bluuebunny/crossref_metadata_2025 huggingface dataset:
Lab-Based and Self-Reported Indices of Fitness Show Lowered Fitness and Insight into Fitness in Individuals at Clinical High Risk for Psychosis
Authors: Damme Katherine S. F. , Sloan Richard P. , Bartels Matthew N. , Ozsan Alara , Ospina Luz H. , Kimhy David , Mittal Vijay A.
Published: May 2020

Introduction

Exercise is a promising intervention for clinical high-risk for psychosis (CHR) populations, who have attenuated positive symptoms, but evidence suggests that these youth may require tailored exercise interventions. Presently, the scope of the problem is unknown, as these youth may not be reliable reporters on fitness. This issue is compounded by the fact that there have been no investigations that utilized a formal fitness assessment in this critical population. The present study aims to determine the level of fitness in CHR youth with lab-based measures, test how effectively self-report measures characterize objective fitness indices, and explore clinical factors that may be interrupting reliable self-report-an important tool if these interventions are to be taken to scale.

Methods

Forty CHR individuals completed an exercise survey and lab-based indices of fitness (i.e., VO2max and BMI). Forty healthy volunteers completed lab indices of fitness and a structured clinical interview ruling out the presence of psychiatric illness.

Results

CHR youth showed greater BMI and lower VO2max compared to healthy volunteers. In the CHR group, abstract self-report items (perceived fitness) did not reflect lab indices of fitness, whereas specific exercise behaviors (intensity of exercise) showed stronger correlations with laboratory-based fitness measurements. Exploratory analyses suggested that positive symptoms involving grandiosity, and negative symptoms such as avolition, correlated with discrepancy between self-perception and laboratory findings of fitness.

Discussion

Results suggest that CHR individuals are less objectively fit than matched controls, and that it will be important to consider unique population characteristics when weighing self-report data.
tRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR
Authors: Guillon Jordan , Toutain Bertrand , Petit Coralie , Coquelet Hugo , Henry Cécile , Boissard Alice , Guette Catherine , Coqueret Olivier
Published: May 2020

Oncogenes or chemotherapy treatments trigger the induction of suppressive pathways such as apoptosis or senescence. Senescence was initially defined as a definitive arrest of cell proliferation but recent results have shown that this mechanism is also associated with cancer progression and chemotherapy resistance. Senescence is therefore much more heterogeneous than initially thought. How this response varies is not really understood, it has been proposed that its outcome relies on the secretome of senescent cells and on the maintenance of their epigenetic marks.

Using experimental models of senescence escape, we now described that the stability of this suppression relies on specific tRNAs and aminoacyl-tRNA synthetases. Following chemotherapy treatment, the DNA binding of the type III RNA polymerase was reduced to prevent tRNA transcription and induce a complete cell cycle arrest. By contrast, during senescence escape, specific tRNAs such as tRNA-Leu-CAA and tRNA-Tyr-GTA were up-regulated. Reducing tRNA transcription appears necessary to control the strength of senescence since RNA pol III inhibition through BRF1 depletion maintained senescence and blocked cell persistence. mTOR inhibition also prevented CIS escape in association with a reduction of tRNA-Leu-CAA and tRNA-Tyr-GTA expression. Further confirming the role of the tRNA-Leu-CAA and tRNA-Tyr-GTA, their corresponding tRNA ligases, YARS and LARS, were necessary for senescence escape. This effect was specific since the CARS ligase had no effect on persistence. YARS and LARS inactivation reduced cell emergence and proteomic analysis indicated that this effect was associated with the down-regulation of E2F1 target genes.

Overall, these findings highlight a new regulation of tRNA biology during senescence and suggest that specific tRNAs and ligases contribute to the strength and heterogeneity of this suppression.
Short-term responses to ocean acidification: effects on relative abundance of eukaryotic plankton from the tropical Timor Sea
Authors: Rahlff Janina , Khodami Sahar , Voskuhl Lisa , Humphreys Matthew P. , Stolle Christian , Arbizu Pedro Martinez , Wurl Oliver , Ribas-Ribas Mariana
Published: May 2020

Anthropogenic carbon dioxide (CO2) emissions drive climate change and pose one of the major challenges of our century. The effects of increased CO2in the form of ocean acidification (OA) on the communities of marine planktonic eukaryotes in tropical regions such as the Timor Sea are barely understood. Here, we show the effects of high CO2(pCO2=1823±161 μatm, pHT=7.46±0.05) versusin situCO2(pCO2=504±42 μatm, pHT=7.95±0.04) seawater on the community composition of marine planktonic eukaryotes immediately and after 48 hours of treatment exposure in a shipboard microcosm experiment. Illumina sequencing of the V9 hypervariable region of 18S rRNA (gene) was used to study the eukaryotic community composition. Down-regulation of extracellular carbonic anhydrase occurred faster in the high CO2treatment. Increased CO2significantly suppressed the relative abundances of different eukaryotic operational taxonomic units (OTUs), including important primary producers. These effects were consistent between abundant (DNA-based) and active (cDNA-based) taxa after 48 hours, e.g., for the diatomsTrieres chinensisandStephanopyxis turris. Effects were also very species-specific among different diatoms. Planktonic eukaryotes showed adaptation to the CO2treatment over time, but many OTUs were adversely affected by decreasing pH. OA effects might fundamentally impact the base of marine biodiversity, suggesting profound outcomes for food web functioning in the future ocean.
Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity
Authors: Hwang Duhyeong , Dismuke Taylor , Tikunov Andrey , Rosen Elias P. , Kagel John R. , Ramsey Jacob D. , Lim Chaemin , Zamboni William , Kabanov Alexander V. , Gershon Timothy R. , Sokolsky-Papkov Marina
Published: May 2020

