bluuebunny/crossref_metadata_2025 huggingface dataset:
Can we shift belief in the ‘Law of Small Numbers’?
Authors: Bishop D. V. M. , Thompson Jackie , Parker Adam J.
Published: March 2022

‘Sample size neglect’ is a tendency to underestimate how the variability of mean estimates changes with sample size. We studied 100 participants, from science or social science backgrounds, to test whether a training task showing different-sized samples of data points (the ‘beeswarm’ task) can help overcome this bias. Ability to judge if two samples came from the same population improved with training, and 38% of participants reported that they had learned to wait for larger samples before making a response. Before and after training, participants completed a 12-item estimation quiz, including items testing sample size neglect (S-items). Bonus payments were given for correct responses. The quiz confirmed sample size neglect: 20% of participants scored zero on S-items, and only two participants achieved more than 4/6 items correct. Performance on the quiz did not improve after training, regardless of how much learning had occurred on the beeswarm task. Error patterns on the quiz were generally consistent with expectation, though there were some intriguing exceptions that could not readily be explained by sample size neglect. We suggest that training with simulated data might need to be accompanied by explicit instruction to be effective in counteracting sample size neglect more generally.
The effect of promoting hydrogen bond aggregation based on PEMTC on the mechanical properties and shape memory function of polyurethane elastomers
Authors: Wang Muqun , Liang Shaofeng , Gao Wei , Qin Yuxuan
Published: March 2022

In this work, small molecule diols named PEMTC were synthesized from isophorone diisocyanate, N-(2-hydroxyethyl)acrylamide and trimethylolpropane by a semi-directional method. PEMTC (2-(prop-2-enamido)ethyl N-{3-[({[2-ethyl-3-hydroxy-2(hydroxymethyl)propoxy]carbonyl}amino)methyl]-3,5,5-trimethylcyclohexyl}carbamate) contains hydrogen bond active site and light-initiated C=C. We introduced it as a branch chain block into poly(ε-caprolactone) (PCL). By feeding and monitoring the reaction process, we synthesized a large number of polyurethane elastomers, hydrogen bonds PCL-based elastomer (HPE), which contain a large number of dynamic hydrogen bonds. Under UV irradiation, PEMTC can make HPE molecules aggregate and cross-link, improve the degree of internal hydrogen bonding interaction of HPE materials and endow HPE materials with good elasticity, toughness, heat resistance and shape memory ability. After 270 nm UV irradiation, the elongation at break of HPE materials decreased from 607.14–1463.95% to 426.60–610.36%, but the strength at break of HPE materials increased from 3.36–13.52 to 10.28–41.52 MPa, and the toughness increased from 16.36–129.71 to 40.48–172.22 MJ m−3. In addition, the highest shape fixation rate of HPE after UV irradiation was 98.0%, and the recovery rate was 93.7%.
Linking photoacclimation responses and microbiome shifts between depth-segregated sibling species of reef corals
Authors: Prada Carlos , López-Londoño Tomás , Pollock F. Joseph , Roitman Sofia , Ritchie Kim B. , Levitan Don R. , Knowlton Nancy , Woodley Cheryl , Iglesias-Prieto Roberto , Medina Mónica
Published: March 2022

Metazoans host complex communities of microorganisms that include dinoflagellates, fungi, bacteria, archaea and viruses. Interactions among members of these complex assemblages allow hosts to adjust their physiology and metabolism to cope with environmental variation and occupy different habitats. Here, using reciprocal transplantation across depths, we studied adaptive divergence in the corals
Orbicella annularis
and
O. franksi
, two young species with contrasting vertical distribution in the Caribbean. When transplanted from deep to shallow,
O. franksi
experienced fast photoacclimation and low mortality, and maintained a consistent bacterial community. By contrast,
O. annularis
experienced high mortality and limited photoacclimation when transplanted from shallow to deep. The photophysiological collapse of
O. annularis
in the deep environment was associated with an increased microbiome variability and reduction of some bacterial taxa. Differences in the symbiotic algal community were more pronounced between coral species than between depths. Our study suggests that these sibling species are adapted to distinctive light environments partially driven by the algae photoacclimation capacity and the microbiome robustness, highlighting the importance of niche specialization in symbiotic corals for the maintenance of species diversity. Our findings have implications for the management of these threatened Caribbean corals and the effectiveness of coral reef restoration efforts.
Behavioural variation among workers promotes feed-forward loops in a simulated insect colony
Authors: Easter Carrie , Leadbeater Ellouise , Hasenjager Matthew J.
Published: March 2022

