bluuebunny/crossref_metadata_2025 huggingface dataset:
The development of referential hierarchy effects in
Sahaptian
Authors: Gildea Spike , Jansen Joana
Published: July 2018

Sahaptin and Nez Perce, the two languages of the Sahaptian family,
have both been cited as case studies in the typological literature
on hierarchical patterns in main clause grammar. Nez Perce has
ergative case marking on only third person singular transitive
subjects, plus a minor pattern of indexation of SAP participants via
(rarely occurring) second position enclitics. Sahaptin has one of
the more complex hierarchical systems ever described, with SAP
indexation via enclitics, third person indexation on verbs,
differential object marking, an inverse verbal direction prefix, and
two distinct ergative suffixes, each restricted to a subset of third
person singular transitive subjects (one when objects are SAP, the
other when objects are third person). This paper begins by
reviewing, evaluating, and occasionally expanding on existing
knowledge: we summarize the hierarchical patterns in Sahaptian and characterize each distinct construction. Then we compare relevant Sahaptin
morphemes with cognates in Nez Perce, and review their
reconstruction to Proto-Sahaptian. The primary contribution of this
paper is organizing the morphemes (and their accompanying
hierarchical patterns) in both languages into cognate
constructions, then reconstructing each to its
Proto-Sahaptian origins. We conclude by reviewing and evaluating
proposals for Pre-Proto-Sahaptian developments claimed to explain
the origins of hierarchical patterns that reconstruct to
Proto-Sahaptian. The mechanisms we identify as having created the
Sahaptian hierarchical effects are diverse, some motivated and
others not, some arising from internal sources, others arguably from
contact.
Diachrony and the referential hierarchy in Old Irish
Authors: Griffith Aaron
Published: July 2018

A set of Old Irish clitic person markers may co-index subject or
object markers on the verb. Only one clitic of this set may appear
at a time, however. The clitic, if present, indexes the verbal
argument highest on the scale 1st person > 2nd person > 3rd
person animate > inanimate. The restriction of one clitic per
verb, a prerequisite for the hierarchy, is explained here as a
result of the deictic origin of the clitic set. The deictic origin
further favors the marking of local persons over non-local persons.
For the upper and lower end of the hierarchy, however, the ranking
appears to be determined rather by considerations of function. Since
the clitics can mark topics, they favor 1st persons over 2nd and
animates over inanimates.
Are the Tupi-Guarani hierarchical indexing systems really
motivated by the person hierarchy?
Authors: Rose Françoise
Published: July 2018

Tupi-Guarani languages are supposedly perfect examples of
hierarchical indexing systems, where the relative ranking of A and P
on the 1 > 2 > 3 person hierarchy determines the selection of
the person markers. This chapter questions the relevance of the
person hierarchy as a synchronic and diachronic explanation for such
systems, with data from 28 languages. First, only SAP > 3 can
really be posited in the actual languages, and second, it explains
only part of the facts that it is supposed to account for in
Proto-Tupi-Guarani. The chapter ends by suggesting that these
systems do not result from the person hierarchy as a functional
motivation. Instead, they may result from grammaticalization of
pronominal paradigms lacking third-person forms.
An unexpected world population variation of MCT1 polymorphism 1470T > A involved in lactate transport
Authors: Onali Federico , Calò Carla M. , Massidda Myosotis , Álvarez‐Álvarez Miguel M. , Esteban Maria Esther
Published: July 2018

A common missense mutation (1470T > A) in gene SLC16A1 responsible for an amino acid substitution in protein MCT1 has been associated with differential lactate transport and hence, differences in physical performance and muscle injuries in relation to physical exercise. This study describes, for the first time, the worldwide variation of MCT1 variant 1470T > A at an intra‐ and inter‐continental level. Two thousand five hundred and four individual genotypes of 26 populations clustered in 5 population groups have been analysed with data downloaded from the public database 1000 Genomes Phase 3 Browser. Several parameters of population differentiation and structure have been explored as well as selection signatures in the whole gene. Allele T, the common variant, shows extremely high values in Sub‐Saharan African groups (frequencies 86–91%) as compared with the remaining world regions (69–49%). TT genotype also predominates in African groups, showing significant differences with the rest of world populations. In view of the evidence that the TT genotype is associated with clinical implications and a better predisposition to sprint/power performances, we suggest that the high presence of the TT genotype in African populations should be taken into account in future association studies at both medical and sports fields.
A Year of Phytobiomes
Authors: Young Carolyn A. , Kinkel Linda L.
Published: July 2018

It is hard to believe that we have just celebrated the one-year anniversary of our first issue of the Phytobiomes journal! As we celebrate our first year, and as the term ‘phytobiome’ becomes more deeply embedded in our science, it is worth pausing to reflect on the impetus and science behind the phytobiome concept, and on the next steps for our journal.
Smoking and Accelerated Lung Function Decline in HIV-Positive Individuals: A Secondary Analysis of the START Pulmonary Substudy
Authors: MacDonald David M. , Melzer Anne C. , Collins Gary , Avihingsanon Anchalee , Crothers Kristina , Ingraham Nicholas E. , Mugerwa Henry , Ristola Matti , Shuter Jonathan , Kunisaki Ken M. ,   for the INSIGHT START Pulmonary Substudy Group
Published: July 2018

Background:

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability globally. Both cigarette smoking and HIV have been identified as independent risk factors for COPD. We used data from the strategic timing of antiretroviral treatment (START) Pulmonary Substudy to quantify the impact of smoking on rate of lung function decline in HIV.

