events appears to be greater than estimated previously. Ozone depletion and the increase of hazardous UVB continues to be important, but new effects come to the fore. Muon irradiation on the ground and hundreds of meters down into the ocean will increase cancer and mutation rates, the differences being most notable in terrestrial megafauna and benthic organisms. Typically larger organisms live long enough to develop cancer; in microorganisms the primary effects would be associated with mutation rates. Atmospheric ionization in the troposphere will greatly increase lightning rates, with a concomitant increase in the rate of wildfires.
White Matter Hyperintensities and Cognitive Decline in de Novo Parkinson’s Disease Patients
Authors: Dadar Mahsa , Zeighami Yashar , Yau Yvonne , Fereshtehnejad Seyed-Mohammad , Maranzano Josefina , Postuma Ronald B. , Dagher Alain , Collins D. Louis
Published: December 2017

Objective

White Matter Hyperintensities (WMHs) are associated with cognitive decline in normative aging and Alzheimer’s disease. However, the pathogenesis of cognitive decline in Parkinson’s disease (PD) is not directly related to vascular causes, and therefore the role of WMHs in PD remains unclear. If WMH has a higher impact on cognitive decline in PD, vascular pathology should be assessed and treated with a higher priority in this population. Here we investigate whether WMH leads to increased cognitive decline in PD, and if these effects relate to cortical thinning

Methods

To investigate the role of WMHs in PD, it is essential to study recently-diagnosed/non-treated patients.De novoPD patients and age-matched controls (NPD=365,NControl=174) with FLAIR/T2-weighted scans at baseline were selected from Parkinson’s Progression Markers Initiative (PPMI). WMHs and cortical thickness were measured to analyse the relationship between baseline WMHs and future cognitive decline (follow-up:4.09±1.14 years) and cortical thinning (follow-up:1.05±0.10 years).

Results

High WMH load (WMHL) at baseline in PD was associated with increased cognitive decline, significantly more than i) PDs with low WMHL and ii) controls with high WMHL. Furthermore, PD patients with higher baseline WMHL showed more cortical thinning in right frontal lobe than subjects with low WMHL. Cortical thinning of this region also predicted decline in performance on a cognitive test.

Interpretation

Presence of WMHs inde novoPD patients predicts greater future cognitive decline and cortical thinning than in normal aging. Recognizing WMHs as a potential predictor of cognitive deficit in PD provides an opportunity for timely interventions.
Diversity and evolution of the emerging Pandoraviridae family
Authors: Legendre Matthieu , Fabre Elisabeth , Poirot Olivier , Jeudy Sandra , Lartigue Audrey , Alempic Jean-Marie , Beucher Laure , Philippe Nadège , Bertaux Lionel , Labadie Karine , Couté Yohann , Abergel Chantal , Claverie Jean-Michel
Published: December 2017

With DNA genomes up to 2.5 Mb packed in particles of bacterium-like shape and dimension, the first two Acanthamoeba-infectingPandoravirusesremained the most spectacular viruses since their description in 2013. Our isolation of three new strains from distant locations and environments allowed us to perform the first comparative genomics analysis of the emerging worldwide-distributed Pandoraviridae family. Thorough annotation of the genomes combining transcriptomic, proteomic, and bioinformatic analyses, led to the discovery of many non-coding transcripts while significantly reducing the former set of predicted protein-coding genes. We found that the Pandoraviridae exhibit an open pan genome, the enormous size of which is not adequately explained by gene duplications or horizontal transfers. As most of the strain specific genes have no extant homolog and exhibit statistical features comparable to intergenic regions, we suggests thatde novogene creation is a strong component in the evolution of the giant Pandoravirus genomes.
Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH
Authors: Nadtochiy Sergiy M. , Wang Yves T. , Nehrke Keith , Munger Joshua , Brookes Paul S.
Published: December 2017