Coordinated responses in eusocial insect colonies arise from worker interaction networks that enable collective processing of ecologically relevant information. Previous studies have detected a structural motif in these networks known as the feed-forward loop, which functions to process information in other biological regulatory networks (e.g. transcriptional networks). However, the processes that generate feed-forward loops among workers and the consequences for information flow within the colony remain largely unexplored. We constructed an agent-based model to investigate how individual variation in activity and movement shaped the production of feed-forward loops in a simulated insect colony. We hypothesized that individual variation along these axes would generate feed-forward loops by driving variation in interaction frequency among workers. We found that among-individual variation in activity drove over-representation of feed-forward loops in the interaction networks by determining the directionality of interactions. However, despite previous work linking feed-forward loops with efficient information transfer, activity variation did not promote faster or more efficient information flow, thus providing no support for the hypothesis that feed-forward loops reflect selection for enhanced collective functioning. Conversely, individual variation in movement trajectory, despite playing no role in generating feed-forward loops, promoted fast and efficient information flow by linking together otherwise unconnected regions of the nest.
Analysis of the superdeterministic Invariant-set theory in a hidden-variable setting
Authors: Sen Indrajit
Published: March 2022

A recent proposal for a superdeterministic account of quantum mechanics, named Invariant-set theory, appears to bring ideas from several diverse fields like chaos theory, number theory and dynamical systems to quantum foundations. However, a clear cut hidden-variable model has not been developed, which makes it difficult to assess the Proposal from a quantum foundational perspective. In this article, we first build a hidden-variable model based on the Proposal, and then critically analyse several aspects of the Proposal using the model. We show that several arguments related to counter-factual measurements, nonlocality, non-commutativity of quantum observables, measurement independence etcetera that appear to work in the Proposal fail when considered in our model. We further show that our model is not only superdeterministic but also nonlocal, with an ontic quantum state. We argue that the bit string defined in the model is a hidden variable and that it contains redundant information. Lastly, we apply the analysis developed in a previous work (Sen I, Valentini A, 2020
Proc. R. Soc. A
,
476
, 20200214) to illustrate the issue of superdeterministic conspiracy in the model. Our results lend further support to the view that superdeterminism is unlikely to solve the puzzle posed by the Bell correlations.
Strategies for guided acoustic wave inspection using mobile robots
Authors: Zhang Jie , Niu Xudong , Croxford Anthony J. , Drinkwater Bruce W.
Published: March 2022

Continuous non-destructive monitoring of large-scale structures is extremely challenging with traditional manual inspections. In this paper, we explore possible strategies that a collection of inspection robots could adopt to address this challenge. We envision the continuous inspection of a plate performed by multiple robots or a single robot that combines measurements from multiple locations. The robots use guided ultrasonic waves to interrogate a localized region for defects such as cracking or corrosion. In the detection stage, the receiver operating characteristic defines a detection zone in which a defect is thought to be present. In the localization stage, further measurements are made to locate the defect within this zone to a certain accuracy. We then address the question of what additional measurements are needed to achieve a given level of performance in the presence of uncertainty in robot locations? We explore this problem with Monte Carlo simulations that reveal the compromise between number of robots and performance in terms of defect location accuracy. In an experimental validation example on an aluminium plate, we show that six measurements arranged in a pentagon with a central measurement point leads to localization errors of similar magnitude to the uncertainty in sensor location.
The influence of knowledge level on the proportion of wealth in the stock market
Authors: Hu Chunhua , Lai Shaoyong
Published: March 2022

The kinetic theory is applied to investigate the impact of knowledge level on the proportion of wealth in the stock market. Assume that each agent’s wealth is non-negative in the financial market and agents are allowed to choose their own portfolios in the stock and bond. The nonlinear Boltzmann models describing the investment proportion of wealth between the two assets and knowledge formation are discussed. In the models, the agent’s knowledge level and psychological factors affect their investment strategies and risk prediction. A value function containing the current price and intrinsic value of the stock is used to depict the agent’s psychological factors. The asymptotic procedure is employed to obtain the Fokker–Planck equation relating to the Boltzmann model. The numerical simulation experiments illustrate that knowledge has the potential to increase the proportion of wealth invested in the stock and improve the wealth status of agents.
Accumulation time of diffusion in a two-dimensional singularly perturbed domain
Authors: Bressloff P. C.
Published: March 2022

A general problem of current interest is the analysis of diffusion problems in singularly perturbed domains, within which small subdomains are removed from the domain interior and boundary conditions imposed on the resulting holes. One major application is to intracellular diffusion, where the holes could represent organelles or biochemical substrates. In this paper, we use a combination of matched asymptotic analysis and Green’s function methods to calculate the so-called accumulation time for relaxation to steady state. The standard measure of the relaxation rate is in terms of the principal non-zero eigenvalue of the negative Laplacian. However, this global measure does not account for possible differences in the relaxation rate at different spatial locations, is independent of the initial conditions, and relies on the assumption that the eigenvalues have sufficiently large spectral gaps. As previously established for diffusion-based morphogen gradient formation, the accumulation time provides a better measure of the relaxation process.
Sex ratio in the mother's environment affects offspring population dynamics: maternal effects on population regulation
Authors: Li Wenjie , Niu Cuijuan , Bian Shijun
Published: March 2022