Methods:

We included START Pulmonary Substudy participants who contributed at least 2 good quality spirometry measures during the study. Slope of forced expiratory volume in 1 second (FEV1) was estimated using a repeated-measures model adjusted for the treatment group (immediate vs deferred treatment arm of START), age, sex, race, baseline COPD, and region.

Results:

Of 1026 START Pulmonary Substudy participants, 915 (89%) were included in this analysis. Median follow-up time was 3.9 years. Smokers and nonsmokers were similar in baseline age (median 36 years), but smokers were more likely to be white, male, and from Europe/Israel/Australia. Smokers had faster average FEV1 decline compared with nonsmokers [−38.3 mL/yr vs −25.1 mL/yr; difference of −13.2 mL/yr (95% confidence interval: −23.6 to −2.7); P = 0.013], were more likely to meet criteria for rapid FEV1 decline [7.2%–11.7% more likely (P = 0.09–P = 0.002), depending on the definition of rapid decline], and had borderline, but not statistically significant, higher incident COPD during follow-up (9.7% vs 5.8%, P = 0.06).

Conclusions:

Compared to nonsmokers, HIV-positive smokers experience faster decline in lung function. These results underscore the need for a better understanding of how to best support smoking cessation among HIV-positive populations.
Wavelet analysis techniques in cavitating flows
Authors: Brandner Paul A. , Venning James A. , Pearce Bryce W.
Published: July 2018

Cavitating and bubbly flows involve a host of physical phenomena and processes ranging from nucleation, surface and interfacial effects, mass transfer via diffusion and phase change to macroscopic flow physics involving bubble dynamics, turbulent flow interactions and two-phase compressible effects. The complex physics that result from these phenomena and their interactions make for flows that are difficult to investigate and analyse. From an experimental perspective, evolving sensing technology and data processing provide opportunities for gaining new insight and understanding of these complex flows, and the continuous wavelet transform (CWT) is a powerful tool to aid in their elucidation. Five case studies are presented involving many of these phenomena in which the CWT was key to data analysis and interpretation. A diverse set of experiments are presented involving a range of physical and temporal scales and experimental techniques. Bubble turbulent break-up is investigated using hydroacoustics, bubble dynamics and high-speed imaging; microbubbles are sized using light scattering and ultrasonic sensing, and large-scale coherent shedding driven by various mechanisms are analysed using simultaneous high-speed imaging and physical measurement techniques. The experimental set-up, aspect of cavitation being addressed, how the wavelets were applied, their advantages over other techniques and key findings are presented for each case study.

This paper is part of the theme issue ‘Redundancy rules: the continuous wavelet transform comes of age’.
Continuous wavelet transform and higher-order spectrum: combinatory potentialities in breath sound analysis and electroencephalogram-based pain characterization
Authors: Hadjileontiadis Leontios J.
Published: July 2018

The combination of the continuous wavelet transform (CWT) with a higher-order spectrum (HOS) merges two worlds into one that conveys information regarding the non-stationarity, non-Gaussianity and nonlinearity of the systems and/or signals under examination. In the current work, the third-order spectrum (TOS), which is used to detect the nonlinearity and deviation from Gaussianity of two types of biomedical signals, that is, wheezes and electroencephalogram (EEG), is combined with the CWT to offer a time–scale representation of the examined signals. As a result, a CWT/TOS field is formed and a time axis is introduced, creating a time–bifrequency domain, which provides a new means for wheeze nonlinear analysis and dynamic EEG-based pain characterization. A detailed description and examples are provided and discussed to showcase the combinatory potential of CWT/TOS in the field of advanced signal processing.

