bluuebunny/crossref_metadata_2025 huggingface dataset:
An evidence synthesis approach for combining different data sources illustrated using entomological efficacy of insecticides for indoor residual spraying
Authors: Green Nathan , Agossa Fiacre , Yovogan Boulais , Oxborough Richard , Kitau Jovin , Müller Pie , Constant Edi , Rowland Mark , Tchacaya Emile FS , Benjamin Koudou G , Churcher Thomas S , Betancourt Michael , Sherrard-Smith Ellie
Published: May 2021

Background

Prospective malaria public health interventions are initially tested for entomological impact using standardised experimental hut trials. In some cases, data are collated as aggregated counts of potential outcomes from mosquito feeding attempts given the presence of an insecticidal intervention. Comprehensive data i.e. full breakdowns of probable outcomes of mosquito feeding attempts, are more rarely available. Bayesian evidence synthesis is a framework that explicitly combines data sources to enable the joint estimation of parameters and their uncertainties. The aggregated and comprehensive data can be combined using an evidence synthesis approach to enhance our inference about the potential impact of vector control products across different settings over time.

Methods

Aggregated and comprehensive data from a meta-analysis of the impact of Actellic® 300CS (Syngenta), an indoor residual spray (IRS) product, used on wall surfaces to kill mosquitoes and reduce malaria transmission, were analysed using a series of statistical models to understand the benefits and limitations of each.

Results

Many more data are available in aggregated format (N = 23 datasets, 5 studies) relative to comprehensive format (N = 3 datasets, 2 studies). The evidence synthesis model was most robust at predicting the probability of mosquitoes dying or surviving and blood-feeding. Generating odds ratios from the correlated Bernoulli random sample indicates that when mortality and blood-feeding are positively correlated, as exhibited in our data, the number of successfully fed mosquitoes will be under-estimated. Analysis of either dataset alone is problematic because aggregated data require an assumption of independence and there are few and variable data in the comprehensive format.

Conclusions

We developed an approach to combine sources from trials to maximise the inference that can be made from such data. Bayesian evidence synthesis enables inference from multiple datasets simultaneously to give a more informative result and highlight conflicts between sources. Advantages and limitations of these models are discussed.

Key messages

Statistical models are developed to best infer key mosquito IRS statistics from disparate data sources.

Naïve methods, previously adopted, of combining different data sources can create bias and must be explicitly considered.

Mosquitoes are highly likely to feed in experimental hut trials using indoor residual spraying of insecticides so the assumption of independence in the probability of mosquitoes dying is reflective of trial data.

We provide code for practitioners to implement this approach themselves in both BUGS and Stan languages running from R.
Parallel processing of olfactory and mechanosensory information in the honeybee antennal lobe
Authors: Tiraboschi Ettore , Leonardelli Luana , Segata Gianluca , Rigosi Elisa , Haase Albrecht
Published: May 2021

We report that airflow produces a complex activation pattern in the antennal lobes of the honeybee Apis mellifera. Glomerular response maps provide a stereotypical code for the intensity and the dynamics of mechanical stimuli that is superimposed on the olfactory code. We show responses to modulated stimuli suggesting that this combinatorial code could provide information about the intensity, direction, and dynamics of the airflow during flight and waggle dance communication.
Dysfunctions of the paraventricular hypothalamic nucleus induce hypersomnia in human and mice
Authors: Chen Chang-Rui , Zhong Yu-Heng , Jiang Shan , Xu Wei , Wang Zan , Xiao Lei , Qu Wei-Min , Huang Zhi-Li
Published: May 2021

Hypersomnolence disorder (HD) is characterized by excessive sleep, which is a common sequela following stroke, infections or tumorigenesis. HD was traditionally thought to be associated with lesions of wake-promoting nuclei. However, lesion of a single, even two or more wake-promoting nucleuses simultaneously did not exert serious HD. The specific nucleus and neural circuitry for HD remain unknown. Here, we observed that three patients with lesions around the paraventricular nucleus of the hypothalamus (PVH) showed hypersomnolence lasting more than 20 h per day and their excessive sleep decreased with the recovery of the PVH area. Therefore, we hypothesized that the PVH might play an essential role in the occurrence of HD. Using multichannel electrophysiological recording and fiber photometry, we found that PVHvglut2 neurons were preferentially active during wakefulness. Chemogenetic activation of PVHvglut2 neurons potently induced 9-h wakefulness, and PVHCRH, PVHPDYN and PVHOT neuronal activation also exerted wakefulness. Most importantly, ablation of PVHvglut2 neurons drastically induced hypersomnia-like behaviors (30.6% reduction in wakefulness). These results indicate that dysfunctions of the PVH is crucial for physiological arousal and pathogenesis underlying HD.
Hierarchical confounder discovery in the experiment–machine learning cycle
Authors: Rogozhnikov Alex , Ramkumar Pavan , Bedi Rishi , Kato Saul , Escola G. Sean
Published: May 2021

