bluuebunny/crossref_metadata_2025 huggingface dataset:
Discarding orbital decay in WASP-19b after one decade of transit observations★†
Authors: Petrucci R , Jofré E , Gómez Maqueo Chew Y , Hinse T C , Mašek M , Tan T-G , Gómez M
Published: October 2019

We present a empirical study of orbital decay for the exoplanet WASP-19b, based on mid-time measurements of 74 complete transits (12 newly obtained by our team and 62 from the literature), covering a 10-year baseline. A linear ephemeris best represents the mid-transit times as a function of epoch. Thus, we detect no evidence of the shortening of WASP-19b’s orbital period and establish an upper limit of its steady changing rate, $\dot{P}=-2.294$ ms yr−1, and a lower limit for the modified tidal quality factor $Q^{\prime }_{\star } = (1.23 \pm 0.231) \times 10^{6}$. Both are in agreement with previous works. This is the first estimation of $Q^{\prime }_{\star }$ directly derived from the mid-times of WASP-19b obtained through homogeneously analyzed transit measurements. Additionally, we do not detect periodic variations in the transit timings within the measured uncertainties in the mid-times of transit. We are therefore able to discard the existence of planetary companions in the system down to a few M⊕ in the first order mean-motion resonances 1:2 and 2:1 with WASP-19b, in the most conservative case of circular orbits. Finally, we measure the empirical $Q^{\prime }_{\star }$ values of 15 exoplanet host stars which suggest that stars with Teff ≲ 5600K dissipate tidal energy more efficiently than hotter stars. This tentative trend needs to be confirmed with a larger sample of empirically measured $Q^{\prime }_{\star }$.
EDGE: the mass–metallicity relation as a critical test of galaxy formation physics
Authors: Agertz Oscar , Pontzen Andrew , Read Justin I , Rey Martin P , Orkney Matthew , Rosdahl Joakim , Teyssier Romain , Verbeke Robbert , Kretschmer Michael , Nickerson Sarah
Published: October 2019

We introduce the ‘Engineering Dwarfs at Galaxy Formation’s Edge’ (EDGE) project to study the cosmological formation and evolution of the smallest galaxies in the Universe. In this first paper, we explore the effects of resolution and sub-grid physics on a single low-mass halo ($M_{\rm halo}=10^{9}{\, \rm M}_\odot$), simulated to redshift z = 0 at a mass and spatial resolution of $\sim 20{\, \rm M}_\odot$ and ∼3 pc. We consider different star formation prescriptions, supernova feedback strengths, and on-the-fly radiative transfer (RT). We show that RT changes the mode of galactic self-regulation at this halo mass, suppressing star formation by causing the interstellar and circumgalactic gas to remain predominantly warm (∼104 K) even before cosmic reionization. By contrast, without RT, star formation regulation occurs only through starbursts and their associated vigorous galactic outflows. In spite of this difference, the entire simulation suite (with the exception of models without any feedback) matches observed dwarf galaxy sizes, velocity dispersions, V-band magnitudes, and dynamical mass-to-light-ratios. This is because such structural scaling relations are predominantly set by the host dark matter halo, with the remaining model-to-model variation being smaller than the observational scatter. We find that only the stellar mass–metallicity relation differentiates the galaxy formation models. Explosive feedback ejects more metals from the dwarf, leading to a lower metallicity at a fixed stellar mass. We conclude that the stellar mass–metallicity relation of the very smallest galaxies provides a unique constraint on galaxy formation physics.
How Is Love of the Neighbour Possible? A Løgstrupian Response to a Lutheran Critique of Levinas—and Vice Versa
Authors: Stern Robert
Published: October 2019

This paper considers how both Levinas and Løgstrup seek to explain how love of the neighbour is possible. It focuses on a criticism of Levinas made by Merold Westphal, which follows Kierkegaard in arguing on Lutheran grounds that such love first requires a relation to God as a “middle term,” but that Levinas cannot appeal to this relation to account for neighbour love, as for him the God relation itself arises through love of the neighbour. In response, the paper explores how Løgstrup, while working in a Lutheran tradition, like Levinas also sees neighbour love as arising without any prior God relation, showing how the accounts that each offer of how this is possible serve to complement each other.
Capacities, capabilities, and the societal impact of the humanities
Authors: Sigurðarson Eiríkur Smári
Published: October 2019

This article explores new theoretical directions for understanding societal impact of the humanities and in a wider context. Arguing from the position that current evaluation policies and practises are in many cases ill-suited to research in the humanities, with risk of goal displacement, it takes up the debate about what the proper goals of research in the humanities are. Asking: If we risk goal displacement, what are the proper goals researchers are being led away from? Using Miranda Fricker’s theory of epistemic justice and Amartya Sen’s capability approach, it argues for the need for a ‘capability theory’ for social capacities to understand societal impact. On the basis of this, a better understanding of the societal impact of research in the humanities can be developed, as well as new ways of assessing (ex ante and ex post) the societal impact of research projects and programmes in the humanities.
Distinct cerebellar regions for body motion discrimination
Authors: Ferrari Chiara , Ciricugno Andrea , Battelli Lorella , Grossman Emily D , Cattaneo Zaira
Published: October 2019