This article is part of the theme issue ‘Redundancy rules: the continuous wavelet transform comes of age’.
Quantitative feature analysis of continuous analytic wavelet transforms of electrocardiography and electromyography
Authors: Wachowiak Mark P. , Wachowiak-Smolíková Renata , Johnson Michel J. , Hay Dean C. , Power Kevin E. , Williams-Bell F. Michael
Published: July 2018

Theoretical and practical advances in time–frequency analysis, in general, and the continuous wavelet transform (CWT), in particular, have increased over the last two decades. Although the Morlet wavelet has been the default choice for wavelet analysis, a new family of analytic wavelets, known as generalized Morse wavelets, which subsume several other analytic wavelet families, have been increasingly employed due to their time and frequency localization benefits and their utility in isolating and extracting quantifiable features in the time–frequency domain. The current paper describes two practical applications of analysing the features obtained from the generalized Morse CWT: (i) electromyography, for isolating important features in muscle bursts during skating, and (ii) electrocardiography, for assessing heart rate variability, which is represented as the ridge of the main transform frequency band. These features are subsequently quantified to facilitate exploration of the underlying physiological processes from which the signals were generated.

This article is part of the theme issue ‘Redundancy rules: the continuous wavelet transform comes of age’.
Accuracy of a commercial multiplex PCR for the diagnosis of bacterial vaginosis
Authors: van der Veer Charlotte , van Houdt Robin , van Dam Alje , de Vries Henry , Bruisten Sylvia
Published: July 2018

Purpose. Bacterial vaginosis (BV) is a common clinical condition characterized by odorous vaginal discharge, vaginal itching and/or burning. BV can occur when vaginal lactobacilli are depleted and replaced by diverse anaerobic bacteria. We evaluated a commercial multiplex PCR (ATRiDA) for the diagnosis of BV.

Methods. Cervicovaginal samples were included from women reporting urogenital symptoms and from women notified for sexually transmitted infections (STI) – who were not (necessarily) symptomatic. Clinical BV diagnoses were obtained from electronic patient files. The ATRiDA test measures the loads of Gardnerella vaginalis, Atopobium vaginae and Lactobacillus species in relation to overall bacterial load. The ATRiDA test outcome was compared to the clinical BV diagnosis and to vaginal microbiota composition, determined by 16SrRNA gene sequencing.

Results. We included samples from 185 women reporting urogenital symptoms, of whom 81 had BV and 93 women who were notified for an STI, of whom 16 had BV. Overall, compared to the clinical BV diagnosis, the ATRiDA test demonstrated high sensitivity (96.9 %) and moderate specificity (70.2 %). The negative predictive value was high (>97.3). The positive predictive value differed by study group and was highest in women reporting urogenital symptoms (78.2 %). Sequencing showed that 54 % of women who had an ATRiDA BV-positive test outcome, but who were not clinically diagnosed with BV, had diverse anaerobic vaginal microbiota (asymptomatic vaginal dysbiosis).

Conclusion. The ATRiDA test is a sensitive method for the detection of BV but, given the high occurrence of asymptomatic vaginal dysbiosis, a positive test outcome should be interpreted together with clinical symptoms.
Scrublet: computational identification of cell doublets in single-cell transcriptomic data
Authors: Wolock Samuel L. , Lopez Romain , Klein Allon M.
Published: July 2018

Single-cell RNA-sequencing has become a widely used, powerful approach for studying cell populations. However, these methods often generate multiplet artifacts, where two or more cells receive the same barcode, resulting in a hybrid transcriptome. In most experiments, multiplets account for several percent of transcriptomes and can confound downstream data analysis. Here, we present Scrublet (Single-Cell Remover of Doublets), a framework for predicting the impact of multiplets in a given analysis and identifying problematic multiplets. Scrublet avoids the need for expert knowledge or cell clustering by simulating multiplets from the data and building a nearest neighbor classifier. To demonstrate the utility of this approach, we test Scrublet on several datasets that include independent knowledge of cell multiplets.
Substrate-assisted Enzymatic Formation of Lysinoalanine in Duramycin
Authors: An Linna , Cogan Dillon P. , Navo Claudio D. , Jiménez-Osés Gonzalo , Nair Satish K. , van der Donk Wilfred A.
Published: July 2018

Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, inhibitor of viral entry, therapeutic for cystic fibrosis, and tumor and vasculature imaging agent. Duramycin contains a β-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalanine (Lal) crosslink. The mechanism of Lal formation is not known. We here show that Lal is installed stereospecifically by DurN via addition of Lys19 to a dehydroalanine. The structure of DurN reveals an unusual dimer with a new fold. Surprisingly, in the structure of duramycin bound to DurN, no residues of the enzyme are near the Lal. Instead, Hya15 of the substrate makes interactions with Lal suggesting it acts as a base to deprotonate Lys19 during catalysis. Biochemical data suggest that DurN preorganizes the reactive conformation of the substrate, such that the Hya15 of the substrate can serve as the catalytic base for Lal formation.
Identification of Transcription Factor Binding Sites using ATAC-seq
Authors: Li Zhijian , Schulz Marcel H. , Zenke Martin , Costa Ivan G.
Published: July 2018

