bluuebunny/crossref_metadata_2025 huggingface dataset:
Shared loci of telomere length with brain morphology, and pleiotropy in transcriptomic and epigenomic profiles of brain
Authors: Pathak Gita A , Wendt Frank R , Levey Daniel F , Mecca Adam P , van Dyck Christopher H , Gelernter Joel , Polimanti Renato
Published: August 2020

Premature shortening of telomere length is observed in neuropsychiatric disorders. We tested genetic colocalization of seven and nine leukocyte telomere length (LTL) loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively (total n=60,601) with brain morphology measures for 101 region-of-interests (ROI) (n=21,821). The posterior probability (>90%) was observed for ‘fourth ventricle’, ‘gray matter’ and ‘cerebellar vermal lobules I-IV’ volumes. We found regulatory genes (p ≤2.47 x10−6) by integrating transcriptomic (EAS=4;EUR=5) and methylation data (EUR=17; EAS=4) of brain tissues using Summary-based Mendelian Randomization (SMR). The LTL SNP associations were tested for brain-based chromatin profiles using H-MAGMA (EUR=50; EAS=97; p ≤ 1.02 x10−6). Pathway enrichment of tissue-specific genes highlighted calcium ion transport (fetal brain) and G2/M cell cycle transition (adult brain). This study provides evidence that previously reported LTL associations with neuropsychiatric disorders could be related to a shared genetic relationship between LTL and brain structural and regulatory traits.
Self-powered piezo-bioelectronic device mediates tendon repair through modulation of mechanosensitive ion channels
Authors: Fernandez-Yague Marc A. , Trotier Alex , Abbah Sunny Akogwu , Larrañaga Aitor , Thirumaran Arun , Stapleton Aimee , Tofail Syed A. M. , Palma Matteo , Pandit Abhay , Biggs Manus J
Published: August 2020

Tendon disease constitutes an unmet clinical need and remains a critical challenge in the field of orthopaedic surgery. Innovative solutions are required to overcome the limitations of current tendon grafting approaches, and bioelectronic therapies are showing promise in the treatment of musculoskeletal disease, accelerating functional recovery through the activation of tissue regeneration signalling pathways (guided regeneration). Self-powered bioelectronic devices, and in particular piezoelectric materials represent a paradigm shift in biomedicine, negating the need for battery or external powering and complementing existing mechanotherapy to accelerate the repair processes. Here, we show the dynamic response of tendon cells to a piezoelectric collagen-analogue scaffold comprised of aligned nanoscale fibres made of the ferroelectric material poly(vinylidenefluoride-co-trifluoroethylene), (PVDF-TrFE). We demonstrate that electromechanical stimulation of tendon tissue results in guided regeneration by ion channel modulation. Finally, we show the potential of the bioelectronic device in regulating the progression of tendinopathy associated processes using a rat Achilles tendinopathy model. This study indicates that body motion-powered electromechanical stimulation can control the expression of TRPA1 and PIEZO2 receptors and stimulate tendon-specific tissue repair processes.
Distracting stimuli evoke ventral tegmental area responses in rats during ongoing saccharin consumption
Authors: Peters Kate Z , Young Andrew M J , McCutcheon James E
Published: August 2020

Disruptions in attention, salience and increased distractibility are implicated in multiple psychiatric conditions. The ventral tegmental area (VTA) is a potential site for converging information about external stimuli and internal states to be integrated and guide adaptive behaviours. Given the dual role of dopamine signals in both driving ongoing behaviours (e.g. feeding) and monitoring salient environmental stimuli, understanding the interaction between these functions is crucial. Here we investigate VTA neuronal activity during distraction from ongoing feeding. We developed a task to assess distraction exploiting self-paced licking in rats. Rats trained to lick for saccharin were given a distraction test, in which three consecutive licks within 1 second triggered a random distractor (e.g. light and tone stimulus). On each trial they were quantified as distracted or not based on the length of their pauses in licking behaviour. We expressed GCaMP6s in VTA neurons and used fibre photometry to record calcium fluctuations during this task as a proxy for neuronal activity. Distractor stimuli caused rats to interrupt their consumption of saccharin, a behavioural effect which quickly habituated with repeat testing. VTA neural activity showed consistent increases to distractor presentations and, furthermore, these responses were greater on distracted trials compared to non-distracted trials. Interestingly, neural responses show a slower habituation than behaviour with consistent VTA responses seen to distractors even after they are no longer distracting. These data highlight the complex role of the VTA in maintaining ongoing appetitive and consummatory behaviours while also monitoring the environment for salient stimuli.
A miR-137-related biological pathway of risk for Schizophrenia is associated with human brain emotion processing
Authors: Pergola G. , Rampino A. , Di Carlo P. , Marakhovskaia A. , Quarto T. , Fazio L. , Papalino M. , Torretta S. , Amoroso N. , Castro M. N. , Domenici E. , Dukart J. , Khlghatyan J. , Monaco A. , Popolizio T. , Romano R. , Sportelli L. , Zunuer H. , Blasi G. , Beaulieu J.M. , Bertolino A.
Published: August 2020

Genome-Wide-Association studies have involved miR-137 in schizophrenia. However, the biology underlying this statistical evidence is unclear. Statistical polygenic risk for schizophrenia is associated with working memory, while other biological evidence involves miR-137 in emotion processing. We investigated the function of miR-137 target schizophrenia risk genes in humans.