The promise of using machine learning (ML) to extract scientific insights from high dimensional datasets is tempered by the frequent presence of confounding variables, and it behooves scientists to determine whether or not a model has extracted the desired information or instead may have fallen prey to bias. Due both to features of many natural phenomena and to practical constraints of experimental design, complex bioscience datasets tend to be organized in nested hierarchies which can obfuscate the origin of a confounding effect and obviate traditional methods of confounder amelioration. We propose a simple non-parametric statistical method called the Rank-to-Group (RTG) score that can identify hierarchical confounder effects in raw data and ML-derived data embeddings. We show that RTG scores correctly assign the effects of hierarchical confounders in cases where linear methods such as regression fail. In a large public biomedical image dataset, we discover unreported effects of experimental design. We then use RTG scores to discover cross-modal correlated variability in a complex multi-phenotypic biological dataset. This approach should be of general use in experiment–analysis cycles and to ensure confounder robustness in ML models.
Orexin A excites the rat olivary pretectal nucleus via OX2 receptor in a daily manner
Authors: Chrobok Lukasz , Alwani Anna , Pradel Kamil , Klich Jasmin Daniela , Lewandowski Marian Henryk
Published: May 2021

Pronounced environmental changes between the day and night forced living organisms to evolve specialised mechanisms organising their daily physiology, named circadian clocks. Currently, it has become clear that the master clock in the suprachiasmatic nuclei of the hypothalamus is not an exclusive brain site to generate daily rhythms. Indeed, several brain areas, including the subcortical visual system have been recently shown to change their neuronal activity across the daily cycle. Here we focus our investigation on the olivary pretectal nucleus (OPN) – a retinorecipient structure primarily involved in the pupillary light reflex. Using the multi-electrode array technology ex vivo we provide evidence for OPN neurons to elevate their firing during the behaviourally quiescent light phase. Additionally, we report the robust sensitivity to orexin A via the identified OX2 receptor in this pretectal centre, with higher responsiveness noted during the night. Interestingly, we likewise report a daily variation in the response to PAC1 receptor activation, with implications for the convergence of orexinergic and visual input on the same OPN neurons. Altogether, our report is first to suggest a daily modulation of the OPN activity via intrinsic and extrinsic mechanisms, organising its temporal physiology.

GRAPHICAL ABSTRACT

HIGHLIGHTS

Neurons in the olivary pretectal nucleus (OPN) increase their firing during the day

Orexin A robustly excites the OPN via the OX2 receptor

Orexin A and the activation of PAC1 receptor are more effective during the night
Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria
Authors: Georgiadou Athina , Dunican Claire , Soro-Barrio Pablo , Lee Hyun Jae , Kaforou Myrsini , Cunnington Aubrey J.
Published: May 2021

Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. Plasmodium yoelii 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. Our data will aid selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.
The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ
Authors: Nachmanson Daniela , Officer Adam , Mori Hidetoshi , Gordon Jonathan , Evans Mark F. , Steward Joseph , Yao Huazhen , O’Keefe Thomas , Hasteh Farnaz , Stein Gary S. , Jepsen Kristen , Weaver Donald L. , Hirst Gillian L. , Sprague Brian L. , Esserman Laura J. , Borowsky Alexander D. , Stein Janet L. , Harismendy Olivier
Published: May 2021