1

Transposase-Accessible Chromatin (ATAC) followed by sequencing (ATAC-seq) is a simple and fast protocol for detection of open chromatin. However, computational footprinting in ATAC-seq, i.e. search for regions with depletion of cleavage events due to transcription factor binding sites, has been poorly explored so far. We propose HINT-ATAC, a footprinting method that addresses ATAC-seq specific protocol artifacts. HINT-ATAC uses a probabilistic framework based on Variable-order Markov models to learn the complex sequence cleavage preferences of the transposase enzyme. Moreover, we observed specific strand specific cleavage patterns around the binding sites of transcription factors, which are determined by local nucleosome architecture. HINT-ATAC explores local nucleosome architecture to significantly outperform competing footprinting methods in predicting transcription factor binding sites by ChIP-seq. HINT-ATAC is an open source software and available online at www.regulatory-genomics.org/hint
The immune cell landscape in kidneys of lupus nephritis patients
Authors: Arazi Arnon , Rao Deepak A. , Berthier Celine C. , Davidson Anne , Liu Yanyan , Hoover Paul J. , Chicoine Adam , Eisenhaure Thomas M. , Jonsson A. Helena , Li Shuqiang , Lieb David J. , Browne Edward P. , Noma Akiko , Sutherby Danielle , Steelman Scott , Smilek Dawn E. , Tosta Patti , Apruzzese William , Massarotti Elena , Dall’Era Maria , Park Meyeon , Kamen Diane L. , Furie Richard A. , Payan-Schober Fernanda , Buyon Jill P. , Petri Michelle A. , Putterman Chaim , Kalunian Kenneth C. , Woodle E. Steve , Lederer James A. , Hildeman David A. , Nusbaum Chad , Wofsy David , Kretzler Matthias , Anolik Jennifer H. , Brenner Michael B. ,   the Accelerating Medicines Partnership in RA/SLE network, Hacohen Nir , Diamond Betty
Published: July 2018

Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.
Ancestral Roles of the Fam20C Family of Secreted Protein Kinases Revealed by Functional Analysis inC. elegans
Authors: Gerson-Gurwitz Adina , Worby Carolyn A. , Lee Kian-Yong , Khaliullin Renat , Bouffard Jeff , Cheerambathur Dhanya , Cram Erin J. , Oegema Karen , Dixon Jack E. , Desai Arshad
Published: July 2018

Fam20C is a secreted protein kinase mutated in Raine syndrome, a human skeletal disorder. In vertebrates, bone and enamel proteins are major Fam20C substrates. However, Fam20 kinases are conserved in invertebrates lacking bone and enamel, suggesting other ancestral functions. We show that FAMK-1, theC. elegansFam20C ortholog, contributes to fertility, embryogenesis, and development. These functions are not fulfilled when FAMK-1 is retained in the early secretory pathway. During embryogenesis, FAMK-1 maintains inter-cellular partitions and prevents multinucleation; notably, temperature elevation or lowering cortical stiffness reduces requirement for FAMK-1 in this context. FAMK-1 is expressed in multiple adult tissues that undergo repeated mechanical strain, and selective expression in the spermatheca restores fertility. Informatic, biochemical and functional analysis implicate lectins as FAMK-1 substrates. These findings suggest that FAMK-1 phosphorylation of substrates, including lectins, in the late secretory pathway is important in embryonic and tissue contexts where cells are subjected to mechanical strain.
Integrated Disease Surveillance and Response (IDSR) in Malawi: Implementation Gaps and Challenges for Timely Alert
Authors: Wu Tsung-Shu Joseph , Kagoli Matthew , Kaasbøll Jens Johan , Bjune Gunnar Aksel
Published: July 2018

Objective

The emerging and recent 2014 Ebola Virus Disease (EVD) outbreaks rang the bell to call upon efforts from globe to assist resource-constrained countries to strengthen public health surveillance system for early response. Malawi adopted the Integrated Disease Surveillance and Response (IDSR) strategy to develop its national surveillance system since 2002 and revised its guideline to fulfill the International Health Regulation (IHR) requirements in 2014. This study aimed to understand the state of IDSR implementation and differences between guideline and practice for future disease surveillance system strengthening.

Methods

This was a mixed-method observational study. Quantitative data were to analyze completeness and timeliness of surveillance system performance from national District Health Information System 2 (DHIS2). Qualitative data were collected through interviews with 29 frontline health service providers from the selected district and key informants of the IDSR system implementation and administration at district and national levels.

Findings

The current IDSR system showed relatively good completeness (76.4%) but poor timeliness (41.5%) of total expected monthly reports nationwide and zero weekly reports. The challenges of IDSR implementation revealed through qualitative data included lack of supervision, inadequate resources for training and difficulty to implement weekly report due to overwhelming paperwork at frontline health services.