Visual processing of human movements is critical for adaptive social behavior. Cerebellar activations have been observed during biological motion discrimination in prior neuroimaging studies, and cerebellar lesions may be detrimental for this task. However, whether the cerebellum plays a causal role in biological motion discrimination has never been tested. Here, we addressed this issue in three different experiments by interfering with the posterior cerebellar lobe using transcranial magnetic stimulation (TMS) during a biological discrimination task. In Experiments 1 and 2, we found that TMS delivered at onset of the visual stimuli over the vermis (vermal lobule VI), but not over the left cerebellar hemisphere (left lobule VI/Crus I), interfered with participants’ ability to distinguish biological from scrambled motion compared to stimulation of a control site (vertex). Interestingly, when stimulation was delivered at a later time point (300 ms after stimulus onset), participants performed worse when TMS was delivered over the left cerebellar hemisphere compared to the vermis and the vertex (Experiment 3). Our data show that the posterior cerebellum is causally involved in biological motion discrimination and suggest that different sectors of the posterior cerebellar lobe may contribute to the task at different time points.
Insights into hookworm prevalence in Asia: a systematic review and meta-analysis
Authors: Zibaei Mohammad , Nosrati Mohammad Reza Chaechi , Shadnoosh Farnosh , Houshmand Elham , Karami Maryam Fasihi , Rafsanjani Mandana Khorsandi , Majidiani Hamidreza , Ghaffarifar Fatemeh , Cortes Hélder Carola Espiguinha , Dalvand Sahar , Badri Milad
Published: October 2019

Introduction

Hookworm infections are neglected tropical diseases of humans and animals worldwide. A meta-analysis and systematic review was designed to evaluate the prevalence of hookworm infection in animal and human hosts in Asia until July 2018.

Methods

The available online articles of five English databases (PubMed, Scopus, Science Direct, Web of Science and Google Scholar) were explored.

Results

The most parasitized carnivores were jackal (48%, CI: 4 to 91%), followed by dog (41%, CI: 29 to 53%), cat (26%, CI: 14 to 38%) and the red fox (19%, CI: 13 to 24%). The weighted prevalence of Ancylostoma braziliensis, A. caninum, A. ceylanicum, A. tubaeforme and Uncinaria stenocephala isolated from different canids were found to be 27% (CI: 21 to 33%), 23% (CI: 7.0 to 53%), 24% (CI: 12 to 35%), 44% (CI: 37 to 51%) and 37% (CI: 18 to 55%), respectively. In total, 98 records were obtained for human hookworms from 3209 760 examined individuals and the calculated weighted prevalence in this population was 19% (CI: 17 to 20%).

Conclusions

These findings highlight a desirable ecological milieu for parasite survival and transmission in such territories, which implicates revisiting control programs and public health infrastructures in those areas.
The receptor‐receptor interaction between mGluR1 receptor and NMDA receptor: a potential therapeutic target for protection against ischemic stroke
Authors: Lai Terence K. Y. , Zhai Dongxu , Su Ping , Jiang Anlong , Boychuk Jay , Liu Fang
Published: October 2019

Ischemic stroke is one of the leading causes of long‐term disability worldwide. It arises when the blood flow to the brain is severely impaired, causing brain infarction. The current therapies for ischemic stroke are tissue plasminogen activator and mechanical thrombectomy, which re‐establishes blood circulation to the brain but offers no neuroprotective effects. Excitotoxicity, particularly through the N‐methyl‐D‐aspartate receptor (NMDAR), has been heavily implicated in the pathophysiology of brain infarction resulting from ischemic stroke. Here we investigated the interaction between NMDAR and metabotropic glutamate receptor 1 (mGluR1) as a novel target to develop potential neuroprotective agents for ischemic stroke. Through coimmunoprecipitation and affinity binding assay, we revealed that the interaction is mediated through 2 distinct sites on the mGluR1 C terminus. We then found that the disruption of mGluR1‐GluN2A subunit of NMDAR (GluN2A) protected the primary mouse hippocampal neurons against NMDAR‐mediated excitotoxicity and reversed the NMDAR‐mediated regulation of ERK1/2 in rat hippocampal slices. The same protection was also observed in an animal model of ischemic stroke, alleviating brain infarction and yielding better motor recovery. These findings confirmed the existence of a receptor‐receptor interaction between NMDAR and mGluR1, implicating this interconnection as a potential treatment target site for ischemic stroke.—Lai, T. K. Y., Zhai, D. Su, P., Jiang, A., Boychuk, J., Liu, F. The receptor‐receptor interaction between mGluR1 receptor and NMDA receptor: a potential therapeutic target for protection against ischemic stroke. FASEB J. 33, 14423‐14439 (2019). www.fasebj.org
The Integrated Voxel Analysis Method (IVAM) to Diagnose Onset of Alzheimer’s Disease and Identify Brain Regions through Structural MRI Images
Authors: Hur Matthew , Aghajanyan Armen
Published: October 2019