We report a novel, nanoparticle formulation of the SHH pathway inhibitor vismodegib that improves efficacy for medulloblastoma treatment while reducing toxicity. Systemic therapies for brain tumors are complicated by restricted blood-brain barrier (BBB) permeability and dose-limiting extraneural toxicity, therefore improved delivery approached are needed. Here we show how a nanoparticle delivery system addresses these obstacles, bringing new efficacy to previously ineffective therapy. Vismodegib has been a promising agent for patients with SHH- subgroup medulloblastoma and is FDA-approved for basal cell carcinoma. However, vismodegib has limited benefit for patients with SHH-driven medulloblastoma, due to off-target toxicities and the development of resistance during therapy. We encapsulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo using transgenic mice engineered to develop endogenous medulloblastomas, testing the novel agent in a preclinical model with native vasculature and tumor microenvironment. POx-vismo showed improved CNS pharmacokinetics and reduced systemic and bone toxicity. Mechanistic studies show that POx nanoparticles did not enter the CNS, but rather acted within the vascular compartment to improve drug delivery by decreasing drug binding to serum proteins and reducing the volume of distribution. POx-vismo demonstrated improved efficacy, extending the survival of medulloblastoma-bearing mice. Our results show the potential for a simple, non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to enhance vismodegib therapy for SHH-driven cancers.
SARS-CoV-2 genomes recovered by long amplicon tiling multiplex approach using nanopore sequencing and applicable to other sequencing platforms
Authors: Resende Paola Cristina , Motta Fernando Couto , Roy Sunando , Appolinario Luciana , Fabri Allison , Xavier Joilson , Harris Kathryn , Matos Aline Rocha , Caetano Braulia , Orgeswalska Maria , Miranda Milene , Garcia Cristiana , Abreu André , Williams Rachel , Breuer Judith , Siqueira Marilda M
Published: May 2020

Genomic surveillance has become a useful tool for better understanding virus pathogenicity, origin and spread. Obtaining accurately assembled, complete viral genomes directly from clinical samples is still a challenging. Here, we describe three protocols using a unique primer set designed to recover long reads of SARS-CoV-2 directly from total RNA extracted from clinical samples. This protocol is useful, accessible and adaptable to laboratories with varying resources and access to distinct sequencing methods: Nanopore, Illumina and/or Sanger.
Identification of disease treatment mechanisms through the multiscale interactome
Authors: Ruiz Camilo , Zitnik Marinka , Leskovec Jure
Published: May 2020

Most diseases disrupt multiple proteins, and drugs treat such diseases by restoring the functions of the disrupted proteins. How drugs restore these functions, however, is often unknown as a drug’s therapeutic effects are not limited only to the proteins that the drug directly targets. Here, we develop the multiscale interactome, a powerful approach to explain disease treatment. We integrate disease-perturbed proteins, drug targets, and biological functions into a multiscale interactome network, which contains 478,728 interactions between 1,661 drugs, 840 diseases, 17,660 human proteins, and 9,798 biological functions. We find that a drug’s effectiveness can often be attributed to targeting proteins that are distinct from disease-associated proteins but that affect the same biological functions. We develop a random walk-based method that captures how drug effects propagate through a hierarchy of biological functions and are coordinated by the protein-protein interaction network in which drugs act. On three key pharmacological tasks, we find that the multiscale interactome predicts what drugs will treat a given disease more effectively than prior approaches, identifies proteins and biological functions related to treatment, and predicts genes that interfere with treatment to alter drug efficacy and cause serious adverse reactions. Our results indicate that physical interactions between proteins alone are unable to explain the therapeutic effects of drugs as many drugs treat diseases by affecting the same biological functions disrupted by the disease rather than directly targeting disease proteins or their regulators. We provide a general framework for identifying proteins and biological functions relevant in treatment, even when drugs seem unrelated to the diseases they are recommended for.
Optimised biomolecular extraction for metagenomic analysis of microbial biofilms from high-mountain streams
Authors: Busi Susheel Bhanu , Pramateftaki Paraskevi , Brandani Jade , Fodelianakis Stylianos , Peter Hannes , Halder Rashi , Wilmes Paul , Battin Tom J.
Published: May 2020