We identified a prefrontal co-expression pathway of schizophrenia-associated miR-137 targets and validated the association with miR-137 expression in neuroblastoma cells. Alleles predicting greater co-expression of this pathway were associated with greater prefrontal activation during emotion processing in two independent cohorts of healthy volunteers (N1=222; N2=136). Statistical polygenic risk for schizophrenia was instead associated with prefrontal activation during working memory.

A co-expression pathway links miR-137 and its target genes to emotion processing and risk for schizophrenia. Low prefrontal miR-137 expression may be related with SCZ risk via increased expression of target risk genes, itself associated with increased prefrontal activation during emotion processing.
Theta-burst TMS of lateral occipital cortex reduces BOLD responses across category-selective areas in ventral temporal cortex
Authors: Groen Iris I A , Silson Edward H , Pitcher David , Baker Chris I
Published: August 2020

Human visual cortex contains three scene-selective regions in the lateral, medial and ventral cortex, termed the occipital place area (OPA), medial place area (MPA) and parahippocampal place area (PPA). Using functional magnetic resonance imaging (fMRI), all three regions respond more strongly when viewing visual scenes compared with isolated objects or faces. To determine how these regions are functionally and causally connected, we applied transcranial magnetic stimulation to OPA and measured fMRI responses before and after stimulation, using a theta-burst paradigm (TBS). To test for stimulus category-selectivity, we presented a range of visual categories (scenes, buildings, objects, faces). To test for specificity of any effects to TBS of OPA we employed two control conditions: Sham, with no TBS stimulation, and an active TBS-control with TBS to a proximal face-selective cortical region (occipital face area, or OFA). We predicted that TBS to OPA (but not OFA) would lead to decreased responses to scenes and buildings (but not other categories) in other scene-selective cortical regions. Across both ROI and whole-volume analyses, we observed decreased responses to scenes in PPA as a result of TBS. However, these effects were neither category specific, with decreased responses to all stimulus categories, nor limited to scene-selective regions, with decreases also observed in face-selective fusiform face area (FFA). Furthermore, similar effects were observed with TBS to OFA, thus effects were not specific to the stimulation site in the lateral occipital cortex. Whilst these data are suggestive of a causal, but non-specific relationship between lateral occipital and ventral temporal cortex, we discuss several factors that could have underpinned this result, such as the differences between TBS and online TMS, the role of anatomical distance between stimulated regions and how TMS effects are operationalised. Furthermore, our findings highlight the importance of active control conditions in brain stimulation experiments to accurately assess functional and causal connectivity between specific brain regions.
Maternal iron deficiency perturbs embryonic cardiovascular development
Authors: Kalisch-Smith Jacinta I. , Ved Nikita , Szumska Dorota , Munro Jacob , Troup Michael , Harris Shelley E. , Jacquemot Aimée , Miller Jack J. , Stuart Eleanor M. , Wolna Magda , Hardman Emily , Prin Fabrice , Lana-Elola Eva , Aoidi Rifdat , Fisher Elizabeth M. C. , Tybulewicz Victor L. J. , Mohun Timothy J. , Lakhal-Littleton Samira , Giannoulatou Eleni , Sparrow Duncan B.
Published: August 2020

Congenital heart disease (CHD) is the most common type of birth defect, with a global prevalence of 0.9% of live births1. Most research in the last 30 years has focused on finding genetic causes of CHD. However, despite the association of over 100 genes with CHD, mutations in these genes only explain ~30% of cases2. Many of the remaining cases of CHD are caused by in utero exposure to environmental factors3. Here we have identified a completely new environmental teratogen causing CHD: maternal iron deficiency. In humans, iron deficiency anaemia is a major global health problem. 38% of pregnant women worldwide are anaemic4, and at least half of these are due to iron deficiency, the most prevalent micronutrient deficiency. We describe a mouse model of maternal iron deficiency anaemia that causes severe cardiovascular defects in her offspring. We show that these defects likely arise from increased retinoic acid signalling in iron deficient embryos, probably due to reduced activity of the iron-dependent retinoic acid catabolic CYP26 enzymes. The defects can be prevented by maternal iron administration early in pregnancy, and are also greatly reduced in offspring of mothers deficient in both iron and the retinoic acid precursor vitamin A. Finally, one puzzling feature of many genetic forms of CHD in humans is the considerable variation in penetrance and severity of defects. We show that maternal iron deficiency acts as a significant modifier of heart and craniofacial phenotype in a mouse model of Down syndrome. Given the high incidence of maternal iron deficiency, peri-conceptional iron monitoring and supplementation could be a viable strategy to reduce the prevalence and severity of CHD in human populations worldwide.
Phylogenomic Insights into the Origin of Primary Plastids
Authors: Irisarri Iker , Strassert Jürgen F. H. , Burki Fabien
Published: August 2020

