bluuebunny/crossref_metadata_2025 huggingface dataset:
Variation in intraspecific demography drives localised concordance but species-wide discordance in responses to Plio-Pleistocene climatic change
Authors: Buckley Sean James , Brauer Chris , Unmack Peter J. , Hammer Michael P. , Beheregaray Luciano B.
Published: September 2021

Understanding how species biology may facilitate resilience to climate change remains a critical factor in detecting and protecting species at risk of extinction. Many studies have focused on the role of particular ecological traits in driving species responses, but less so on demographic history and levels of standing genetic variation. We used environmental and genomic datasets to reconstruct the phylogeographic histories of two ecologically similar and largely co-distributed freshwater fishes to assess the degree of concordance in their responses to Plio-Pleistocene climatic changes. Although several co-occurring populations demonstrated concordant demographic histories, idiosyncratic population size changes were found at the range edges of the more spatially restricted species. Discordant responses between species were associated with low standing genetic variation in peripheral populations. This might have hindered adaptive potential, as documented in recent population declines and extinctions of the two species. Our results highlight both the role of spatial scale in the degree of concordance in species responses to climate change, and the importance of standing genetic variation in facilitating range shifts. Even when ecological traits are similar between species, long-term genetic diversity and historical population demography may lead to discordant responses to ongoing and future climate change.
Neural signatures of compression in the retelling of past events
Authors: Musz Elizabeth , Chen Janice
Published: September 2021

When we retell our past experiences, we aim to reproduce some version of the original events; this reproduced version is often temporally compressed relative to the original. How does such compression of memories manifest in brain activity? One possibility is that a compressed retrieved memory manifests as a neural pattern which is more dissimilar to the original, relative to a more detailed or vivid memory. However, we argue that measuring raw dissimilarity alone is insufficient, as it confuses a variety of interesting and uninteresting changes. To address this problem, we examine brain pattern changes that are consistent across people. We show that temporal compression in individuals’ retelling of past events predicts systematic encoding-to-recall transformations in a number of higher associative regions. These findings elucidate how neural representations are not simply reactivated, but can also be transformed due to temporal compression during a universal form of human memory expression: verbal retelling.
Polygenic score accuracy in ancient samples: quantifying the effects of allelic turnover
Authors: Carlson Maryn O. , Rice Daniel P. , Berg Jeremy J. , Steinrücken Matthias
Published: September 2021

Polygenic scores link the genotypes of ancient individuals to their phenotypes, which are often unobservable, offering a tantalizing opportunity to reconstruct complex trait evolution. In practice, however, interpretation of ancient polygenic scores is subject to numerous assumptions. For one, the genome-wide association (GWA) studies from which polygenic scores are derived, can only estimate effect sizes for loci segregating in contemporary populations. Therefore, a GWA study may not correctly identify all loci relevant to trait variation in the ancient population. In addition, the frequencies of trait-associated loci may have changed in the intervening years. Here, we devise a theoretical framework to quantify the effect of this allelic turnover on the statistical properties of polygenic scores as functions of population genetic dynamics, trait architecture, power to detect significant loci, and the age of the ancient sample. We model the allele frequencies of loci underlying trait variation using the Wright-Fisher diffusion, and employ the spectral representation of its transition density to find analytical expressions for several error metrics, including the correlation between an ancient individual’s polygenic score and true phenotype, referred to as polygenic score accuracy. Our theory also applies to a two-population scenario and demonstrates that allelic turnover alonemayexplain a substantial percentage of the reduced accuracy observed in cross-population predictions, akin to those performed in human genetics. Finally, we use simulations to explore the effects of recent directional selection, a bias-inducing process, on the statistics of interest. We find that even in the presence of bias, weak selection induces minimal deviations from our neutral expectations for the decay of polygenic score accuracy. By quantifying the limitations of polygenic scores in an explicit evolutionary context, our work lays the foundation for the development of more sophisticated statistical procedures to analyze both temporally and geographically resolved polygenic scores.
Extrasynaptic signaling enables an asymmetric juvenile motor circuit to produce a symmetric undulation
Authors: Lu Yangning , Ahamed Tosif , Mulcahy Ben , Meng Jun , Witvliet Daniel , Guan Sihui Asuka , Holmyard Douglas , Hung Wesley , Wen Quan , Chisholm Andrew D , Samuel Aravinthan DT , Zhen Mei
Published: September 2021

In many animals, there is a direct correspondence between the motor patterns that drive locomotion and the motor neuron innervation onto the muscle groups. For example, the adult C. elegans moves with symmetric and alternating dorsal-ventral bending waves arising from symmetric motor neuron input onto the dorsal and ventral muscles. In contrast to the adult, the C. elegans motor circuit at the juvenile larval stage has asymmetric wiring between motor neurons and muscles, but still generates adult-like bending waves with dorsal-ventral symmetry. We show that in the juvenile circuit, wiring between excitatory and inhibitory motor neurons coordinates the contraction of dorsal muscles with relaxation of ventral muscles, producing dorsal bends. However, ventral bending is not driven by analogous wiring. Instead, ventral muscles are excited uniformly by premotor interneurons through extrasynaptic signaling. Ventral bends occur in anti-phasic entrainment to activity of the same motor neurons that drive dorsal bends. During maturation, the juvenile motor circuit is replaced by two motor subcircuits that separately drive dorsal and ventral bending. Modeling reveals that the juvenile’s immature motor circuit is an adequate solution to generate adult-like dorsal-ventral bending before the animal matures. Developmental rewiring between functionally degenerate circuit solutions, that both generate symmetric bending patterns, minimizes behavioral disruption across maturation.