Micro-environmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding the development of prevention strategies and the safe testing of treatment de-escalation. We addressed methodological barriers and characterized the mutational, transcriptional, histological and microenvironmental landscape across 85 multiple micro-dissected regions from 39 cases. Most somatic alterations, including whole genome duplications, were clonal, but genetic divergence increased with physical distance. Phenotypic and subtype heterogeneity frequently associated with underlying genetic heterogeneity and regions with low-risk features preceded those with high-risk features according to the inferred phylogeny. B- and T-lymphocytes spatial analysis identified 3 immune states, including an epithelial excluded state located preferentially at DCIS regions, and characterized by histological and molecular features of immune escape, independently from molecular subtypes. Such breast pre-cancer atlas with uniquely integrated observations will help scope future expansion studies and build finer models of outcomes and progression risk.
Incorporating topological and age uncertainty into event-based biogeography supports paleo-islands in Galapagos and ancient connections among Neotropical dry forests
Authors: Magalhaes Ivan L. F. , Santos Adalberto J. , Ramírez Martín J.
Published: May 2021

Event-based biogeographic methods, such as dispersal-extinction-cladogenesis, have become increasingly popular for attempting to reconstruct the biogeographic history of organisms. Such methods employ distributional data of sampled species and a dated phylogenetic tree to estimate ancestral distribution ranges. Because the input tree is often a single consensus tree, uncertainty in topology and age estimates are seldom taken into account, even when they may affect the outcome of biogeographic estimates. Even when such uncertainties are taken into account for estimates of ancestral ranges, they are usually ignored when researchers compare competing biogeographic hypotheses. We explore the effect of incorporating this uncertainty in a biogeographic analysis of the 21 species of sand spiders (Sicariidae: Sicarius) from Neotropical xeric biomes, based on a total-evidence phylogeny including a complete sampling of the genus. By using a custom R script made available here, we account for uncertainty in ages and topology by estimating ancestral ranges over a sample of trees from the posterior distribution of a Bayesian analysis, and for uncertainty in biogeographic estimates by using stochastic maps. This approach allows for counting biogeographic events such as dispersal among areas, counting lineages through time per area, and testing biogeographic hypotheses, while not overestimating the confidence in a single topology. Including uncertainty in ages indicates that Sicarius dispersed to the Galapagos Islands when the archipelago was formed by paleo-islands that are now drowned; model comparison strongly favors a scenario where dispersal took place before the current islands emerged. We also investigated past connections among currently disjunct Neotropical dry forests; failing to account for topological uncertainty underestimates possible connections among the Caatinga and Andean dry forests in favor of connections among Caatinga and Caribbean+Mesoamerican dry forests. Additionally, we find that biogeographic models including a founder-event speciation parameter (“+J”) are more prone to suffer from the overconfidence effects of estimating ancestral ranges using a single topology. This effect is alleviated by incorporating topological and age uncertainty while estimating stochastic maps, increasing the similarity in the inference of biogeographic events between models with or without a founder-event speciation parameter. We argue that incorporating phylogenetic uncertainty in biogeographic hypothesis-testing is valuable and should be a commonplace approach in the presence of rogue taxa or wide confidence intervals in age estimates, and especially when using models including founder-event speciation.
A clusterability measure for single-cell transcriptomics reveals phenotypic subpopulations
Authors: Mircea Maria , Hochane Mazène , Fan Xueying , de Sousa Lopes Susana M. Chuva , Garlaschelli Diego , Semrau Stefan
Published: May 2021

The ability to discover new cell populations by unsupervised clustering of single-cell transcriptomics data has revolutionized biology. Currently, there is no principled way to decide, whether a cluster of cells contains meaningful subpopulations that should be further resolved. Here we present SIGMA, a clusterability measure derived from random matrix theory, that can be used to identify cell clusters with non-random sub-structure, testably leading to the discovery of previously overlooked phenotypes.
Climate risks to carbon sequestration in US forests
Authors: Anderegg William R.L. , Chegwidden Oriana S. , Badgley Grayson , Trugman Anna T. , Cullenward Danny , Abatzoglou John T. , Hicke Jeffrey A. , Freeman Jeremy , Hamman Joseph J.
Published: May 2021

