bluuebunny/crossref_metadata_2025 huggingface dataset:
The genomic footprint of coastal earthquake uplift
Authors: Parvizi Elahe , Fraser Ceridwen I. , Dutoit Ludovic , Craw Dave , Waters Jonathan M.
Published: July 2020

Theory suggests that catastrophic earth-history events can drive rapid biological evolution, but empirical evidence for such processes is scarce. Destructive geological events such as earthquakes can represent large-scale natural experiments for inferring such evolutionary processes. We capitalized on a major prehistoric (800 yr BP) geological uplift event affecting a southern New Zealand coastline to test for the lasting genomic impacts of disturbance. Genome-wide analyses of three co-distributed keystone kelp taxa revealed that post-earthquake recolonization drove the evolution of novel, large-scale intertidal spatial genetic ‘sectors’ which are tightly linked to geological fault boundaries. Demographic simulations confirmed that, following widespread extirpation, parallel expansions into newly vacant habitats rapidly restructured genome-wide diversity. Interspecific differences in recolonization mode and tempo reflect differing ecological constraints relating to habitat choice and dispersal capacity among taxa. This study highlights the rapid and enduring evolutionary effects of catastrophic ecosystem disturbance and reveals the key role of range expansion in reshaping spatial genetic patterns.
Seasonal regulation of behaviour: what role do hormone receptors play?
Authors: Watts Heather E.
Published: July 2020

Many animals differentially express behaviours across the annual cycle as life stages are coordinated with seasonal environmental conditions. Understanding of the mechanistic basis of such seasonal changes in behaviour has traditionally focused on the role of changes in circulating hormone levels. However, it is increasingly apparent that other endocrine regulation mechanisms such as changes in local hormone synthesis and receptor abundance also play a role. Here I review what is known about seasonal changes in steroid hormone receptor abundance in relation to seasonal behaviour in vertebrates. I find that there is widespread, though not ubiquitous, seasonal variation in the expression of steroid hormone receptors in the brain, with such variation being best documented in association with courtship, mating and aggression. The most common pattern of seasonal variation is for there to be upregulation of sex steroid receptors with the expression of courtship and mating behaviours, when circulating hormone levels are also high. Less well-documented are cases in which seasonal increases in receptor expression could compensate for low circulating hormone levels or seasonal downregulation that could serve a protective function. I conclude by identifying important directions for future research.
Variation in the strength of allometry drives rates of evolution in primate brain shape
Authors: Sansalone G. , Allen K. , Ledogar J. A. , Ledogar S. , Mitchell D. R. , Profico A. , Castiglione S. , Melchionna M. , Serio C. , Mondanaro A. , Raia P. , Wroe S.
Published: July 2020

Large brains are a defining feature of primates, as is a clear allometric trend between body mass and brain size. However, important questions on the macroevolution of brain shape in primates remain unanswered. Here we address two: (i), does the relationship between the brain size and its shape follow allometric trends and (ii), is this relationship consistent over evolutionary time? We employ three-dimensional geometric morphometrics and phylogenetic comparative methods to answer these questions, based on a large sample representing 151 species and most primate families. We found two distinct trends regarding the relationship between brain shape and brain size. Hominoidea and Cercopithecinae showed significant evolutionary allometry, whereas no allometric trends were discernible for Strepsirrhini, Colobinae or Platyrrhini. Furthermore, we found that in the taxa characterized by significant allometry, brain shape evolution accelerated, whereas for taxa in which such allometry was absent, the evolution of brain shape decelerated. We conclude that although primates in general are typically described as large-brained, strong allometric effects on brain shape are largely confined to the order's representatives that display more complex behavioural repertoires.
Post-contact immobility and half-lives that save lives
Authors: Sendova-Franks Ana B. , Worley Alan , Franks Nigel R.
Published: July 2020

A wide variety of animals become completely immobile after initial contact with a potential predator. This behaviour is considered to be a last-ditch escape strategy. Here, we test the hypothesis that such immobility should have an extremely unpredictable duration. We find that it spans more than three orders of magnitude in antlion larvae. We also analyse the second period of immobility that follows the first bout of immobility, and consider the distributions of both first and second immobility periods within the context of the intermittence that characterizes the movement of most organisms. Both immobility durations were fitted best by exponential distributions. Therefore, both were characterized by high variability and hence, unpredictability. The immobility half-life, its mean duration and standard deviation were greater for the first than the second immobility. Furthermore, individual consistency was weak or absent in repeated measures of the first immobility and between the first and second immobilities. Our quantitative approach can be replicated across taxa and would help link an understanding of immobility after an initial predator contact in both vertebrates and invertebrates. To facilitate this, we contend that the terminology should be simplified, and we advocate the use of the term post-contact immobility (PCI).
Endosymbiotic
Rickettsiella
causes cytoplasmic incompatibility in a spider host
Authors: Rosenwald Laura C. , Sitvarin Michael I. , White Jennifer A.
Published: July 2020