Magnetic Resonance Imaging (MRI) provides three-dimensional anatomical and physiological details of the human brain. We describe the Integrated Voxel Analysis Method (IVAM) which, through machine learning, classifies MRI images of brains afflicted with early Alzheimer’s Disease (AD). This fully automatic method uses an extra trees regressor model in which the feature vector input contains the intensities of voxels, whereby the effect of AD on a single voxel can be predicted. The resulting tree predicts based on the following two steps: a K-nearest neighbor (KNN) algorithm based on Euclidean distance with the feature vector to classify whole images based on their distribution of affected voxels and a voxel-by-voxel classification by the tree of every voxel in the image. An Ising model filter follows voxel-by-voxel tree-classification to remove artifacts and to facilitate clustering of classification results which identify significant voxel clusters affected by AD. We apply this method to T1-weighted MRI images obtained from the Open Access Series of Imaging Studies (OASIS) using images belonging to normal and early AD-afflicted individuals associated with a Client Dementia Rating (CDR) which we use as the target in the supervised learning. Furthermore, statistical analysis using a pre-labeled brain atlas automatically identifies significantly affected brain regions. While achieving 90% AD classification accuracy on 198 images in the OASIS dataset, the method reveals morphological differences caused by the onset of AD.
Machine learning-based imaging biomarkers improve statistical power in clinical trials
Authors: Lou Carolyn , Habes Mohamad , Davatzikos Christos , Shinohara Russell T. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: October 2019

Radiomic models, which leverage complex imaging patterns and machine learning, are increasingly accurate in predicting patient response to treatment and clinical outcome on an individual patient basis. In this work, we show that this predictive power can be utilized in clinical trials to significantly increase statistical power to detect treatment effects or reduce the sample size required to achieve a given power. Akin to the historical control paradigm, we propose to utilize a radiomic prediction model to generate a pseudo-control sample for each individual in the trial of interest. We then incorporate these pseudo-controls into the analysis of the clinical trial of interest using classical and well established statistical tools, and investigate statistical power. Effectively, this approach utilizes each individual’s radiomics-based predictor of outcome for comparison with the actual outcome, potentially increasing statistical power considerably, depending on the accuracy of the predictor. In simulations of treatment effects based on real radiomic predictive models from brain cancer and prodromal Alzheimer’s Disease, we show that this methodology can decrease the required sample sizes by as much as a half, depending on the strength of the radiomic predictor. We further find that this method is most helpful when treatment effect sizes are small and that power grows with the accuracy of radiomic prediction.
From frail to fit after allogeneic hematopoietic cell transplantation: Scope of the problem and a strength-based solution
Authors: Sweetnam Jason , Twohey Eric , Skendzel Sasha , Stingle John , Arora Mukta , Baraki Austin , Cao Qing , Grillo Sonya , Holtan Shernan G.
Published: October 2019

Background

Frailty is a common but underdiagnosed syndrome among long-term survivors of allogeneic hematopoietic cell transplantation (HCT). Conditions such as malnutrition, fatigue, and weakness may suggest frailty despite patients not receiving a formal diagnosis. Furthermore, the optimal interventions to overcome frailty in long-term survivors of allogeneic HCT is not yet established.

Patients and Methods

This study consists of a retrospective and prospective component. First, we completed a retrospective review using diagnosis data from the electronic medical record to estimate the prevalence of components of frailty in 1077 recipients of allogeneic HCT through 5 years post-transplant. Second, we developed a community-based pilot study of strength training for long-term survivors of allogeneic HCT that addressed several common barriers exercise engagement and adherence. Four allogeneic HCT recipients (2 males, 2 females) and 4 controls (2 males, 2 females) completed the strength training pilot study, consisting of a baseline assessment, 10 weeks of personalized and supervised strength programming at least once weekly as a group, and an end-of-study assessment to measure progress in strength, body composition, and a standardized measure of self-efficacy.

Results

Despite a lack of a formal diagnosis, approximately 80% of HCT recipients in this series received a diagnosis of a component of frailty (weakness, fatigue, or malnutrition), and over 1/3 of HCT recipients had symptoms extending beyond 1 year. Over the course of the strength training pilot study, both pre-frail/frail allogeneic HCT recipients and healthy controls doubled their total strength, lost body fat, and gained muscle mass. Self-efficacy improved from baseline in allogeneic HCT recipients after the strength training pilot program.

Discussion

Based upon the prevalence of frailty-related diagnoses among long-term survivors of HCT, a comprehensive mitigation strategy needs to be developed for this population. A community-based strength training program that includes a personalized component, a group setting, and caregiver/partner involvement appears feasible and overcomes several established barriers to exercise engagement and adherence.
Lower limb muscle activity underlying temporal gait asymmetry post-stroke
Authors: Rozanski Gabriela M. , Huntley Andrew H. , Crosby Lucas D. , Schinkel-Ivy Alison , Mansfield Avril , Patterson Kara K.
Published: October 2019

Objective

Asymmetric walking after stroke is common, detrimental, and difficult to treat, but current knowledge of underlying physiological mechanisms is limited. This study investigated electromyographic (EMG) features of temporal gait asymmetry (TGA).

