bluuebunny/crossref_metadata_2025 huggingface dataset:
Local ecological knowledge, catch characteristics and evidence of elasmobranch depletions in Western Ghana
Authors: Seidu Issah , Brobbey Lawrence K. , Danquah Emmanuel , Oppong Samuel K. , van Beuningen David , Dulvy Nicholas K.
Published: January 2021

Local Ecological Knowledge has the potential to improve fishery management by providing new data on the fishing efforts, behavior, and abundance trends of fish and other aquatic animals. Here, we relied on local knowledge of fishers to investigate ecological factors that affect elasmobranch fishers‟ operations and the changes in stock status of sharks and rays from 1980 to 2020 in five coastal communities in Ghana. Data were gathered from fishers using participant observation, interviews, focus group discussions, and participatory rural appraisal techniques. The results revealed fisher‟s understanding of six main ecological variables, which are mostly applied to enhance their fishing operations: season and weather conditions, lunar phase, bait type, presence of seabirds and fish movement, color of seawater, and sea current. These ecological features have been applied over the years to enhance fishing operations as well as maximize fisher catch. Fishers reported a profound decline in shark and ray catch from 1980 to 2020 and attributed the decline in size, number, and composition of their catch to overfishing and Illegal, Unreported and Unregulated (IUU) fishing operations. In general, most shark and ray species were abundant in 1980 but have been severely depleted as of 2020, with the exception of Blue Shark (Prionace glauca)and Devil rays (Mobulaspp), which were reported to be common by the interviewed fishers. The first species depleted were the Thresher sharks (Alopiidae), Tiger Shark (Galeocerdo cuvier), Blackchin Guitarfish (Glaucostegus cemiculus), and Lemon Shark (Negaprion brevirostris), which were depleted early in the 2000s. The next depletions of Hammerhead sharks (Sphyrnidae), Bull Shark (Carcharhinus leucas), Sand Tiger Shark (Carcharias taurus), Stingrays (Fontitrygonspp), and Spineback Guitarfish (Rhinobatos irvinei) occurred in the 2010s. We found Local Ecological Knowledge of fishers to be surprisingly consistent with scholarly knowledge and call for their inclusion in research, decision-making and management interventions by biologists and policy makers.
De novo assembly, annotation, and comparative analysis of 26 diverse maize genomes
Authors: Hufford Matthew B. , Seetharam Arun S. , Woodhouse Margaret R. , Chougule Kapeel M. , Ou Shujun , Liu Jianing , Ricci William A. , Guo Tingting , Olson Andrew , Qiu Yinjie , Coletta Rafael Della , Tittes Silas , Hudson Asher I. , Marand Alexandre P. , Wei Sharon , Lu Zhenyuan , Wang Bo , Tello-Ruiz Marcela K. , Piri Rebecca D. , Wang Na , Kim Dong won , Zeng Yibing , O’Connor Christine H. , Li Xianran , Gilbert Amanda M. , Baggs Erin , Krasileva Ksenia V. , Portwood John L. , Cannon Ethalinda K.S. , Andorf Carson M. , Manchanda Nancy , Snodgrass Samantha J. , Hufnagel David E. , Jiang Qiuhan , Pedersen Sarah , Syring Michael L. , Kudrna David A. , Llaca Victor , Fengler Kevin , Schmitz Robert J. , Ross-Ibarra Jeffrey , Yu Jianming , Gent Jonathan I. , Hirsch Candice N. , Ware Doreen , Dawe R. Kelly
Published: January 2021

We report de novo genome assemblies, transcriptomes, annotations, and methylomes for the 26 inbreds that serve as the founders for the maize nested association mapping population. The data indicate that the number of pan-genes exceeds 103,000 and that the ancient tetraploid character of maize continues to degrade by fractionation to the present day. Excellent contiguity over repeat arrays and complete annotation of centromeres further reveal the locations and internal structures of major cytological landmarks. We show that combining structural variation with SNPs can improve the power of quantitative mapping studies. Finally, we document variation at the level of DNA methylation, and demonstrate that unmethylated regions are enriched for cis-regulatory elements that overlap QTL and contribute to changes in gene expression.

One sentence summary

A multi-genome analysis of maize reveals previously unknown variation in gene content, genome structure, and methylation.
Evolution of cytokine production capacity in ancient and modern European populations
Authors: Domínguez-Andrés Jorge , Kuijpers Yunus , Bakker Olivier B. , Jaeger Martin , Xu Cheng-Jian , van der Meer Jos W.M. , Jakobsson Mattias , Bertranpetit Jaume , Joosten Leo A.B. , Li Yang , Netea Mihai G.
Published: January 2021

As our ancestors migrated throughout the different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits influencing the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.
Microclimates can be accurately predicted across ecologically important remote ecosystems
Authors: Baker D.J. , Dickson C.R. , Bergstrom D.M. , Whinam J. , Maclean I.M.D , McGeoch M.A.
Published: January 2021