Classic population regulation theories usually concern the influence of immediate factors on current populations, but studies investigating the effect of parental environment factors on their offspring populations are scarce. The maternal environments can affect offspring life-history traits across generations, which may affect population dynamics and be a mechanism of population regulation. In cyclical parthenogens, sexual reproduction is typically linked with dormancy, thereby providing a negative feedback to population growth. In this study, we manipulated population sex ratios in the mother's environment to investigate whether this factor affected future population dynamics by regulating offspring sexual reproduction in the rotiferBrachionus calyciflorus. Compared with females in male-biased environments, those in female-biased environments produced fewer mictic (sexual) offspring, and their amictic (asexual) offspring also produced a lower proportion of mictic females at a gradient of population densities. Moreover, populations that were manipulated under male-biased conditions showed significantly smaller population sizes than those under female-biased conditions. Our results indicated that in cyclical parthenogens, mothers could adjust the sexual reproduction of their offspring in response to the current population sex ratio, thus providing fine-scale regulation of population dynamics in addition to population density.
Simultaneous determination of HCV genotype and NS5B resistance associated substitutions using dried serum spots from São Paulo state, Brazil
Authors: Adeboyejo Kazeem , Grosche Victória Riquena , José Diego Pandeló , Ferreira Giulia Magalhães , Shimizu Jacqueline Farinha , King Barnabas J. , Tarr Alexander W. , Soares Márcia Maria Costa Nunes , Ball Jonathan K. , McClure C. Patrick , Jardim Ana Carolina Gomes
Published: March 2022

Hepatitis C virus (HCV) is responsible for more than 180 million infections worldwide, and about 80 % of infections are reported in Low and Middle-income countries (LMICs). Therapy is based on the administration of interferon (INF), ribavirin (RBV) or more recently Direct-Acting Antivirals (DAAs). However, amino acid substitutions associated with resistance (RAS) have been extensively described and can contribute to treatment failure, and diagnosis of RAS requires considerable infrastructure, not always locally available. Dried serum spots (DSS) sampling is an alternative specimen collection method, which embeds drops of serum onto filter paper to be transported by posting to a centralized laboratory. Here, we assessed feasibility of genotypic analysis of HCV from DSS in a cohort of 80 patients from São Paulo state Brazil. HCV RNA was detected on DSS specimens in 83 % of samples of HCV infected patients. HCV genotypes 1a, 1b, 2a, 2c and 3a were determined using the sequence of the palm domain of NS5B region, and RAS C316N/Y, Q309R and V321I were identified in HCV 1b samples. Concerning therapy outcome, 75 % of the patients who used INF +RBV as a previous protocol of treatment did not respond to DAAs, and 25 % were end-of-treatment responders. It suggests that therapy with INF plus RBV may contribute for non-response to a second therapeutic protocol with DAAs. One patient that presented RAS (V321I) was classified as non-responder, and combination of RAS C316N and Q309R does not necessarily imply in resistance to treatment in this cohort of patients. Data presented herein highlights the relevance of studying circulating variants for a better understanding of HCV variability and resistance to the therapy. Furthermore, the feasibility of carrying out genotyping and RAS phenotyping analysis by using DSS card for the potential of informing future treatment interventions could be relevant to overcome the limitations of processing samples in several location worldwide, especially in LMICs.
When and where to count? Implications of migratory connectivity and non-breeding distribution to population censuses in a migratory bird population
Authors: Piironen Antti , Fox Anthony D. , Kampe-Persson Hakon , Skyllberg Ulf , Therkildsen Ole Roland , Laaksonen Toni
Published: March 2022

Migratory connectivity is a metric of the co-occurrence of migratory animals originating from different breeding sites, and like their spatio-temporal distributions, can vary substantially during the annual cycle. Together, both these properties affect the optimal times and sites of population censusing.

We tracked taiga bean geese(Anser fabalis fabalis)during 2014–2021 to study their migratory connectivity and non-breeding movements, and determine optimal periods to assess the size of their main flyway population. We also compared available census data with tracking data, to examine how well two existing censuses covered the population.

Daily Mantel’s correlation between breeding and non-breeding sites lay between 0 and 0.5 during most of the non-breeding season, implying birds from different breeding areas were not strongly separated other times in the annual cycle. However, the connectivity was higher among birds from the westernmost breeding areas compared to the birds breeding elsewhere. Daily Minimum Convex Polygons showed tracked birds were highly aggregated at census times, confirming their utility. The number of tracked birds absent at count sites during the censuses however exceeded numbers double-counted at several sites, indicating that censuses might have underestimated the true population size.

Our results show that connectivity can vary in different times during the non-breeding period, and should be studied throughout the annual cycle. Our results also confirm previous studies, which have found that estimates using marked individuals usually produce higher population size estimates than total counts. This should be considered when using total counts to assess population sizes in the future.
Identification of protein aggregates in the aging vertebrate brain with prion-like and phase separation properties
Authors: Harel Itamar , Chen Yiwen R. , Ziv Inbal , Singh Param Priya , Negredo Paloma Navarro , Goshtchevsky Uri , Wang Wei , Astre Gwendoline , Moses Eitan , McKay Andrew , Machado Ben E. , Hebestreit Katja , Yin Sifei , Alvarado Alejandro Sánchez , Jarosz Daniel F. , Brunet Anne
Published: March 2022

Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during normal brain aging remains unknown. Here we use quantitative proteomics in the African turquoise killifish to identify protein aggregates that accumulate in old vertebrate brains. These aggregates are enriched for prion-like RNA binding proteins, notably the ATP-dependent RNA helicase DDX5. We validate that DDX5 forms mislocalized cytoplasmic aggregates in the brains of old killifish and mice. Interestingly, DDX5’s prion-like domain allows these aggregates to propagate across many generations in yeast. In vitro, DDX5 phase separates into condensates. Mutations that abolish DDX5 prion propagation also impair the protein’s ability to phase separate. DDX5 condensates exhibit enhanced enzymatic activity, but they can mature into inactive, solid aggregates. Our findings suggest that protein aggregates with prion-like properties form during normal brain aging, which could have implications for the age-dependency of cognitive decline.
Hidden potential of the supporting scaffold as a structural module for plant cystatin design
Authors: Tremblay Jonathan , Goulet Marie-Claire , Goulet Charles , Michaud Dominique
Published: March 2022

Protein engineering approaches have been proposed to improve the inhibitory properties of plant cystatins towards herbivorous pest digestive Cys proteases, typically involving sequence alterations in the inhibitory loops and/or N-terminal trunk of the protein interacting with specific amino acid residues of the target protease. In this study, we assessed whether the loops-supporting frame, or scaffold, would represent a valuable structural module for cystatin function improvement. Twenty hybrid cystatins were designed in silico, consisting of the N-terminal trunk and two inhibitory loops of a given donor cystatin grafted onto the scaffold of an alternative, recipient cystatin. Synthetic genes for the hybrids were expressed in E. coli, and the resulting proteins assessed for their potency to inhibit model Cys protease papain and the digestive Cys proteases of Colorado potato beetle (Leptinotarsa decemlineata) used as an insect pest model. In line with the occurrence of positively selected amino acids presumably influencing inhibitory activity in the scaffold region of plant cystatins, grafting the N-terminal trunk and inhibitory loops of a given cystatin onto the scaffold of an alternative cystatin generally had an effect on the inhibitory potency of these function-related elements against Cys proteases. For instance, hybrid cystatins including the three structural elements of model tomato cystatin SlCYS8 grafted on the scaffold of cystatins from other plant families showed Ki values altered by up to 3-fold for papain, and inhibitory efficiencies increased by up to 8-fold against L. decemlineata cathepsin L-like proteases, compared to wild-type SlCYS8 bearing the original scaffold. Our data point to a significant influence of the cystatin scaffold on the inhibitory activity of the N-terminal trunk and protease inhibitory loops. They also suggest the potential of this structural element as a module for plant cystatin design to generate functional variability against Cys proteases, including the digestive proteases of herbivorous pests.
Assessment of dynamics of global DNA methylation during the cryopreservation process of Pinus pinaster embryogenic lines
Authors: Mendoza-Poudereux Isabel , Cano María , Solís María Teresa , Esteve-Díaz Francisco , Testillano Pilar S. , Segura Juan , Sales Ester , Arrillaga Isabel
Published: March 2022

Long-term in vitro maintenance of embryogenic lines of Pinus species has been associated with lower maturation capacity, because of this, cryopreservation protocols for the embryogenic lines are needed to maintain valuable genotypes. Since cryopreservation may induce epigenetic variations, we evaluate changes in DNA methylation levels through the course of the cryopreservation of maritime pine embryogenic lines, as compared to those lines maintained by repeated subcultures. Six maritime pine embryogenic lines were cryopreserved following a protocol that includes pre-treatments inducing osmotic stress in liquid media. The percentage of methylated cytosines (%5-mC) in total DNA was determined by using a colorimetric assay. Reactive oxygen species (ROS) accumulation in cell lines was also determined by quantifying dihydroethidium (DHE) fluorescence under a confocal laser-scanning microscope. In the first experiment, we found that global DNA methylation was significantly reduced during the cryopreservation protocol. Subsequently, we evaluated the methylation status of both cryopreserved and no cryopreserved lines (maintained by subcultures) and found differences among embryogenic lines but overall, cryopreservation did not alter %5-mC of the recovered lines while periodical subcultures increased methylation rates. In addition, maltose pretreatment did not increase significantly ROS production in embryogenic lines. Our results demonstrate that the genetic stability during cryopreservation highly depends on the embryogenic line studied, but the protocol allows maintaining methylation DNA rates in most of the recovered lines.
Development of Dry Powder Formulations of AS01Bcontaining vaccines using Thin-Film Freeze-Drying
Authors: AboulFotouh Khaled , Xu Haiyue , Williams Robert O. , Cui Zhengrong
Published: March 2022