Methods

Participants post-stroke with or without TGA and control adults (n=27, 8, and 9, respectively) performed self-paced overground gait trials. EMG, force plate, and motion capture data were collected. Lower limb muscle activity was compared across groups and sides (more/less affected). Correlation between burst timing variables and asymmetry ratios was examined.

Results

Significant group by side interaction effects were found: fewer TGA group dorsiflexor bursts during swing (p=.0009), more affected plantarflexor stance activity ended early (p=.0006) and less affected dorsiflexor on/off time was delayed (p<.01) in persons with asymmetry compared to symmetric and normative controls. Less affected side EMG timing correlated most with swing time ratio (r=0.68-0.90, p<.001).

Conclusions

Temporal patterns of muscular activation, particularly about the ankle around the stance-to-swing transition period, are associated with TGA. The results may reflect specific impairments or compensations that affect locomotor coordination.

Significance

Neuromuscular underpinnings of spatiotemporal asymmetry have not been previously characterized. These novel findings may inform targeted therapeutic strategies to improve gait quality after stroke.
DeepCAGE: Incorporating Transcription Factors in Genome-wide Prediction of Chromatin Accessibility
Authors: Liu Qiao , Hua Kui , Zhang Xuegong , Wong Wing Hung , Jiang Rui
Published: October 2019

Although computational approaches have been complementing high-throughput biological experiments for the identification of functional regions in the human genome, it remains a great challenge to systematically decipher interactions between transcription factors and regulatory elements to achieve interpretable annotations of chromatin accessibility across diverse cellular contexts. Towards this problem, we propose DeepCAGE, a deep learning framework that integrates sequence information and binding status of transcription factors, for the accurate prediction of chromatin accessible regions at a genome-wide scale in a variety of cell types. DeepCAGE takes advantage of a densely connected deep convolutional neural network architecture to automatically learn sequence signatures of known chromatin accessible regions, and then incorporates such features with expression levels and binding activities of human core transcription factors to predict novel chromatin accessible regions. In a series of systematic comparisons with existing methods, DeepCAGE exhibits superior performance in not only the classification but also the regression of chromatin accessibility signals. In detailed analysis of transcription factor activities, DeepCAGE successfully extracts novel binding motifs and measures the contribution of a transcription factor to the regulation with respect to a specific locus in a certain cell type. When applied to whole-genome sequencing data analysis, our method successfully prioritizes putative deleterious variants underlying a human complex trait, and thus provides insights into the understanding of disease-associated genetic variants. DeepCAGE can be downloaded from https://github.com/kimmo1019/DeepCAGE.
Host gill attachment enables blood-feeding by the salmon louse (Lepeophtheirus salmonis) chalimus larvae and alters parasite development and transcriptome
Authors: Heggland Erna Irene , Dondrup Michael , Nilsen Frank , Eichner Christiane
Published: October 2019

Blood-feeding is a common strategy among parasitizing arthropods, including the ectoparasitic salmon louse (Lepeophtheirus salmonis), feeding off its salmon host’s skin and blood. Blood is rich in nutrients, among these iron and heme. These are essential molecules for the louse, yet their oxidative properties render them toxic to cells if not handled properly. Blood-feeding might therefore alter parasite gene expression. We infected Atlantic salmon with salmon louse copepodids and sampled the lice in two different experiments at day 10 and 18 post infestation. Parasite development and presence of host blood in their intestines were determined. We find that lice start feeding on blood when becoming mobile preadults if sitting on the fish body, however they may initiate in blood-feeding at the chalimus I stage if attached to gills. Lice attached to gills develop at a slower rate. Lice of similar instar age from gills versus lice from skin epidermis were analyzed for gene expression by RNA-sequencing in samples taken at day 10 for both experiments and at day 18 for one of the experiments. By differential expression analysis, we found 355 transcripts elevated in lice sampled from gills and 202 transcripts elevated in lice sampled from skin consistent in all experiments. Genes annotated with “peptidase activity” are among the ones elevated in lice sampled from gills, while in the other group genes annotated with “phosphorylation” and “phosphatase” is pervasive. Transcripts elevated in lice sampled from gills are often genes relatively highly expressed in the louse intestine compared with other tissues, while this was not the case for transcripts found elevated in lice sampled from skin. In both groups, more than half the transcripts are from genes higher expressed after attachment. In conclusion, blood-feeding results in an alteration in gene expression, and a premature onset of blood-feeding likely causes the parasite to develop at a slower pace.
Predicting MMSE Score from Finger-Tapping Measurement
Authors: Jian Ma
Published: October 2019

Dementia is a leading cause of diseases for the elderly. Early diagnosis is very important for the elderly living with dementias. In this paper, we propose a method for dementia diagnosis by predicting MMSE score from finger-tapping measurement with machine learning pipeline. Based on measurement of finger tapping movement, the pipeline is first to select finger-tapping attributes with copula entropy and then to predict MMSE score from the selected attributes with predictive models. Experiments on real world data show that the predictive models such developed present good prediction performance. As a byproduct, the associations between certain finger-tapping attributes (‘Number of taps’ and ‘SD of inter-tapping interval’) and MMSE score are discovered with copula entropy, which may be interpreted as the biological relationship between cognitive ability and motor ability and therefore makes the predictive models explainable. The selected finger-tapping attributes can be considered as dementia biomarkers.
Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery
Authors: Dreyfuss Jonathan M , Yuchi Yixing , Pan Hui , Dong Xuehong , Simonson Donald C. , Vernon Ashley , Aryal Pratik , Konkar Anish , Sebastian Yinong , Higgs Brandon W , Grimsby Joseph , Rondinone Cristina M. , Kasif Simon , Kahn Barbara B. , Foster Kathleen , Goldfine Allison , Patti Mary-Elizabeth
Published: October 2019

Molecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify analytes that mediate improvement in outcomes, we developed a high-throughput mediation analysis method (Hitman), which is significantly more powerful than existing methods. Top-ranking analyte mediators of glycemia improvement were growth hormone receptor and prolylhydroxyproline, which were more significant than any clinical mediator, including BMI. Beta-alanine and Histidine Metabolism (both including CNDP1) were top differentially regulated pathways, and Valine, Leucine and Isoleucine Degradation was also a top differentially-regulated pathway and a top mediator of improvement in insulin resistance. The identified analytes may serve as novel targets for T2D therapy. More broadly, Hitman can identify analyte mediators of outcomes in randomized trials for which high-throughput data are available.
CCSeq: Clusters of Colocalized Sequences
Authors: Golas Stefan
Published: October 2019

0.1

Motivation

Potential transcription factor (TF) complexes may be identified by testing whether the binding sequences of individual TF proteins form clusters with each other. These clusters may also indicate TF inhibition due to competitive occupancy of enhancer regions. Genome annotation data containing the coordinates of enhancer sequences is highly accessible via position-weight matrix tools.

0.2

Results

An algorithm called CCSeq (Clusters of Colocalized Sequences) was developed for identifying clusters of sequences along a one-dimensional line, such as a chromosome, given genome annotation files and a cut-off distance as inputs. The algorithm was applied to the binding sequences of the constituent proteins of two known transcription factor complexes, the HSF1 homotrimer and one form of the NF-κB complex, a dimer of NFKB2 and RELB. 28 clusters of HSF1 trimer binding sequences were identified on chromosome Y, and 16 clusters of the NFKB2 and RELB dimer were identified on chromosome 17, compared to 0 clusters identified in any of the five simulated random distributions for each of the two sets of TF proteins. Additionally, structural patterns of these binding sequence clusters are described.

0.3

Availability and Implementation

This algorithm is freely available as an R package on the open source R repository CRAN at the following link:https://cran.r-project.org/package=colocalized. Genome annotation files were obtained from the PWMScan tool athttps://ccg.epfl.ch/pwmtools/pwmscan.phphosted by the Swiss Insitute of Bioinformatics (2) (3).
Brain networks processing temporal information in dynamic facial expressions
Authors: Skiba Rafal M. , Vuilleumier Patrik
Published: October 2019

Perception of emotional expressions in faces relies on the integration of distinct facial features. We used fMRI to examine the role of local and global motion information in facial movements during exposure to novel dynamic face stimuli. We found that synchronous expressions distinctively engaged medial prefrontal areas in the ventral anterior cingulate cortex (vACC), supplementary premotor areas, and bilateral superior frontal gyrus (global temporal-spatial processing). Asynchronous expressions in which one part of the face (e.g., eyes) unfolded before the other (e.g., mouth) activated more the right superior temporal sulcus (STS) and inferior frontal gyrus (local temporal-spatial processing). DCM analysis further showed that processing of asynchronous expression features was associated with a differential information flow, centered on STS, which received direct input from occipital cortex and projected to the amygdala. Moreover, STS and amygdala displayed selective interactions with vACC where the integration of both local and global motion cues (present in synchronous expressions) could take place. These results provide new evidence for a role of both local and global temporal dynamics in emotional expressions, extracted in partly separate brain pathways. Importantly, we show that dynamic expressions with synchronous movement cues may distinctively engage brain areas responsible for motor execution of expressions.
Quality-quantity tradeoffs drive functional trait evolution in a model microalgal “climate change winner”
Authors: Lindberg Rasmus T. , Collins Sinéad
Published: October 2019

Phytoplankton are the unicellular photosynthetic microbes that form the base of aquatic ecosystems, and their responses to global change will impact everything from food web dynamics to global nutrient cycles. Some taxa respond to environmental change by increasing population growth rates in the short-term, and, based on this, are projected to increase in frequency over decades. To gain insight into how functional traits in these projected “climate change winners” change over different timescales, we evolved populations of microalgae in ameliorated environments for several hundred generations. While populations initially responded to environmental amelioration by increasing photosynthesis and population growth rates as expected, this response was not sustained. Instead, most populations evolved to allocate a smaller proportion of carbon to growth while increasing their ability to tolerate and metabolise reactive oxygen species (ROS). This diversion of fixed carbon from growth to catabolism underlies a quality-quantity tradeoff in daughter cell production which drives the evolution of population growth rates and of functional traits that underlie the ecological and biogeochemical roles of phytoplankton. There is intraspecific variation in the trait combinations that evolve, but all are consistent with mitigating ROS production and accumulation in ameliorated environments over hundreds of generations. This offers both an evolutionary and a metabolic framework for understanding how functional traits can change in primary producers projected to be “climate change winners”, and suggests that short-term population booms and associated trait shifts have the potential to be dampened or reversed if environmental amelioration persists.
Molecular Tuning of Styryl Dyes Leads to Versatile and Efficient Plasma Membrane Probes for Cell and Tissue Imaging
Authors: Collot Mayeul , Boutant Emmanuel , Fam Kyong Tkhe , Danglot Lydia , Klymchenko Andrey S.
Published: October 2019