Conclusions

The differences between IDSR technical guideline and actual practice were huge. The developing information technology infrastructure in Malawi and emerging mobile health (mHealth) technology can be opportunities for the country to overcome these challenges and improve surveillance system to have better timeliness for the outbreaks and unusual events detection.
Self-assembling Manifolds in Single-cell RNA Sequencing Data
Authors: Tarashansky Alexander J. , Xue Yuan , Li Pengyang , Quake Stephen R. , Wang Bo
Published: July 2018

Single-cell RNA sequencing has spurred the development of computational methods that enable researchers to classify cell types, delineate developmental trajectories, and measure molecular responses to external perturbations. Many of these technologies rely on their ability to detect genes whose cell-to-cell variations arise from the biological processes of interest rather than transcriptional or technical noise. However, for datasets in which the biologically relevant differences between cells are subtle, identifying these genes is a challenging task. We present the self-assembling manifold (SAM) algorithm, an iterative soft feature selection strategy to quantify gene relevance and improve dimensionality reduction. We demonstrate its advantages over other state-of-the-art methods with experimental validation in identifying novel stem cell populations of Schistosoma, a prevalent parasite that infects hundreds of millions of people. Extending our analysis to a total of 56 datasets, we show that SAM is generalizable and consistently outperforms other methods in a variety of biological and quantitative benchmarks.
Algorithm for Reliable Detection of Beat Onsets in Cerebral Blood Flow Velocity Signals
Authors: Canac Nicolas , Ranjbaran Mina , O’Brien Michael J. , Asgari Shadnaz , Scalzo Fabien , Thorpe Samuel G. , Jalaleddini Kian , Thibeault Corey M. , Wilk Seth J. , Hamilton Robert B.
Published: July 2018

Transcranial Doppler (TCD) ultrasound has been demonstrated to be a valuable tool for assessing cerebral hemodynamics via measurement of cerebral blood flow velocity (CBFV), with a number of established clinical indications. However, CBFV waveform analysis depends on reliable pulse onset detection, an inherently difficult task for CBFV signals acquired via TCD. We study the application of a new algorithm for CBFV pulse segmentation, which locates pulse onsets in a sequential manner using a moving difference filter and adaptive thresholding. The test data set used in this study consists of 92,012 annotated CBFV pulses, whose quality is representative of real world data. On this test set, the algorithm achieves a true positive rate of 99.998% (2 false negatives), positive predictive value of 99.998% (2 false positives), and mean temporal offset error of 6.10 ± 4.75 ms. We do note that in this context, the way in which true positives, false positives, and false negatives are defined caries some nuance, so care should be taken when drawing comparisons to other algorithms. Additionally, we find that 97.8% and 99.5% of onsets are detected within 10 ms and 30 ms, respectively, of the true onsets. The algorithm’s performance in spite of the large degree of variation in signal quality and waveform morphology present in the test data suggests that it may serve as a valuable tool for the accurate and reliable identification of CBFV pulse onsets in neurocritical care settings.
Expression reflects population structure
Authors: Brown Brielin C , Bray Nicolas L. , Pachter Lior
Published: July 2018

Population structure in genotype data has been extensively studied, and is revealed by looking at the principal components of the genotype matrix. However, no similar analysis of population structure in gene expression data has been conducted, in part because a naïve principal components analysis of the gene expression matrix does not cluster by population. We identify a linear projection that reveals population structure in gene expression data. Our approach relies on the coupling of the principal components of genotype to the principal components of gene expression via canonical correlation analysis. Futhermore, we analyze the variance of each gene within the projection matrix to determine which genes significantly influence the projection. We identify thousands of significant genes, and show that a number of the top genes have been implicated in diseases that disproportionately impact African Americans.

Author Summary

High dimensional, multi-modal genomics datasets are becoming increasingly common, which warrants investigation into analysis techniques that can reveal structure in the data without over-fitting. Here, we show that the coupling of principal component analysis to canonical correlation analysis offers an efficient approach to exploratory analysis of this kind of data. We apply this method to the GEUVADIS dataset of genotype and gene expression values of European and Yoruban individuals, finding as-of-yet unstudied population structure in the gene expression values. Moreover, many of the top genes identified by our method have been previously implicated in diseases that disproportionately impact African Americans.
A common neural substrate for elevated PTSD symptoms and reduced pulse rate variability in combat-exposed veterans
Authors: Grupe Daniel W. , Imhoff-Smith Ted , Wielgosz Joseph , Nitschke Jack B. , Davidson Richard J.
Published: July 2018

Background

Previous studies have identified reduced heart rate variability (HRV) in posttraumatic stress disorder (PTSD), which may temporally precede the onset of the disorder. A separate line of functional neuroimaging research suggests that the ventromedial prefrontal cortex (vmPFC) — a key aspect of a descending neuromodulatory system that exerts inhibitory control over heart rate — shows functional and structural abnormalities in PTSD. No research to date, however, has simultaneously investigated whether altered vmPFC activation is associated with reduced HRV and elevated PTSD symptoms in the same individuals.