Microclimate information is often crucial for understanding ecological patterns and processes, including under climate change, but is typically absent from ecological and biogeographic studies owing to difficulties in obtaining microclimate data. Recent advances in microclimate modelling, however, suggest that microclimate conditions can now be predicted anywhere at any time using hybrid physically- and empirically-based models. Here, for the first time, we test the utility of this approach across a remote, inaccessible, and climate change threatened polar island ecosystem at ecologically relevant scales. Microclimate predictions were generated at a 100 × 100 m grain (at a height of 4 cm) across the island, with models parameterised using either meteorological observations from the island’s weather station (AWS) or climate reanalysis data (CRA). AWS models had low error rates and were highly correlated with observed seasonal and daily temperatures (root mean squared error of predicted seasonal average Tmean≤ 0.6 °C; Pearson’s correlation coefficient (r) for the daily Tmean≥ 0.86). By comparison, CRA models had a slight warm bias in all seasons and a smaller diurnal range in the late summer period thanin situobservations. Despite these differences, the modelled relationship between the percentage cover of the threatened endemic cushion plantAzorella macquariensisand microclimate varied little with the source of microclimate data (r = 0.97), suggesting that both model parameterisations capture similar patterns of spatial variation in microclimate conditions across the island ecosystem. Here, we have shown that the accurate prediction of microclimate conditions at ecologically relevant spatial and temporal scales is now possible using hybrid physically- and empirically-based models across even the most remote and climatically extreme environments. These advances will help add the microclimate dimension to ecological and biogeographic studies, which could be critical for delivering climate change-resilient conservation planning in climate-change exposed ecosystems.
Discovery and functional assessment of a novel adipocyte population driven by intracellular Wnt/β-catenin signaling in mammals
Authors: Liu Zhi , Chen Tian , Zhang Sicheng , Yang Tianfang , Gong Yun , Deng Hong-Wen , Bai Ding , Tian Weidong , Chen YiPing
Published: January 2021

Wnt/β-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/β-catenin signaling, as revealed by theTcf/Lef-Gfpreporter allele, in embryonic and adult mouse fat depots, named as Wnt+adipocytes. We showed that the β-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survival. Such adipocytes are distinct from classical ones in transcriptomic and genomic signatures and can be induced from various sources of mesenchymal stromal cells including human cells. Genetic lineage-tracing and targeted cell ablation studies revealed that these adipocytes convert into beige adipocytes directly and are also required for beige fat recruitment under thermal challenge, demonstrating both cell autonomous and non-cell autonomous roles in adaptive thermogenesis. Furthermore, mice bearing targeted ablation of these adipocytes exhibited glucose intolerance, while mice receiving exogenously supplied such cells manifested enhanced glucose utilization. Our studies uncover a unique adipocyte population in regulating beiging in adipose tissues and systemic glucose homeostasis.
Using Bayesian Optimization to Identify Optimal Exoskeleton Parameters Targeting Propulsion Mechanics: A Simulation Study
Authors: Kim GilHwan , Sergi Fabrizio
Published: January 2021

In this study, we determined the feasibility of modeling the relationship between robot control parameters and propulsion mechanics as a Gaussian process. Specifically, we used data obtained in a previous experiment that used pulses of torque applied at the hip and knee joint, at early and late stance, to establish the relationship a 3D control parameter space and the resulting changes in hip extension and propulsive impulse. We estimated Gaussian models both at the group level and for each subject. Moreover, we used the estimated subject-specific models to simulate virtual human-in-the-loop optimization (HIL) experiments based on Bayesian optimization to establish their convergence under multiple combinations of acquisition functions and seed point selection methods.

Results of the group-level model are in agreement with those obtained with linear mixed effect model, thus establishing the feasibility of Gaussian process modeling. The estimated subject-specific optimal conditions have large between-subject variability in the metric of propulsive impulse, with only 31% of subjects featuring a subject-specific optimal point in the surrounding of the group-level optimal point. Virtual HIL experiments indicate that expected improvement is the most effective acquisition method, while no significant effect of seed point selection method was observed. Our study may have practical effects on the adoption of HIL robot-assisted training methods focused on propulsion.
Myoglobin primary structure reveals multiple convergent transitions to semi-aquatic life in the world’s smallest mammalian divers
Authors: He Kai , Eastman Triston G. , Czolacz Hannah , Li Shuhao , Shinohara Akio , Kawada Shin-ichiro , Springer Mark S. , Berenbrink Michael , Campbell Kevin L.
Published: January 2021