The plasma membrane (PM) plays a major role in many biological processes; therefore its proper fluorescence staining is required in bioimaging. Among the commercially available PM probes, styryl dye FM1-43 is one of the most widely used. In this work, we demonstrated that fine chemical modifications of FM1-43 can dramatically improve the PM staining. The newly developed probes, SP-468 and SQ-535 were found to display enhanced photophysical properties (reduced crosstalk, higher brightness, improved photostability) and unlike FM1-43, provided excellent and immediate PM staining in 5 different mammalian cell lines including neurons (primary culture and tissue imaging). Additionally, we showed that the new probes displayed differences in their internalization pathways compared to their parent FM1-43. Finally, we demonstrated that the modifications made to FM1-43 did not impair the ability of the new probes to stain the PM of plant cells. Overall, this work presents new useful probes for PM imaging in cells and tissues and provides insights on the molecular design of new PM targeting molecules.
Phylogeographic structure of the pygmy shrew: revisiting the roles of southern and northern refugia in Europe
Authors: Vega Rodrigo , McDevitt Allan D. , Stojak Joanna , Mishta Alina , Wójcik Jan M. , Kryštufek Boris , Searle Jeremy B.
Published: October 2019

Southern and northern glacial refugia are considered paradigms that explain the complex phylogeographic patterns and processes of European biota. Although the Eurasian pygmy shrewSorex minutusLinnaeus, 1766 (Eulipotyphla, Soricidae) has been used a model species to study geographic isolation and genetic diversification in Mediterranean peninsulas in the Last Glacial Maximum (LGM), and post-glacial population expansion from cryptic northern glacial refugia in Western and Central Europe, there has been incomplete knowledge about the phylogeographic structure, genetic differentiation and demographic history within these regions. Here, we provide a revisited statistical phylogeographic study ofS. minutuswith greater sampling coverage in terms of numbers of individuals and geographic range, making it the most comprehensive investigation of this species to date. The results showed support for genetically distinct and diverse phylogeographic groups consistent with southern and northern glacial refugia, as expected from previous studies, but also identified geographical barriers concordant with glaciated mountain ranges during the LGM, early diversification events dated between the Upper Pleistocene and Lower Holocene for the main phylogeographic groups, and recent (post-LGM) patterns of demographic expansions. The results have implications for the conservation of intraspecific diversity and the preservation of the evolutionary potential ofS. minutus.
Live-Cell Imaging and Quantification of PolyQ Aggregates by Stimulated Raman Scattering of Selective Deuterium Labeling
Authors: Miao Kun , Wei Lu
Published: October 2019

Huntington’s disease, a major neurodegenerative disorder, involves deposition of aggregation-prone proteins with long polyglutamine (polyQ) expansions. The ability to non-perturbatively visualize the formation of aggregates could offer new molecular insight for their pathologic roles. Here, we propose stimulated Raman scattering imaging of deuterium-labeled glutamine to investigate native polyQ aggregates in live cells with subcellular resolution. Through the enrichment of deuterated glutamine in the polyQ sequence of mutant Huntingtin (mHtt) proteins, we first achieved sensitive and specific SRS imaging of carbon-deuterium bonds (C-D) from aggregates without GFP labeling. These aggregates become 1.8-fold denser compared to those with GFP. Second, we performed ratiometric quantification, which revealed a dependence of protein compositions on aggregation sizes. Moreover, we calculated the absolute concentrations for sequestered mHtt and non-mHtt proteins within the same aggregates. Our method may readily reveal new features of polyQ aggregates and could be suited forin vivoinvestigations on multicellular organisms.
HPV-positive head and neck cancer derived exosomal miR-9 induces M1 macrophage polarization and increases tumor radiosensitivity
Authors: Tong Fangjia , Zhang Siwei , Xie Huanhuan , Yan Bingqing , Song Lianhao , Wei Lanlan
Published: October 2019

Human papillomavirus (HPV) is an etiological risk factor for a subset of head and neck squamous cell carcinoma (HNSCC). HPV+ HNSCC is significant more radiosensitive than HPV-HNSCC, but the underlying mechanism is still unknown. Tumor microenvironment can affect tumor response to radiation therapy. Cancer secreted exosomes are emerging as crosstalk mediators between tumor cells and the tumor microenvironment. The main objectives of this study were to determine the role of HPV+ HNSCC-derived exosomes in increased radiation sensitivity. Here, we found that exosomes derived from HPV+ HNSCC cells activate macrophages into the M1 phenotype, which then increases the radiosensitivity of HNSCC cells. miR-9 was enriched in exosomes released from HPV+ HNSCC cells and it could be transported to macrophages, leading to altered cellular functions. Overexpression of miR-9 in macrophages induced polarization into the M1 phenotype via downregulation of PPARδ. Increased radiosensitivity was observed for HNSCC cells co-cultured with macrophages in which miR-9 was upregulated or treated with M1 macrophages. These observations suggest that HPV+ HNSCC cells secrete miR-9-rich exosomes, which then polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC cells. Hence, miR-9 may be a potential treatment strategy for HNSCC.