Methods

We collected fMRI data during alternating conditions of threat of shock and safety from shock in 51 male, combat-exposed veterans with either high or low levels of PTSD symptoms. Pulse rate variability (PRV) – an HRV surrogate calculated from pulse oximetry – was assessed during a subsequent resting scan. Correlational analyses tested for hypothesized relationships between vmPFC activation, PRV, and distinct dimensions of PTSD symptomatology.

Results

Re-experiencing PTSD symptoms were inversely associated with high-frequency (HF)-PRV, thought to primarily reflect parasympathetic control of heart rate, in veterans with elevated PTSD symptoms. Lower HF-PRV was associated with reduced vmPFC activation for the contrast of safety-threat in a region that also showed an inverse relationship with re-experiencing symptoms.

Conclusions

Reduced vmPFC responses to safety vs. threat were associated with both reduced HF-PRV and increased re-experiencing symptoms. These results tie together previous observations of reduced HRV/PRV and impaired vmPFC function in PTSD and call for further research on reciprocal brain-body relationships in understanding PTSD pathophysiology.
Extreme nuclear branching in healthy epidermal cells of theXenopustail fin
Authors: Arbach Hannah E. , Harland-Dunaway Marcus , Chang Jessica K. , Wills Andrea E.
Published: July 2018

Changes in nuclear morphology contribute to regulation of complex cell properties, including differentiation and tissue elasticity. Perturbations of nuclear morphology are associated with pathologies that include, progeria, cancer, and muscular dystrophy. The mechanisms governing nuclear shape changes in healthy cells remain poorly understood, partially because there are few healthy models of nuclear shape variation. Here, we introduce nuclear branching in epidermal fin cells ofXenopus tropicalisas a model for extreme variation of nuclear morphology in a diverse population of healthy cells. We find that nuclear branching arises and elaborates during embryonic development. They contain broadly distributed marks of transcriptionally active chromatin and heterochromatin and have active cell cycles. We find that nuclear branches are disrupted by loss of filamentous actin and depend on epidermal expression of the nuclear lamina protein Lamin B1. Inhibition of nuclear branching disrupts fin morphology, suggesting that nuclear branching may be involved in fin development. This study introduces the nuclei of the fin as a powerful new model for extreme nuclear morphology in healthy cells to complement studies of nuclear shape variation in pathological contexts.

List of abbreviations and symbols

LINC-Linker of Nucleoskeleton and Cytoskeleton, HGPS – Hutchinson-Gilford Progeria Syndrome, TEM – Transmission electron microscopy, PH3 – Phosphorylated Histone 3, Lat B – Latrunculin B, WT-Wild type, Cyto D-Cytochalasin D,Lmnb1CRISPR –lmnb1mutants generated by CRISPR/Cas9, E-Lmnb1 CRISPR – epidermal specificlmnb1mutants generated by CRISPR/Cas9, Scrmbl-tadpoles injected with a scrambled version of thelmnb1targeted sgRNA, Lmnb1-rod – dominant-negative Lamin B1 containing only the rod domain

Summary Statement

Nuclei are highly branched throughout the heterogeneous population of healthy epidermal cells that comprise theXenopustail fin periphery, and disruption of nuclear branching mechanisms results in improper fin morphology.
Dissociable forms of uncertainty-driven representational change across the human brain
Authors: Nassar Matthew R. , McGuire Joseph T. , Ritz Harrison , Kable Joseph
Published: July 2018

Environmental change can lead decision makers to shift rapidly among different behavioral regimes. These behavioral shifts can be accompanied by rapid changes in the firing pattern of neural networks. However, it is unknown what the populations of neurons that participate in such “network reset” phenomena are representing. Here we examined 1) whether and where rapid changes in multivariate activity patterns are observable with fMRI during periods of rapid behavioral change, and 2) what types of representations give rise to these phenomena. We did so by examining fluctuations in multi-voxel patterns of BOLD activity from human subjects making sequential inferences about the state of a partially observable and discontinuously changing variable. We found that, within the context of this sequential inference task, the multivariate patterns of activity in a number of cortical regions contain representations that change more rapidly during periods of uncertainty following a change in behavioral context. In motor cortex, this phenomenon was indicative of discontinuous change in behavioral outputs, whereas in visual regions the same basic phenomenon was evoked by tracking of salient environmental changes. In most other cortical regions, including dorsolateral prefrontal and anterior cingulate cortex, the phenomenon was most consistent with directly encoding the degree of uncertainty. However, in a few other regions, including orbitofrontal cortex, the phenomenon was best explained by representations of a shifting context that evolve more rapidly during periods of rapid learning. These representations may provide a dynamic substrate for learning that facilitates rapid disengagement from learned responses during periods of change.
Non-random associations of maternally transmitted symbionts in insects: The roles of drift versus co-transmission and selection
Authors: Hugo Mathé-Hubert , Kaech Heidi , Hertaeg Corinne , Vorburger Christoph
Published: July 2018