Many arthropod hosts are infected with bacterial endosymbionts that manipulate host reproduction, but few bacterial taxa have been shown to cause such manipulations. Here, we show that a bacterial strain in the genus
Rickettsiella
causes cytoplasmic incompatibility (CI) between infected and uninfected hosts. We first surveyed the bacterial community of the agricultural spider
Mermessus fradeorum
(Linyphiidae) using high throughput sequencing and found that individual spiders can be infected with up to five different strains of maternally inherited symbiont from the genera
Wolbachia
,
Rickettsia
, and
Rickettsiella
. The
Rickettsiella
strain was pervasive, found in all 23 tested spider matrilines. We used antibiotic curing to generate uninfected matrilines that we reciprocally crossed with individuals infected only with
Rickettsiella
. We found that only 13% of eggs hatched when uninfected females were mated with
Rickettsiella
-infected males; in contrast, at least 83% of eggs hatched in the other cross types. This is the first documentation of
Rickettsiella
, or any Gammaproteobacteria, causing CI. We speculate that induction of CI may be much more widespread among maternally inherited bacteria than previously appreciated. Further, our results reinforce the importance of thoroughly characterizing and assessing the inherited microbiome before attributing observed host phenotypes to well-characterized symbionts such as
Wolbachia
.
Weed diversity is driven by complex interplay between multi-scale dispersal and local filtering
Authors: Bourgeois Bérenger , Gaba Sabrina , Plumejeaud Christine , Bretagnolle Vincent
Published: July 2020

Arable weeds are key organisms for biodiversity maintenance and ecosystem service provision in agroecosystems. Disentangling the drivers of weed diversity is critical to counteract the global decline of farmland biodiversity. Even if distinct scale-dependent processes were alternatively proposed, no general framework unifying the multi-scale drivers of weed dynamics has yet emerged. Here, we investigate the joint effects of field- and landscape-scale processes on weed assemblages in 444 arable fields. First, field margins sheltered greater weed diversity than field core, evidencing their role as biodiversity refugia. Second, community similarity between field core and margin decreased with the distance to margin, highlighting a major role of local dispersal. Third, weed diversity at field margins increased with organic field cover in the landscape, pointing out massive regional dispersal. Fourth, while both local and landscape dispersal explained up to 41% of field core weed diversity, crop type strongly modulated their strength, depicting an intense filtering effect by agricultural management. This study sheds new light on the complex multi-scale interactions shaping weed diversity, field margins playing a key role by strengthening regional dispersal and sustaining local dispersal. Land-sharing strategies improving habitat heterogeneity both locally and regionally should largely promote agroecosystem multifunctionality and sustainability.
Numerical ordinality in a wild nectarivore
Authors: Vámos Tas I. F. , Tello-Ramos Maria C. , Hurly T. Andrew , Healy Susan D.
Published: July 2020

Ordinality is a numerical property that nectarivores may use to remember the specific order in which to visit a sequence of flowers, a foraging strategy also known as traplining. In this experiment, we tested whether wild, free-living rufous hummingbirds (
Selasphorus rufus
) could use ordinality to visit a rewarded flower. Birds were presented with a series of linear arrays of 10 artificial flowers; only one flower in each array was rewarded with sucrose solution. During training, birds learned to locate the correct flower independent of absolute spatial location. The birds' accuracy was independent of the rewarded ordinal position (1st, 2nd, 3rd or 4th), which suggests that they used an object-indexing mechanism of numerical processing, rather than a magnitude-based system. When distance cues between flowers were made irrelevant during test trials, birds could still locate the correct flower. The distribution of errors during both training and testing indicates that the birds may have used a so-called working up strategy to locate the correct ordinal position. These results provide the first demonstration of numerical ordinal abilities in a wild vertebrate and suggest that such abilities could be used during foraging in the wild.
Limited specificity of serologic tests for SARS-CoV-2 antibody detection, Benin, Western Africa
Authors: Yadouleton Anges , Sander Anna-Lena , Moreira-Soto Andres , Tchibozo Carine , Hounkanrin Gildas , Badou Yvette , Fischer Carlo , Krause Nina , Akogbeto Petas , de Oliveira Filho Edmilson F. , Dossou Anges , Brünink Sebastian , Joël AÏssi Melchior A. , Djingarey Mamoudou Harouna , Hounkpatin Benjamin , Nagel Michael , Drexler Jan Felix
Published: July 2020

Testing 68 RT-PCR-confirmed COVID-19 cases and controls from Benin, Western Africa with commercially available SARS-CoV-2 antibody ELISAs revealed up to 25% false-positive results, likely due to unspecific antibody responses elicited by acute malaria. Serologic tests must be carefully evaluated to robustly assess SARS-CoV-2 spread and immunity in tropical regions.
Motor and Activity Psychosis-Risk (MAP-R) Scale: An exploration of scale structure with replication and validation
Authors: Damme Katherine S. F. , Schiffman Jason , Ellman Lauren M. , Mittal Vijay A.
Published: July 2020

Background

Motor abnormalities precede and predict the onset of psychosis. Despite the practical utility of motor abnormalities for early identification, prediction, and individualized medicine applications, there is currently no dedicated self-report instrument designed to capture these important behaviors. The current study assessed and validated a questionnaire designed for use in individuals at clinical high-risk for psychosis (CHR).