Glacier-fed streams (GFS) are harsh ecosystems dominated by microbial life organized in benthic biofilms, yet the biodiversity and ecosystem functions provided by these communities remain under-appreciated. To better understand the microbial processes and communities contributing to GFS ecology, it is necessary to leverage high throughput sequencing. Low biomass and high inorganic particle load in GFS sediment samples may affect nucleic acid extraction efficiency using extraction methods tailored to other extreme environments such as deep-sea sediments. Here, we benchmarked the utility and efficacy of four extraction protocols, including an up-scaled phenol-chloroform protocol. We found that established protocols for comparable sample types consistently failed to yield sufficient high-quality DNA, delineating the extreme character of GFS. The methods differed in the success of downstream applications such as library preparation and sequencing. An adapted phenol-chloroform-based extraction method resulted in higher yields and better recovered the expected taxonomic profile and abundance of reconstructed genomes when compared to commercially-available methods. Affordable and straight-forward, this method consistently recapitulated the abundance and genomes of a “mock” community, including eukaryotes. Moreover, by increasing the amount of input sediment, the protocol is readily adjustable to the microbial load of the processed samples without compromising protocol efficiency. Our study provides a first systematic and extensive analysis of the different options for extraction of nucleic acids from glacier-fed streams for high-throughput sequencing applications, which may be applied to other extreme environments.
Personality, Subjective Well-Being, and the Serotonin 1a Receptor Gene in Common Marmosets (Callithrix jacchus)
Authors: Weiss Alexander , Yokoyama Chihiro , Hayashi Takuya , Inoue-Murayama Miho
Published: May 2020

Studies of personality traits in common marmosets (Callithrix jacchus) indicate that there are five or six constructs—sociability, dominance, neuroticism, openness, and two related to conscientiousness—that define personality in common marmosets. The present study attempted to determine whether our earlier study of laboratory-housed individuals only yielded three domains—Dominance, Sociability, and Neuroticism—because of a low amount of between-subjects variance. We therefore increased our sample size from 77 to 128. In addition, we ascertained the reliability and validity of ratings and whether polymorphisms related to the serotonin 1a receptor were associated with personality. We found Sociability, Dominance, and Negative Affect factors that resembled three domains found in previous studies, including ours. We also found an Openness and Impulsiveness factor, the latter of which bore some resemblance to Conscientiousness, and two higher-order factors, Pro-sociality and Boldness. Further analyses could not exclude the possibility that Pro-sociality and Boldness represented a higher-level of personality organization. Correlations between personality factors and well-being were consistent with the definitions of the factors. There were no significant associations between personality and genotype. These results are consistent with the possibility that common marmoset personality structure varies as a function of rearing or housing variables that have not yet been investigated systematically.
Upregulation of TRPM3 drives hyperexcitability in nociceptors innervating inflamed tissue
Authors: Mulier Marie , Van Ranst Nele , Corthout Nikky , Munck Sebastian , Berghe Pieter Vanden , Vriens Joris , Voets Thomas , Moilanen Lauri J
Published: May 2020

Genetic ablation or pharmacological inhibition of the heat-activated cation channel TRPM3 alleviates heat hyperhyperalgesia in animal models of inflammation, but the mechanisms whereby the channel contributes to inflammatory pain are unknown. Here, we induced unilateral inflammation of the hind paw in mice, and directly compared expression and function of TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) in sensory neurons innervating the ipsilateral and contralateral paw. We detected increased Trpm3 mRNA levels in dorsal root ganglion neurons innervating the inflamed paw, as well as augmented TRP channel-mediated calcium responses, both in the cell bodies and the intact peripheral endings of nociceptors. Notably, inflammation provoked a pronounced increase in nociceptors co-expressing functional TRPM3 with TRPV1 and TRPA1, and pharmacological inhibition of TRPM3 caused normalization of TRPV1- and TRPA1-mediated responses. These new insights into the mechanisms underlying inflammatory heat hypersensitivity provide a rationale for developing TRPM3 antagonists to treat pathological pain.
Child specific activation in left auditory cortex predicts behavioral performance in inhibition tasks
Authors: van Bijnen Sam , Parkkonen Lauri , Parviainen Tiina
Published: May 2020

Sensory processing during development is important for the emerging cognitive skills underlying goal-directed behavior. Yet, it is not known how auditory processing in children is related to their cognitive functions. Here, we utilized combined magneto- and electroencephalographic (M/EEG) measurements to show that child-unique auditory cortical activity at ∼250 ms after auditory stimulation predicts the performance in inhibition tasks. While unaffected by task demands, the amplitude of the left-hemisphere activation pattern was significantly correlated with the variability of behavioral response time. Since this activation pattern is not present in adults, our results suggest divergent brain mechanisms in adults and children for consistent performance in auditory-based cognitive tasks. This difference can be explained as a shift in cortical resources for cognitive control from sensorimotor associations in the auditory cortex of children to top–down regulated control processes involving (pre)frontal and cingulate areas in adults.
Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus
Authors: Terrier Olivier , Dilly Sébastien , Pizzorno Andrés , Henri Julien , Berenbaum Francis , Lina Bruno , Fève Bruno , Adnet Frédéric , Sabbah Michèle , Rosa-Calatrava Manuel , Maréchal Vincent , Schwok Anny Slama
Published: May 2020