Virtually all higher organisms form holobionts with associated microbiota. To understand the biology of holobionts we need to know how species assemble and interact. Controlled experiments are suited to study interactions between particular symbionts, but they can only inform about a tiny portion of the diversity within each species. Alternatively, interactions can be inferred from associations among symbionts in the field that are more or less frequent than expected under random assortment. However, random assortment may not be a valid null hypothesis for maternally transmitted symbionts in finite populations, where drift alone can result in associations. Here we report results from a European field survey of endosymbionts in the pea aphid (Acyrthosiphon pisum), and we develop a model to study the effect of drift on symbiont associations under different population sizes, considering varying rates of horizontal and maternal transmission. The model showed that even though horizontal transmissions and maternal transmission failures tend to randomise symbiont associations, drift can induce significant departures from random assortment, at least in moderate-sized populations. Based on these results, we carefully interpret our field survey and we re-visit the association betweenSpiroplasmaandWolbachiainDrosophila neotestaceareported by Jaenikeet al. (2010). For this and for several significant associations between symbionts in European pea aphids we conclude that under reasonable assumptions of effective population size, they are indeed likely to be maintained by biased co-transmission or selection. Our study shows that formulating appropriate null expectations can strengthen the biological inference from co-occurrence patterns in the field.
The PedS2/PedR2 two-component system is crucial for the rare earth element switch in Pseudomonas putida KT2440
Authors: Wehrmann Matthias , Berthelot Charlotte , Billard Patrick , Klebensberger Janosch
Published: July 2018

In Pseudomonas putida KT2440, two pyrroloquinoline quinone-dependent ethanol dehydrogenases (PQQ-EDHs) are responsible for the periplasmic oxidation of a broad variety of volatile organic compounds (VOCs). Depending on the availability of rare earth elements (REEs) of the lanthanide series (Ln3+), we have recently described that the transcription of the genes encoding the Ca2+-utilizing enzyme PedE and the Ln3+-utilizing enzyme PedH are inversely regulated. With adaptive evolution experiments, site-specific mutations, transcriptional reporter fusions, and complementation approaches, we herein demonstrate that the PedS2/PedR2 (PP_2671/PP_2672) two-component system (TCS) plays a central role in the observed REE-mediated switch of PQQ-EDHs in P. putida. We provide evidence that in the absence of lanthanum (La3+), the sensor histidine kinase PedS2 phosphorylates its cognate LuxR-type response regulator PedR2, which in turn not only activates pedE gene transcription but is also involved in repression of pedH. Our data further suggests that the presence of La3+ lowers kinase activity of PedS2, either by the direct binding of the metal ions to the periplasmic region of PedS2 or by an uncharacterized indirect interaction, leading to reduced levels of phosphorylated PedR2. Consequently, the fading pedE expression and concomitant alleviation of pedH repression causes – in conjunction with the transcriptional activation of the pedH gene by a yet unknown regulatory module – the Ln3+-dependent transition from PedE to PedH catalysed oxidation of alcoholic VOCs.

IMPORTANCE

The function of lanthanides for methano- and methylotrophic bacteria is gaining increasing attention, while knowledge about the role of rare earth elements (REEs) in non-methylotrophic bacteria is still limited. The present study investigates the recently described differential expression of the two PQQ-EDHs of P. putida in response to lanthanides. We demonstrate that a specific TCS is crucial for their inverse regulation and provide evidence for a dual regulatory function of the LuxR-type response regulator involved. Thus, our study represents the first detailed characterization of the molecular mechanism underlying the REE switch of PQQ-EDHs in a non-methylotrophic bacterium and stimulates subsequent investigations for the identification of additional genes or phenotypic traits that might be co-regulated during REE-dependent niche adaptation.
NHA2 promotes cyst development in an in vitro model of polycystic kidney disease
Authors: Prasad Hari , Dang Donna K. , Kondapalli Kalyan C. , Natarajan Niranjana , Cebotaru Valeriu , Rao Rajini
Published: July 2018