AS01Bis a liposomal formulation of two immunostimulants namely 3-O-desacyl-4’-monophosphoryl lipid A (MPL) and QS-21. The liposomal formulation of AS01Breduces the endotoxicity of MPL and the lytic activity of QS-21; however, it renders the adjuvant sensitive to accidental slow freezing. The liposomal formulation also represents a major challenge towards the formulation of dry powders of vaccines containing AS01B. In the present study, we tested the feasibility of applying thin-film freeze-drying (TFFD) to engineer dry powders of the AS01Bliposomal adjuvant alone or vaccines containing AS01Bas an adjuvant. Initially, we showed that after the AS01Bliposomal adjuvant was subjected to TFFD using sucrose as a stabilizer at 4%w/v, the particle size distribution of AS01Bliposomes reconstituted from the dry powder was identical to the liquid adjuvant before drying. We then showed using ovalbumin (OVA) as a model antigen adjuvanted with AS01B(AS01B/OVA) that subjecting the AS01B/OVA vaccine to TFFD and subsequent reconstitution did not negatively affect the AS01Bliposome integrity, nor the immunogenicity of the vaccine. Importantly, the thin-film freeze-dried vaccine was not sensitive to repeated freezing-and-thawing. Finally, the feasibility of using TFFD to prepare dry powders of AS01B-adjuvanted vaccines was further confirmed using AS01B-adjuvanted Fluzone Quadrivalent and Shingrix, which contains AS01B. It is concluded that the TFFD technology can enable the formulation of AS01B-adjuvanted vaccines as freezing-insensitive dry powders in single-vial presentation.
Blood-brain barrier permeability to enrofloxacin in Pengze crucian carp (Carassius auratus var. Pengze)
Authors: Zhang Fan , Wang Runping , Huang Jianzhen , Zhang Haixin , Wang Long , Zhong Zhiwei , Ruan Jiming , Liu Huazhong
Published: March 2022

To explore the permeability of blood-brain barrier (BBB) to enrofloxacin (ENR) and the role of brain injury markers in the evaluation of brain damage, crucian carp (Carassius auratus var. Pengze) was employed in this work as the research object treated by a single oral administration of the antibiotic. Results showed that ENR residues could be detected in brain of crucian carp exposed to both half lethal dose (LD50) and safe dose (SD) of ENR throughout the trial period, indicating that ENR had an ability of permeating the BBB of crucian carp. Evans blue (EB) dispersively distributed in brain tissue of fish exposed to SD ENR, but not in the vehicle-treated fish brain, which suggested structural failure of BBB by ENR. Expression levels of BBB-related molecules, occludin and P-glycoprotein (P-gp), were significantly down-regulated by ENR. Brain injury markers, NSE, S100B and GFAP were improved that were demonstrated by elevated contents of proteins in brain and serum. According to the data of correlation analysis, it was observed that ENR residue was closely related to S100B and GFAP, indicating that S100B and GFAP could be used as evaluation indicators for brain injury of crucian carp. All findings mentioned above suggest that ENR may cause structural change of BBB, resulting in biological brain damage in crucian carp.
Acinetobase: the comprehensive database and repository of Acinetobacter strains
Authors: Valcek Adam , Collier James , Botzki Alexander , Van der Henst Charles
Published: March 2022

Background

Acinetobacter baumannii is one of the most problematic nosocomial pathogens that can efficiently thrive within hospital settings, mainly due to resistances towards antibiotics, desiccation, disinfectants, human serum and oxidative stress. Recently, increased resistance against last resort antibiotics earns this bacterium the highest priority concern classified by the CDC and the WHO. An obvious hallmark of this bacterium is the high heterogeneity observed amongst A. baumannii isolates, with a limited core genome. This feature complexifies the study of A. baumannii bacteria as an entity, subsequently reflected in a diversity of phenotypes of not only antimicrobial and environmental resistance but also virulence.

Main body

High degree of genome plasticity, along with the use of a limited subset of established reference strains, can lead to strain-specific observations, decreasing the global understanding of this pathogenic agent. Phenotypic variability of A. baumannii strains is easily observable such as with the macrocolony morphologies, in vitro and in vivo virulence, natural competence level, production of different capsular polysaccharide structures and cellular densities. Some strains encode an extensive amount of virulence factors while other, including the reference strains, lack several key ones. The lack/excess of genes or specific physiological processes might interfere with in vivo and in vitro experiments, thus providing limited impact on the global understanding of Acinetobacter bacteria as a whole.

Conclusion

As an answer to the high heterogeneity amongst A. baumannii strains, we propose a first comprehensive database that includes the bacterial strains and the associated phenotypic and genetic data. This new repository, freely accessible to the entire scientific community, allow selecting the best bacterial isolate(s) related to any biological question, using an efficient and fast exchange platform.
The nuclear receptor NR4A1 restrains neutrophil granulocyte mediated brain damage in cerebral ischemia
Authors: Strecker Jan-Kolja , Liebmann Marie , Revenstorff Julian , Beuker Carolin , Schmidt-Pogoda Antje , Hucke Stephanie , Vogl Thomas , Roth Johannes , Thomas Christian , Kuhlmann Tanja , Wiendl Heinz , Klotz Luisa , Minnerup Jens
Published: March 2022