Stimulation of the cytosolic NAD+ dependent deacetylase SIRT1 is cardioprotective against ischemia-reperfusion (IR) injury. NAD+ precursors including nicotinamide mononucleotide (NMN) are thought to induce cardioprotection via SIRT1. Herein, while NMN protected perfused hearts against IR (functional recovery: NMN 42±7% vs. vehicle 11±3%), this protection was insensitive to the SIRT1 inhibitor splitomicin (recovery 47±8%). Although NMN-induced cardioprotection was absent in Sirt3-/- hearts (recovery 9±5%), this was likely due to enhanced baseline injury in Sirt3-/- (recovery 6±2%), since similar injury levels in WT hearts also blunted the protective efficacy of NMN. Considering alternative cardiac effects of NMN, and the requirement of glycolysis for NAD+, we hypothesized NMN may confer protection via direct stimulation of cardiac glycolysis. In primary cardiomyocytes, NMN induced cytosolic and extracellular acidification and elevated lactate. In addition, [U-13C]glucose tracing in intact hearts revealed that NMN stimulated glycolytic flux. Consistent with a role for glycolysis in NMN-induced protection, hearts perfused without glucose (palmitate as fuel source), or hearts perfused with galactose (no ATP from glycolysis) exhibited no benefit from NMN (recovery 11±4% and 15±2% respectively). Acidosis during early reperfusion is known to be cardioprotective (i.e., acid post-conditioning), and we also found that NMN was cardioprotective when delivered acutely at reperfusion (recovery 39±8%). This effect of NMN was not additive with acidosis, suggesting overlapping mechanisms. We conclude that the acute cardioprotective benefits of NMN are mediated via glycolytic stimulation, with the downstream protective mechanism involving enhanced ATP synthesis during ischemia and/or enhanced acidosis during reperfusion.
Resolving the Full Spectrum of Human Genome Variation using Linked-Reads
Authors: Marks Patrick , Garcia Sarah , Barrio Alvaro Martinez , Belhocine Kamila , Bernate Jorge , Bharadwaj Rajiv , Bjornson Keith , Catalanotti Claudia , Delaney Josh , Fehr Adrian , Fiddes Ian T. , Galvin Brendan , Heaton Haynes , Herschleb Jill , Hindson Christopher , Holt Esty , Jabara Cassandra B. , Jett Susanna , Keivanfar Nikka , Kyriazopoulou-Panagiotopoulou Sofia , Lek Monkol , Lin Bill , Lowe Adam , Mahamdallie Shazia , Maheshwari Shamoni , Makarewicz Tony , Marshall Jamie , Meschi Francesca , O’keefe Chris , Ordonez Heather , Patel Pranav , Price Andrew , Royall Ariel , Ruark Elise , Seal Sheila , Schnall-Levin Michael , Shah Preyas , Williams Stephen , Wu Indira , Xu Andrew Wei , Rahman Nazneen , MacArthur Daniel , Church Deanna M.
Published: December 2017

Large-scale population based analyses coupled with advances in technology have demonstrated that the human genome is more diverse than originally thought. To date, this diversity has largely been uncovered using short read whole genome sequencing. However, standard short-read approaches, used primarily due to accuracy, throughput and costs, fail to give a complete picture of a genome. They struggle to identify large, balanced structural events, cannot access repetitive regions of the genome and fail to resolve the human genome into its two haplotypes. Here we describe an approach that retains long range information while harnessing the advantages of short reads. Starting from only ∼1ng of DNA, we produce barcoded short read libraries. The use of novel informatic approaches allows for the barcoded short reads to be associated with the long molecules of origin producing a novel datatype known as ‘Linked-Reads’. This approach allows for simultaneous detection of small and large variants from a single Linked-Read library. We have previously demonstrated the utility of whole genome Linked-Reads (lrWGS) for performing diploid, de novo assembly of individual genomes (Weisenfeld et al. 2017). In this manuscript, we show the advantages of Linked-Reads over standard short read approaches for reference based analysis. We demonstrate the ability of Linked-Reads to reconstruct megabase scale haplotypes and to recover parts of the genome that are typically inaccessible to short reads, including phenotypically important genes such as STRC, SMN1 and SMN2. We demonstrate the ability of both lrWGS and Linked-Read Whole Exome Sequencing (lrWES) to identify complex structural variations, including balanced events, single exon deletions, and single exon duplications. The data presented here show that Linked-Reads provide a scalable approach for comprehensive genome analysis that is not possible using short reads alone.
A deep mutational scan of an acidic activation domain
Authors: Staller Max V. , Holehouse Alex S. , Swain-Lenz Devjanee , Das Rahul K. , Pappu Rohit V. , Cohen Barak A.
Published: December 2017

Transcriptional activation domains are intrinsically disordered peptides with little primary sequence conservation. These properties have made it difficult to identify the sequence features that define activation domains. For example, although acidic activation domains were discovered 30 years ago, we still do not know what role, if any, acidic residues play in these peptides. To address this question we designed a rational mutagenesis scheme to independently test four sequence features theorized to control the strength of activation domains: acidity (negative charge), hydrophobicity, intrinsic disorder, and short linear motifs. To test enough mutants to deconvolve these four features we developed a method to quantify the activities of thousands of activation domain variants in parallel. Our results with Gcn4, a classic acidic activation domain, suggest that acidic residues in particular regions keep two hydrophobic motifs exposed to solvent. We also found that the specific activity of the Gcn4 activation domain increases during amino acid starvation. Our results suggest that Gcn4 may have evolved to have low activity but high inducibility. Our results also demonstrate that high-throughput rational mutation scans will be powerful tools for unraveling the properties that control how intrinsically disordered proteins function.
Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats
Authors: de Guglielmo Giordano , Conlisk Dana E. , Barkley-Levenson Amanda M. , Palmer Abraham A. , George Olivier
Published: December 2017

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders.