The origin of plastids was a major evolutionary event that paved the way for an astonishing diversification of photosynthetic eukaryotes. Plastids originated by endosymbiosis between a heterotrophic eukaryotic host and a cyanobacterium, presumably in a common ancestor of all primary photosynthetic eukaryotes (Archaeplastida). A single origin of primary plastids is well supported by plastid evidence but not by nuclear phylogenomic analyses, which have consistently failed to recover the monophyly of Archaeplastida hosts. Importantly, the monophyly of both plastid and host (nuclear) genomes is required to support a single ancestral endosymbiosis, whereas non-monophyletic hosts could be explained under scenarios of independent or serial eukaryote-to-eukaryote endosymbioses. Here, we assessed the strength of the signal for the Archaeplastida host monophyly in four available phylogenomic datasets. The effect of phylogenetic methodology, data quality, alignment trimming strategy, gene and taxon sampling, and the presence of outlier genes loci were investigated. Our analyses revealed a general lack of support for host monophyly in the shorter individual datasets. However, when analyzed together under rigorous data curation and complex mixture evolutionary models, the combined dataset consistently recovered the monophyly of Archaeplastida hosts. This study represents an important step towards better understanding the eukaryotic evolution and the origin of plastids.
De novodesign of ACE2 protein decoys to neutralize SARS-CoV-2
Authors: Linsky Thomas W. , Vergara Renan , Codina Nuria , Nelson Jorgen W. , Walker Matthew J. , Su Wen , Hsiang Tien-Ying , Esser-Nobis Katharina , Yu Kevin , Hou Yixuan J. , Priya Tanu , Mitsumoto Masaya , Pong Avery , Lau Uland Y. , Mason Marsha L. , Chen Jerry , Chen Alex , Berrocal Tania , Peng Hong , Clairmont Nicole S. , Castellanos Javier , Lin Yu-Ru , Josephson-Day Anna , Baric Ralph , Walkey Carl D. , Swanson Ryan , Gale Michael , Blancas-Mejia Luis M. , Yen Hui-Ling , Silva Daniel-Adriano
Published: August 2020

There is an urgent need for the ability to rapidly develop effective countermeasures for emerging biological threats, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the ongoing coronavirus disease 2019 (COVID-19) pandemic. We have developed a generalized computational design strategy to rapidly engineerde novoproteins that precisely recapitulate the protein surface targeted by biological agents, like viruses, to gain entry into cells. The designed proteins act as decoys that block cellular entry and aim to be resilient to viral mutational escape. Using our novel platform, in less than ten weeks, we engineered, validated, and optimizedde novoprotein decoys of human angiotensin-converting enzyme 2 (hACE2), the membrane-associated protein that SARS-CoV-2 exploits to infect cells. Our optimized designs are hyperstable de novo proteins (∼18-37 kDa), have high affinity for the SARS-CoV-2 receptor binding domain (RBD) and can potently inhibit the virus infection and replication in vitro. Future refinements to our strategy can enable the rapid development of other therapeuticde novoprotein decoys, not limited to neutralizing viruses, but to combat any agent that explicitly interacts with cell surface proteins to cause disease.
Functional Predictors of CausativeCis-Regulatory Mutations in Mendelian Disease
Authors: Bengani Hemant , Grozeva Detelina , Moyon Lambert , Bhatia Shipra , Louros Susana R , Hope Jilly , Jackson Adam , Prendergast James G , Owen Liusaidh J. , Naville Magali , Rainger Jacqueline , Grimes Graeme , Halachev Mihail , Murphy Laura C , Spasic-Boskovic Olivera , van Heyningen Veronica , Kind Peter , Abbott Catherine M , Osterweil Emily , Raymond F Lucy , Crollius Hugues Roest , FitzPatrick David R
Published: August 2020

Undiagnosed neurodevelopmental disease is significantly associated with rare variants incis-regulatory elements (CRE) but demonstrating causality is challenging as target gene consequences may differ from a causative variant affecting the coding region. Here, we address this challenge by applying a procedure to discriminate likely diagnostic regulatory variants from those of neutral/low-penetrant effect. We identified six rare CRE variants using targeted and whole genome sequencing in 48 unrelated males with apparent X-linked intellectual disability (XLID) but without detectable coding region variants. These variants segregated appropriately in families and altered conserved bases in predicted CRE targeting known XLID genes. Three were unique and three were rare but too common to be plausibly causative for XLID. We compared thecis-regulatory activity of wild-type and mutant alleles in zebrafish embryos using dual-color fluorescent reporters. Two variants showed striking changes: one plausibly causative (FMR1CRE) and the other likely neutral/low-penetrant (TENM1CRE). These variants were “knocked-in” to mice and both altered embryonic neural expression of their target gene. OnlyFmr1CREmice showed disease-relevant behavioral defects.FMR1CREis plausibly disease-associated resulting in complex misregulation ofFmr1/FMRP rather than loss-of-function. This is consistent both with absence of Fragile X syndrome in the probands and the observed electrophysiological anomalies in theFMR1CREmouse brain. Although disruption ofin vivopatterns of endogenous gene expression in disease-relevant tissues by CRE variants cannot be used as strong evidence for Mendelian disease association, in conjunction with extreme rarity in human populations and with relevant knock-in mouse phenotypes, such variants can become likely pathogenic.
Internetwork connectivity of molecular networks across species of life
Authors: Mahajan Tarun , Dar Roy D
Published: August 2020

Background

Molecular interactions have been studied as independent complex networks in systems biology. However, molecular networks dont exist independently of each other. In a network of networks approach (called multiplex), we uncover the design principles for the joint organization of transcriptional regulatory network (TRN) and protein-protein interaction (PPI) network.