Highlights

C. elegans larvae generate symmetric motor pattern with an asymmetrically wired motor circuit.

Synaptic wiring between excitatory and inhibitory motor neurons drives dorsal bending.

Extrasynaptic excitation by premotor interneurons entrains ventral muscles for anti-phasic ventral bending.

A developmental strategy to enable mature motor pattern before the circuit structurally matures.
Urethane Anesthesia Exhibits Neurophysiological Correlates of Unconsciousness and is Distinct from Sleep
Authors: Mondino Alejandra , González Joaquín , Li Duan , Mateos Diego , Osorio Lucía , Cavelli Matías , Costa Alicia , Vanini Giancarlo , Mashour George , Torterolo Pablo
Published: September 2021

Urethane is a general anesthetic widely used in animal research. It is unique among anesthetics because urethane anesthesia alternates between macroscopically distinct electrographic states: a slow-wave state that resembles NREM sleep (NREMure), and an activated state with features of both REM sleep and wakefulness (REMure). However, the relationship between urethane anesthesia and physiological sleep is still unclear. In this study, electroencephalography (EEG) and electromyography were recorded in chronically prepared rats during natural sleep-wake states and during urethane anesthesia. We subsequently analyzed the EEG signatures associated with the loss of consciousness and found that, in comparison to natural sleep-wake states, the power, coherence, directed connectivity and complexity of brain oscillations are distinct during urethane. We also demonstrate that both urethane states have clear EEG signatures of general anesthesia. Thus, despite superficial similarities that have led others to conclude that urethane is a model of sleep, the electrocortical traits of depressed and activated states during urethane anesthesia differ from physiological sleep states.
An 8 week randomized Dietary Guidelines for Americans -based diet intervention improves the omega-3 index of healthy women
Authors: Richardson Christine E. , Krishnan Sridevi , Gray Ira J. , Keim Nancy L. , Newman John W.
Published: September 2021

Background

The Dietary Guidelines for Americans (DGA) recommends consuming >1.75g/wk of long-chain omega-3 fatty acids to reduce the risk of cardiovascular disease (CVD) through triglyceride reduction, however individual responses to treatment vary.

Objective

We sought to determine if a DGA-conforming diet (DGAD) can increase the omega-3 index (OM3I), a diet-sensitive biomarker of omega-3 fatty acid status, into a health promoting range and reduce fasting triglycerides in 8 weeks. We further explored determinants of the basal OM3I and its response to treatment.

Design

This is a secondary analysis of a randomized, double-blind 8wk dietary intervention of overweight/obese women fed an 8d rotating DGAD (n =22) or typical American diet (TAD; n =20) registered at www.clinicaltrials.gov as NCT02298725. The DGAD and TAD provided individuals with 16 ± 2 g/wk and 1.2 ± 0.12 g/wk of eisocapentaenoic acid (EPA) + docosahexaenoic acid (DHA), respectively. Habitual diet and body composition were determined at baseline. OM3I, fasting triglycerides, glucose and insulin were measured at 0, 2 and 8wk.

Results

Baseline OM3I (5.8 ± 1.3; n =42) was positively correlated to the dietary (EPA+DHA):dietary fat ratio (p =0.006), negatively correlated to the android fat mass (p =0.0007) and was not different between diet groups. At 8wk, while the TAD-group average OM3I was unchanged (5.8 ± 0.76), the DGAD-group OM3I increased (7.33 ± 1.36; p <0.001). In the DGAD-group 9 of 22 (i.e. 41%) participants achieving an OM3I >8%. Subgroup analyses of the DGAD-group revealed that body fat content and distribution influenced the baseline-dependent response to treatment. Fasting triglyceride and OM3I changes did not correlate.

Conclusions

An 8wk TAD stabilized the OM3I in a healthy range, while a DGAD increased the OM3I into a health-promoting range, but did not reduce fasting triglycerides. Fat distribution and basal omega-3 status are primary factors influencing omega-3 efficacy in overweight/obese women.
Automated Multilabel Diagnosis on Electrocardiographic Images and Signals
Authors: Sangha Veer , Mortazavi Bobak J. , Haimovich Adrian D. , Ribeiro Antônio H. , Brandt Cynthia A. , Jacoby Daniel L. , Schulz Wade L. , Krumholz Harlan M. , Ribeiro Antonio Luiz P. , Khera Rohan
Published: September 2021

Aims

The application of artificial intelligence (AI) for automated diagnosis of electrocardiograms (ECGs) can improve access to high quality diagnostic care in remote settings but is limited by the reliance on signal-based data that are not routinely available. We sought to develop a multilabel automated diagnosis model for electrocardiographic images, more suitable for broader use.