Identifying the phylogenomic underpinnings of specialized phenotypes that fueled transitions into new adaptive zones is central to evolutionary biology but is often confounded by a fragmentary fossil record, morphological convergence, and unresolved phylogenetic relationships. The speciose mammalian order Eulipotyphla (e.g., moles, shrews, hedgehogs, solenodons) combines an unusual diversity of semi-aquatic, semi-fossorial, and fossorial forms that arose from terrestrial forbearers, yet the ecomorphological pathways leading to these lifestyles have been disputed for a century and more, calling for novel approaches. Here we resolve previously intractable eulipotyphlan intra-family relationships and establish the net surface charge of the oxygen-storing muscle protein myoglobin-readily determined from its primary structure-as a molecular signature to trace ancient lifestyle transitions based on protein sequence alone. Our analyses confidently resolve fossorial habits having evolved twice in talpid moles and reveal five independent origins of a semi-aquatic lifestyle in the order housing the world’s smallest endothermic divers.
Identifying Plasmodium falciparum transmission patterns through parasite prevalence and entomological inoculation rate
Authors: Amoah Benjamin , McCann Robert S. , Kabaghe Alinune N. , Mburu Monicah , Chipeta Michael G. , Moraga Paula , Gowelo Steven , Tizifa Tinashe , van den Berg Henk , Mzilahowa Themba , Takken Willem , van Vugt Michéle , Phiri Kamija S. , Diggle Peter J. , Terlouw Dianne J. , Giorgi Emanuele
Published: January 2021

Monitoring malaria transmission is a critical component of efforts to achieve targets for elimination and eradication. Two commonly monitored metrics of transmission intensity are parasite prevalence (PR) and the entomological inoculation rate (EIR). Using geostatistical methods, we investigate the relationship betweenPlasmodium falciparumPR and EIR using data collected over 38 months in a rural area of Malawi. Our results indicate that hotspots identified through the EIR and PR partly overlapped during high transmission seasons but not during low transmission seasons. The estimated relationship showed a one-month delayed effect of EIR on PR such that at low transmission levels increases in EIR are associated with rapid rise in PR, but at high transmission levels, decreases in EIR do not translate into notable reductions in PR. Our study emphasises the need for integrated malaria control strategies that combines vector and human host managements monitored by both entomological and parasitaemia indices.
Frequency preference response in covalent modification cycles under substrate sequestration conditions
Authors: Szemere Juliana Reves , Rotstein Horacio G , Ventura Alejandra C
Published: January 2021

Covalent modification cycles (CMCs) are basic units of signaling systems and their properties are well understood. However, the behavior of such systems has been mostly characterized in situations where the substrate is in excess over the modifying enzymes. Experimental data on protein abundance suggest that the enzymes and their target proteins are present in comparable concentrations, leading to a different scenario in which the substrate is mostly sequestered by the enzymes. In this enzyme-in-excess regime, CMCs have been shown to exhibit signal termination, the ability of the product to return to a stationary value lower than the its peak in response to constant stimulation, while this stimulation is still active, with possible implications for the ability of systems to adapt to environmental inputs. We characterize the conditions leading to signal termination in CMCs in the enzyme-in-excess regime. We also demonstrate that this behavior leads to a preferred frequency response (band-pass filters) when the cycle is subjected to periodic stimulation, while the literature reports that CMCs investigated so far behave as low pass filters. We characterize the relationship between signal termination and the preferred frequency response to periodic inputs and we explore the dynamic mechanism underlying these phenomena. Finally, we describe how the behavior of CMCs is reflected in similar types of responses in the cascades of which they are part. Evidence of protein abundancein vivoshows that enzymes and substrates are present in comparable concentrations, thus suggesting that signal termination and frequency preference response to periodic inputs are also important dynamic features of cell signaling systems, which have been overlooked.
Multiplatform Integrative Analyses of Immunosuppressive Signatures in Cortisol-secreting Adrenocortical Carcinoma
Authors: Baechle Jordan J. , Hanna David N. , Konjeti Sekhar R. , Rathmell Jeffrey C. , Rathmell W. Kimryn , Baregamian Naira
Published: January 2021

Adrenocortical carcinoma (ACC) is a rare but highly aggressive malignancy and nearly half of ACC tumors have been shown to overproduce and secrete adrenal steroids. Excess cortisol secretion, in particular, has been associated with poor prognosis among ACC patients. Furthermore, recent immunotherapy clinical trials demonstrated significant immunoresistance among cortisol-secreting ACC (CS-ACC) patients when compared to their non-Cortisol-secreting (nonCS-ACC) counterparts. The immunosuppressive role of excess glucocorticoid therapies and secretion is well established, however, the impact of the cortisol hypersecretion on ACC tumor microenvironment (TME), immune expression profiles, and immune cell responses remain largely undefined. In this study, we characterized the TME of ACC patients and compared the immunogenomic profiles of nonCS-ACC and CS-ACC tumors to assess the impact of differentially expressed genes (DEGs) related to immune processes on patient prognosis. Comprehensive multiplatform immunogenomic computational analyses of ACC tumors deciphered an immunosuppressive expression profile with a direct impact on patient survival. We identified several primary immunogenomic prognostic indicators and potential targets within the tumor immune landscape of CS-ACC that define a distinct TME and provide additional insight into the understanding of potential contributory mechanisms underlying failure of initial immunotherapeutic trials and poor prognosis of patients with CS-ACC.
A sequence-based method for predicting extant fold switchers that undergo α-helix <-> β-strand transitions
Authors: Mishra Soumya , Looger Loren L. , Porter Lauren L.
Published: January 2021