Results

We find that TRN and PPI networks are non-randomly coupled in the TRN-PPI multiplex across five different eukaryotic species. Gene degrees in TRN (number of downstream genes) are positively correlated with protein degrees in PPI (number of interacting protein partners). Gene-gene interactions in TRN and protein-protein interactions in PPI also non-randomly overlap in the multiplex. These design principles are conserved across the five eukaryotic species. We show that the robustness of the TRN-PPI multiplex is dependent on these design principles. Further, functionally important genes and proteins, such as essential, disease-related and those involved in host-pathogen PPI networks, are preferentially situated in essential parts of the human multiplex with highly overlapping interactions.

Conclusion

We unveil the multiplex architecture of TRN and PPI networks across different species. Multiplex architecture may thus define a general framework for studying molecular networks across the different species of life. This approach may uncover the building blocks of the hierarchical organization of molecular interactions.
PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Reveals Important Insights into the Outbreak
Authors: Maitra Arindam , Raghav Sunil , Dalal Ashwin , Ali Farhan , Paynter Vanessa Molin , Paul Dhiraj , Biswas Nidhan K , Ghosh Arup , Jani Kunal , Chinnaswamy Sreedhar , Pati Sanghamitra , Sahu Arvind , Mitra Debashis , Bhat Manoj Kumar , Mayor Satyajit , Sarin Apurva ,   The PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Consortium, Sauche Yogesh S. , Seshasayee Aswin Sai Narain , Palakodeti Dasaradhi , Bashyam Murali D. , Parida Ajay , Das Saumitra
Published: August 2020

The PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Consortium has achieved its initial goal of completing the sequencing of 1000 SARS-CoV-2 genomes from nasopharyngeal and oropharyngeal swabs collected from individuals testing positive for COVID-19 by Real Time PCR. The samples were collected across 10 states covering different zones within India. Given the importance of this information for public health response initiatives investigating transmission of COVID-19, the sequence data is being released in GISAID database. This information will improve our understanding on how the virus is spreading, ultimately helping to interrupt the transmission chains, prevent new cases of infection, and provide impetus to research on intervention measures. This will also provide us with information on evolution of the virus, genetic predisposition (if any) and adaptation to human hosts.

One thousand and fifty two sequences were used for phylodynamic, temporal and geographic mutation patterns and haplotype network analyses. Initial results indicate that multiple lineages of SARS-CoV-2 are circulating in India, probably introduced by travel from Europe, USA and East Asia. A2a (20A/B/C) was found to be predominant, along with few parental haplotypes 19A/B. In particular, there is a predominance of the D614G mutation, which is found to be emerging in almost all regions of the country. Additionally, mutations in important regions of the viral genome with significant geographical clustering have also been observed. The temporal haplotype diversities landscape in each region appears to be similar pan India, with haplotype diversities peaking between March-May, while by June A2a (20A/B/C) emerged as the predominant one. Within haplotypes, different states appear to have different proportions. Temporal and geographic patterns in the sequences obtained reveal interesting clustering of mutations. Some mutations are present at particularly high frequencies in one state as compared to others. The negative estimate Tajimas D (D = −2.26817) is consistent with the rapid expansion of SARS-CoV-2 population in India. Detailed mutational analysis across India to understand the gradual emergence of mutants at different regions of the country and its possible implication will help in better disease management.
Comparative genomics and community curation further improve gene annotations in the nematodePristionchus pacificus
Authors: Athanasouli Marina , Witte Hanh , Weiler Christian , Loschko Tobias , Eberhardt Gabi , Sommer Ralf J. , Rödelsperger Christian
Published: August 2020

Background

Nematode model organisms such asCaenorhabditis elegansandPristionchus pacificusare powerful systems for studying the evolution of gene function at a mechanistic level. However, the identification ofP. pacificusorthologs of candidate genes known fromC. elegansis complicated by the discrepancy in the quality of gene annotations, a common problem in nematode and invertebrate genomics.

Results

Here, we combine comparative genomic screens for suspicious gene models with community-based curation to further improve the quality of gene annotations inP. pacificus. We extend previous curations of one-to-one orthologs to larger gene families and also orphan genes. Cross-species comparisons of protein lengths and screens for atypical domain combinations and species-specific orphan genes resulted in 4,221 candidate genes that were subject to community-based curation. Corrections for 2,851 gene models were implemented in a new version of theP. pacificusgene annotations. The new set of gene annotations contains 28,896 genes and has a single copy ortholog completeness level of 97.6%.