There is an urgent need for specific antiviral drugs directed against SARS-CoV-2 both to prevent the most severe forms of COVID-19 and to reduce viral excretion and subsequent virus dissemination; in the present pandemic context, drug repurposing is a priority. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus in order to inhibit its association with viral RNA could be a strategy to impeding viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, belonging to the NSAID family, previously demonstrated against Influenza A virus, were evaluated against SARS-CoV-2. Naproxen binding to the nucleoprotein of SARS-CoV2 was shown by molecular modeling. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2 induced-damage. The benefit of naproxen addition to the standard of care is tested in an on-going clinical study.
Downregulation of Perilipin1 by IMD leads to LD reconfiguration and adaptation to bacterial infection inDrosophila
Authors: Wang Lei , Lin Jiaxin , Yu Junjing , Yang Kaiyan , Sun Li , Tang Hong , Pan Lei
Published: May 2020

Lipid droplets (LDs) are dynamic intracellular organelles critical for lipid metabolism. Dynamic alterations in the configurations and functions of LDs during innate immune response to bacterial infections and the underlying mechanisms however, remain largely unknown. Herein, we trace the time-course morphology of LDs in fat bodies ofDrosophilaafter transient bacterial infection. Detailed analysis shows thatperilipin1(plin1), a core gene regulating lipid metabolism of LDs is suppressed by IMD/Relish, an innate immune signaling. During immune activation, downregulatedplin1promotes the enlargement of LDs, which in turn alleviates immune reaction-associated reactive oxygen species (ROS) stress. Thus, the growth of LDs is likely an active adaptation to maintain redox homeostasis in response to IMD activation. Therefore, our study provides evidence thatplin1serves as a modulator on LDs’ reconfiguration in regulating infection-induced pathogenesis, and Plin1 might be a potential therapeutic target for coordinating inflammation resolution and lipid metabolism.
Niche and neutral processes leave distinct structural imprints on indirect interactions in mutualistic networks
Authors: Simmons Benno I. , Beckerman Andrew P. , Hansen Katrine , Maruyama Pietro K. , Televantos Constantinos , Vizentin-Bugoni Jeferson , Dalsgaard Bo
Published: May 2020

Indirect interactions are central to ecological and evolutionary dynamics in pollination communities, yet we have little understanding about the processes determining patterns of indirect interactions, such as those between pollinators through shared flowering plants. Instead, research has concentrated on the processes responsible for direct interactions and whole-network structures. This is partly due to a lack of appropriate tools for characterising indirect interaction structures, because traditional network metrics discard much of this information. The recent development of tools for counting motifs (subnetworks depicting interactions between a small number of species) in bipartite networks enable detailed analysis of indirect interaction patterns. Here we generate plant-hummingbird pollination networks based on three major assembly processes – neutral effects (species interacting in proportion to abundance), morphological matching and phenological overlap – and evaluate the motifs associated with each one. We find that different processes produce networks with significantly different patterns of indirect interactions. Neutral effects tend to produce densely-connected motifs, with short indirect interaction chains, and motifs where many specialists interact indirectly through a single generalist. Conversely, niche-based processes (morphology and phenology) produced motifs with a core of interacting generalists, supported by peripheral specialists. These results have important implications for understanding the processes determining indirect interaction structures.
Sex-specific vasopressin signaling buffers stress-dependent synaptic changes in female mice
Authors: Loewen Spencer P. , Baimoukhametova Dinara , Bains Jaideep S.
Published: May 2020

In many species, social networks provide benefit for both the individual and the collective. In addition to transmitting information to others, social networks provide an emotional buffer for distressed individuals. Our understanding about the cellular mechanisms that contribute to buffering is poor. Stress has consequences for the entire organism, including a robust change in synaptic plasticity at glutamate synapses onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN). In females, however, this stress-induced metaplasticity is buffered by the presence of a naïve partner. This buffering may be due to discrete behavioral interactions, signals in the context in which the interaction occurs (i.e. olfactory cues), or it may be influenced by local signaling events in the PVN. Here, we show that local vasopressin (VP) signaling in PVN buffers the short-term potentiation (STP) at glutamate synapses after stress. This social buffering of metaplasticity, which requires the presence of another individual, was prevented by pharmacological inhibition of the VP 1a receptor in female mice. Exogenous VP mimicked the effects of social buffering and reduced STP in CRHPVNneurons from females but not males. These findings implicate VP as a potential mediator of social buffering in female mice.