Statement of significance

HPV+ HNSCC through the release of miR-9-rich exosomes polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC.
12-oxophytodienoic acid reductase 3 (OPR3) functions as NADPH-dependent α,β-ketoalkene reductase in detoxification and monodehydroascorbate reductase in redox homeostasis
Authors: Maynard Daniel , Kumar Vijay , Sproß Jens , Dietz Karl-Josef
Published: October 2019

Arabidopsis (Arabidopsis thaliana) 12-oxophytodienoic acid reductase isoform 3 (OPR3) is involved in the synthesis of jasmonic acid by reducing the α,β-unsaturated double bond of the cyclopentenone moiety in 12-oxo-phytodienoic acid. Recent research revealed that jasmonic acid synthesis is not strictly dependent on the peroxisomal OPR3. In addition, OPR3 is able to reduce trinitrotoluene suggesting that the old yellow enzyme homologue OPR3 has additional functions. Here we demonstrate that OPR3 catalyzes the reduction of a wide spectrum of electrophilic species that share a reactivity towards the major redox buffers glutathione (GSH) and ascorbate (ASC). Furthermore, we demonstrate that OPDA reacts with ascorbate to form an ASC-OPDA adduct, but in addition OPR3 has the ability to regenerate ASC from monodehydroascorbate (MDHA). The presented data characterize OPR3 as a bifunctional enzyme with NADPH-dependent α,β-ketoalkene double bond reductase and monodehydroascorbate reductase activities (MDHAR).opr3mutants exhibited a slightly less reduced ASC pool in leaves in line with the MDHAR activity of OPR3in vitro. These functions link redox homeostasis as mediated by ASC and GSH with OPR3 activity and metabolism of reactive electrophilic species (RES).
De novo indol-3-ylmethyl glucosinolate biosynthesis, and not long-distance transport, contributes to defence of Arabidopsis against powdery mildew
Authors: Hunziker Pascal , Ghareeb Hassan , Wagenknecht Lena , Crocoll Christoph , Halkier Barbara Ann , Lipka Volker , Schulz Alexander
Published: October 2019

Powdery mildew is a fungal disease that affects a wide range of plants and reduces crop yield worldwide. As obligate biotrophs, powdery mildew fungi manipulate living host cells to suppress defence responses and to obtain nutrients. Members of the plant order Brassicales produce indole glucosinolates that effectively protect them from attack by non-adapted fungi. Indol-3-ylmethyl glucosinolates are constitutively produced in the phloem and transported to epidermal cells for storage. Upon attack, indol-3-ylmethyl glucosinolates are activated by CYP81F2 to provide broad-spectrum defence against fungi. How de novo biosynthesis and transport contribute to defence of powdery mildew-attacked epidermal cells is unknown. Bioassays and glucosinolate analysis indicate that GTR glucosinolate transporters are not involved in antifungal defence. Using quantitative live-cell imaging of fluorophore-tagged markers, we show that accumulation of the glucosinolate biosynthetic enzymes CYP83B1 and SUR1 is induced in epidermal cells attacked by the non-adapted barley powdery mildew Blumeria graminis f.sp. hordei. By contrast, glucosinolate biosynthesis is attenuated during interaction with the virulent powdery mildew Golovinomyces orontii. Interestingly, SUR1 induction is delayed during the Golovinomyces orontii interaction. We conclude that epidermal de novo synthesis of indol-3-ylmethyl glucosinolate contributes to CYP81F2-mediated broad-spectrum antifungal resistance and that adapted powdery mildews may target this process.
Generalizing RNA velocity to transient cell states through dynamical modeling
Authors: Bergen Volker , Lange Marius , Peidli Stefan , Wolf F. Alexander , Theis Fabian J.
Published: October 2019

The introduction of RNA velocity in single cells has opened up new ways of studying cellular differentiation. The originally proposed framework obtains velocities as the deviation of the observed ratio of spliced and unspliced mRNA from an inferred steady state. Errors in velocity estimates arise if the central assumptions of a common splicing rate and the observation of the full splicing dynamics with steady-state mRNA levels are violated. With scVelo (https://scvelo.org), we address these restrictions by solving the full transcriptional dynamics of splicing kinetics using a likelihood-based dynamical model. This generalizes RNA velocity to a wide variety of systems comprising transient cell states, which are common in development and in response to perturbations. We infer gene-specific rates of transcription, splicing and degradation, and recover the latent time of the underlying cellular processes. This latent time represents the cell’s internal clock and is based only on its transcriptional dynamics. Moreover, scVelo allows us to identify regimes of regulatory changes such as stages of cell fate commitment and, therein, systematically detects putative driver genes. We demonstrate that scVelo enables disentangling heterogeneous subpopulation kinetics with unprecedented resolution in hippocampal dentate gyrus neurogenesis and pancreatic endocrinogenesis. We anticipate that scVelo will greatly facilitate the study of lineage decisions, gene regulation, and pathway activity identification.
Effects of physiological parameter evolution on the dynamics of tonic-clonic seizures
Authors: Deeba Farah , Sanz-Leon Paula , Robinson P. A.
Published: October 2019