Conclusions

Our work demonstrates the effectiveness of comparative genomic screens to identify suspicious gene models and the scalability of community-based approaches to improve the quality of thousands of gene models. Similar community-based approaches can help to improve the quality of gene annotations in other invertebrate species, including parasitic nematodes.
Interannual variability of net ecosystem carbon production and its climatic and biotic mechanism during 2005-2018 in a rain-fed maize ecosystem
Authors: Zhang Hui , Zhao Tianhong , Lyu Sidan , Wu Hang , Yang Yang , Wen Xuefa
Published: August 2020

The interannual variation (IAV) of net ecosystem carbon production (NEP) plays an important role in understanding the mechanisms of the carbon cycle in the agriculture ecosystem. In this study, the IAV of NEP, which were expressed as annual values and anomalies, and its climatic and biotic controls mechanism, were investigated based on an eddy covariance dataset of rain-fed spring maize during 2005–2018 in the northeast of China. The annual NEP was 270±115 g C m−2yr−1. Annual values and anomalies of NEP were positively correlated with that of precipitation (PPT), gross ecosystem production (GEP) and daily maximum NEP (NEPmax). Annual anomalies of NEP were dominantly and positively controlled by the soil water content (SWC) through GEP and the soil temperature (Ts) through RE. In comparison, annual anomalies of NEP were dominantly and negatively controlled by summer VPD through the NEPmax, positively adjusted by spring precipitation and the effective accumulative temperature through the beginning date (BDOY) of the affecting carbon uptake period (CUP), and by autumn precipitation and leaf area index through the end date (EDOY) of the affecting CUP. Residues restrained the carbon release at the beginning of the year, and accelerated the carbon release at the end of the year. Our results hightlight that NEP might be more sensitive to the change of water condition (such as PPT, SWC and VPD) induced by the climate changes.
Marine reserve benefits and recreational fishing yields: the winners and the losers
Authors: Kayal Mohsen , Cigala Marine , Cambra Eléonore , Soulat Nelly , Mercader Manon , Lebras Audrey , Ivanoff Pauline , Sébési Léa , Lassus-Debat Aurélie , Hartmann Virginie , Bradtke Mélissa , Lenfant Philippe , Jabouin Coraline , Dubreuil Julien , Pelletier Dominique , Joguet Manon , Le Mellionnec Solène , Brichet Marion , Binche Jean-Louis , Payrot Jérôme , Saragoni Gilles , Crec’hriou Romain , Verdoit-Jarraya Marion
Published: August 2020

Marine reserves constitute effective tools for preserving fish stocks and associated human benefits. However, not all reserves perform equally, and predicting the response of marine communities to management actions in the long run is challenging. Our decadal-scale survey of recreational fishing yields at France’s 45-year old Cerbère-Banyuls marine reserve indicated significant protection benefits, with 40-50% higher fishing yields per unit effort in the partial-protection zone of the reserve (where fishing is permitted but at a lower level) than in surrounding non-reserve areas. Over the period 2005-2014, catch per unit effort (CPUE) showed a similar pattern of decline inside and outside the reserve while weight per unit effort (WPUE) increased by 131% inside and decreased by 60% outside. Different CPUE and WPUE trajectories among fish families indicated changing catch assemblages, with yields increasing for the family most valued by fisheries, Sparidae (the ecological winners). However, reserve benefits were restricted to off-shore fishermen (the social winners), as on-shore yields were ∼4 times lower and declining, even inside the reserve. Our study illustrates how surveys of recreational fishing yields can help evaluate the effectiveness of marine protected areas for key social and ecological protagonists. We show that, more than four decades after its establishment, fishing efficiencies at the historical Cerbère-Banyuls marine reserve are still changing, but benefits in terms of catch abundance, weight, and composition remain predominantly restricted to off-shore fishermen. Further regulations appear necessary to guarantee that conservation strategies equitably benefit societal groups.
Similarity between mutation spectra in hypermutated genomes of rubella virus and in SARS-CoV-2 genomes accumulated during the COVID-19 pandemic
Authors: Klimczak Leszek J. , Randall Thomas A. , Saini Natalie , Li Jian-Liang , Gordenin Dmitry A.
Published: August 2020

Genomes of tens of thousands of SARS-CoV2 isolates have been sequenced across the world and the total number of changes (predominantly single base substitutions) in these isolates exceeds ten thousand. We compared the mutational spectrum in the new SARS-CoV-2 mutation dataset with the previously published mutation spectrum in hypermutated genomes of rubella - another positive single stranded (ss) RNA virus. Each of the rubella isolates arose by accumulation of hundreds of mutations during propagation in a single subject, while SARS-CoV-2 mutation spectrum represents a collection events in multiple virus isolates from individuals across the world. We found a clear similarity between the spectra of single base substitutions in rubella and in SARS-CoV-2, with C to U as well as A to G and U to C being the most prominent in plus strand genomic RNA of each virus. Of those, U to C changes universally showed preference for loops versus stems in predicted RNA secondary structure. Similarly, to what was previously reported for rubella, C to U changes showed enrichment in the uCn motif, which suggested a subclass of APOBEC cytidine deaminase being a source of these substitutions. We also found enrichment of several other trinucleotide-centered mutation motifs only in SARS-CoV-2 - likely indicative of a mutation process characteristic to this virus. Altogether, the results of this analysis suggest that the mutation mechanisms that lead to hypermutation of the rubella vaccine virus in a rare pathological condition may also operate in the background of the SARS-CoV-2 viruses currently propagating in the human population.
CRISPR interference as low burden logic inverters in synthetic circuits: characterization and tuning
Authors: Bellato Massimo , Chiacchiera Angelica Frusteri , Salibi Elia , Casanova Michela , De Marchi Davide , De Angelis Maria Gabriella Cusella , Pasotti Lorenzo , Magni Paolo
Published: August 2020