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The molecular pathways linking polycystins to cyst development in ADPKD are still unclear. Intracystic fluid secretion via ion transporters and channels plays a crucial role in cyst expansion in ADPKD. Unexpectedly, we observed significant and selective up-regulation of NHA2, a member of the SLC9B family of Na+/H+ exchangers that correlated with cyst size and disease severity in ADPKD patients. Using three-dimensional cultures of MDCK cells to model cystogenesis in vitro, we show that ectopic expression of NHA2 is causal to increased cyst size. Induction of PC1 in MDCK cells inhibited NHA2 expression with concordant inhibition of Ca2+ influx through store-dependent and independent pathways, whereas reciprocal activation of Ca2+ influx by a dominant negative, membrane-anchored C-terminal tail fragment of PC1 elevated NHA2. We show that NHA2 is a target of Ca2+/NFAT signaling and is transcriptionally induced by methylxanthine drugs such as caffeine and theophylline, which are contraindicated in ADPKD patients. Finally, we observe robust induction of NHA2 by vasopressin, which is physiologically consistent with increased levels of circulating vasopressin and up-regulation of vasopressin V2 receptors in ADPKD. Our findings have mechanistic implications on the emerging use of vasopressin V2 receptor antagonists such as tolvaptan as safe and effective therapy for PKD and reveal a potential new regulator of transepithelial salt and water transport in the kidney.
Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells
Authors: Earle Ashley J. , Kirby Tyler J. , Fedorchak Gregory R. , Isermann Philipp , Patel Jineet , Iruvanti Sushruta , Moore Steven A. , Bonne Gisèle , Wallrath Lori L. , Lammerding Jan
Published: July 2018

Mutations in the humanLMNAgene, which encodes the nuclear envelope (NE) proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found thatLmnamutations caused extensive NE abnormalities, consisting of chromatin protrusions into the cytoplasm and transient rupture of the NE in skeletal muscle cells. NE damage was associated with DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, NE damage resulted from nuclear migration in maturing skeletal muscle cells, rather than actomyosin contractility. NE damage and DNA damage was reduced by either depletion of kinesin-1 or disruption of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. LINC complex disruption rescued myofiber function and viability inLmnamutant myofibers, indicating that the myofiber dysfunction is the result of mechanically induced NE damage. The extent of NE damage and DNA damage inLmnamouse models correlated with the disease onset and severityin vivo. Moreover, inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients withLMNAmuscular dystrophy revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor forLMNAskeletal muscle diseases.
Bayesian Model Selection Maps for group studies using M/EEG data
Authors: Harris Clare D. , Rowe Elise G. , Randeniya Roshini , Garrido Marta I.
Published: July 2018

Predictive coding postulates that we make (top-down) predictions about the world and that we continuously compare incoming (bottom-up) sensory information with these predictions, in order to update our models and perception so as to better reflect reality. That is, our so-called ‘Bayesian brains’ continuously create and update generative models of the world, inferring (hidden) causes from (sensory) consequences. Neuroimaging datasets enable the detailed investigation of such modelling and updating processes, and these datasets can themselves be analysed with Bayesian approaches. These offer methodological advantages over classical statistics. Specifically, any number of models can be compared, the models need not be nested, and the ‘null model’ can be accepted (rather than only failing to be rejected as in frequentist inference). This methodological paper explains how to construct posterior probability maps (PPMs) for Bayesian Model Selection (BMS) at the group level using electroencephalography (EEG) or magnetoencephalography (MEG) data. The method has only recently been used for EEG data, after originally being developed and applied in the context of functional magnetic resonance imaging (fMRI) analysis. Here, we describe how this method can be adapted for EEG using the Statistical Parametric Mapping (SPM) software package for MATLAB. The method enables the comparison of an arbitrary number of hypotheses (or explanations for observed responses), at each and every voxel in the brain (source level) and/or in the scalp-time volume (scalp level), both within participants and at the group level. The method is illustrated here using mismatch negativity (MMN) data from a group of participants performing an audio-spatial oddball attention task. All data and code are provided in keeping with the Open Science movement. In so doing, we hope to enable others in the field of M/EEG to implement our methods so as to address their own questions of interest.
White matter connectivity disruptions in the pre-clinical continuum of psychosis: A connectome study
Authors: Oestreich Lena K. L. , Randeniya Roshini , Garrido Marta I.
Published: July 2018

Background

Widespread white matter disruptions in schizophrenia have been commonly reported, but it remains unanswered whether these abnormalities are associated with schizophrenia specifically or whether they range along a psychotic continuum into the healthy population. Investigating the extent of white matter connectivity disruptions specific to psychotic-like experiences in healthy individuals is insofar important as it is a necessary first step towards the development of prodromal psychosis biomarkers.

Methods

High resolution, multi-shell diffusion-weighted magnetic resonance images were acquired from 89 healthy individuals. Whole-brain white matter fiber tracking was performed to quantify the strength of white matter connections. Network-based statistics were applied to white matter connections in a regression model in order to test for a linear relationship between streamline count and psychotic-like experiences.

Results

A significant subnetwork was identified whereby streamline count declined with increasing quantity of psychotic-like experiences. This network of significant connectivity reductions affected all cortical lobes, subcortical structures and the cerebellum.

Conclusion

A widespread network of linearly declining connectivity strength with increasing number of psychotic-like experiences was identified in healthy individuals. This finding is in line with white matter connectivity reductions reported from early to chronic stages of schizophrenia. We suggest that these white matter changes might be a potential biomarker for the identification of individuals at high risk for transitioning to psychosis.