Immigration and activation of immune cells play a significant role in damage progression after ischemic stroke. It has been shown that the nuclear receptor NR4A1 exerts a crucial role within the inflammatory response of various immune diseases via regulating immune cell activation. In this study, we investigated the role of NR4A1 on the activation and recruitment of brain resident and peripheral immune cells after cerebral ischemia. Here, we show that NR4A1 mediates an anti-inflammatory and damage limiting effect after ischemic stroke through immigrating neutrophil granulocytes. Importantly, NR4A1-activation with its ligand Cytosporone-B improves functional outcome and diminishes brain damage. Therefore, modulation of NR4A1 is a promising therapeutic target in the treatment of stroke.
Mettl3-mediated m6A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration
Authors: Jiang Fu-Qing , Chen Jia-Xuan , Chen Wu-Yun , Zhao Wan-Ling , Song Guo-Hua , Liang Chi-Qian , Zhou Yi-Min , Huang Huan-Lei , Huang Rui-Jin , Zhao Hui , Park Kyu-Sang , Ju Zhen-Yu , Cai Dong-Qing , Qi Xu-Feng
Published: March 2022

Cardiovascular disease is the leading cause of death worldwide due to the inability of adult heart to regenerate after injury. N6-methyladenosine (m6A) methylation catalyzed by the enzyme methyltransferase-like 3 (Mettl3) plays important roles in various physiological and pathological bioprocesses. However, the role of m6A in heart regeneration remains largely unclear. To study m6A function in heart regeneration, we modulated Mettl3 expression in vitro and in vivo. Knockdown of Mettl3 significantly increased the proliferation of cardiomyocytes and accelerated heart regeneration following heart injury in neonatal and adult mice. However, Mettl3 overexpression decreased cardiomyocyte proliferation and suppressed heart regeneration in postnatal mice. Conjoint analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq identified Fgf16 as a downstream target of Mettl3-mediated m6A modification during postnatal heart regeneration. RIP-qPCR and luciferase reporter assays revealed that Mettl3 negatively regulates Fgf16 mRNA expression in an m6A-Ythdf2-dependent manner. The silencing of Fgf16 suppressed the proliferation of cardiomyocytes. However, the overexpression of ΔFgf16, in which the m6A consensus sequence was mutated, significantly increased cardiomyocyte proliferation and accelerated heart regeneration in postnatal mice compared with wild-type Fgf16. Our data demonstrate that Mettl3 post-transcriptionally reduces Fgf16 mRNA levels through an m6A-Ythdf2-dependen pathway, thereby controlling cardiomyocyte proliferation and heart regeneration.
A clinically annotated post-mortem approach to study multi-organ somatic mutational clonality in histologically healthy tissues
Authors: Luijts Tom , Elliott Kerryn , Siaw Joachim T. , Van de Velde Joris , Beyls Elien , Claeys Arne , Lammens Tim , Larsson Erik , Willaert Wouter , Vral Anne , Van den Eynden Jimmy
Published: March 2022

Recent research on histologically healthy human tissues identified omnipresent mutational microclones, driven by somatic mutations known to be responsible for carcinogenesis (e.g., in TP53 or NOTCH1). These new insights are fundamentally changing current tumour evolution models, with broad oncological implications. Most studies are based on surgical remnant tissues, which are not available for many organs and rarely in a pan-organ setting (multiple organs from the same individual). Here, we describe an approach based on clinically annotated post-mortem tissues, derived from whole-body donors that are routinely used for educational purposes at human anatomy units. We validated this post-mortem approach using UV-exposed and unexposed epidermal skin tissues and confirm the presence of positively selected NOTCH1/2-, TP53- and FAT1-driven clones. No selection signals were detected in a set of immune genes or housekeeping genes. Additionally, we provide the first evidence for smoking-induced clonal changes in oral epithelia, likely underlying the origin of head and neck carcinogenesis. In conclusion, the whole-body donor-based approach provides a nearly unlimited healthy tissue resource to study mutational clonality and gain fundamental mutagenic insights in the presumed earliest stages of tumour evolution.
microRNA-1 represses signaling pathway components to impact embryonic structures derived from all three germ layers
Authors: Sampilo Nina Faye , Song Jia L.
Published: March 2022

microRNAs are evolutionarily conserved non-coding RNAs that direct post-transcriptional regulation of target transcripts. We use the sea urchin embryo to achieve a comprehensive understanding of miR-1’s function in a developing embryo. Results indicate that miR-1 regulates gut contractions, specification, and positioning of serotonergic neurons, as well as mesodermally-derived muscles, pigment cells, and skeletogenic cells. Gain-of-function of miR-1 generally leads to more severe developmental defects than its loss-of-function. We identified that miR-1 directly suppresses Ets1/2, Tbr, and VegfR7 of the skeletogenic gene regulatory network, and Notch, Nodal, and Wnt1 signaling components. We found that miR-1’s direct suppression of Nodal may indirectly regulate FoxQ2 to impact serotonergic neurons. Excess miR-1 may lead to decreased Nodal and Notch that result in decreased circumpharnygeal muscle fibers and the number of pigment cells. The striking ectopic skeletal branching induced by miR-1 mimic injections may be explained by miR-1’s direct suppression of Nodal that leads to expression changes of Vegf3, and Fgfa that mediate skeletogenesis. This work demonstrates that miR-1 plays a diverse regulatory role that impacts tissues derived from all germ layers.