Extant fold-switching proteins remodel their secondary structures and change their functions in response to cellular stimuli, regulating biological processes and affecting human health. In spite of their biological importance, these proteins remain understudied. Few representative examples of fold switchers are available in the Protein Data Bank, and they are difficult to predict. In fact, all 96 experimentally validated examples of extant fold switchers were stumbled upon by chance. Thus, predictive methods are needed to expedite the process of discovering and characterizing more of these shapeshifting proteins. Previous approaches require a solved structure or all-atom simulations, greatly constraining their use. Here, we propose a high-throughput sequence-based method for predicting extant fold switchers that transition from α-helix in one conformation to β-strand in the other. This method leverages two previous observations: (1) α-helix <-> β-strand prediction discrepancies from JPred4 are a robust predictor of fold switching, and (2) the fold-switching regions (FSRs) of some extant fold switchers have different secondary structure propensities when expressed in isolation (isolated FSRs) than when expressed within the context of their parent protein (contextualized FSRs). Combining these two observations, we ran JPred4 on the sequences of isolated and contextualized FSRs from 14 known extant fold switchers and found α-helix <->β-strand prediction discrepancies in every case. To test the overall robustness of this finding, we randomly selected regions of proteins not expected to switch folds (single-fold proteins) and found significantly fewer α-helix <-> β-strand prediction discrepancies (p < 4.2*10−20, Kolmogorov-Smirnov test). Combining these discrepancies with the overall percentage of predicted secondary structure, we developed a classifier that often robustly identifies extant fold switchers (Matthews Correlation Coefficient of 0.70). Although this classifier had a high false negative rate (6/14), its false positive rate was very low (1/211), suggesting that it can be used to predict a subset of extant fold switchers from billions of available genomic sequences.
Impact of K-Pg Mass Extinction Event on Crocodylomorpha Inferred from Phylogeny of Extinct and Extant Taxa
Authors: Magee Andrew F. , Höhna Sebastian
Published: January 2021

Crocodilians and their allies have survived several mass extinction events. However, the impact of the K-Pg mass extinction event on crocodylomorphs is considered as minor or non-existent although other clades of archosaurs, e.g., non-avian dinosaurs and pterosaurs, went extinct completely. Previous approaches using fossil occurrence data alone have proven inconclusive. In this paper, we take a phylogenetic approach using extant and extinct species. The time-calibrated phylogeny of extant crocodilians provides insights into the pattern of recent biodiversity changes whereas fossil occurrence data provide insights about the more ancient past. The two data sources combined into a single phylogeny with extinct and extant taxa provide a holistic view of the historical biodiversity. To utilize this combined data and to infer the impact of the K-Pg mass extinction event, we derive the likelihood function for a time-varying (episodic) serially sampled birth-death model that additionally incorporates mass extinctions and bursts of births. We implemented the likelihood function in a Bayesian framework with recently developed smoothing priors to accommodate for both abrupt and gradual changes in speciation, extinction and fossilization rates. Contrary to previous research, we find strong evidence for the K-Pg extinction event in crocodiles and their allies. This signal is robust to uncertainty in the phylogeny and the prior on the mass extinctions. Through simulated data analyses, we show that there is high power to detect this mass extinction and little risk of false positives.
A processing pipeline for image reconstructed fNIRS analysis using both MRI templates and individual anatomy
Authors: Forbes Samuel H. , Wijeakumar Sobanawartiny , Eggebrecht Adam T. , Magnotta Vincent A. , Spencer John P.
Published: January 2021

Aim

We demonstrate a pipeline with accompanying code to allow users to clean and prepare optode location information, prepare and standardize individual anatomical images, create the light model, run the 3D image reconstruction, and analyze data in group space.

Approach

We synthesize a combination of new and existing software packages to create a complete pipeline, from raw data to analysis.

Results

This pipeline has been tested using both templates and individual anatomy, and on data from different fNIRS data collection systems. We show high temporal correlations between channel-based and image-based fNIRS data. In addition, we demonstrate the reliability of this pipeline with a sample dataset that included 74 children as part of a longitudinal study taking place in Scotland. We demonstrate good correspondence between data in channel space and image reconstructed data.

Conclusions

The pipeline presented here makes a unique contribution by integrating multiple tools to assemble a complete pipeline for image reconstruction in fNIRS. We highlight further issues that may be of interest to future software developers in the field.