Methods

The current study included both exploratory (n=3,009) and validation(n=439) analytic datasets– that included individuals at CHR (n=84)-who completed the novel Motor Abnormalities and Psychosis-Risk (MAP-R) Scale, clinical interviews and a finger tapping task. The structure of the scale and reliability of items were consistent across two analytic datasets. The resulting scales were assessed for discriminant validity across CHR, community sample non-psychiatric volunteer, and clinical groups.

Results

The scale showed a consistent structure across independent data points across two analytic datasets subscale structure. The resultant subscale structure was consistent with conceptual models of motor pathology in psychosis (coordination and dyskinesia) in both the exploratory and the validation analytic dataset. Further, these subscales showed discriminant, predictive and convergent validity. The motor abnormality scales discriminated CHR from community sample non-psychiatric controls and clinical samples. Finally, these subscales predicted to risk calculator scores and showed convergent validity with motor performance on a finger tapping task.

Conclusion

The MAP-R scale demonstrated good internal validity, discriminant validity, predictive validity, and convergent validity, and subscales map on to conceptually relevant motor circuits. This scale showed great promise in characterizing a novel area of detection of psychosis risk.
Impact of a diabetes disease management program on quality of care and costs: propensity score-matched real-world data from Switzerland
Authors: Carlander Maria , Höglinger Marc , Trottmann Maria , Rhomberg Birgitta , Caviglia Cornelia , Rohrbasser Adrian , Frei Christian , Eichler Klaus
Published: July 2020

Objectives

Structured treatment programs have been recommended for management of patients with chronic conditions to overcome ill-coordinated care. We aimed to evaluate a disease management program (DMP) for diabetes mellitus patients in Switzerland.

Methods

We performed a prospective observational study with a propensity score-matched usual care control group from a claims database. We included type-1 and type-2 diabetes patients from a primary care setting. The DMP (intervention) comprised a structured treatment approach with an individual treatment plan, treatment goals and an interprofessional team approach. Our outcome comprehensive measures included quality of life (QOL: EQ-5D-5L), pre-defined indicators for diabetes guideline adherence, number of used services and direct medical costs. We applied a difference-in-difference (DID) approach to compare DMP with usual care (follow-up 1 year). Costs were calculated with non-parametric bootstrapping (2017 Swiss Francs, CHF; conversion rate to Euros: 0.85) from a third-party payer perspective (Swiss health care insurance).

Results

QOL in a sub-sample of 80 patients did not change during follow-up (mean utility 0.89 at baseline and follow-up; p=0.94). Guideline adherence showed slight improvements for DMP. For example, “non-adherence” (baseline DMP: 19%) decreased in the DMP group by −3 %-points (DID; 95%-CI: −0.07 to 0.01) but not in the control group. A general trend emerged, though mostly not statistically significant, with less used services in the DMP group compared to the control group. Costs increased in both groups during follow-up, but the increase was higher in the control group (DID, mean total costs per patient per year: CHF −950.00 [95%-CI: −1959.53 to 59.56]). Such a negative difference-in-difference estimate in favor of DMP also emerged for cost sub-categories (e.g. costs for inpatient and outpatient care).

Conclusions

The structured treatment program under evaluation is a promising approach to improve diabetes care in a Swiss primary care setting but more follow-up data are needed.
Predicting species distributions and community composition using remote sensing products
Authors: Pinto-Ledezma Jesús N. , Cavender-Bares Jeannine
Published: July 2020

Accurate predictions of species composition and diversity are critical to the development of conservation actions and management strategies. In this paper using oak assemblages distributed across the conterminous United States as study model, we assessed the performance of stacked species distribution models (S-SDMs) and remote sensing products in building the next-generation of biodiversity models. This study represents the first attempt to evaluate the integrated predictions of biodiversity models—including assemblage diversity and composition—obtained by stacking next-generation SDMs. We found three main results. First, environmental predictors derived entirely from remote sensing products represent adequate covariates for biodiversity modeling. Second, applying constraints to assemblage predictions, such as imposing the probability ranking rule, results in more accurate species diversity predictions. Third, independent of the stacking procedure (bS-SDM versus cS-SDM), biodiversity models do not recover the observed species composition with high spatial resolution, i.e., correct species identities at the scale of individual plots. However, they do return reasonable predictions at macroecological scales (1 km). Our results provide insights for the prediction of assemblage diversity and composition at different spatial scales. An important task for future studies is to evaluate the reliability of combining S-SDMs with direct detection of species using image spectroscopy to build a new generation of biodiversity models to accurately predict and monitor ecological assemblages through time and space.
Studying models of balancing selection using phase-type theory
Authors: Zeng Kai , Charlesworth Brian , Hobolth Asger
Published: July 2020