Forests are currently a substantial carbon sink globally. Many climate change mitigation strategies rely on forest preservation and expansion, but the effectiveness of these approaches hinges on forests sequestering carbon for centuries despite anthropogenic climate change. Yet climate-driven disturbances pose critical risks to the long-term stability of forest carbon. We quantify the key climate drivers that fuel wildfire, drought, and insects, for the United States over 1984-2018 and project future disturbance risks over the 21st century. We find that current risks are widespread and projected to increase across different emission scenarios by a factor of 4-14 for fire and 1.3-1.8 for drought and insects. Our results provide insights for carbon cycle modeling, conservation, and climate policy, underscoring the escalating climate risks facing forests and the need for emissions reductions to mitigate climate change.
Modeling SARS-CoV-2 and Influenza Infections and Antiviral Treatments in Human Lung Epithelial Tissue Equivalents
Authors: Zarkoob Hoda , Allué-Guardia Anna , Chen Yu-Chi , Jung Olive , Garcia-Vilanova Andreu , Song Min Jae , Park Jun-Gyu , Oladunni Fatai , Miller Jesse , Tung Yen-Ting , Kosik Ivan , Schultz David , Yewdell Jonathan , Torrelles Jordi B. , Martinez-Sobrido Luis , Cherry Sara , Ferrer Marc , Lee Emily M.
Published: May 2021

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third coronavirus in less than 20 years to spillover from an animal reservoir and cause severe disease in humans. High impact respiratory viruses such as pathogenic beta-coronaviruses and influenza viruses, as well as other emerging respiratory viruses, pose an ongoing global health threat to humans. There is a critical need for physiologically relevant, robust and ready to use, in vitro cellular assay platforms to rapidly model the infectivity of emerging respiratory viruses and discover and develop new antiviral treatments. Here, we validate in vitro human alveolar and tracheobronchial tissue equivalents and assess their usefulness as in vitro assay platforms in the context of live SARS-CoV-2 and influenza A virus infections. We establish the cellular complexity of two distinct tracheobronchial and alveolar epithelial air liquid interface (ALI) tissue models, describe SARS-CoV-2 and influenza virus infectivity rates and patterns in these ALI tissues, the viral-induced cytokine production as it relates to tissue-specific disease, and demonstrate the pharmacologically validity of these lung epithelium models as antiviral drug screening assay platforms.
Energy Landscape of the SARS-CoV-2 Reveals Extensive Conformational Heterogeneity
Authors: Mashayekhi Ghoncheh , Vant John , Singharoy Abhishek , Ourmazd Abbas
Published: May 2021

Cryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying energy landscape of the spike protein. As for any protein, some of the spike’s conformational motions are expected to be biophysically relevant, but cannot be interpreted only by static models. Using experimental cryo-EM images, we present the energy landscape of the spike protein conformations, and identify molecular rearrangements along the most-likely conformational path in the vicinity of the open (so called 1RBD-up) state. The resulting global and local atomic refinements reveal larger movements than those expected by comparing the reported 1RBD-up and 1RBD-down cryo-EM models. Here we report greater degrees of “openness” in global conformations of the 1RBD-up state, not revealed in the single-model interpretations of the density maps, together with conformations that overlap with the reported models. We discover how the glycan shield contributes to the stability of these conformations along the minimum free-energy pathway. A local analysis of seven key binding pockets reveals that six out them, including those for engaging ACE2, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, and protein-glycan interaction sites, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This is reminiscent of a conformational pre-equilibrium. We found only one binding pocket, namely antibody AB-C135 to remain closed along the entire minimum free energy path, suggesting an induced fit mechanism for this enzyme.
RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (Inavolisib) efficacy
Authors: Song Kyung W. , Edgar Kyle A. , Hanan Emily J. , Hafner Marc , Oeh Jason , Merchant Mark , Sampath Deepak , Nannini Michelle A. , Hong Rebecca , Phu Lilian , Forrest William F. , Stawiski Eric , Schmidt Stephen , Endres Nicholas , Guan Jane , Wallin Jeffrey J. , Cheong Jonathan , Plise Emile , Philips Gail , Salphati Laurent , Heffron Timothy P. , Olivero Alan , Malek Shiva , Staben Steven T. , Kirkpatrick Donald S. , Dey Anwesha , Friedman Lori S.
Published: May 2021

PIK3CA is one of the most frequently mutated oncogenes; the p110α protein it encodes plays a central role in tumor cell proliferation and survival. Small molecule inhibitors targeting the PI3K p110α catalytic subunit have entered clinical trials, with early-phase GDC-0077 (Inavolisib) studies showing anti-tumor activity and a manageable safety profile in patients with PIK3CA-mutant, hormone receptor-positive breast cancer as a single agent or in combination therapy. Despite this, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression, resulting in enhanced apoptosis and greater efficacy. This unique mechanism against mutant p110α reveals a new strategy for creating inhibitors that specifically target mutant tumors with selective degradation of the mutant oncoprotein and also provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer.
Remote spatially variant debiased profiling of cell and tissue mechanical properties
Authors: Mason Jonathan H , Luo Lu , Reinwald Yvonne , Taffetani Matteo , Hallas-Potts Amelia , Herrington C Simon , Srsen Vlastimil , Lin Chih-Jen , Barroso Inês A , Zhang Zhihua , Zhang Zhibing , Ghag Anita K. , Yang Ying , Waters Sarah , Haj Alicia El , Bagnaninchi Pierre O
Published: May 2021