Methods and Results

A total of 2,228,236 12-lead ECGs from 811 municipalities in Minas Gerais, Brazil were sampled into 90% (training):5%(validation):5%(held-out test), and were transformed to ECG images with varying lead locations and formats. We trained a convolutional neural network (CNN) using an EfficientNet-based architecture on ECG images to identify 6 physician-defined clinical labels spanning rhythm and conduction disorders, as well as a hidden label for gender. We trained another CNN for signal-based classification. The image-based model performed well on the held-out test set (average AUROC 0.99, AUPRC 0.68). This was replicated in a distinct test set from Brazil validated by at least two cardiologists (average AUROC 0.99, AUPRC 0.86) as well as an external validation set of 21,785 ECGs from Germany (average AUROC 0.97, AUPRC 0.73), with performance superior to signal-based models. Expert review of 120 out of 120 high confidence false positive predictions on the held-out and external validation sets were confirmed to be true positives with incorrect labels. The model learned generalizable features, confirmed using Gradient-weighted Class Activation Mapping (Grad-CAM).

Conclusion

We developed an externally validated model that extends the automated diagnosis of key rhythm and conduction disorders to printed ECGs as well as to the identification of hidden features, allowing the application of AI to ECGs captured across broad settings.
Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis: a cohort study in UK Biobank
Authors: Briggs Sarah E.W. , Law Philip , East James E. , Wordsworth Sarah , Dunlop Malcolm , Houlston Richard , Hippisley-Cox Julia , Tomlinson Ian
Published: September 2021

Objectives

To evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC).

Design

Population based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women.

Setting and participants

UK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts.

Main outcome measures

Prediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models.

Findings

PRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds.

Conclusions

Integrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted.

Summary Box

What is already known on this topic

Risk stratification based on genetic or environmental risk factors could improve cancer screening outcomes

No previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond age

QCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRC

What this study adds

Adding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention
Cost-effectiveness of psychosocial assessment for individuals who present to hospital following self-harm in England: a model-based retrospective analysis
Authors: McDaid David , Park A-La , Tsiachristas Apostolos , Brand Fiona , Casey Deborah , Clements Caroline , Geulayov Galit , Kapur Nav , Ness Jennifer , Waters Keith , Hawton Keith
Published: September 2021

Aims

There are substantial costs to health care systems and society associated with self-harm. Moreover, individuals who have presented to hospital following self-harm have a much higher risk of suicide within the following year compared to the general population. National guidance in England recommends psychosocial assessment when presenting to hospital following self-harm but adherence to this guidance is variable. There is some limited evidence suggesting that psychosocial assessment is associated with lower risk of subsequent presentation to hospital for self-harm. The aim of this study was to assess the potential cost-effectiveness of psychosocial assessment for hospital-presenting self-harm in England compared to no assessment.

Methods

We constructed a three-state four-cycle Markov model to assess the cost-effectiveness of psychosocial assessment after self-harm compared with no assessment over two years. Data on risk of subsequent self-harm and hospital costs of treating different types of self-harm were drawn from prior analysis of the Multicentre Study of Self-Harm in England, while estimates of the effectiveness of psychosocial assessment on risk of self-harm, quality of life impacts and other costs were supplemented by a literature review. Incremental cost-effectiveness ratios (ICERs) were estimated in terms of cost per Quality Adjusted Life Year (QALY) gained and parameter uncertainty was addressed in univariate and probabilistic sensitivity analyses. Costs were reported in 2020 UK Pounds from the healthcare and societal perspective (that included productivity loss) and a discount rate of 3.5% was applied to future costs and QALYs.

Results

The cost per QALY gained from psychosocial assessment was £10,962 (95% uncertainty interval (UI) £15,538 - £9,219) from the NHS perspective, and £9,980 (95% UI £14,538, £6,938) from the societal perspective. Baseline results were generally robust to changes in model assumptions; the relative risk of self-harm after psychosocial assessment would have to be 0.73 or lower for the ICER to be below £20,000. The cost-effectiveness acceptability curve showed that the probability of the ICER to be below a £20,000 threshold was 78%, rising to 91% with a £30,000 threshold.

Conclusions

Psychosocial assessment as implemented in the English NHS is likely to be cost-effective. This evidence could support adherence to NICE guidelines. However, further evidence is still needed about the precise impact of psychosocial assessment on self-harm repetition and costs to individuals affected by self-harm and their families beyond immediate hospital stay.
Update of transmission modelling and projections of gambiense human African trypanosomiasis in the Mandoul focus, Chad
Authors: Rock Kat S , Huang Ching-I , Crump Ronald E , Bessell Paul R , Brown Paul E , Tirados Inaki , Solano Philippe , Antillon Marina , Picado Albert , Mbainda Severin , Darnas Justin , Crowley Emily H , Torr Steve J , Peka Mallaye
Published: September 2021

Background

In recent years, an integrated programme of vector control, screening and treatment of gambiense human African trypanosomiasis (gHAT) infections has led to a rapid decline in cases in the Mandoul disease focus of Chad. In this study, we assess whether elimination of transmission has already been achieved in the region despite low-level case reporting, quantify the role of intensified interventions in transmission reduction, and predict the trajectory of gHAT in Mandoul for the next decade under a range of control scenarios.