Balancing selection (BLS) is the evolutionary force that maintains high levels of genetic variability in many important genes. To further our understanding of its evolutionary significance, we analyse models with BLS acting on a biallelic locus: an equilibrium model with long-term BLS, a model with long-term BLS and recent changes in population size, and a model of recent BLS. Using phase-type theory, a mathematical tool for analysing continuous time Markov chains with an absorbing state, we examine how BLS affects polymorphism patterns in linked neutral regions, as summarised by nucleotide diversity, the expected number of segregating sites, the site frequency spectrum, and the level of linkage disequilibrium (LD). Long-term BLS affects polymorphism patterns in a relatively small genomic neighbourhood, and such selection targets are easier to detect when the equilibrium frequencies of the selected variants are close to 50%, or when there has been a population size reduction. For a new mutation subject to BLS, its initial increase in frequency in the population causes linked neutral regions to have reduced diversity, an excess of both high and low frequency derived variants, and elevated LD with the selected locus. These patterns are similar to those produced by selective sweeps, but the effects of recent BLS are weaker. Nonetheless, compared to selective sweeps, non-equilibrium polymorphism and LD patterns persist for a much longer period under recent BLS, which may increase the chance of detecting such selection targets. An R package for analysing these models, among others (e.g., isolation with migration), is available.
The genetic architecture of host response reveals the importance of arbuscular mycorrhizae to maize cultivation
Authors: Ramírez-Flores M. Rosario , Perez-Limón Sergio , Li Meng , Barrales-Gamez Benjamin , Olalde-Portugal Víctor , Sawers Ruairidh J. H.
Published: July 2020

Arbuscular mycorrhizal fungi (AMF) are ubiquitous in cultivated soils, forming symbiotic relationships with the roots of major crop species. Although studies in controlled conditions have demonstrated the potential of the symbiosis to enhance host plant nutrition and alleviate environmental stress, practical difficulties make it hard to estimate the actual benefit in cultivated fields, not least because of the lack of availability of suitable AMF-free controls. Furthermore, the response can vary depending on the plant variety in a manner which is not fully understood. Here, we implemented a novel strategy based on the selective incorporation of AMF-resistance into a genetic mapping population to evaluate maize response in the field. We found AMF to account for about one third of the grain production in a rain-fed medium input field, as well as to impact the relative performance of plant varieties. Characterization of the genetic architecture of host response allowed us to distinguish mycorrhizal benefit from dependence and indicated a trade-off between mycorrhizal and non-mycorrhizal performance, both at the level of individual QTL and genomewide. This approach is applicable to other crop species, permits further mechanistic analysis and is scalable to full yield trials.
Translating insights from the seed metabolome into improved prediction for healthful compounds in oat (Avena sativa L.)
Authors: Campbell Malachy T. , Hu Haixiao , Yeats Trevor H. , Caffe-Treml Melanie , Gutiérrez Lucía , Smith Kevin P. , Sorrells Mark E. , Gore Michael A. , Jannink Jean-Luc
Published: July 2020

Oat (Avena sativaL.) seed is a rich resource of beneficial lipids, soluble fiber, protein, and antioxidants, and is considered a healthful food for humans. Despite these characteristics, little is known regarding the genetic controllers of variation for these compounds in oat seed. We sought to characterize natural variation in the mature seed metabolome using untargeted metabolomics on 367 diverse lines and leverage this information to improve prediction for seed quality traits. We used a latent factor approach to define unobserved variables that may drive covariance among metabolites. One hundred latent factors were identified, of which 21% were enriched for compounds associated with lipid metabolism. Through a combination of whole-genome regression and association mapping, we show that latent factors that generate covariance for many metabolites tend to have a complex genetic architecture. Nonetheless, we recovered significant associations for 23% of the latent factors. These associations were used to inform a multi-kernel genomic prediction model, which was used to predict seed lipid and protein traits in two independent studies. Predictions for eight of the 12 traits were significantly improved compared to genomic best linear unbiased prediction when this prediction model was informed using associations from lipid-enriched factors. This study provides new insights into variation in the oat seed metabolome and provides genomic resources for breeders to improve selection for health-promoting seed quality traits. More broadly, we outline an approach to distill high-dimensional ‘omics’ data to a set of biologically-meaningful variables and translate inferences on these data into improved breeding decisions.
Genome-wide shifts in histone modifications at early stage of rice infection with Meloidogyne graminicola
Authors: Atighi Mohammad Reza , Verstraeten Bruno , De Meyer Tim , Kyndt Tina
Published: July 2020

Epigenetic processes play a crucial role in the regulation of plant stress responses, but their role in plant-pathogen interactions remains poorly understood. Although histone modifying enzymes have been observed to be deregulated in galls induced by root-knot nematodes (RKN,Meloidogyne graminicola) in rice, their influence on plant defence and their genome-wide impact have not been comprehensively investigated.

In this study, we applied 3 chemical inhibitors of histone modifying enzymes on rice 24h before inoculation with RKN. Despite their distinct described effects on histone modifications, application of different concentrations led in all cases to reduced susceptibility to RKN. Infection assays on two overexpression lines of histone lysine methyltransferases and one histone deacetylase showed contrasting results in susceptibility, indicating that each histone mark has a specific role in plant defence against RKN in rice. At genome-wide level, three histone marks, H3K9ac, H3K9me2 and H3K27me3 were studied by chromatin-immunoprecipitation (ChIP)-sequencing on RKN-induced galls at 3 days post inoculation. While levels of H3K9ac and H3K27me3 were strongly enriched, H3K9me2 was generally depleted in galls versus control root tips. Differential histone peaks were generally associated with plant defence related genes. In conclusion, our results indicate that histone modifications respond dynamically to RKN infection, and specifically target plant-defence related genes.