The role of the mechanical environment in defining tissue function, development and growth has been shown to be fundamental. Assessment of the changes in stiffness of tissue matrices at multiple scales has relied mostly on invasive and often specialist equipment such as AFM or mechanical testing devices poorly suited to the cell culture workflow.In this paper, we have developed a novel unbiased passive optical coherence elastography method, exploiting ambient vibrations in the sample that enables real-time noninvasive quantitative profiling of cells and tissues. We demonstrate a robust method that decouples optical scattering and mechanical properties by actively compensating for scattering associated noise bias and reducing variance. The efficiency for the method to retrieve ground truth is validated in silico and in vitro, and exemplified for key applications such as time course mechanical profiling of bone and cartilage spheroids, tissue engineering cancer models, tissue repair models and single cell. Our method is readily implementable with any commercial optical coherence tomography system without any hardware modifications, and thus offers a breakthrough in tissue mechanical assessment for novel on line assessment of spatial mechanical properties for organoids, soft tissues and tissue engineering.
Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2
Authors: Sun Shiyu , Cai Yueqi , Song Tian-Zhang , Pu Yang , Cheng Lin , Xu Hairong , Meng Chaoyang , Lin Yifan , Sun Jing , Zhang Silin , Gao Yu , Han Jian-Bao , Feng Xiao-Li , Yu Dan-Dan , Zhu Yalan , Gao Pu , Tang Haidong , Zhao Jincun , Zhang Zheng , Yang Jiaming , Hu Zenxiang , Fu Yang-Xin , Zheng Yong-Tang , Peng Hua
Published: May 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used solely for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLN. A low dose of I-R-F induces not only high titer long-lasting neutralizing antibodies but also comprehensive T cell responses than RBD, and even provides comprehensive protection in one dose without adjuvant. This study shows that the I-R-F vaccine provides rapid and complete protection throughout upper and lower respiratory tracts against high dose SARS-CoV-2 challenge in rhesus macaques. Due to its potency and safety, this engineered vaccine may become one of the next-generation vaccine candidates in the global race to defeat COVID-19.
First description of two immune escape indian B.1.1.420 and B.1.617.1 SARS-CoV2 variants in France
Authors: Garcia Vincent , Vig Véronique , Peillard Laurent , Ramdani Alaa , Mohamed Sofiane , Halfon Philippe
Published: May 2021

Following the outbreak of the SARS-CoV2 virus worldwide in 2019, the rapid widespread overtime of variants suggests today an undergoing positive selection of variants which could potentially provide advantageous genetic property of the virus. Numerous variants have already been described across different countries including N501Y, E484K or L452R mutations on gene coding to spike protein. Most recently, 2 new Indian variants with N440K and E484Q and L452R mutations associated with impaired antibody response and immune reactions were identified in India. The potential consequences of emerging variants are increased transmissibility, increased pathogenicity and the ability to escape natural or vaccine-induced immunity.

We described for the first time in France both variants: the N440K immune escape variant within a new strain detected in France in a couple of patients who did not have any history of travel abroad and the new E484Q and L452R Indian variant from a patient travelling from Indian to Marseille to embark on a ship as a crew member.

Such study of the circulating viral strains and their variants within the increasing number of infected people worldwide will provide further insights into the viral dissemination. Hence, real time close monitoring variant could help the scientific community to prevent fast-spreading and raise alarms towards potentially harmful variants.
OVarFlow: a resource optimized GATK 4 based Open source Variant calling workFlow
Authors: Bathke Jochen , Lühken Gesine
Published: May 2021

Background

Next generation sequencing technologies are opening new doors to researchers. One application is the direct discovery of sequence variants that are causative for a phenotypic trait or a disease. The detection of an organisms alterations from a reference genome is know as variant calling, a computational task involving a complex chain of software applications. One key player in the field is the Genome Analysis Toolkit (GATK). The GATK Best Practices are commonly referred recipe for variant calling on human sequencing data. Still the fact the Best Practices are highly specialized on human sequencing data and are permanently evolving is often ignored. Reproducibility is thereby aggravated, leading to continuous reinvention of pretended GATK Best Practice workflows.