The rational design of complex biological systems through the interconnection of single functional building blocks is hampered by many unpredictability sources; this is mainly due to the tangled context-dependency behavior of those parts once placed into an intrinsically complex living system. Among others, the finite amount of translational resources in prokaryotic cells leads to load effects in heterologous protein expression. As a result, hidden interactions among protein synthesis rates arise, leading to unexpected and counterintuitive behaviors. To face this issue in rational design of synthetic circuits in bacterial cells, CRISPR interference is here evaluated as genetic logic inverters with low translational resource usage, compared with traditional transcriptional regulators. This system has been studied and characterized in several circuit configurations. Each module composing the circuit architecture has been optimized in order to meet the desired specifications, and its reduced metabolic load has been eventually demonstrated via in-vivo assays.
Early prediction of declining health in small ruminants with accelerometers and machine learning
Authors: Montout Axel X. , Bhamber Ranjeet S. , Lange Debbie S. , Ndlovu Doreen Z. , Morgan Eric R. , Ioannou Christos C. , Terrill Thomas H. , van Wyk Jan A. , Burghardt Tilo , Dowsey Andrew W.
Published: August 2020

Assessment of the health status of individual animals is a key step in the timely and targeted treatment of infections, which is critical in the fight against anthelmintic and antimicrobial resistance. The FAMACHA scoring system has been used successfully to detect anaemia caused by infection with the parasitic nematodeHaemonchus contortusin small ruminants and is an effective way to identify individuals in need of treatment. However, assessing FAMACHA is labour-intensive and costly as individuals must be manually examined at frequent intervals. Here, we used accelerometers to measure the individual activity of extensively grazing small ruminants (sheep and goats) exposed to naturalHaemonchus contortusworm infection in southern Africa over long time scales (13+ months). When combined with machine learning, this activity data can predict poorer health (increases in FAMACHA score), as well as those individuals that respond to treatment, all with precision up to 83%. We demonstrate that these classifiers remain robust over time. Interpretation of trained classifiers reveals that poorer health significantly affects the night-time activity levels in the sheep. Our study thus reveals behavioural patterns across two small ruminant species, which lowcost biologgers can exploit to detect subtle changes in animal health and enable timely and targeted intervention. This has real potential to improve economic outcomes and animal welfare as well as limit the use of anthelmintic drugs and diminish pressures on anthelmintic resistance in both commercial and resource-poor communal farming.
Modular low-cost homemade radiation shields for forest ecology field experiments
Authors: Morales N.S.
Published: August 2020

Abiotic variables are important in understanding several forest ecosystems processes. Hence, temporal, accurate, and precise measurements are vital to any experiment including abiotic variables as part of its objectives.

In general, field experiments require several types of sensors to represent intra-site variability. For temperature and humidity measurements in particular, accessories to decrease biases such as radiation shields are indispensable. However, this kind of experimental setup can make project costs escalate quickly.

Low-cost alternatives to commercially available radiation shields have proven to be adequate in their ability to decrease measurement bias. Despite this advantage (low cost), the materials used in some of these cannot last long under field conditions (e.g. cardboard, aluminium foil).

A custom-made low-cost solution was designed to withstand rugged conditions to perform temporal measurements using sensors. The radiation shields proved to meet the technical and budgetary needs of the project while lasting the entire duration of the project (approx. 3 years). At the end of the project they were still in good enough condition to use in future studies, and they were donated to the School of Environmental Sciences (University of Auckland).
Separating noise and function in systems of animal communication: a comparative study of aggressive signaling in crayfish
Authors: Graham Zackary A. , Angilletta Michael J.
Published: August 2020

A primary issue in the study of dishonest signaling is the researcher’s ability to detect and describe a signal as being dishonest. However, by understanding the relative honesty of a signal as a statistical property of an individual or population, researchers have recently quantitively describe dishonest communication. Thus, dishonesty signals can be understood as when there is a breakdown in the correlation between a signal and its underlying meaning; creating variation within a signaling system. However, such variation in signaling systems may not be attributed to dishonesty, because of inherent noise within biological systems driven by evolutionary or physiological noise. Here, we try to separate out functional variation within honest or dishonesty signaling systems from inherent biological noise by leveraging homologous structures that have evolved for separate functions – the enlarged claws of freshwater crayfish. Because burrowing species of freshwater crayfish claws have not evolved as signals, the variability in the size and strength of their claws should be minimal when compared to claws of non-burrowing species that evolved as signals during aggression. We found that despite the claws of burrowing and nonburrowing crayfish claws having evolved to serve difference functions, the claws of all species in our study were inherently noisy. Furthermore, although claws that unreliably correlate to the strengthen the wielder may function as dishonest signals in other crustaceans, we did not find support for this hypothesis; because crayfish escalated aggression based on relative body size.
Central and peripheral GLP-1 systems independently and additively suppress eating
Authors: Brierley Daniel I. , Holt Marie K. , Singh Arashdeep , de Araujo Alan , Vergara Macarena , Afaghani Majd H. , Lee Shin Jae , Scott Karen , Langhans Wolfgang , Krause Eric , de Kloet Annette , Gribble Fiona M. , Reimann Frank , Rinaman Linda , de Lartigue Guillaume , Trapp Stefan
Published: August 2020