One-sentence summary

Post-translational histone modifications show a dynamic genome-wide response to root-knot nematode infection in rice and are specifically associated with plant defence genes.
Diversity of tRNA Clusters in the Chloroviruses
Authors: Duncan Garry A. , Dunigan David D. , Van Etten James L.
Published: July 2020

Viruses rely on their host’s translation machinery for the synthesis of their own proteins. Problems belie viral translation when the host has a codon usage bias (CUB) that is different from an infecting virus with differences in the GC content between the host/virus genome. Here, we evaluate the hypothesis that chloroviruses adapted to host CUB by acquisition and selection of tRNAs that at least partially favor their own CUB. The genomes of 41 chloroviruses comprising three clades of three different algal hosts have been sequenced, assembled and annotated. All 41 viruses not only encode tRNAs, but their tRNA genes are located in clusters. One tRNA gene was common to all three clades of chloroviruses, while differences were observed between clades and even within clades. By comparing the codon usage of one chlorovirus algal host, whose genome has been sequenced and annotated (67% GC content), to that of two of its viruses (40% GC content), we found that the viruses were able to at least partially overcome the host’s CUB by encoding tRNAs that recognize AU-rich codons. In addition, 39/41 chloroviruses encode a putative lysidine synthase, which alters the anticodon of tRNAmetthat normally recognizes AUG to recognize the codon AUA, a codon for isoleucine. This is advantageous to the viruses because the AU-rich codon AUA is 12-13 times more common in the chloroviruses than their host. Evidence is presented that supports the concept that chlorovirus tRNA clusters were acquired prior to events that separated them into the three clades.

IMPORTANCE

Chloroviruses are members of a group of giant viruses that infect freshwater green algae around the world. More than 40 chloroviruses have been sequenced and annotated. In order to propagate efficiently, chloroviruses with low GC content must overcome the high GC content and codon usage bias (CUB) of their hosts. We provide support for one mechanism by which viruses can overcome host CUB. Specifically, the chloroviruses examined herein encode tRNAs whose cognate codons are common in the viruses but not in the host. Virus-encoded tRNAs that recognize AU-rich codons enable more efficient protein synthesis, thus enhancing viral propagation. The tRNA genes are located in clusters and the original tRNA gene cluster was acquired by the most recent common ancestor of the four chlorovirus clades. Furthermore, we show some conservation among all clades, but also substantial variation between and within clades, demonstrating the dynamics of viral evolution.
The S-phase Cyclin Clb5 Promotes rDNA Stability by Maintaining Replication Initiation Efficiency in rDNA
Authors: Goto Mayuko , Sasaki Mariko , Kobayashi Takehiko
Published: July 2020

Regulation of replication origins is important for complete duplication of the genome, but the effect of origin activation on the cellular response to replication stress is poorly understood. The budding yeast ribosomal RNA gene (rDNA) forms tandem repeats and undergoes replication fork arrest at the replication fork barrier (RFB), inducing DNA double-strand breaks (DSBs) and genome instability accompanied by copy number alterations. Here we demonstrate that the S-phase cyclin Clb5 promotes rDNA stability. Absence of Clb5 led to reduced efficiency of replication initiation in rDNA but had little effect on the amount of replication forks arrested at the RFB, suggesting that arrival of the converging fork is delayed and forks are more stably arrested at the RFB. Deletion ofCLB5affected neither DSB formation nor its repair at the RFB, but led to an accumulation of recombination intermediates. Therefore, arrested forks at the RFB may be subject to DSB-independent, recombination-dependent rDNA instability. The rDNA instability inclb5Δ was not completely suppressed by the absence of Fob1, which is responsible for fork arrest at the RFB. Thus, Clb5 establishes the proper interval for active replication origins and shortens the travel distance for DNA polymerases, which may reduce Fob1-independent DNA damage.
A Sardinian founder mutation in GP1BB that impacts thrombocytopenia
Authors: Busonero Fabio , Steri Maristella , Orrù Valeria , Sole Gabriella , Olla Stefania , Marongiu Michele , Sidore Carlo , Lai Sandra , Mulas Antonella , Maschio Andrea , Zoledziewska Magdalena , Floris Matteo , Pala Mauro , Forabosco Paola , Asunis Isadora , Pitzalis Maristella , Deidda Francesca , Masala Marco , Caria Cristian Antonio , Barella Susanna , Abecasis Goncalo R. , Schlessinger David , Sanna Serena , Fiorillo Edoardo , Cucca Francesco
Published: July 2020

To investigate the genetic regulation of platelet (PLT) levels we carried out a whole-genome association analysis in 6,528 Sardinians from the general population of the Lanusei valley. We found 6 variants significantly influencing PLT levels, including a novel rare missense mutation (p.Pro27Ser) in the GP1BB protein that is associated with PLT reduction (P=1.17×10−16). This mutation is rare in the SardiNIA population cohort (frequency of 0.45%), even rarer in the rest of the Sardinian island (frequency of 0.16%), and not reported elsewhere. Notably, GP1BB is involved in Bernard-Soulier syndrome (BSS), a rare autosomal recessive bleeding disorder caused by a defect in the platelet GPIb-IX-V protein complex. Consistently, the 57 identified individuals heterozygous for the p.P27S mutation showed mild thrombocytopenia, morphologically enlarged platelets (P=2.13×10−10), and reduced expression of two GPIb-IX-V-complex components: GPIbα (−26.51%, P=3.66×10−8) and GPIX (−24.69%, P=2.66×10−6). Molecular modeling infers a corresponding reduction in the stability of GP1BB. These observations predict that in homozygosity as well as in individuals carrying specific compound heterozygous configurations, this variant likely causes BSS.
Predicting Health Disparities in Regions at Risk of Severe Illness to inform Healthcare Resource Allocations during Pandemics
Authors: Fusillo Tara
Published: July 2020