Results

Here we present an automatized variant calling workflow, for the detection of SNPs and indels, that is broadly applicable for model as well as non-model diploid organisms. It is derived from the GATK Best Practice workflow for “Germline short variant discovery”, without being focused on human sequencing data. The workflow has been highly optimized to achieve parallelized data evaluation and also maximize performance of individual applications to shorten overall analysis time. Optimized Java garbage collection and heap size settings for the GATK applications SortSam, MarkDuplicates, HaplotypeCaller and GatherVcfs were determined by thorough benchmarking. In doing so, runtimes of an example data evaluation could be reduced from 67 h to less than 35 h.

Conclusions

The demand for standardized variant calling workflows is proportionally growing with the dropping costs of next generation sequencing methods. Our workflow perfectly fits into this niche, offering automatization, reproducibility and documentation of the variant calling process. Moreover resource usage is lowered to a minimum. Thereby variant calling projects should become more standardized, reducing the barrier further for smaller institutions or groups.
Responsive robotic prey reveal how predators adapt to predictability in escape tactics
Authors: Szopa-Comley Andrew W. , Ioannou Christos C.
Published: May 2021

To increase their chances of survival, prey often respond to predators by being unpredictable when escaping, but the response of predators to such tactics is unknown. We programmed interactive robot-controlled prey to flee from an approaching blue acara predator (Andinoacara pulcher), allowing us to manipulate the predictability of the prey’s initial escape direction. When repeatedly exposed to predictable prey, the predators adjusted their behaviour before the prey even began to escape: prey programmed to escape directly away were approached more rapidly than prey escaping at an acute angle. These faster approach speeds compensated for a longer time needed to capture such prey during the subsequent pursuit phase, and predators showed greater acceleration when pursuing unpredictable prey. Collectively, these behaviours resulted in the prey’s predictability having no net effect on the time to capture prey. Rather than minimising capture times, predators adjust their behaviour to maintain an adequate level of performance.
Comparative Transcriptome Profiling of High and Low oil yielding Santalum album L.
Authors: Fatima Tanzeem , Krishnan Rangachari , Srivastava Ashutosh , Hanur Vageeshbabu S. , Rao M. Srinivasa
Published: May 2021

East Indian Sandalwood (Santalum album L.) is highly valued for its heartwood and its oil. There have been no efforts to comparative study of high and low oil yielding genetically identical sandalwood trees grown in similar climatic condition. Thus we intend to study a genome wide transcriptome analysis to identify the corresponding genes involved in high oil biosynthesis in S. album. In this study, 15 years old S. album (SaSHc and SaSLc) genotypes were targeted for analysis to understand the contribution of genetic background on high oil biosynthesis in S. album. A total of 28,959187 and 25,598869 raw PE reads were generated by the Illumina sequencing. 2.12 million and 1.811 million coding sequences were obtained in respective accessions. Based on the GO terms, functional classification of the CDS 21262, & 18113 were assigned into 26 functional groups of three GO categories; (4,168; 3,641) for biological process (5,758;4,971) cellular component and (5,108;4,441) for molecular functions. Total 41,900 and 36,571 genes were functionally annotated and KEGG pathways of the DEGs resulted 213 metabolic pathways. In this, 14 pathways were involved in secondary metabolites biosynthesis pathway in S. album. Among 237 cytochrome families, nine groups of cytochromes were participated in high oil biosynthesis. 16,665 differentially expressed genes were commonly detected in both the accessions (SaHc and SaSLc). The results showed that 784 genes were upregulated and 339 genes were downregulated in SaHc whilst 635 upregulated 299 downregulated in SaSLc S. album. RNA-Seq results were further validated by quantitative RT-PCR. Maximum Blast hits were found to be against Vitis vinifera. From this study we have identified additional number of cytochrome family in SaHc. The accessibility of a RNA-Seq for high oil yielding sandalwood accessions will have broader associations for the conservation and selection of superior elite samples/populations for further genetic improvement program.
A de novo protein structure prediction by iterative partition sampling, topology adjustment, and residue-level distance deviation optimization
Authors: Liu Jun , Zhao Kai-Long , He Guang-Xing , Wang Liu-Jing , Zhou Xiao-Gen , Zhang Gui-Jun
Published: May 2021

Motivation

With the great progress of deep learning-based inter-residue contact/distance prediction, the discrete space formed by fragment assembly cannot satisfy the distance constraint well. Thus, the optimal solution of the continuous space may not be achieved. Designing an effective closed-loop continuous dihedral angle optimization strategy that complements the discrete fragment assembly is crucial to improve the performance of the distance-assisted fragment assembly method.