Method

We utilise human case data (2000–2019) to update a previous model of transmission of gHAT in Mandoul. We also test the updated model, which now has refined assumptions on diagnostic specificity of the current algorithm and an improved fitting method, via a data censoring approach.

Results

We conclude that passive detection rates have increased due to improvements in diagnostic availability in fixed health facilities since 2015, by 2.1-fold for stage 1 detection, and by 1.5-fold for stage 2. We find that whilst the diagnostic algorithm for active screening is estimated to be highly specific (99.93%, 95% CI: 99.91–99.95%), the high screening level and limited remaining infection means that some recently reported cases might be false positives, especially the ones that were not parasitologically confirmed. We also find that the focus-wide tsetse vector reduction estimated through model fitting (99.1%, 95% CI: 96.1–99.6%) is comparable to the very high reduction previously measured by the decline in catches of tsetse from monitoring traps. In line with previous results, the model suggests that transmission was likely interrupted in 2015 as a result of intensified interventions.

Conclusions

We recommend that additional confirmatory testing is performed in Mandoul in order that the endgame can be carefully monitored now that infection levels are so low. More specific measurement of cases would better inform when it is safe to stop active screening and vector control.
Periodic attention operates faster during more complex visual search
Authors: Merholz Garance , Grabot Laetitia , VanRullen Rufin , Dugué Laura
Published: September 2021

Attention has been found to sample visual information periodically, in a wide range of frequencies below 20 Hz. This periodicity may be supported by brain oscillations at corresponding frequencies. We propose that part of the discrepancy in periodic frequencies observed in the literature is due to differences in attentional demands, resulting from heterogeneity in tasks performed. To test this hypothesis, we used visual search and manipulated task complexity, i.e., target discriminability (high, medium, low) and number of distractors (set size), while electro-encephalography was simultaneously recorded. We replicated previous results showing that the phase of pre-stimulus low-frequency oscillations predicts search performance. Crucially, such effects were observed at increasing frequencies within the theta-alpha range (6-18 Hz) for decreasing target discriminability. In medium and low discriminability conditions, correct responses were further associated with higher post-stimulus phase-locking than incorrect ones, in increasing frequency and latency. Finally, the larger the set size, the later the post-stimulus effect peaked. Together, these results suggest that increased complexity (lower discriminability or larger set size) requires more attentional cycles to perform the task, partially explaining discrepancies between reports of attentional sampling. Low-frequency oscillations structure the temporal dynamics of neural activity and aid top-down, attentional control for efficient visual processing.
Expedited gene delivery for osteochondral defect repair in a rabbit knee model: a one-year investigation
Authors: Nagelli Christopher V. , De La Vega Rodolfo E. , Coenen Michael , de Lopez Consuelo Padilla , Panos Joseph A. , Tovar Alejandro , Müller Sebastian A. , Evans Christopher H.
Published: September 2021

Objective

To evaluate a single-step, gene-based procedure for repairing osteochondral lesions.

Design

Osteochondral lesions were created in the patellar groove of skeletally mature rabbits. Autologous bone marrow aspirates were mixed with adenovirus vectors carrying cDNA encoding green fluorescent protein (Ad.GFP) or transforming growth factor-β1 (Ad.TGF-β1) and allowed to clot. The clotted marrow was press-fit into the defects. Animals receiving Ad.GFP were euthanized at 2 weeks and intra-articular expression of GFP examined by fluorescence microscopy. Animals receiving Ad.TGF-β1 were euthanized at 3 months and 12 months; repair was compared to empty defects using histology and immunohistochemistry. Complementary in vitro experiments assessed transgene expression and chondrogenesis in marrow clots and fibrin gels. In a subsequent pilot study, repair at 3 months using a fibrin gel to encapsulate Ad.TGF-β1 was evaluated.

Results

At 2 weeks, GFP expression was seen at variable levels within the cartilaginous lesion. At 3 months, there was a statistically significant improvement in healing of lesions receiving Ad.TGF-β1, although variability was high. At 12 months, there was no difference between the empty defects and those receiving Ad.TGF-β1 in overall score and cartilage score, but the bone healing score remained higher. Variability was again high. In vitro experiments suggested that variability reflected variable transduction efficiency and chondrogenic activity of the marrow clots; using fibrin gels instead of marrow provided more uniformity in healing.