Significance

Image reconstruction of fNIRS data is a useful technique for transforming channel-based fNIRS into a volumetric representation and managing spatial variance based on optode location. We present a novel integrated pipeline for image reconstruction of fNIRS data using either MRI templates or individual anatomy.
Variational autoencoders learn universal latent representations of metabolomics data
Authors: Gomari Daniel P. , Schweickart Annalise , Cerchietti Leandro , Paietta Elisabeth , Fernandez Hugo , Al-Amin Hassen , Suhre Karsten , Krumsiek Jan
Published: January 2021

Dimensionality reduction approaches are commonly used for the deconvolution of high-dimensional metabolomics datasets into underlying core metabolic processes. However, current state-of-the-art methods are widely incapable of detecting nonlinearities in metabolomics data. Variational Autoencoders (VAEs) are a deep learning method designed to learn nonlinear latent representations which generalize to unseen data. Here, we trained a VAE on a large-scale metabolomics population cohort of human blood samples consisting of over 4,500 individuals. We analyzed the pathway composition of the latent space using a global feature importance score, which showed that latent dimensions represent distinct cellular processes. To demonstrate model generalizability, we generated latent representations of unseen metabolomics datasets on type 2 diabetes, schizophrenia, and acute myeloid leukemia and found significant correlations with clinical patient groups. Taken together, we demonstrate for the first time that the VAE is a powerful method that learns biologically meaningful, nonlinear, and universal latent representations of metabolomics data.
The Supplementary Eye Field Tracks Cognitive Efforts
Authors: Claron Julien , Royo Julie , Arcizet Fabrice , Deffieux Thomas , Tanter Mickael , Pouget Pierre
Published: January 2021

Pupil dilation is known to be an index of cognitive effort. Nevertheless, our lack of knowledge of the precise dynamics through which pupil size and activity of the medial prefrontal cortex are conjugated during cognitive tasks highlights the need for its further investigation before, during, and after changes in pupil size. Here, we tested whether pupil dynamics are related to the activity of the supplementary eye field (SEF) during a mixed pro/anti-saccade oculomotor task in two macaque monkeys. We used functional ultrasound imaging (fUS) to examine temporal changes in brain activity at the 0.1-s time scale and 0.1-mm spatial resolution in relation to behavioral performance and pupil dynamics. By combining the pupil signals and real-time imaging of NHP during cognitive tasks, we were able to infer localized CBV responses within a restricted part of the dorsomedial prefrontal cortex, referred to as the SEF, an area in which anti-saccade preparation activity is also recorded. Inversely, SEF neurovascular activity measured by fUS imaging was found to be a robust predictor of specific variations in pupil diameter over short and long time scales. Furthermore, we directly manipulated pupil diameter and CBV in the SEF using reward and cognitive effort. These results demonstrate that the SEF is an underestimated but pivotal cortical area for the monitoring and implementation of cognitive effort signals.
GAD65Cre drives reporter expression in multiple taste cell types
Authors: Larson Eric D. , Vandenbeuch Aurelie , Anderson Catherine B. , Kinnamon Sue C.
Published: January 2021

In taste buds, Type I cells represent the majority of cells (50-60%) and primarily have a glial-like function in taste buds. However, recent studies suggest that they have additional sensory and signaling functions including amiloride-sensitive salt transduction, oxytocin modulation of taste, and substance P mediated GABA release. Nonetheless, the overall function of Type I cells in transduction and signaling remains unclear, primarily because of the lack of a reliable reporter for this cell type. GAD65 expression is specific to Type I taste cells and GAD65 has been used as a Cre driver to study Type I cells in salt taste transduction. To test the specificity of transgene-driven expression, we crossed GAD65Cre mice with floxed tdTomato and Channelrhodopsin (ChR2) lines and examined the progeny with immunochemistry, chorda tympani recording, and calcium imaging. We report that while many tdTomato+ taste cells express NTPDase2, a specific marker of Type I cells, we see expression of tdTomato in both Gustducin and SNAP25 positive taste cells. We also see ChR2 in cells just outside the fungiform taste buds. Chorda tympani recordings in the GAD65Cre/ChR2 mice show large responses to blue light, larger than any response to standard taste stimuli. Further, several isolated tdTomato positive taste cells responded to KCl depolarization with increases in intracellular calcium, indicating the presence of voltage-gated calcium channels. Taken together, these data suggest that GAD65Cre mice drive expression in multiple taste cell types and thus cannot be considered a reliable reporter of Type I cell function.
Reconstructing tumor trajectories during therapy through integration of multiple measurement modalities
Authors: Griffiths Jason I. , Chen Jinfeng , Winblad Onalisa , O’Dea Anne , Sharma Priyanka , Trivedi Meghna , Kalinsky Kevin , Wisinski Kari B. , O’Regan Ruth , Makhoul Issam , Yuan Yuan , Spring Laura M. , Bardia Aditya , Jahanzeb Mohammad , Adler Frederick R. , Cohen Adam L. , Bild Andrea H. , Khan Qamar J.
Published: January 2021

Background

Accurately determining changes in tumor size during therapy is essential to evaluating response or progression. However, individual imaging methodologies often poorly reflect pathologic response and long-term treatment efficacy in patients with estrogen receptor positive (ER+) early-stage breast cancer. Mathematical models that measure tumor progression over time by integrating diverse imaging and tumor measurement modalities are not currently used but could increase accuracy in measuring response and provide biological insights into cancer evolution.