Results

In this article, we proposed a de novo protein structure prediction method called IPTDFold based on closed-loop iterative partition sampling, topology adjustment and residue-level distance deviation optimization. First, local dihedral angle crossover and mutation operators are designed to explore the conformational space extensively and achieve information exchange between the conformations in the population. Then, the dihedral angle rotation model of loop region with partial inter-residue distance constraints is constructed, and the rotation angle satisfying the constraints is obtained by differential evolution algorithm, so as to adjust the spatial position relationship between the secondary structures. Lastly, the residue distance deviation is evaluated according to the difference between the conformation and the predicted distance, and the dihedral angle of the residue is optimized with biased probability. The final model is generated by iterating the above three steps. IPTDFold is tested on 462 benchmark proteins, 24 FM targets of CASP13, and 20 FM targets of CASP14. Results show that IPTDFold is significantly superior to the distance-assisted fragment assembly method Rosetta_D (Rosetta with distance). In particular, the prediction accuracy of IPTDFold does not decrease as the length of the protein increases. When using the same FastRelax protocol, the prediction accuracy of IPTDFold is significantly superior to that of trRosetta without orientation constraints, and is equivalent to that of the full version of trRosetta.

Availability

The source code and executable are freely available at https://github.com/iobio-zjut/IPTDFold.

Contact

zgj@zjut.edu.cn
A gene expression panel for estimating age in males and females of the sleeping sickness vector Glossina morsitans
Authors: Lucas Eric R. , Darby Alistair C. , Torr Stephen J. , Donnelly Martin J.
Published: May 2021

Many vector-borne diseases are controlled by methods that kill the insect vectors responsible for disease transmission. Recording the age structure of vector populations provides information on mortality rates and vectorial capacity, and should form part of the detailed monitoring that occurs in the wake of control programmes, yet tools for obtaining estimates of individual age remain limited. We investigate the potential of using markers of gene expression to predict age in tsetse flies, which are the vectors of deadly and economically damaging African trypanosomiases. We use RNAseq to identify candidate expression markers, and test these markers using qPCR in laboratory-reared Glossina morstians morsitans of known age. Measuring the expression of six genes was sufficient to obtain a prediction of age with root mean squared error of less than 8 days, while just two genes were sufficient to classify flies into age categories of ≤ 15 and >15 days old. Further testing of these markers in field-caught samples and in other species will determine the accuracy of these markers in the field.
Robust detection of natural selection using a probabilistic model of tree imbalance
Authors: Dilber Enes , Terhorst Jonathan
Published: May 2021

Neutrality tests such as Tajima’sD(Tajima, 1989) and Fay and Wu’sH(Fay and Wu, 2000) are standard implements in the population genetics toolbox. One of their most common uses is to scan the genome for signals of natural selection. However, it is well understood that deviance measures likeDandHare confounded by other evolutionary forces—in particular, population expansion—that may be unrelated to selection. Because they are not model-based, it is not clear how to deconfound these statistics in a principled way.

In this paper we derive new likelihood-based methods for detecting natural selection which are robust to confounding by fluctuations in effective population size. At the core of our method is a novel proba-bilistic model of tree imbalance, which generalizes Kingman’s coales-cent to allow certain aberrant tree topologies to arise more frequently than is expected under neutrality. We derive a frequency spectrum-based estimator which can be used in place ofD, and also extend to the case where genealogies are first estimated. We benchmark our meth-ods on real and simulated data, and provide an open source software implementation.
Scale-free behavioral dynamics directly linked with scale-free cortical dynamics
Authors: Jones Sabrina A. , Barfield Jacob H. , Norman V. Kindler , Shew Woodrow L.
Published: May 2021

Naturally occurring body movements and collective neural activity both exhibit complex dynamics, often with scale-free, fractal spatiotemporal structure. Scale-free dynamics of both brain and behavior are each associated with functional benefits to the organism. Despite their similarities, scale-free brain activity and scale-free behavior have been studied separately, without a unified explanation. Here we show that scale-free dynamics of behavior and certain subsets of cortical neurons are strongly related. Surprisingly, the scale-free neural subsets exhibit stochastic winner-take-all competition with other neural subsets. This observation is inconsistent with current theory of critical phenomena in neural systems. We develop a computational model which incorporates known cell-type-specific circuit structure, explaining our findings with a new type of criticality. Our results establish neural underpinnings of scale-free behavior and clear behavioral relevance of scale-free neural activity.