Pandemics including COVID-19 have disproportionately affected socioeconomically vulnerable populations. To create a repeatable modelling process to identify regional population centers with pandemic vulnerability, readily available COVID-19 and socioeconomic variable datasets were compiled, and linear regression models were built during the early days of the COVID-19 pandemic. The models were validated later in the pandemic timeline using actual COVID-19 mortality rates in states with high population densities, with New York, New Jersey, Connecticut, Massachusetts, Louisiana, Michigan and Pennsylvania showing the strongest predictive results. Our models have been shared with the Department of Health Commissioners of each of these states as input into a much needed “pandemic playbook” for local healthcare agencies in allocating medical testing and treatment resources.
Chloroquine for treatment of COVID-19 - a pig in a poke?
Authors: Brüggemann R.J. , Moes D.J.A.R. , van Rhee K.P. , van ’t Veer N.E. , Koch B.C.P. , van Rossum M. , den Tweel A. Vermeulen Windsant - van , Reijers M.H.E. , van Kimmenade R.R.J. , Rahamat- Langedoen J.C. , Rettig T.C.D. , van Raalte R. , van Paassen J. , Polderman F.N. , van der Linden P.D. , Frenzel T. , de Mast Q. , Burger D.M. , Schouten J. , van de Veerdonk F.L. , Pickkers P. , ter Heine R.
Published: July 2020

Structured abstract

Objective

Chloroquine has been frequently administered for treatment of coronavirus disease 2019 but there are serious concerns about its efficacy and cardiac safety. Our objective was to investigate the pharmacokinetics and safety of chloroquine in hospitalized COVID-19 patients.

Design

A prospective observational study.

Setting

Dutch hospitals

Patients

Patients admitted to the hospital for treatment of COVID-19.

Interventions

Pharmacokinetic sampling

Measurements

The plasma concentrations of chloroquine and desethylchloroquine and QTc time.

Main Results

A total of 83 patients were included. The median (IQR) plasma concentration chloroquine during treatment was 1.05 μmol/L (0.63 - 1.55 μmol/L). None of the patients reached exposure exceeding the concentration to inhibit SARS-CoV-2 replication by 90% (IC90) of 6.9 μM. Furthermore, ΔQTc >60 milliseconds occurred after initiation of chloroquine treatment in 34% patients and during treatment QTc ≥500 milliseconds was observed in 46% of patients.

Conclusions

Recommended dose chloroquine treatment results in plasma concentrations that are unlikely to inhibit viral replication. Furthermore, the incidence of QTc prolongation was high. The preclinical promise of chloroquine as antiviral treatment in patients with COVID-19 is overshadowed by its cardiac toxicity and lack of effective exposure. It is unlikely that a positive clinical effect will be found with chloroquine for treatment of COVID-19.
NMD is required for timely cell fate transitions by fine-tuning gene expression and controlling translation
Authors: Galimberti Elena , Sehlke Robert , Huth Michelle , Garmhausen Marius , Romeike Merrit , Ramesmayer Julia , Stummer Sarah , Titz-Teixeira Fabian , Herzog Veronika , Chugunova Anastasia , Leesch Katrin Friederike , Holcik Laurenz , Weipoltshammer Klara , Santini Laura , Lackner Andreas , von Haeseler Arndt , Bücker Christa , Pauli Andrea , Schoefer Christian , Ameres Stefan L. , Smith Austin , Beyer Andreas , Leeb Martin
Published: July 2020

Cell fate transitions depend on balanced rewiring of transcription and translation programmes to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls the translation initiation factorEif4a2and its premature termination codon encoding isoform (Eif4a2PTC). NMD deficiency leads to translation of a specific truncated Eif4a2 protein, which elicits increased translation rates and causes significant delays in mouse ESC differentiation. Thereby a previously unknown feedback loop between NMD and translation initiation is established. Our results illustrate a clear hierarchy between KOs in severity of target deregulation and differentiation phenotype (Smg5>Smg6>Smg7), which highlights heterodimer-independent functions for Smg5 and Smg7. Together, our findings expose an intricate link between mRNA stability and translation initiation control that must be maintained for normal dynamics of cell state transitions.
Most of Tobacco Male Meiocytes Are Involved in Intercellular Nuclear Migration at the First Meiotic Prophase
Authors: Mursalimov Sergey , Ohno Nobuhiko , Matsumoto Mami , Bayborodin Sergey , Deineko Elena
Published: July 2020