Methods

For ER+ breast cancer patients enrolled on a neoadjuvant clinical trial, we reconstructed their tumor size trajectories during therapy by combining all available information on tumor size, including different imaging modalities, physical examinations and pathological assessment data. Tumor trajectories during six months of treatment were generated, using a Gaussian process and the most probable trajectories were evaluated, based on clinical data, using measurement models that account for biases and differences in precision between tumor measurement methods, such as MRI, ultrasound and mammograms.

Results

Reconstruction of tumor trajectories during treatment identified five distinct patterns of tumor size changes, including rebound growth not evident from any single modality. These results increase specificity to distinguish innate or acquired resistance compared to using any single measurement alone. The speed of therapeutic response and extent of subsequent rebound tumor growth quantify sensitivity or resistance in this patient population.

Conclusions

Tumor trajectory reconstruction integrating multiple modalities of tumor measurement accurately describes tumor progression on therapy and reveals various patterns of patient responses. Mathematical models can integrate diverse response assessments and account for biases in tumor measurement, thereby providing insights into the timing and rate at which resistance emerges.
The role of mental simulation in primate physical inference abilities
Authors: Rajalingham Rishi , Piccato Aida , Jazayeri Mehrdad
Published: January 2021

Primates can richly parse sensory inputs to infer latent information, and adjust their behavior accordingly. It has been hypothesized that such flexible inferences are aided by simulations of internal models of the external world. However, evidence supporting this hypothesis has been based on behavioral models that do not emulate neural computations. Here, we test this hypothesis by directly comparing the behavior of humans and monkeys in a ball interception task to that of recurrent neural network (RNN) models with or without the capacity to “simulate” the underlying latent variables. Humans and monkeys had strikingly similar behavioral patterns suggesting common underlying neural computations. Comparison between primates and a large class of RNNs revealed that only RNNs that were optimized to simulate the position of the ball were able to accurately capture key features of the behavior such as systematic biases in the inference process. These results are consistent with the hypothesis that primates use mental simulation to make flexible inferences. Moreover, our work highlights a general strategy for using model neural systems to test computational hypotheses of higher brain function.
Auto-qPCR: A Python-based web app for automated and reproducible analysis of qPCR data
Authors: Maussion Gilles , Thomas Rhalena A. , Demirova Iveta , Gu Gracia , Cai Eddie , Chen Carol X.-Q , Abdian Narges , Strauss Theodore J.P. , Kelaï Sabah , Nauleau-Javaudin Angela , Beitel Lenore K. , Ramoz Nicolas , Gorwood Philip , Durcan Thomas M.
Published: January 2021

Quantifying changes in DNA and RNA levels is essential in numerous molecular biology protocols. Quantitative real time PCR (qPCR) techniques have evolved to become commonplace, however, data analysis includes many time-consuming and cumbersome steps, which can lead to mistakes and misinterpretation of data. To address these bottlenecks, we have developed an open-source Python software to automate processing of result spreadsheets from qPCR machines, employing calculations usually performed manually. Auto-qPCR is a tool that saves time when computing qPCR data, helping to ensure reproducibility of qPCR experiment analyses. Our web-based app (https://auto-q-pcr.com/) is easy to use and does not require programming knowledge or software installation. Using Auto-qPCR, we provide examples of data treatment, display and statistical analyses for four different data processing modes within one program: (1) DNA quantification to identify genomic deletion or duplication events; (2) assessment of gene expression levels using an absolute model, and relative quantification (3) with or (4) without a reference sample. Our open access Auto-qPCR software saves the time of manual data analysis and provides a more systematic workflow, minimizing the risk of errors. Our program constitutes a new tool that can be incorporated into bioinformatic and molecular biology pipelines in clinical and research labs.
Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs
Authors: Goldfarb Christine N. , Waxman David J.
Published: January 2021

While nuclear transcription and RNA processing and localization are well established for protein coding genes (PCGs), these processes are poorly understood for lncRNAs. Here, we characterize global patterns of transcript expression, maturation and localization for mouse liver RNA, including more than 15,000 lncRNAs. PolyA-selected liver RNA was isolated and sequenced from four subcellular fractions (chromatin, nucleoplasm, total nucleus, and cytoplasm), and from the chromatin-bound fraction without polyA selection. Transcript processing, determined from normalized intronic to exonic sequence read density ratios, progressively increased for PCG transcripts in going from the chromatin-bound fraction to the nucleoplasm and then on to the cytoplasm. Transcript maturation was similar for lncRNAs in the chromatin fraction, but was significantly lower in the nucleoplasm and cytoplasm. LncRNAs were 11-fold more likely to be significantly enriched in the nucleus than cytoplasm, and 100-fold more likely to be significantly chromatin-bound than nucleoplasmic. Sequencing chromatin-bound RNA greatly increased the sensitivity for detecting lowly expressed lncRNAs and enabled us to discover and localize hundreds of novel regulated liver lncRNAs, including lncRNAs showing sex-biased expression or responsiveness to a xenobiotic agonist ligand of constitutive androstane receptor (Nr1i3). Integration of our findings with prior studies and lncRNA annotations identified candidate regulatory lncRNAs for a variety of hepatic functions based on gene co-localization within topologically associating domains or transcription divergent or antisense to PCGs associated with pathways linked to hepatic physiology and diseases.
Determine independent gut microbiota-diseases association by eliminating the effects of human lifestyle factors
Authors: Wang Xin , Yang Yuqing , Li Jianchu , Jiang Rui , Chen Ting , Zhu Congmin
Published: January 2021