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which respectively define the peripheral and central GLP-1 systems. As peripheral satiation signals are integrated in the nucleus tractus solitarius (NTS), PPGNTSneurons are assumed to link the peripheral and central GLP-1 systems, forming a unified GLP-1 gut-brain satiation circuit. This hypothesis, however, remains unsubstantiated. We report that PPGNTSneurons encode satiation in mice, consistent with vagal gastrointestinal distension signalling. However, PPGNTSneurons predominantly receive vagal input from oxytocin receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. Furthermore, PPGNTSneurons are not necessary for eating suppression induced by the GLP-1 receptor agonists liraglutide or semaglutide, and semaglutide and PPGNTSneuron activation additively suppress eating. Central and peripheral GLP-1 systems thus suppress eating via independent gut-brain circuits, hence PPGNTSneurons represent a rational pharmacological target for anti-obesity combination therapy with GLP-1 receptor agonists.

Abstract Figure

Graphical Abstract:
Pairwise Linkage Disequilibrium Estimation for Polyploids
Authors: Gerard David
Published: August 2020

Many tasks in statistical genetics involve pairwise estimation of linkage disequilibrium (LD). The study of LD in diploids is mature. However, in polyploids, the field lacks a comprehensive characterization of LD. Polyploids also exhibit greater levels of genotype uncertainty than diploids, and yet no methods currently exist to estimate LD in polyploids in the presence of such genotype uncertainty. Furthermore, most LD estimation methods do not quantify the level of uncertainty in their LD estimates. Our paper contains three major contributions. (i) We characterize haplotypic and composite measures of LD in polyploids. These composite measures of LD turn out to be functions of common statistical measures of association. (ii) We derive procedures to estimate haplotypic and composite LD in polyploids in the presence of genotype uncertainty. We do this by estimating LD directly from genotype likelihoods, which may be obtained from many genotyping platforms. (iii) We derive standard errors of all LD estimators that we discuss. We validate our methods on both real and simulated data. Our methods are implemented in the R package ldsep, available on the Comprehensive R Archive Networkhttps://cran.r-project.org/package=ldsep.
How do zebrafish respond to MK-801 and amphetamine? Relevance for assessing schizophrenia-relevant endophenotypes in alternative model organisms
Authors: Benvenutti Radharani , Gallas-Lopes Matheus , Sachett Adrieli , Marcon Matheus , Strogulski Nathan Ryzewski , Rosa Reis Carlos Guilherme , Chitolina Rafael , Piato Angelo , Herrmann Ana Paula
Published: August 2020

Background and Purpose

Schizophrenia pathophysiology has been associated with dopaminergic hyperactivity, loss of parvalbumin-positive GABAergic interneurons, NMDA receptor hypofunction, and redox dysregulation. Most behavioral assays and animal models to study this condition were developed in rodents, leaving room for species-specific biases that could be avoided by cross-species approaches. As MK-801 and amphetamine are largely used in mice and rats to mimic schizophrenia features, this study aimed to investigate the effects of these drugs in zebrafish.

Experimental Approach

Adult zebrafish were exposed to MK-801 (1, 5, and 10 μM) or amphetamine (0.625, 2.5, and 10 mg·L-1) and observed in paradigms of locomotor activity and social behavior. Oxidative parameters relevant to schizophrenia were quantified in brain tissue.

Key Results

MK-801 disrupted social interaction, an effect that resembles the negative symptoms of schizophrenia. It also altered locomotion in a context-dependent manner, with hyperactivity when fish were tested in the presence of social cues and hypoactivity when tested alone. On the other hand, exposure to amphetamine was devoid of effects on locomotion and social behavior, while increased lipid peroxidation in the brain.