Serial block-face scanning electron microscopy was used here to study tobacco male meiosis. Three-dimensional ultrastructural analyses revealed that intercellular nuclear migration (INM) occurs in 90–100% of tobacco meiocytes. At the very beginning of meiosis, every meiocyte connected with neighboring cells by more than 100 channels was capable of INM. At leptotene and zygotene, the nucleus in most tobacco meiocytes approached the cell wall and formed nuclear protuberances (NPs) that crossed the cell wall through the channels and got into the cytoplasm of a neighboring cell. The NPs did not separate from the migrating nuclei and never produced micronuclei. Approximately 70% of NPs reached nuclei of neighboring cells. The NPs and the nuclei they reached got very close, and the gap between their nuclear membranes became indistinguishable in some cases. At pachytene, NPs detached from the nuclei of neighboring cells and came back into their own cells. After that, the INM stopped. The reason for such behavior of nuclei is unclear. INM probably causes a short-lived fusion of two nuclei and thus has a potential to form aneuploid or unreduced pollen. We consider INM a normal part of tobacco meiosis.
IL-23 production is regulated via an MSK1/2 – CREB dependent signalling pathway downstream of Toll like receptors
Authors: Houslay Kirsty F. , van Gijsel-Bonnello Manuel , Petrova Tsvetana , Naqvi Shaista , Arthur J. Simon C.
Published: July 2020

IL-23 is an IL-12 family cytokine that is important in promoting Th17 responses and has been strongly linked to autoimmunity and psoriasis. It is a heterodimeric cytokine made up of a p19 subunit unique to IL-23 and a p40 subunit that is shared with IL-12. We show here that in response to LPS, the induction of IL-23p19 mRNA is regulated by a MSK1/2 – CREB dependent pathway downstream of ERK1/2 and p38α MAPK. Knockout of MSK1/2 resulted in a decrease in both IL-23p19 mRNA transcription and IL-23 secretion in GM-CSF differentiated bone marrow cells. Similar effects were seen when the MSK1/2 phosphorylation site in CREB was mutated to alanine. Stimulation with PGE2 promotes the nuclear localisation of CRTC3, a co-activator for CREB. In combination with LPS, PGE2 promoted IL-23p19 mRNA transcription and this was blocked by knockdown of CRTC3. Imiquimod induced skin inflammation in mice has been used as a model for psoriasis and is dependent on IL-23. While MSK1/2 knockout reduced the induction of IL-23 in vivo following i.p. injection of LPS, the knockout mice were not protected from Imiquimod induced skin inflammation. MSK1/2 knockout did not reduce the induction of IL-17 producing γδT cells following Imiquimod treatment, although MSK1/2 knockout did reduce the levels of these cells in mice receiving a control cream. The lack of protection in the Imiquimod model may be due to the known anti-inflammatory roles or MSKs, such as its contribution to the induction of IL-10.
ATrypanosoma cruziZinc Finger protein that controls expression of epimastigote specific genes and affects metacyclogenesis
Authors: Tavares Thais Silva , Mügge Fernanda Lins Brandão , Grazielle-Silva Viviane , Valente Bruna Mattioly , Goes Wanessa Moreira , Oliveira Antonio Edson Rocha , Belew Ashton Trey , Guarneri Alessandra Aparecida , Pais Fabiano Sviatopolk-Mirsky , El-Sayed Najib M. , Teixeira Santuza Maria Ribeiro
Published: July 2020

Trypanosoma cruzihas three biochemically and morphologically distinct developmental stages that are programed to rapidly respond to environmental changes the parasite faces during its life cycle. Unlike other eukaryotes, Trypanosomatid genomes contain protein coding genes that are transcribed into polycistronic pre-mRNAs and control of gene expression relies on mechanisms acting at the post-transcriptional level. Transcriptome analyses comparing epimastigote, trypomastigote and intracellular amastigote stages revealed changes in gene expression that reflect the parasite adaptation to distinct environments. Several genes encoding RNA binding proteins (RBP), known to act as key post-transcriptional regulatory factors, were also differentially expressed. We characterized oneT. cruziRBP (TcZH3H12) that contains a zinc finger domain, and whose transcripts are upregulated in epimastigotes compared to trypomastigotes and amastigotes. TcZC3H12 knockout epimastigotes showed decreased growth rates and increased capacity to differentiate into metacyclic trypomastigotes. Comparative transcriptome analysis revealed a TcZC3H12-dependent expression of epimastigote specific genes encoding amino acid transporters and proteins associated with differentiation (PAD), among others. RNA immunoprecipitation assays showed that transcripts from the PAD family interact with TcZC3H12. Taken together, these findings suggest that TcZC3H12 positively regulates the expression of genes involved in epimastigote proliferation and also acts as a negative regulator of metacyclogenesis.
Decorin, a novel negative modulator of E-cadherin in inflammatory breast cancer
Authors: Hu Xiaoding , Villodre Emilly S , Larson Richard , Rahal Omar M , Wang Xiaoping , Gong Yun , Song Juhee , Krishnamurthy Savitri , Ueno Naoto T. , Tripathy Debu , Woodward Wendy A , Debeb Bisrat G.
Published: July 2020

Inflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cellsin vitroand inhibited IBC tumor growth and metastasisin vivo. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology.
Integrating Engineered Macro Vessels with Self-assembled Capillaries in 3D Implantable Tissue for Promoting Vascular Integration In-vivo
Authors: Debbi Lior , Zohar Barak , Shandalov Yulia , Levenberg Shulamit
Published: July 2020