Human lifestyle and physiological variables on human disease risk have been revealed to be mediated by gut microbiota. Low concordance between many case-control studies for detecting disease-associated microbe existed and it is likely due to the limited sample size and the population-wide bias in human lifestyle and physiological variables. To infer association between whole gut microbiota and diseases accurately, we propose to build machine learning models by including both human variables and gut microbiota based on the American Gut Project data, the largest known publicly available human gut bacterial microbiota dataset. When the model's performance with both gut microbiota and human variables is better than the model with just human variables, the independent association of gut microbiota with the disease will be confirmed. We found that gut microbes showed different association strengths with different diseases. Adding gut microbiota into human variables enhanced the association strengths with inflammatory bowel disease (IBD) and unhealthy status; showed no effect on association strengths with Diabetes and IBS; reduced the association strengths with small intestinal bacterial overgrowth,C. difficileinfection, lactose intolerance, cardiovascular disease and mental disorders. Our results suggested that although gut microbiota was reported to be associated with many diseases, a considerable proportion of these associations may be spurious. We also proposed a list of microbes as biomarkers to classify IBD and unhealthy status, and validated them by reference to previously published research.

IMPORTANCE

we reexamined the association between gut microbiota and multiple diseases via machine learning models on a large-scale dataset, and by considering the effect of human variables ignored by previous studies, truly independent microbiota-disease associations were estimated. We found gut microbiota is associated independently with IBD and overall health of human, but more evidence is needed to judge associations between microbiota and other diseases. Further functional investigations of our reported disease-related microbes will improve understanding of the molecular mechanism of human diseases.
SARS-CoV-2 viral load distribution reveals that viral loads increase with age: a retrospective cross-sectional cohort study
Authors: Euser Sjoerd , Aronson Sem , Manders Irene , van Lelyveld Steven , Herpers Bjorn , Sinnige Jan , Kalpoe Jayant , van Gemeren Claudia , Snijders Dominic , Jansen Ruud , Stekhoven Sophie Schuurmans , van Houten Marlies , Lede Ivar , Stuart James Cohen , Megelink Fred Slijkerman , Kapteijns Erik , den Boer Jeroen , Sanders Elisabeth , Wagemakers Alex , Souverein Dennis
Published: January 2021

Objective

To describe the SARS-CoV-2 viral load distribution in different patient groups and age categories.

Methods

All SARS-CoV-2 RT-PCR results from nasopharyngeal (NP) and oropharyngeal (OP) swabs (first PCR from unique patients only) that were collected between January 1 and December 1, 2020, predominantly in the Public Health Services regions Kennemerland and Hollands Noorden, province of North Holland, the Netherlands were included in this study. Swabs were derived from patients with respiratory symptoms who were presented at the general practitioner (GP), hospital, or hospital health care workers (HCWs) of four regional hospitals, nursing home residents and HCWs of multiple nursing homes, and in majority (>75%) from Public Health testing facilities of the two Public Health Services. SARS-CoV-2 PCR crossing point (Cp) values were used to estimate viral loads (higher Cp-values indicate lower viral loads).

Results

In total, 278.455 unique patients were tested of whom 9·1% (n=25.374) were SARS-CoV-2 positive. As there were differences in viral load distribution between tested populations, further analyses focused on PCRs performed by public health services (n=211.914) where sampling and inclusion were uniform. These data reveal a clear relation between age and SARS-CoV-2 viral load, with especially children aged<12 years showing lower viral loads than shown in adults (β: −0·03, 95CI% −0·03 to −0·02, p<0·001), independent of sex and/or symptom duration. Interestingly, the median Cp-values between the oldest (>79 years) and youngest (<12 years) population differed by over 4 PCR cycles, suggesting approximately a 16-fold difference in viral load. In addition, the proportion of children aged <12 years with a low load (Cp-value >30) was significantly higher compared to the other patients (31·1% vs. 17·2%, p-value<0.001).

Conclusion

We observed that in patients tested by Public Health Services, SARS-CoV2 viral load increases significantly with age. Previous studies suggest that young children (<12 years) play a limited role in SARS-CoV-2 transmission. Currently, the relation between viral load and infectivity is not yet well understood, and further studies should elucidate whether the lower viral load in children is indeed related to their suggested limited role in SARS-CoV-2 transmission. Moreover, as rapid antigen tests are less sensitive than PCR, these results suggest that SARS-CoV-2 antigen tests could have lower sensitivity in children than in adults.
Non-invasive brain stimulation effectiveness in anxiety disorder treatment: a meta-analysis on sham/behavior-controlled studies
Authors: Vergallito Alessandra , Gallucci Alessia , Pisoni Alberto , Caselli Gabriele , Ruggiero Giovanni M. , Sassaroli Sandra , Lauro Leonor J. Romero
Published: January 2021

Background

Recently, the possibility of using non-invasive brain stimulation (NIBS) to treat mental disorders received considerable attention. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are considered effective treatments for depressive symptoms. However, no recommendation is available for anxiety disorders, suggesting that evidence is still limited.