Summary statement

This study identifies wide-ranging regulatory roles and regulatory mechanisms of miR-1 that impact structures derived from all three germ layers during embryonic development.
Greenscreen decreases Type I Errors and increases true peak detection in genomic datasets including ChIP-seq
Authors: Klasfeld Sammy , Wagner Doris
Published: March 2022

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is used widely to identify both factor binding to genomic DNA and chromatin modifications. Analysis of ChIP-seq data is impacted by regions of the genome which generate ultra-high artifactual signals. To remove these signals from ChIP-seq data, ENCODE developed blacklists, comprehensive sets of regions defined by low mappability and ultra-high signals for human, mouse, worm, and flies. Currently, blacklists are not available for many model and non-model species. Here we describe an alternative approach for removing false-positive peaks we called “greenscreen”. Greenscreen is facile to implement, requires few input samples, and uses analysis tools frequently employed for ChIP-seq. We show that greenscreen removes artifact signal as effectively as blacklists in Arabidopsis and human ChIP-seq datasets while covering less of the genome, dramatically improving ChIP-seq data quality. Greenscreen filtering reveals true factor binding overlap and of occupancy changes in different genetic backgrounds or tissues. Because it is effective with as few as three inputs, greenscreen is readily adaptable for use in any species or genome build. Although developed for ChIP-seq, greenscreen also identifies artifact signals from other genomic datasets including CUT&RUN. Finally, we present an improved ChIP-seq pipeline which incorporates greenscreen, that detects more true peaks than published methods.

One Sentence Summary

A facile method for removing artifact signal from ChIP-seq that improves downstream analyses
BayesRB: a markov chain Monte Carlo-based polygenic genetic risk score algorithm for dichotomous traits
Authors: Shan Ying , Weeks Daniel E.
Published: March 2022

Abstract

Identifying high-risk individuals with diseases through reliable prediction models guides screening and preventive treatment. Most complex diseases have a genetic basis influenced by multiple genes and so disease risk can be estimated using polygenic risk score (PRS) algorithms. Many PRS algorithms have been developed so far. Among them, BayesR shows good characteristics of unbiasedness, accuracy, sparseness, and robustness. It detects the associated SNPs, estimates the SNP effects, and makes prediction of disease risks based on all SNPs simultaneously. However, this method assumes that the phenotypes follow a Gaussian distribution, which cannot be met in case-control studies. Here, we made an extension of the BayesR method, called BayesRB, by adding auxiliary variables to the BayesR model. We explored the characteristics, efficacy, and accuracy of BayesRB when estimating SNP effects and predicting disease risks compared with three traditional algorithms under different conditions using both simulated data and real data from the Welcome Trust Case Control Consortium (WTCCC). For SNP effect estimation, BayesRB shows unbiasedness and sparseness for big and small effect SNPs, respectively. For disease risk prediction, BayesRB had the best performance among the methods. This study provides a theoretical basis for complex disease risk prediction and disease prevention
An Alzheimer’s disease pathway uncovered by functional omics: the risk gene CELF1 regulates KLC1 splice variant E expression, which drives Aβ pathology
Authors: Kikuchi Masataka , Viet Justine , Nagata Kenichi , Sato Masahiro , David Géraldine , Audic Yann , Silverman Michael A. , Yamamoto Mitsuko , Akatsu Hiroyasu , Hashizume Yoshio , Chiba Kyoko , Takeda Shuko , Akamine Shoshin , Miyamoto Tesshin , Uozumi Ryota , Gotoh Shiho , Mori Kohji , Ikeda Manabu , Paillard Luc , Morihara Takashi
Published: March 2022

In an era when numerous disease-associated genes have been identified, determining the molecular mechanisms of complex diseases is still difficult. The CELF1 region was identified by genome-wide association studies as an Alzheimer’s disease (AD) risk locus. Using transcriptomics and cross-linking and immunoprecipitation sequencing (CLIP-seq), we found that CELF1, an RNA-binding protein, binds to KLC1 RNA and regulates its splicing. Analysis of two brain banks revealed that CELF1 expression is correlated with inclusion of KLC1 exons downstream of the CELF1-binding region identified by CLIP-seq. In AD, low CELF1 levels result in high levels of KLC1 splice variant E (KLC1_vE), an amyloid-β (Aβ) pathology-driving gene product. Cell culture experiments confirmed regulation of KLC1_vE by CELF1. Analysis of mouse strains with different propensities for Aβ accumulation confirmed that Klc1_vE drives Aβ pathology. Using omics methods, we revealedthe molecular pathway of a complex disease supported by human and mouse genetics.
Seroincidence of Enteric Fever in Juba, South Sudan
Authors: Aiemjoy Kristen , Rumunu John , Hassen Juma John , Wiens Kirsten E. , Garrett Denise , Kamenskaya Polina , Harris Jason B. , Azman Andrew S. , Teunis Peter , Seidman Jessica , Wamala Joseph F. , Andrews Jason R. , Charles Richelle C.
Published: March 2022

We apply a new serosurveillance tool to estimate typhoidal Salmonella burden from dried blood spots in Juba, South Sudan, finding a seroincidence rate of 35 per 100 person-years and cumulative incidence of 78% over four years.
Risk Factors and Pivotal Periods: Marital Status over 28 Years for Parents of Individuals with Autism
Authors: Bahri Niki , Sterrett Kyle , Lord Catherine
Published: March 2022