Conclusions

This approach to improving the repair of osteochondral lesions holds promise but needs further refinement to reduce variability and provide a more robust outcome.
Explicit expression of mesophyll conductance in the traditional leaf photosynthesis–transpiration coupled model and its physiological significances
Authors: Luo Hong , Carriquí Marc , Nadal Miquel , Han Tuo , Werner Christiane , Huang Jian-feng , Zhang Jiao-lin , Yu Zhi-guo , Li Feng-min , Fang Xiang-wen , Xue Wei
Published: September 2021

Almost all terrestrial biosphere models (TBMs) still assume infinite mesophyll conductance (gm) to estimate photosynthesis and transpiration. This assumption has caused low accuracy of TBMs to predict leaf gas exchange under certain conditions.

In this study, we developed a photosynthesis-transpiration coupled model that explicitly considers gm and designed an optimized parameterization solution through evaluating four different gm estimation methods in 19 C3 species at 31 experimental treatments.

Results indicated that temperature responses of the maximum carboxylation rate (Fcmax) and the electron transport rate (Jmax) estimated by fusing the Bayesian retrieval algorithm and the Sharkey online calculator together with gm temperature response estimated by fusing the chlorophyll fluorescence-gas exchange method and anatomy method predicted leaf gas exchange more accurately. The gm temperature response exhibited activation energy (ΔHa) of 63.13 ± 36.89 kJ mol-1 and entropy (ΔS) of 654.49 ± 11.36 J K-1 mol-1. The gm optimal temperature (Topt_gm) explained 58% of variations in photosynthesis optimal temperature (ToptA). The gm explicit expression has equally important effects on photosynthesis and transpiration estimations.

Results advanced understandings of better representation of plant photosynthesis and transpiration in TBMs.
Altered synaptic connectivity in anin vitrohuman model of STXBP1 encephalopathy
Authors: McLeod Faye , Dimtsi Anna , Lewis-Smith David , Thomas Rhys , Clowry Gavin J , Trevelyan Andrew J
Published: September 2021

Early infantile developmental and epileptic encephalopathies are devastating conditions, generally of genetic origin, but the pathological mechanisms often remain obscure. A major obstacle in this field of research is the difficulty of studying cortical brain development in humans,in utero. To address this, we established anin vitroassay to study the impact of gene variants on the developing human brain, using living organotypic cultures of the human subplate and neighbouring cortical regions, prepared from ethically sourced, 14-17 post conception week brain tissue (www.hdbr.org). We were able to maintain cultures for several months, during which time, the gross anatomical structures of the cortical plate, subplate and marginal zone persisted, while neurons continued to develop morphologically, and form new synaptic networks. This preparation thus permits the study of genetic manipulations, and their downstream effects upon an intact developing human cortical network. We focused upon STXBP1 haploinsufficiency, which is among the most common genetic causes of developmental and epileptic encephalopathy. This was induced using shRNA interference, leading to impaired synaptic function and a drop in the number of glutamatergic synapses. We thereby provide a critical proof-of-principle for how to study the impact of any gene of interest on the development of the human cortex.
The impact of genetic risk for Alzheimer’s disease on the structural brain networks of young adults
Authors: Mirza-Davies Anastasia , Foley Sonya , Caseras Xavier , Baker Emily , Holmans Peter , Escott-Price Valentina , Jones Derek K. , Harrison Judith R. , Messaritaki Eirini
Published: September 2021

We investigated the structural brain networks of 562 young adults in relation to polygenic risk for Alzheimer’s disease, using magnetic resonance imaging (MRI) and genotype data from the Avon Longitudinal Study of Parents and Children. Diffusion MRI data were used to perform whole-brain tractography and to generate structural brain networks for the whole-brain connectome, and for the default mode, limbic and visual subnetworks. The mean clustering coefficient, mean betweenness centrality, characteristic path length, global efficiency and mean nodal strength were calculated for these networks, for each participant. The connectivity of the rich-club, feeder and local connections was also calculated. Polygenic risk scores (PRS), estimating each participant’s genetic risk, were calculated at genome-wide level and for nine specific disease pathways. Correlations were calculated between the PRS and a) the graph theoretical metrics of the structural networks and b) the rich-club, feeder and local connectivity of the whole-brain networks.

In the visual subnetwork, the mean nodal strength was negatively correlated with the genomewide PRS (r=−0.19, p=1.3×10−5), the mean betweenness centrality was positively correlated with the plasma lipoprotein particle assembly PRS (r=0.16, p=9.2×10−4), and the mean clustering coefficient was negatively correlated with the tau protein binding PRS (r=−0.16, p=9.2×10−4). In the default mode network, the mean nodal strength was negatively correlated with the genomewide PRS (r=−0.14, p=1.5×10−3). The rich-club and feeder connectivities were negatively correlated with the genome-wide PRS (r=−0.16, p=3.7×10−4; r=−0.15, p=8.8×10−4). Our results indicate small reductions in brain connectivity in young adults at risk of developing Alzheimer’s disease in later life.
Integrated phylogenomics and fossil data illuminate the evolution of beetles
Authors: Cai Chenyang , Tihelka Erik , Giacomelli Mattia , Lawrence John F. , Ślipiński Adam , Kundrata Robin , Yamamoto Shûhei , Thayer Margaret K. , Newton Alfred F. , Leschen Richard A. B. , Gimmel Matthew L. , Lü Liang , Engel Michael S. , Huang Diying , Pisani Davide , Donoghue Philip C.J.
Published: September 2021