Significance Statement

In many organisms, including rodents and humans, social groups are beneficial to overall health and well-being. Moreover, it is through these social interactions that the harmful effects of stress can be mitigated—a phenomenon known as social buffering. In the present study, we describe a critical role for the neuropeptide vasopressin in social buffering of synaptic metaplasticity in stress-responsive corticotropin-releasing hormone neurons in female mice. These effects of vasopressin do not extend to social buffering of stress behaviors, suggesting this is a very precise and local form of sex-specific neuropeptide signaling.
The Rotating Snake Illusion is a straightforward consequence of non-linearity in arrays of standard motion detectors
Authors: Bach Michael , Atala-Gérard Lea
Published: May 2020

The Rotating Snakes illusion is a motion illusion based on repeating, asymmetric luminance patterns. Recently, we found certain grey-value conditions where a weak, illusory motion occurs in the opposite direction. Of the four models for explaining the illusion, one (Backus and Oruç, 2005) also explains the unexpected perceived opposite direction. We here present a simple new model, without free parameters, based on an array of standard correlation-type motion detectors with a subsequent non-linearity (e.g., saturation) before summing the detector outputs. The model predicts (1) the pattern-appearance motion illusion for steady fixation, (2) an illusion under the real-world situation of saccades across or near the pattern (pattern shift), (3) a relative maximum of illusory motion for the same grey values where it is found psychophysically, and (4) the inverse illusion for certain luminance values. We submit that the model’s sparseness of assumptions justifies adding a fifth model to explain this illusion.
Is a Simple Sensorimotor Reaction Really Simple?
Authors: Kulakov Alexey A.
Published: May 2020

The simple sensorimotor reaction (SSR) is widely used in psychophysiological research. It was previously shown, that the SSR latency is not constant. We studied changes in the SSR latency as a function of the waiting time from the moment of the previous response to the moment of the start of the stimulation. We performed the stimulation using light, sound and air impulse. As a response, we used a “labial sound”, a finger touch and blinking of the eyes. In all cases, where the objects of the study were humans, the SSR latency had constant and variable components. The constant SSR component was the shortest in response to closing the eyes to sound (120 ms). For “lip reaction” and finger response to sound it was 174–178 ms and 178–182 ms, respectively, but for “lip reaction” and finger response to light it was 220–226 ms. The variable SSR component represented exponential latency decay with an increase in the waiting time interval. In this case, the decay consisted of at least two components, with an apparent relaxation time in the range 30–150 ms and 600–1300 ms. Alternating stimulation of paired organs of the reception or alternating fingers reduced the apparent relaxation time of the SSR latency decay. Moreover, the latency of the human corneal reflex during eye stimulation with an air pulse also had the latency decay with three components of apparent relaxation time 9.5, 68.2 and 1,086 ms and the constant latency of 34.2 ms.

The latency of the corneal reflex in a young cat was constant and had a value of 14.6 ms. Thus, it has been shown, that the SSR latency has a complex structure and, like any conditioned reflex, is strongly influenced by the cortex. We believe that a choice is made in the centers for analysis of receiving signals from reception organs and centers sending signals to reacting organs, i.e. essentially, the SSR is also a choice reaction.
Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis
Authors: Adiutori Rocco , Puentes Fabiola , Bremang Michael , Lombardi Vittoria , Zubiri Irene , Leoni Emanuela , Aarum Johan , Sheer Denise , McArthur Simon , Pike Ian , Malaspina Andrea
Published: May 2020

Blood-based biomarkers can be informative of brain disorders where protein aggregation play a major role. The proteome of plasma and circulating protein aggregates (CPA) reflect the inflammatory and metabolic state of the organism and can be predictive of system-level and/or organ-specific pathologies. CPA are enriched with heavy chain neurofilaments (NfH), key axonal constituents involved in brain aggregates formation and biomarkers of the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Here we show that CPA and brain protein aggregates (BPA) from ALS differ in protein composition and appear as a combination of electron-dense large globular and small filamentous formations on transmission electron microscopy. CPA are highly enriched with proteins involved in the proteasome and energy metabolism. Compared to the human proteome, proteins within aggregates show distinct and tissue-dependent chemical features of aggregation propensity. The use of a TMTcalibrator™ proteomics workflow with ALS brain as calibrant reveals 4973 brain-derived low-abundance proteins in CPA, including the products of translation of 24 ALS risk genes. 285 of these (5.7%) are regulated in ALS CPA including FUS (p<0.05). CPA from both ALS and healthy controls affect cell viability when testing endothelial and PC12 neuronal cell lines, while CPA from ALS exert a more toxic effect at lower concentrations. The analysis of resistance to protease enzymes hydrolysis indicates an ALS-specific digestion pattern for NfH using enterokinase. This study reveals how peripheral protein aggregates are significantly enriched with brain proteins which are highly representative of ALS pathology and a potential alternative source of biomarkers and therapeutic targets for this incurable disorder.