Fabrication of a functional hierarchical vascular network remains an unmet need for cultivation and transplantation of 3D engineered tissues. In this work, an effective approach was developed to fabricate a functional, perfusable and biocompatible, multi-scale vascular network (MSVT) within thick, implantable engineered tissues. Using a templating technique, macro-vessels were patterned in a 3D biodegradable polymeric scaffold seeded with endothelial and support cells within a collagen gel. The lumen of the macro-vessel was lined with endothelial cells, which further sprouted and anastomosed with the surrounding self-assembled capillaries. Anastomoses between the two-scaled vascular systems displayed tightly bonded cell junctions, as indicated by vascular endothelial cadherin expression. Moreover, MSVT functionality and patency were demonstrated by dextran passage through the interconnected hierarchical vasculature. Additionally, physiological flow conditions were applied with home-designed flow bioreactors, to achieve a MSVT with a natural endothelium structure. Finally, implantation of a multi-scale-vascularized graft in a mouse model resulted in a clear beneficial effect, as reflected by extensive host vessel penetration into the graft and an increase in blood perfusion via the engineered vessels as compared to control microscale-vascularized graft. Designing and fabricating such multi-scale vascular architectures within 3D engineered tissues is essential, both for in-vitro models and for therapeutic translation research.
A Small interfering RNA lead targeting RNA-dependent RNA-polymerase effectively inhibit the SARS-CoV-2 infection in Golden Syrian hamster and Rhesus macaque
Authors: Gu Se Hun , Yu Chi Ho , Song Youngjo , Kim Na Young , Sim Euni , Choi Jun Young , Song Dong Hyun , Hur Gyeung Haeng , Shin Young Kee , Jeong Seong Tae
Published: July 2020

A small interfering RNA (siRNA) inhibitors have demonstrated the novel modality for suppressing infectious diseases. Sixty-one siRNA molecules, predicted by the bioinformatics programs, were screened for the possibility of treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using anin vitroplaque assay. Among six siRNA leads with the efficacy of reducing plaque number, the siRNA targeting RNA-dependent RNA polymerase (RdRp) showed a reduction in SARS-CoV-2 infection-induced fever and virus titer in the Golden Syrian hamster and rhesus macaque. These results suggest the potential for RdRp targeting siRNA as a new treatment for the coronavirus disease 2019 (COVID-19).
Cis-regulatory chromatin loops arise before TADs and gene activation, and are independent of cell fate during development
Authors: Espinola Sergio Martin , Götz Markus , Fiche Jean-Bernard , Bellec Maelle , Houbron Christophe , Cardozo Gizzi Andrés M. , Lagha Mounia , Nollmann Marcelo
Published: July 2020

During development, naïve cells gradually acquire distinct cell fates, through sophisticated mechanisms of precise spatio-temporal gene regulation. Acquisition of cell fate is thought to rely on the specific interaction of remotecis-regulatory modules (e.g. enhancers, silencers) (CRM) and target promoters. However, the precise interplay between chromatin structure and gene expression is still unclear, particularly in single cells within multicellular developing organisms. Here we employ Hi-M, a single-cell spatial genomics approach, to systematically detect CRM-promoter looping interactions within topological associating domains (TADs) duringDrosophiladevelopment. By comparingcis-regulatory loops in alternate cell types, we show that physical proximity does not necessarily instruct transcriptional states. Moreover, multi-way analyses revealed the existence of local interactions between multiple remote CRMs to form hubs. We found that loops and CRM hubs are established early during development, prior to the emergence of TADs. Moreover, CRM hubs are formed via the action of the pioneer transcription factor Zelda and precede transcriptional activation. Our approach offers a new perspective on the role of CRM-promoter interactions in defining transcriptional activation and repression states, as well as distinct cell types.
Fgf/Ets signalling inXenopusectoderm initiates neural induction and patterning in an autonomous and paracrine manners
Authors: Hongo Ikuko , Okamoto Harumasa
Published: July 2020

Fibroblast growth factor (Fgf) and anti-bone morphogenetic protein (Bmp) signals are derived from the organiser of mesoderm origin and cooperate to promoteXenopusneural development from the gastrula ectoderm. Using antisense oligos to Fgf2 and Fgf8 and dominant-negative Ets transcription factors, we showed that the expression of Fgf2, Fgf8, and Ets in ectoderm cells is essential to initiate neural induction bothin vivoandin vitro. Our findings show that neural induction is initiated primarily by autonomous signalling in ectoderm cells, rather than by paracrine signalling from organiser cells. The signalling in ectoderm cells is transduced via the Fgf/Ras/Mapk/Ets pathway, independent of Bmp signal inhibition via the Fgf/Ras/Mapk/Smad1 route, as indicated by earlier studies. Through the same pathway, Fgfs activated position-specific neural genes dose-dependently along the anteroposterior axis in cultured ectoderm cells. The expression of these genes coincides with the establishment of the activated Ets gradient within the gastrula ectoderm. Organiser cells, being located posteriorly to the ectoderm, secrete Fgfs as gastrulation proceeds, which among several candidate molecules initially promote neural patterning of the induced neuroectoderm as morphogens.

Summary statement

Fgf/Ets signalling in ectodermal cells is required to initiate the expression of both anterior and posterior neural genes from the late blastula to gastrula stages, independent of anti-Bmp signalling.