With over 380,000 described species and possibly several million more yet unnamed, beetles represent the most biodiverse animal order. Recent phylogenomic studies have arrived at considerably incongruent topologies and widely varying estimates of divergence dates for major beetle clades. Here we use a dataset of 68 single-copy nuclear protein coding genes sampling 129 out of the 194 recognized extant families as well as the first comprehensive set of fully-justified fossil calibrations to recover a refined timescale of beetle evolution. Using phylogenetic methods that counter the effects of compositional and rate heterogeneity we recover a topology congruent with morphological studies, which we use, combined with other recent phylogenomic studies, to propose several formal changes in the classification of Coleoptera: Scirtiformia and Scirtoideasensu nov., Clambiformiaser. nov.and Clamboideasensu nov., Rhinorhipiformiaser. nov., Byrrhoideasensu nov., Dryopoideastat. res., Nosodendriformiaser. nov., and Staphyliniformiasensu nov., alongside changes below the superfamily level. The heterogeneous former superfamily Cucujoidea is divided into three monophyletic groups: Erotyloideastat. nov., Nitiduloideastat. nov., and Cucujoideasensu nov.Our divergence time analysis recovered an evolutionary timescale congruent with the fossil record: a late Carboniferous origin of Coleoptera, a late Paleozoic origin of all modern beetle suborders, and a Triassic–Jurassic origin of most extant families. While fundamental divergences within beetle phylogeny did not coincide with the hypothesis of a Cretaceous Terrestrial Revolution, many polyphagan superfamilies exhibited increases in richness with Cretaceous flowering plants.
IgMAT: immunoglobulin sequence multi-species annotation tool for any species including those with incomplete antibody annotation or unusual characteristics
Authors: Dorey-Robinson Daniel , Maccari Giuseppe , Borne Richard , Hammond John A.
Published: September 2021

The advent and continual improvement of high-throughput sequencing technologies has made immunoglobulin repertoire sequencing accessible and informative regardless of study species. However, to fully map changes in polyclonal dynamics, precise annotation of these constantly rearranging genes is pivotal. For this reason, data agnostic tools able to learn from presented data are required. Most sequence annotation tools are designed primarily for use with human and mouse antibody sequences which use databases with fixed species lists, applying very specific assumptions which select against unique structural characteristics. We present IgMAT, which utilises a reduced amino acid alphabet, incorporates multiple HMM alignments into a single consensus and enables the incorporation of user defined databases to better represent their species of interest.

Availability and implementation

IgMAT has been developed as a python module, and is available on GitHub (https://github.com/TPI-Immunogenetics/igmat) for download under GPLv3 license.

Supplementary information

Model Breakdowns
Oscillatory calcium release and sustained store-operated oscillatory calcium signaling prevents differentiation of human oligodendrocyte progenitor cells
Authors: Seidman Richard A. , Khattab Heba , Polanco Jessie J. , Broome Jacqueline E. , Sim Fraser J.
Published: September 2021

Endogenous remyelination in demyelinating diseases such as multiple sclerosis is contingent upon the successful differentiation of oligodendrocyte progenitor cells (OPCs). Signaling via the Gαq-coupled muscarinic receptor (M1/3R) inhibits human OPC differentiation and impairs endogenous remyelination in experimental models. We hypothesized that calcium release following Gαq-coupled receptor (GqR) activation directly regulates human OPC (hOPC) cell fate. In this study, we show that specific GqR agonists activating muscarinic and metabotropic glutamate receptors induce characteristic oscillatory calcium release in hOPCs and that these agonists similarly block hOPC maturation in vitro. Both agonists induce calcium release from endoplasmic reticulum (ER) stores and store operated calcium entry (SOCE) likely via STIM/ORAI-based channels. siRNA mediated knockdown (KD) of obligate calcium sensors STIM1 and STIM2 decreased the magnitude of muscarinic agonist induced oscillatory calcium release and attenuated SOCE in hOPCs. In addition, STIM2 expression was necessary to maintain the frequency of calcium oscillations and STIM2 KD reduced spontaneous OPC differentiation. Furthermore, STIM2 siRNA prevented the effects of muscarinic agonist treatment on OPC differentiation suggesting that SOCE is necessary for the anti-differentiative action of muscarinic receptor-dependent signaling. Finally, using a gain-of-function approach with an optogenetic STIM lentivirus, we demonstrate that independent activation of SOCE was sufficient to significantly block hOPC differentiation and this occurred in a frequency dependent manner while increasing hOPC proliferation. These findings suggest that intracellular calcium oscillations directly regulate hOPC fate and that modulation of calcium oscillation frequency may overcome inhibitory Gαq-coupled signaling that impairs myelin repair.