Highlights

Alcohol use disorder (AUD) places an enormous burden on society, and there is an urgent need for new druggable targets.

Glo1 inhibition by pBBG dose-dependently reduces alcohol self-administration in both nondependent and dependent animals.

pBBG treatment is more effective in reducing alcohol intake in dependent rats than in nondependent rats.
Prioritizing Parkinson’s Disease genes using population-scale transcriptomic data
Authors: Li Yang I , Wong Garrett , Humphrey Jack , Raj Towfique
Published: December 2017

Genome-wide association studies (GWAS) have identified over41susceptibility loci associated with late-onset Parkinson’s Disease (PD) but identifying putative causal genes and the underlying mechanisms remains challenging. To address this, we leveraged large-scale transcriptomic datasets to prioritize genes that are likely to affect PD. We found29gene associations in peripheral monocytes, and44gene associations whose expression or differential splicing in prefrontal cortex is associated with PD. This includes many novel genes but also known associations such as MAPT, for which we found that variation in exon3splicing explains the common genetic association. Genes identified in our analyses are more likely to interact physically with known PD genes and belong to the same or related pathways including lysosomal and innate immune function. Overall, our study provides a strong foundation for further mechanistic studies that will elucidate the molecular drivers of PD.
Shared understanding is correlated with shared neural responses in the default mode network
Authors: Nguyen Mai , Vanderwal Tamara , Hasson Uri
Published: December 2017

Humans have a striking ability to infer meaning from even the sparsest and most abstract forms of narratives. At the same time, flexibility in the form of a narrative is matched by inherent ambiguity in the interpretation of it. How does the brain represent subtle, idiosyncratic differences in the interpretation of abstract and ambiguous narratives? In this fMRI study, we scanned subjects watching a 7-min original animation that depicts a complex narrative through the movement of simple geometric shapes. We additionally scanned two separate groups listening to concrete verbal descriptions of either the social narrative or the physical properties of the movie. After scanning, all subjects freely recalled their interpretation of the stimulus. Using an intersubject representational similarity analysis, we compared the similarity of narrative interpretation across subjects, as measured using text analysis, with the similarity of neural responses, as measured using intersubject correlation (ISC). We found that the more similar two people’s interpretations of the abstract shape movie were, the more similar their neural responses were in the default mode network (DMN). Moreover, these shared responses were modality invariant: despite vast differences in stimulus properties, we found that the shapes movie and the verbal interpretation of the movie elicited shared responses in linguistic areas and a subset of the DMN when subjects shared interpretations. Together, these results suggest that the DMN is not only sensitive to subtle individual differences in narrative interpretation, but also resilient to large differences in the modality of the narrative.

Significance statement

The same narrative can be both communicated in different ways and interpreted in different ways. How are subtle, idiosyncratic differences in the interpretation of complex narratives presented in different forms represented in the brain? In this fMRI study, we show that the more similarly two people interpreted an ambiguous animation composed of moving shapes, the more similar their neural responses were in the Default Mode Network. In addition, by presenting the same narrative in a different form, we found shared responses across modalities when subjects shared interpretations despite the vast differences in modality of the stimuli. Together, these results suggest that the DMN is at once sensitive to individual differences in narrative interpretation and resilient to differences narrative modality.
LRX- and FER-dependent extracellular sensing coordinates vacuolar size for cytosol homeostasis
Authors: Dünser Kai , Gupta Shibu , Ringli Christoph , Kleine-Vehn Jürgen
Published: December 2017

Cellular elongation requires the defined coordination of intra- and extracellular processes. The vacuole is the biggest plant organelle and its dimension has a role in limiting cell expansion (Löfke et al., 2015; Scheuring et al., 2016). We reveal that the increase in vacuolar occupancy enables cellular elongation with relatively little enlargement of the cytosole. It remains, however, completely unknown how the vacuolar size is coordinated with other growth-relevant processes. Intriguingly, we show that extracellular constraints impact on the intracellular expansion of the vacuole. The underlying cell wall sensing mechanism requires the interaction of the extracellular leucine-rich repeat extensin (LRX) with the receptor-like kinase Feronia (FER). Our data suggests that LRX links the plasma membrane localised FER with the cell wall, allowing this module to jointly sense and convey extracellular signals to the underlying cell. This mechanism coordinates cell wall acidification/loosening with the increase in vacuolar size, contributing cytosol homeostasis during plant cell expansion.
Extended logistic growth model for heterogeneous populations
Authors: Jin Wang , McCue Scott W , Simpson Matthew J
Published: December 2017