The temporal and spectral characteristics of tonic-clonic seizures are investigated using a neural field model of the corticothalamic system in the presence of a temporally varying connection strength between the cerebral cortex and thalamus. Increasing connection strength drives the system into ∼ 10 Hz seizure oscillations once a threshold is passed and a subcritical Hopf bifurcation occurs. In this study, the spectral and temporal characteristics of tonic-clonic seizures are explored as functions of the relevant properties of physiological connection strengths, such as maximum strength, time above threshold, and the ramp rate at which the strength increases or decreases. Analysis shows that the seizure onset time decreases with the maximum connection strength and time above threshold, but increases with the ramp rate. Seizure duration and offset time increase with maximum connection strength, time above threshold, and rate of change. Spectral analysis reveals that the power of nonlinear harmonics and the duration of the oscillations increase as the maximum connection strength and the time above threshold increase. A secondary limit cycle at ∼ 18 Hz, termed a saddle-cycle, is also seen during seizure onset and becomes more prominent and robust with increasing ramp rate. If the time above the threshold is too small, the system does not reach the 10 Hz limit cycle, and only exhibits 18 Hz saddle-cycle oscillations. It is also seen that the times to reach the saturated large amplitude limit-cycle seizure oscillation from both the instability threshold and from the end of the saddle-cycle oscillations are inversely proportional to the square root of the ramp rate.

Author Summary

Epilepsy, which is characterized by recurrent seizures, affects around 1% of the world population at some point in their lives. Tonic-clonic seizures are the most commonly encountered primary generalized seizures and it is widely considered that they can be induced by an increase in the connection strength between the cerebral cortex and the thalamus. In this paper, we analyze the detailed dynamics of tonic-clonic seizures along with their dependence on the parameters of the changing connection strength. We study the relationship of the seizure onset, offset, oscillation strength, and oscillation frequency to the duration, amplitude, and rate of change of the connection strength. A detailed understanding of the dynamics and their dependence on the physiological parameters of the brain may explain the variability of seizure dynamics among patients. It may also help to constitute successful seizure prediction.
The histone methyltransferase DOT1L is essential for humoral immune responses
Authors: Kealy Liam , Di Pietro Andrea , Hailes Lauren , Scheer Sebastian , Dalit Lennard , Groom Joanna R , Zaph Colby , Good-Jacobson Kim L
Published: October 2019

Histone modifiers are essential molecular regulators that underpin the ability of immune cells to reprogram their gene expression during differentiation. The recruitment of the histone methyltransferase DOT1L induces oncogenic gene expression in a subset of B cell leukemia. Despite its importance, little is known about its role in the humoral immune system. Herein, we demonstrate that DOT1L is a critical regulator of B cell biology. Dot1lf/fMb1Cre/+ mice had a block in B cell development, culminating in a significant reduction of mature B cells in the periphery. Upon immunization or influenza infection of Dot1lf/fCd23Cre/+ mice, germinal centers failed to form and class-switched antibody-secreting cells were significantly attenuated. Consequently, immunized mice revealed that DOT1L was essential for the formation of B cell memory populations. Transcriptome, pathway and histological analysis identified a key role for DOT1L in reprogramming gene expression for migration and localization during the initial stages of a humoral response. Together, these results demonstrate an essential role for DOT1L in antigen-dependent B cell differentiation and hence, in generating an effective and lasting humoral immune response.
Testing the basic tenet of the molecular clock and neutral theory by using ancient proteomes
Authors: Liu Tiantian , Huang Shi
Published: October 2019

Early research on orthologous protein sequence comparisons by Margoliash in 1963 discovered the astonishing phenomenon of genetic equidistance, which has inspired thead hocinterpretation known as the molecular clock. Kimura then developed the neutral theory and claimed the molecular clock as its best evidence. However, subsequent studies over the years have largely invalidated the universal molecular clock. Yet, a watered down version of the molecular clock and the neutral theory still reigns as the default model for phylogenetic inferences. The seemingly obvious tenet of the molecular clock on evolutionary time scales remains to be established by using ancient sequences: the longer the time of evolutionary divergence, the larger the genetic distance. We here analyzed the recently published Early Pleistocene enamel proteome from Dmanisi and found that ancient proteins were not closer to an outgroup than their orthologs from the extant sister species were. Together with a previous study, the combined results showed that most ancient proteins were in fact more distant to the outgroup. The results are unexpected from the molecular clock but fully predicted by the notion that genetic distances or diversities are largely at optimum saturation levels as described by the maximum genetic diversity (MGD) theory.