Significance Statement

Molecular mechanism of neurodegeneration like protein aggregation are important brain-specific alterations which need to be addressed therapeutically. Recently described fluid biomarkers of neurodegenerative disorders provide means for stratification and monitoring of disease progression. Here we show that circulating protein aggregates are easily accessible in blood and reproduce important features of brain pathology for an incurable disorder like amyotrophic lateral sclerosis. They represent a source of biomarkers and of novel therapeutics for ALS.
Experience-dependent inhibitory plasticity is mediated by CCK+ basket cells in the developing dentate gyrus
Authors: Feng Ting , Alicea Christian , Pham Vincent , Kirk Amanda , Pieraut Simon
Published: May 2020

Early postnatal experience shapes both inhibitory and excitatory networks in the hippocampus. However, the underlying circuit plasticity is unclear. Using an enriched environment (EE) paradigm, we assessed the circuit plasticity of inhibitory cell-types in the hippocampus. We found that cholecystokinin (CCK)-expressing basket cells strongly increased somatic inhibition on the excitatory granular cells (GC) following EE while another pivotal inhibitory cell-type, parvalbumin (PV)-expressing cells did not show changes. By inhibiting activity of the entorhinal cortex (EC) using a chemogenetic approach, we demonstrate that the projections from the EC is responsible for the developmental plasticity of CCK+ basket cells. Our measurement of the input decorrelation by DG circuit suggests that EE has little effect on pattern separation despite of the altered CCK+ basket cell circuit. Altogether, our study places the activity-dependent remodeling of CCK+ basket cell innervation as a central process to adjust inhibition in the DG, while maintaining the computation in the circuit.
An effective cold storage method for stockpilingHalyomorpha halyseggs for field surveys and laboratory rearing ofTrissolcus japonicus
Authors: Wong Warren H. L. , Walz Matt A. , Oscienny Angela B. , Sherwood Jade L. , Abram Paul K.
Published: May 2020

An effective stockpiling method for egg masses of the invasive brown marmorated stink bug (Halyomorpha halys[Stål]; Hemiptera: Pentatomidae) would be useful for rearing and field studies of its egg parasitoidTrissolcus japonicus(Ashmead) (Hymenoptera: Scelionidae). The current method of stockpilingH. halysegg masses at sub-zero temperatures has lethal and sublethal fitness consequences forT. japonicus. We show that parasitoid emergence from egg masses refrigerated at 8°C for up to two months before parasitism is higher than from frozen egg masses and usually has minimal or no sublethal fitness effects (sex ratio, development time, activity, fecundity, longevity, and weight) on emergingT. japonicus. Only after two months of host egg refrigeration did the emergence ofT. japonicusbegin to decrease significantly (by 9.6% relative to untreated viable egg masses), whereas egg masses previously frozen at -80°C had a 58.8% reduction in parasitoid emergence after 14 days of storage. Refrigerated egg masses that were subsequently exposed to average field temperatures (warm: 22.9°C; cool: 13.2°C) were still suitable forT. japonicusparasitism after 7 days, while viable egg masses exposed to warm temperatures for 7 days before parasitism had 24.1% lower parasitoid emergence. Our results demonstrate that refrigeration at 8°C, while resulting in complete mortality ofH. halysembryos after 10 days, are more suitable forT. japonicusparasitism than those stored at sub-zero temperatures. The quantity and quality ofH. halyseggs that can be stockpiled with this method could facilitateT. japonicuslaboratory colony maintenance, field monitoring, and releases.
A Framework for Automated Construction of Heterogeneous Large-Scale Biomedical Knowledge Graphs
Authors: Callahan Tiffany J. , Tripodi Ignacio J. , Hunter Lawrence E. , Baumgartner William A.
Published: May 2020

Motivation

Although knowledge graphs (KGs) are used extensively in biomedical research to model complex phenomena, many KG construction methods remain largely unable to account for the use of different standardized terminologies or vocabularies, are often difficult to use, and perform poorly as the size of the KG increases in scale. We introduce PheKnowLator (Phenotype Knowledge Translator), a novel KG framework and fully automated Python 3 library explicitly designed for optimized construction of semantically-rich, large-scale biomedical KGs. To demonstrate the functionality of the framework, we built and evaluated eight different parameterizations of a large semantic KG of human disease mechanisms. PheKnowLator is available at:https://github.com/callahantiff/PheKnowLator.
Genome mapping resolves structural variation within segmental duplications associated with microdeletion/microduplication syndromes
Authors: Mostovoy Yulia , Yilmaz Feyza , Chow Stephen K. , Chu Catherine , Lin Chin , Geiger Elizabeth A. , Meeks Naomi J. L. , Chatfield Kathryn. C. , Coughlin Curtis R. , Kwok Pui-Yan , Shaikh Tamim H.
Published: May 2020