Longitudinal, prospective analyses of marital status in parents of individuals with autism are needed. We describe the timing of divorce, and the factors that contribute to divorce in a longitudinal sample of families of individuals with autism. Participants included parents of 219 children, initially referred for autism and other developmental delays, followed to age 30 years. Approximately 36% of individuals with autism in our sample experienced a parental divorce by age 30. Higher rates of divorce were associated with maternal education, race and age at child’s birth, as well as autism symptom severity and diagnosis. Divorces were most common in early years (under age 5) and also in the teenage years and beyond (over age 15). After age 15, higher risk was associated with higher cognitive ability and daily living skills, and being a multiplex family. Results suggest that divorce risk in families of children with autism remains high through childhood into early adulthood. Understanding factors related to changes in marital status may help us better support families across time.
Whole exome sequencing in multi-incident families identifies novel candidate genes for multiple sclerosis
Authors: Horjus J. , Banda T. , Heerings M. , Hakobjan M. , Witte W. De , Heersema D.J. , Jansen A.J. , Strijbis E.M.M. , de Jong B.A. , Slettenaar A.E.J. , Zeinstra E.M.P.E. , Hoogervorst E.L.J. , Franke B. , Kruijer W. , Jongen P.J. , Visser L. , Poelmans G.
Published: March 2022

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with 2 to 4 affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be further studied in cellular and/or animal models.
Convergent coexpression of autism associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies
Authors: Liao Calwing , Moyses-Oliveira Mariana , De Esch Celine EF , Bhavsar Riya , Nuttle Xander , Li Aiqun , Yu Alex , Burt Nicholas D. , Erdin Serkan , Fu Jack M. , Wang Minghui , Morley Theodore , Han Lide ,   CommonMind Consortium, Dion Patrick A. , Rouleau Guy A. , Zhang Bin , Brennand Kristen J. , Talkowski Michael E. , Ruderfer Douglas M.
Published: March 2022

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein function altering variants in many genes have been shown to contribute to ASD risk; however, understanding the biological convergence across so many genes has been difficult and genetic studies depending on presence of deleterious variation may be limited in implicating highly intolerant genes with shorter coding sequences. Here, we demonstrate that coexpression patterns from human post-mortem brain samples (N = 993) are significantly correlated with the transcriptional consequences of CRISPR perturbations (gene editing, interference and activation) in human neurons (N = 17). Across 71 ASD risk genes, there is significant tissue-specific transcriptional convergence that implicates synaptic pathways. Tissue specific convergence of risk genes is a generalizable phenomenon, shown additionally in schizophrenia (brain) and atrial fibrillation (heart). The degree of this convergence in ASD is significantly correlated with the level of association to ASD from sequencing studies (rho = -0.32, P = 3.03 ×10−65) as well as differential expression in post-mortem ASD brains (rho = -0.23, P = 2.39×10−43). After removing all genes statistically associated with ASD, the remaining positively convergent genes showed intolerance to functional mutations, had shorter coding lengths than the ASD genes and were enriched for genes with clinical reports of potential pathogenic contribution to ASD. These results indicate that leveraging convergent coexpression can identify potentially novel risk genes that are unlikely to be discovered by sequencing studies. Overall, this work provides a simple approach to functionally proxy CRISPR perturbation, demonstrates significant context-specific transcriptional convergence among known risk genes of multiple diseases, and proposes novel ASD risk gene candidates.
Risk of Suicide Ideation in Comorbid Substance Use Disorder and Major Depression
Authors: Onaemo Vivian N. , Fawehinmi Timothy O. , D’Arcy Carl
Published: March 2022

Background

Suicidal behaviour is commonly associated with major depression (MD) and substance use disorders (SUDs). However, there is a paucity of research on risk for suicide ideation among individuals with comorbid SUDs and MD in the general population.

Objectives

This study investigated the associated risk of suicide ideation in comorbid SUDs - cannabis use disorder (CUD), alcohol use disorder (AUD), drug use disorder (DUD) with depression in a nationally representative sample.

Methods

Multilevel logistic regression models were used to analyze the 2012 Canadian Community Health Survey (CCHS-MHC) data. This is a cross-sectional survey of nationally representative samples of Canadians (n = 25,113) aged 15 years and older residing in the ten Canadian provinces between January and December 2012. Diagnoses of MD episode, AUD, DUD, CUD, and suicide risk were based on the WHO-CIDI-3.0 derived from DSM-IV diagnostic criteria.

Results

Comorbidity was found to be the strongest predictor of suicide ideation. Compared to those with no diagnosis, individuals with a comorbid diagnosis of AUD with MDE, CUD with MDE, or DUD with MDE were 9 to 16 times more likely to have suicide ideation. A diagnosis of MDE was a significant predictor of suicide ideation with about a 7-fold increased risk.

Conclusion

Suicide is a preventable public health issue. Our study found a significantly increased risk of suicide ideation among persons who have comorbid SUD with MD. Effective integration of mental health and addictions services could mitigate the risk of suicide and contribute to better outcomes.