Significance Statement

In this study, Seidman et al. show that SOCE is a common component of ligand-based Gαq-coupled signaling in hOPCs and that SOCE alone is sufficient to block hOPC differentiation and drive proliferation. Therefore, SOCE blocks differentiation and pathological SOCE could contribute to myelin disease.
Long- and short-term history effects in a spiking network model of statistical learning
Authors: Maes Amadeus , Barahona Mauricio , Clopath Claudia
Published: September 2021

The statistical structure of the environment is often important when making decisions. There are multiple theories of how the brain represents statistical structure. One such theory states that neural activity spontaneously samples from probability distributions. In other words, the network spends more time in states which encode high-probability stimuli. Existing spiking network models implementing sampling lack the ability to learn the statistical structure from observed stimuli and instead often hard-code a dynamics. Here, we focus on how arbitrary prior knowledge about the external world can both be learned and spontaneously recollected. We present a model based upon learning the inverse of the cumulative distribution function. Learning is entirely unsupervised using biophysical neurons and biologically plausible learning rules. We show how this prior knowledge can then be accessed to compute expectations and signal surprise in downstream networks. Sensory history effects emerge from the model as a consequence of ongoing learning.
Idiosyncratic epistasis leads to global fitness-correlated trends
Authors: Bakerlee Christopher W. , Nguyen Ba Alex N. , Shulgina Yekaterina , Rojas Echenique Jose I. , Desai Michael M.
Published: September 2021

Epistasis can dramatically affect evolutionary trajectories. In recent decades, protein-level fitness landscapes have revealed extensive idiosyncratic epistasis among specific mutations. In contrast, other work has found ubiquitous and apparently non-specific patterns of global diminishing-returns and increasing-costs epistasis among mutations across the genome. Here, we use a hierarchical CRISPR gene drive system to construct all combinations of 10 missense mutations from across the genome in budding yeast, and measure their fitness in six environments. We show that the resulting fitness landscapes exhibit global fitness-correlated trends, but that these trends emerge from specific idiosyncratic interactions. This provides the first experimental validation of recent theoretical work that has argued that fitness-correlated trends can emerge as the generic consequence of idiosyncratic epistasis.

One-Sentence Summary

A genome-spanning fitness landscape reveals how idiosyncratic genetic interactions lead to global epistatic patterns.
DcPAR1 is Required for Development and Carotenoid Synthesis in the Dark-Grown Carrot Taproot
Authors: Arias Daniela , Ortega Angélica , González Christian , Quiroz Luis Felipe , Moreno-Romero Jordi , Martínez-García Jaime F. , Stange Claudia
Published: September 2021

Light stimulates carotenoid synthesis in plants during photomorphogenesis through the expression of PHYTOENE SYNTHASE (PSY), a key gene in carotenoid biosynthesis. The orange Daucus carota (carrot) synthesizes and accumulates high amounts of carotenoids in the taproot that grows underground. Contrary to other organs, light impairs carrot taproot development and represses the expression of carotenogenic genes such as DcPSY1 and DcPSY2 reducing carotenoid accumulation. By means of an RNA-seq, in previous analysis we observed that carrot PHYTOCHROME RAPIDLY REGULATED 1 (DcPAR1) is more expressed in the underground grown taproot respect to those grown in light. PAR1 is a transcriptional cofactor with a negative role in the shade avoidance syndrome regulation in Arabidopsis thaliana through the dimerization with PHYTOCHROME INTERACTING FACTORs (PIFs), allowing a moderate synthesis of carotenoids. Here we show that overexpressing AtPAR1 in carrot produces an increment of carotenoids in taproots grown underground as well as higher DcPSY1 expression. The high identity of AtPAR1 and DcPAR1 let us to suggest a functional role of DcPAR1 that was verified through the in vivo binding to AtPIF7 and the overexpression in Arabidopsis, where it increments AtPSY expression and carotenoid accumulation together with a photomorphogenic phenotype. Finally, DcPAR1 antisense carrot lines presented a dramatic decrease in carotenoids levels and in the relative expression of key carotenogenic genes as well as impairment in taproot development. These results let us to propose that DcPAR1 is a key factor for secondary root development, plastid differentiation and carotenoid synthesis in carrot taproot grown underground.

One-sentence summary

DcPAR1 is a key factor for secondary root development, plastid differentiation and carotenoid synthesis in carrot taproot grown underground.
Prescribed versus wildfire impacts on exotic plants and soil microbes in California grasslands
Authors: Glassman Sydney I , Randolph James WJ , Saroa Sameer S , Capocchi Joia K , Walters Kendra E , Pulido-Chavez M. Fabiola , Larios Loralee
Published: September 2021

Prescribed fire is often used as a management tool to decrease exotic plant cover and increase native plant cover in grasslands. These changes may also be mediated by fire impacts on soil microbial communities, which drive plant productivity and function. Yet, the ecological effects of prescribed burns compared to wildfires on either plant or soil microbial composition remain unclear.