Objective

We systematically revised the existing literature, and quantitatively analyzed the effectiveness of rTMS and tDCS in anxiety disorders treatment.

Method

Following PRISMA guidelines, 3 electronic databases were screened to the end of February 2020 to select English-written peer-reviewed articles including (i) a clinical sample of patients with anxiety disorders, (ii) the use of a NIBS technique, (iii) the inclusion of a control condition, and (iv) pre-post scores at a validated questionnaire measuring anxious symptoms.

Results

Eleven papers met the inclusion criteria, comprising 154 participants assigned to the real stimulation condition and 164 to the sham or control group. TheHedge gfor scores at disorder specific and general anxiety questionnaires before and after the treatment was computed as effect size and analyzed in two independent random-effects meta-analyses. Considering the well-known comorbidity between anxiety and depression, a third meta-analysis was run, analyzing depression scores outcomes. Results showed a significant effect of NIBS in reducing questionnaires scores in the real vs. control condition at specific and general anxiety measures, and depressive symptoms.

Conclusion

Albeit preliminary, our findings highlighted that real stimulation reduced anxiety and depression scores compared to the control condition, suggesting that NIBS can alleviate clinical symptoms in patients with anxiety diseases.
Porcine pancreatic ductal epithelial cells transformed with KRASG12Dand SV40T are tumorigenic
Authors: Bailey Katie , Cartwright Sara B. , Patel Neesha S. , Remmers Neeley , Lazenby Audrey J. , Hollingsworth Michael A. , Carlson Mark A.
Published: January 2021

We describe our initial studies in the development of an orthotopic, genetically-defined, large animal model of pancreatic cancer. Primary pancreatic epithelial cells were isolated from pancreatic duct of domestic pigs. A transformed cell line was generated from these primary cells with oncogenic KRAS and SV40T. The transformed cell lines outperformed the primary and SV40T immortalized cells in terms of proliferation, population doubling time, soft agar growth, transwell migration and invasion. The transformed cell line grew tumors when injected subcutaneously in nude mice, forming glandular structures and staining for epithelial markers. Future work will include implantation studies of these tumorigenic porcine pancreatic cell lines into the pancreas of allogeneic and autologous pigs. The resultant large animal model of pancreatic cancer could be utilized for preclinical research on diagnostic, interventional, and therapeutic technologies.
Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory
Authors: Ramaglia Valeria , Dubey Mohit , Malpede M. Alfonso , Petersen Naomi , de Vries Sharon I. , Lee Dennis S.W. , Schenk Geert J. , Gold Stefan M. , Huitinga Inge , Gommerman Jennifer L. , Geurts Jeroen J.G. , Kole Maarten H.P.
Published: January 2021

The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer, and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we further found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by a reduced spike output. Ultimately, we show that these electrophysiological changes were associated with an impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS.
DiversewMel variants ofWolbachia pipientisdifferentially rescue fertility and cytological defects of thebag of marblespartial loss of function mutation inDrosophila melanogaster
Authors: Bubnell Jaclyn E. , Fernandez-Begne Paula , Ulbing Cynthia K.S. , Aquadro Charles F.
Published: January 2021

InDrosophila melanogaster,the maternally inherited endosymbiontWolbachia pipientisinteracts with germline stem cell genes during oogenesis. One such gene,bag of marbles(bam) is the key switch for differentiation and also shows signals of adaptive evolution for protein diversification. These observations have led us to hypothesize thatW. pipientiscould be driving the adaptive evolution ofbamfor control of oogenesis. To test this hypothesis, we must understand the specificity of the genetic interaction betweenbamandW. pipientis. Previously, we documented that theW. pipientisvariant,wMel, rescued the fertility of thebamBWhypomorphic mutant as a transheterozygote over abamnull. However,bamBWwas generated more than 20 years ago in an uncontrolled genetic background and maintained over a balancer chromosome. Consequently, the chromosome carryingbamBWaccumulated mutations that have prevented controlled experiments to further assess the interaction. Here, we used CRISPR/Cas9 to engineer the same single amino acidbamhypomorphic mutation (bamL255F) and a newbamnull disruption mutation into thew1118isogenic background. We assess the fertility of wildtypebam,bamL255F/bamnullhypomorphic, andbamL255F/ bamL255Fmutant females, each infected individually with tenW. pipientis wMel variants representing three phylogenetic clades. Overall, we find that all of theW. pipientisvariants tested here rescuebamhypomorphic fertility defects withwMelCS-like variants exhibiting the strongest rescue effects. Additionally, these variants did not increase wildtypebamfemale fertility. Therefore, bothbamandW. pipientisinteract in genotype-specific ways to modulate female fertility, a critical fitness phenotype.