Cell proliferation is the most important cellular-level mechanism responsible for regulating cell population dynamics in living tissues. Modern experimental procedures show that the proliferation rates of individual cells can vary significantly within the same cell line. However, in the mathematical biology literature, cell proliferation is typically modelled using a classical logistic equation which neglects variations in the proliferation rate. In this work, we consider a discrete mathematical model of cell migration and cell proliferation, modulated by volume exclusion (crowding) effects, with variable rates of proliferation across the total population. We refer to this variability asheterogeneity.Constructing the continuum limit of the discrete model leads to a generalisation of the classical logistic growth model. Comparing numerical solutions of the model to averaged data from discrete simulations shows that the new model captures the key features of the discrete process. Applying the extended logistic model to simulate a proliferation assay using rates from recent experimental literature shows that neglecting the role of heterogeneity can, at times, lead to misleading results.
Efficacy ofAedes aegypticontrol by indoor Ultra Low Volume (ULV) insecticide spraying in Iquitos, Peru
Authors: Gunning Christian , Okamoto Kenichi , Astete Helvio , Vasquez Gissella M. , Erhardt Erik , Aguila Clara Del , Pinedo Raul , Cardenas Roldan , Pacheco Carlos , Chalco Enrique , Rodriguez-Ferruci Hugo , Scott Thomas W. , Lloyd Alun L. , Gould Fred , Morrison Amy C.
Published: December 2017

Background

Aedes aegyptiis a primary vector of dengue, chikungunya, Zika, and urban yellow fever viruses. Indoor, ultra low volume (ULV) space spraying with pyrethroid insecticides is the main approach used forAe. aegyptiemergency control in many countries. Given the widespread use of this method, the lack of large-scale experiments or detailed evaluations of municipal spray programs is problematic.

Methodology/Principal Findings

Two experimental evaluations of non-residual, indoor ULV pyrethroid spraying were conducted in Iquitos, Peru. In each, a central sprayed sector was surrounded by an unsprayed buffer sector. In 2013, spray and buffer sectors included 398 and 765 houses, respectively. Spraying reduced the mean number of adults captured per house by ~83 percent relative to the pre-spray baseline survey. In the 2014 experiment, sprayed and buffer sectors included 1,117 and 1,049 houses, respectively. Here, the sprayed sector’s number of adults per house was reduced ~64 percent relative to baseline. Parity surveys in the sprayed sector during the 2014 spray period indicated an increase in the proportion of very young females. We also evaluated impacts of a 2014 citywide spray program by the local Ministry of Health, which reduced adult populations by ~60 percent. In all cases, adult densities returned to near-baseline levels within one month.

Conclusions/Significance

Our results demonstrate that densities of adultAe. aegyptican be reduced by experimental and municipal spraying programs. The finding that adult densities return to approximately pre-spray densities in less than a month is similar to results from previous, smaller scale experiments. Our results demonstrate that ULV spraying is best viewed as having a short-term entomological effect. The epidemiological impact of ULV spraying will need evaluation in future trials that measure capacity of insecticide spraying to reduce disease transmission.
Emergence of dynamically reconfigurable hippocampal responses by learning to perform probabilistic spatial reasoning
Authors: Kanitscheider Ingmar , Fiete Ila
Published: December 2017

Navigation in natural environments is computationally difficult: Location errors from motion estimation noise accumulate over time, while landmarks can be spatially extended and often look alike, thus providing ambiguous data. The brain contains a number of spatially tuned neurons coding for various navigational variables, but current models do not explain how these circuits could implement navigational computations that involve non-trivial spatial reasoning. We show, using a function-first approach, that neural circuits trained to efficiently solve spatial reasoning problems with performance on par with sequential probabilistic strategies reproduce some key properties of hippocampal coding, including heterogeneous tuning, conjunctive tuning, and low-dimensional dynamics. In addition, the models predict the emergence of tuning to key latent variables that are neither present in the input data nor trained as the end result of the task, and exhibit a spontaneous dynamical reconfiguration of tuning across time during a task as the computational demands evolve, reminiscent of some of the more complex dynamics observed in the hippocampus including a switch between location and displacement coding modes. These results provide a new functional framework for understanding the rich phenomenology and potential capabilities of navigation codes in the hippocampus and associated brain areas.