Here, we investigated the impacts of a spring prescribed fire versus a fall wildfire on plant cover and community composition and bacterial and fungal richness, abundance, and composition in a California grassland. We used qPCR of 16S and 18S to assess impacts on bacterial and fungal abundance and Illumina MiSeq of 16S and ITS2 to assess impacts on bacterial and fungal richness and composition.

Wildfire had stronger impacts than prescribed fire on microbial communities and both fires had similar impacts on plants with both prescribed and wildfire reducing exotic plant cover but neither reducing exotic plant richness. Fungal richness declined after the wildfire but not prescribed fire, but bacterial richness was unaffected by either. Yet increasing char levels in both fire types resulted in reduced bacterial and fungal biomass, and both fire types slightly altered bacterial and fungal composition.

Exotic and native plant diversity differentially affected soil microbial diversity, with native plant diversity leading to increased arbuscular mycorrhizal fungal richness while exotic plant diversity better predicted bacterial richness. However, the remainder of the soil microbial communities were more related to aspects of soil chemistry including cation exchange capacity, organic matter, pH and phosphorous.

Synthesis and applications. Understanding the different ecological effects of prescribed fires and wildfires on plant and soil communities are key to enhancing a prevalent management action and to guide potential management opportunities post wildfires. Our coupled plant and soil community sampling allowed us to capture the sensitivity of the fungal community to fire and highlights the importance of potentially incorporating management actions such as soil or fungal amendments to promote this critical community that mediates native plant performance.
Fitting the Reproduction number from UK coronavirus case data, and why it is close to 1
Authors: Ackland Graeme J , Ackland James A , Antonioletti Mario , Wallace David J.
Published: September 2021

We present a method for rapid calculation of coronavirus growth rates and R-numbers tailored to the publicly available data in the UK. The R-number is derived from time-series of case data, using bespoke data processing to remove systematic and errors and stochastic fluctuations. In principle, growth rate can be obtained by differentiating the reported case numbers, but in fact daily stochastic fluctuations disqualify this method. We therefore assume that the case data comprises a smooth, underlying trend which is differentiable and a noise term. The approach produces, up-to-date estimates of the R-number throughout the period of data availability. Our method is validated against published consensus R-numbers from the UK government, and shown to produce comparable results. A significant advantage of our method is that it is stable up to the most recent data, this enables us to make R-number estimates available over two weeks ahead of the published consensus. The short-lived peaks observed in the R-number and case data cannot be explained by a well-mixed model and are suggestive of spread on a localised network. Such a localised spread model tends to give an Rt number close to 1, regardless of how large R0 is. The case-driven approach is combined with Weight-Shift-Scale (WSS) methods to monitor trends in the epidemic and for medium term predictions. Using case-fatality ratios, we create a narrative for trends in the UK epidemic increased infectiousness of the alpha and delta variants, and the effectiveness of vaccination in reducing severity of infection.
Tracking the temporal variation of COVID-19 surges through wastewater-based epidemiology during the peak of the pandemic: a six-month long study in Charlotte, North Carolina
Authors: Barua Visva Bharati , Islam Juel Md Ariful , Blackwood A. Denene , Clerkin Thomas , Ciesielski Mark , Sorinolu Adeola Julian , Holcomb David A. , Young Isaiah , Kimble Gina , Sypolt Shannon , Engel Lawrence S. , Noble Rachel T. , Munir Mariya
Published: September 2021

The global spread of SARS-CoV-2 has continued to be a serious concern after WHO declared the virus the causative agent of the coronavirus disease 2019 (COVID-19) a global pandemic. Monitoring of wastewater is a useful tool for assessing community prevalence given that fecal shedding of SARS-CoV-2 occurs in high concentrations by infected individuals, regardless of whether they are asymptomatic or symptomatic. Using tools that are part of the wastewater-based epidemiology (WBE) approach, combined with molecular analyses, wastewater monitoring becomes a key piece of information used to assess trends and quantify the scale and dynamics of COVID-19 infection in a specific community, municipality, or area of service. This study investigates a six-month long SARS-CoV-2 RNA quantification in influent wastewater from four municipal wastewater treatment plants (WWTP) serving the Charlotte region of North Carolina (NC) using both RT-qPCR and RT-ddPCR platforms. Influent wastewater was analyzed for the nucleocapsid (N) genes N1 and N2. Both RT-qPCR and RT-ddPCR performed well for detection and quantification of SARS-CoV-2 using the N1 target, while for the N2 target RT-ddPCR was more sensitive. SARS-CoV-2 concentration ranged from 103 to105 copies/L for all four plants. Both RT-qPCR and RT-ddPCR showed a significant moderate to a strong positive correlation between SARS-CoV-2 concentrations and the 7-day rolling average of clinically reported COVID-19 cases using a lag that ranged from 7 to 12 days. A major finding of this study is that despite small differences, both RT-qPCR and RT-ddPCR performed well for tracking the SARS-CoV-2 virus across WWTP of a range of sizes and metropolitan service functions.