Segmental duplications (SDs) are a class of long, repetitive DNA elements whose paralogs share a high level of sequence similarity with each other. SDs mediate chromosomal rearrangements that lead to structural variation in the general population as well as genomic disorders associated with multiple congenital anomalies, including the 7q11.23 (Williams-Beuren Syndrome, WBS), 15q13.3, and 16p12.2 microdeletion syndromes. These three genomic regions, and the SDs within them, have been previously analyzed in a small number of individuals. However, population-level studies have been lacking because most techniques used for analyzing these complex regions are both labor- and cost-intensive. In this study, we present a high-throughput technique to genotype complex structural variation using a single molecule, long-range optical mapping approach. We identified novel structural variants (SVs) at 7q11.23, 15q13.3 and 16p12.2 using optical mapping data from 154 phenotypically normal individuals from 26 populations comprising 5 super-populations. We detected several novel SVs for each locus, some of which had significantly different prevalence between populations. Additionally, we refined the microdeletion breakpoints located within complex SDs in two patients with WBS, one patient with 15q13.3, and one patient with 16p12.2 microdeletion syndromes. The population-level data presented here highlights the extreme diversity of large and complex SVs within SD-containing regions. The approach we outline will greatly facilitate the investigation of the role of inter-SD structural variation as a driver of chromosomal rearrangements and genomic disorders.
Representative diatom and coccolithophore species exhibit divergent responses throughout simulated upwelling cycles
Authors: Lampe Robert H. , Hernandez Gustavo , Lin Yuan Yu , Marchetti Adrian
Published: May 2020

Wind-driven upwelling followed by relaxation results in cycles of cold nutrient-rich water fueling intense phytoplankton blooms followed by nutrient-depletion, bloom decline, and sinking of cells. Surviving cells at depth can then be vertically transported back to the surface with upwelled waters to seed another bloom. As a result of these cycles, phytoplankton communities in upwelling regions are transported through a wide range of light and nutrient conditions. Diatoms appear to be well-suited for these cycles, but their responses to them remain understudied. To investigate the bases for diatoms’ ecological success in upwelling environments, we employed laboratory simulations of a complete upwelling cycle with a common diatom,Chaetoceros decipiens, and coccolithophore,Emiliania huxleyi. We show that while both organisms exhibited physiological and transcriptomic plasticity, the diatom displayed a distinct response enabling it to rapidly shift-up growth rates and nitrate assimilation when returned to light and available nutrients following dark, nutrient-deplete conditions. As observed in natural diatom communities,C. decipienshighly expresses before upwelling, or frontloads, key transcriptional and nitrate assimilation genes coordinating its rapid response to upwelling conditions. Low iron simulations showed thatC. decipiensis capable of maintaining this response when iron is limiting to growth, whereasE. huxleyiis not. Differential expression between iron treatments further revealed specific genes used by each organism under low iron availability. Overall, these results highlight the responses of two dominant phytoplankton groups to upwelling cycles, providing insight into the mechanisms fueling diatom blooms during upwelling events.
Metals alter membership but not diversity of a headwater stream microbiome
Authors: Wolff Brian A. , Clements William H. , Hall Ed K.
Published: May 2020

Metal contamination from mining or natural weathering is a common feature of surface waters in the American west. Traditionally, stream macroinvertebrate community metrics have been used for stream quality assessments. Advances in microbial analyses have created the potential for routine sampling of aquatic microbiomes as a tool to assess the quality of stream habitat. We sought to determine if microbiome diversity and membership were affected by metal contamination in a manner similar to what has been observed for stream macroinvertebrates, and if so, identify candidate microbial taxa to be used to indicate metal stress in stream ecosystems. We evaluated microbiome membership from sediments at multiple sites within the principal drainage of an EPA superfund site near the headwaters of the Upper Arkansas River, Leadville, CO. From each sample, we extracted DNA and sequenced the 16S rRNA gene amplicon on the Illumina MiSeq platform. We used the remaining sediments to simultaneously evaluate environmental metal concentrations. We also conducted an artificial stream mesocosm experiment using sediments collected from two of the observational study sites. The mesocosm experiment had a 2×2 factorial design: 1) location (upstream or downstream of contaminating tributary), and 2) treatment (metal exposure or control). We found no difference in diversity between upstream and downstream sites in the field. Similarly, diversity changed very little following experimental metal exposure. However, microbiome membership differed between upstream and downstream locations and experimental metal exposure changed microbiome membership in a manner that depended on origin of the sediments used in each mesocosm.

Importance

Our results suggest that microbiomes can be reliable indicators of ecosystem metal stress even when surface water chemistry and other metrics used to assess ecosystem health do not indicate ecosystem stress. Several results presented in this study are consistent with the idea that a microbial response to metals at the base of the food web may be affecting consumers one trophic level above. If effects of metals are mediated through shifts in the microbiome, then microbial metrics, as presented here, may aid in the assessment of stream ecosystems health.
Alteration of epigenetic landscape by lamin A mutations: Hallmark of Dilated Cardiomyopathy
Authors: Banerjee Avinanda , Sengupta Kaushik
Published: May 2020

Mutations in lamin A have been reported to be associated with over 16 human diseases including dilated cardiomyopathy (DCM). We have focused on three such DCM causing mutants of lamin A which have to address the contribution of lamins in the pathogenesis of DCM at molecular level. We have elucidated the effect of these mutants for the first time on the epigenetic landscape of a myogenic fibroblast cell line C2C12. C2C12 cells expressing these mutant proteins exhibited alterations in some histone modification marks like H3K4me3, H3K9me3, H3K27me3, H3K36me3 and RNA Polymerase II activity compared to its wild type variants. This report paves the way for further studies involving epigenetic regulation in laminopathies which would be an important step in explaining the molecular mechanism and pathophysiology of the diseases like dilated cardiomyopathy.