Conclusion and Implications

Key outcomes induced by MK-801 in rodents were replicated in zebrafish, which suggests this species is suitable as an alternative model animal to study psychotic disorders. More studies are necessary to further develop preclinical paradigms with this species and ultimately optimize the screening of potential novel treatments.
Human vulnerability to cancer malignancy is enhanced by evolution of higher mesenchymal CD44 expression compared to other mammals
Authors: Ma Xinghong , Dighe Anasuya , Maziarz Jamie , Neumann Edwin , Erkenbrack Eric , Hei Yuan-Yuan , Liu Yansheng , Suhail Yasir , Kshitiz  , Pak Irene , Levchenko Andre , Wagner Günter P.
Published: August 2020

CD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution ofCD44expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase ofCD44expression in SF and ESF is largely due to cis-regulatory effects in the proximal promoter ofCD44. We identify a primate specific acquisition of CEBPB binding sites in the CD44 promoter. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increasedCD44expression in primate skin fibroblasts but is not necessary for high CD44 expression in ESF. All these results suggest that selective modulation ofCD44expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.
In vitromodeling of tumor spheroid interactions to perfused blood vessels
Authors: Kwak Tae Joon , Lee Esak
Published: August 2020

Tumor angiogenesis, the formation of new blood vessels from existing blood vessels in and around the tumor stroma, is orchestrated by multiple biological factors in the tumor microenvironment, including tumor stromal cells, extracellular matrices, and secreted growth factors. Here, we present the processes to define and optimize the biological conditions for robust interactions between tumor spheroids and engineered blood vessels in a microfluidic organ-on-a-chip devicein vitro. Within the device, vascular lumen formation and vessel sprouting in human umbilical vein endothelial cell based engineered blood vessels are observed in a variety of extracellular matrices (collagen, Matrigel, and fibrin), containing metastatic breast tumor cells (MDA-MB-231), and tumor stromal cells (mesenchymal stem cells, and human lung fibroblasts) to show the crosstalk between the tumor spheroids and the perfused blood vasculaturesin vitro.
Centrosomal P4.1-associated protein (CPAP) positively regulates endocytic vesicular transport and lysosome targeting of EGFR
Authors: Gudi Radhika , Palanisamy Viswanathan , Vasu Chenthamarakshan
Published: August 2020

Centrosomal P4.1-associated protein (CPAP) plays a critical role in restricting the centriole length in human cells. Here, we report a novel, positive regulatory role for CPAP in endocytic vesicular transport (EVT) and lysosome targeting of internalized-cell surface receptor EGFR. We observed that higher CPAP levels cause an increase in the abundance of multi-vesicular body (MVB) and EGFR is detectable in CPAP-overexpression induced puncta. While the surface levels, and total and phosphorylated cellular levels of EGFR are higher under CPAP deficiency, ligandengagement induced internalization of this receptor is not impacted by CPAP levels. Furthermore, routing of EGFR into early endosomes is not influenced by CPAP. However, most importantly, we found that CPAP is required for targeting ligand-activated, internalized EGFR to lysosome. Transport of ligand-bound EGFR from early endosome to late endosome/MVB and lysosome is severely diminished in CPAP-depleted cells. Moreover, CPAP depleted cells showed diminished ability to form MVB structures upon EGFR activation. These observations show a positive regulatory role for CPAP in early endosome to late endosome transport and lysosome targeting of ligand-bound EGFR-like cell surface receptors. Overall, identification of this regulatory role for CPAP in endocytic trafficking of EGFR provides new insights in understanding the cellular functions of CPAP.
Structure of SARS-CoV-2 2′-O-methyltransferase heterodimer with RNA Cap analog and sulfates bound reveals new strategies for structure-based inhibitor design
Authors: Rosas-Lemus Monica , Minasov George , Shuvalova Ludmilla , Inniss Nicole , Kiryukhina Olga , Brunzelle Joseph , Satchell Karla J. F.
Published: August 2020

There are currently no antiviral therapies specific against SARS-CoV-2, the virus responsible for the global pandemic disease COVID-19. To facilitate structure-based drug design, we conducted an X-ray crystallographic study of the nsp16/nsp10 2′-O-methyltransferase complex that methylates Cap-0 viral mRNAs to improve viral protein translation and to avoid host immune detection. Heterodimer structures are determined with the methyl donorS-adenosylmethionine (SAM), the reaction productS-adenosylhomocysteine (SAH) or the SAH analog sinefungin (SFG). Furthermore, structures of nsp16/nsp10 with the methylated Cap-0 analog (m7GpppA) and SAM or SAH bound were obtained. Comparative analysis revealed flexible loops in open and closed conformations at the m7GpppA binding pocket. Bound sulfates in several structures suggested the location of the phosphates in the ribonucleotide binding groove. Additional nucleotide binding sites were found on the face of the protein opposite the active site. These various sites and the conserved dimer interface could be exploited for development of antiviral inhibitors.
A dynamical system model for predicting gene expression from the epigenome
Authors: Brunner James D. , Kim Jacob , Downing Timothy , Mjolsness Eric , Kober Kord M.
Published: August 2020

Gene regulation is an important fundamental biological process. The regulation of gene expression is managed through a variety of methods including epigentic processes (e.g., DNA methylation). Understanding the role of epigenetic changes in gene expression is a fundamental question of molecular biology. Predictions of gene expression values from epigenetic data have tremendous research and clinical potential. Despite active research, studies to date have focused on using statistical models to predict gene expression from methylation data. In contrast, dynamical systems can be used to generate a model to predict gene expression using epigenetic data and a gene regulatory network (GRN) which can also serve as a mechanistic hypothesis. Here we present a novel stochastic dynamical systems model that predicts gene expression levels from methylation data of genes in a given GRN. Software for dataset preparation, model parameter fitting and prediction generation, and reporting are available athttps://github.com/kordk/stoch_epi_lib.