High Lights

lamin A K97E mutation predominantly alters H3K9me3 histone modifications landscape

lamin A K97E aggregates within nucleus also sequester the HP1γ

lamin A K97E mutation affects RNA polymerase II distribution pattern
All-Atom Simulation of the HET-s Prion Replication
Authors: Terruzzi Luca , Spagnolli Giovanni , Boldrini Alberto , Requena Jesús R. , Biasini Emiliano , Faccioli Pietro
Published: May 2020

Prions are self-replicative protein particles lacking nucleic acids. Originally discovered for causing infectious neurodegenerative disorders, they have also been found to play several physiological roles in a variety of species. Functional and pathogenic prions share a common mechanism of replication, characterized by the ability of an amyloid conformer to propagate by inducing the conversion of its physiological, soluble counterpart. In this work, we focus on the propagation of the prion forming domain of HET-s, a physiological fungal prion for which high-resolution structural data are available. Since time-resolved biophysical experiments cannot yield a full reconstruction of prion replication, we resort to computational methods. To overcome the computational limitations of plain Molecular Dynamics (MD) simulations, we adopt a special type of biased dynamics called ratchet-and-pawl MD (rMD). The accuracy of this enhanced path sampling protocol strongly depends on the choice of the collective variable (CV) used to define the biasing force. Since for prion propagation a reliable reaction coordinate (RC) is not yet available, we resort to the recently developed Self-Consistent Path Sampling (SCPS). Indeed, in such an approach the CV where the biasing force is applied is not heuristically postulated but is calculated through an iterative refinement procedure. Our atomistic reconstruction of the HET-s replication shows remarkable similarities with a previously reported mechanism of mammalian PrPSc propagation obtained with a different computational protocol. Together, these results indicate that the propagation of prions generated by evolutionary distant proteins shares common features. In particular, in both these cases, prions propagate their conformation through a very similar templating mechanism.
Rampant C->U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses – causes and consequences for their short and long evolutionary trajectories
Authors: Simmonds P.
Published: May 2020

The pandemic of SARS coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a dataset of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean 5.5-9.5 nucleotide differences from each other, commensurate with a mid-range coronavirus substitution rate of 3×10−4substitutions/site/year. Almost half of sequence changes were C->U transitions with an 8-fold base frequency normalised directional asymmetry between C->U and U->C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV and MERS-CoV) and to a decreasing degree in other human coronaviruses (HCoV-NL63, -OC43, -229E and -HKU1) proportionate to their increasing divergence. C->U transitions underpinned almost half of the amino acid differences between SARS-CoV-2 variants, and occurred preferentially in both 5’U/A and 3’U/A flanking sequence contexts comparable to favoured motifs of human APOBEC3 proteins. Marked base asymmetries observed in non-pandemic human coronaviruses (U>>A>G>>C) and low G+C contents may represent long term effects of prolonged C->U hypermutation in their hosts.

Importance

The evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short and long term evolution. Repeated cycles of mutation and reversion in favoured mutational hotspots and the widespread occurrence of amino acid changes with no adaptive value for the virus represents a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks that are typically used in molecular epidemiology investigations.
Non-muscle myosin-2 contractility-dependent actin turnover limits the length of epithelial microvilli
Authors: Chinowsky Colbie R. , Pinette Julia A. , Meenderink Leslie M. , Tyska Matthew J.
Published: May 2020

Epithelial brush borders are large arrays of microvilli that enable efficient solute uptake from luminal spaces. In the context of the intestinal tract, brush border microvilli drive functions that are critical for physiological homeostasis, including nutrient uptake and host defense. However, cytoskeletal mechanisms that regulate the assembly and morphology of these protrusions are poorly understood. The parallel actin bundles that support microvilli have their pointed-end rootlets anchored in a highly crosslinked filamentous meshwork referred to as the “terminal web”. Although classic EM studies revealed complex ultrastructure, the composition, organization, and function of the terminal web remains unclear. Here, we identify non-muscle myosin-2C (NM2C) as a major component of the brush border terminal web. NM2C is found in a dense, isotropic layer of puncta across the sub-apical domain, which transects the rootlets of microvillar actin bundles. Puncta in this network are separated by ∼210 nm, dimensions that are comparable to the expected size of filaments formed by NM2C. In primary intestinal organoid cultures, the terminal web NM2C network is highly dynamic and exhibits continuous remodeling. Using pharmacological and genetic perturbations to disrupt NM2C activity in cultured intestinal epithelial cells, we found that this motor controls the length of growing microvilli by regulating actin turnover in a manner that requires a fully active motor domain. Our findings answer a decades old question on the function of terminal web myosin and hold broad implications for understanding apical morphogenesis in diverse epithelial systems.