Popular Summary

Over the past 2 decades many measurements of brain activity have revealed a peculiar property; the activity is statistically similar when examined at different scales. This self-similar, fractal nature of brain activity has attracted the interest of neuroscientists and physicists alike. In physics, fractal structure shows up in certain non-living systems when they are operating near the tipping point of a phase transition (e.g. liquid water turning into gaseous vapor). This led to the criticality hypothesis, which posits that the brain may also operate near the tipping point of a phase transition, i.e. near criticality.

Initially the criticality hypothesis was very exciting at a basic level - physical principles of phase transitions promised to help us understand how the brain works. However, a important question naturally arose and remains unresolved. What do the scale-free, fractal fluctuations of brain activity have to do with the behavior of the organism? Is it just background noise in the brain or is there something fractal-like about how we behave and interact with the world?

Here we show for the first time that scale-free fluctuations of brain activity are directly related to moment-to-moment fluctuations in behavior. In fact, we show that both the brain activity and mouse behavior have very similar fractal structure. These results take the criticality hypothesis to a new level of biological and, perhaps, psychological relevance. Scale-free brain dynamics are not just background noise; they correspond to the dynamics of behavior.
Programming large target genomic deletion and concurrent insertion via a prime editing-based method: PEDAR
Authors: Jiang Tingting , Zhang Xiao-Ou , Weng Zhiping , Xue Wen
Published: May 2021

Genomic insertions, duplications, and insertion/deletions (indels) account for ~14% of human pathogenic mutations. Current gene editing methods cannot accurately or efficiently correct these abnormal genomic rearrangements, especially larger alterations (>100 bp). Thus, developing a method to accurately delete insertions/duplications and repair the deletion junction could improve the scope of gene therapies. Here, we engineer a novel gene editor, PE-Cas9, by conjugating Cas9 nuclease to reverse transcriptase. Combined with two prime editing guide RNAs (pegRNAs) targeting complementary DNA strands, PE-Cas9 can direct the replacement of a genomic fragment, ranging from to ~1-kb to >10-kb, with a desired sequence at the target site without requiring an exogenous DNA template. In a reporter cell line, thisPE-Cas9-baseddeletionandrepair (PEDAR) method restored mCherry expression through in-frame deletion of a disrupted GFP sequence. We further show that PEDAR efficiency could be enhanced by using pegRNAs with high cleavage activity or increasing transfection efficiency. In tyrosinemia mice, PEDAR removed a 1.38-kb pathogenic insertion within theFahgene and precisely repaired the deletion junction to restore FAH expression in liver. This study highlights PEDAR as a tool for correcting pathogenic mutations.
Fluid intelligence and naturalistic task impairments after focal brain lesions
Authors: Smith Verity , Pinasco Clara , Achterberg Jascha , Mitchell Daniel J. , Das Tilak , Roca Maria , Duncan John
Published: May 2021

Classical executive tasks, such as Wisconsin card-sorting and verbal fluency, are widely used as tests of frontal lobe control functions. Since the pioneering work of Shallice and Burgess (1991), it has been known that complex, naturalistic tasks can capture deficits that are missed in these classical tests. Matching this finding, deficits in several classical tasks are predicted by loss of fluid intelligence, linked to damage in a specific cortical “multiple-demand” (MD) network, while deficits in a more naturalistic task are not. To expand on these previous results, we examined the effect of focal brain lesions on three new tests – a modification of the previously-used Hotel task, a new test of task switching after extended delays, and a test of decision-making in imagined real-life scenarios. As potential predictors of impairment we measured volume of damage to a priori MD and default mode (DMN) networks, as well as cortical damage outside these networks. Deficits in the three new tasks were substantial, but were not explained by loss of fluid intelligence, or by volume of damage to either MD or DMN networks. Instead, deficits were associated with diverse lesions, and not strongly correlated with one another. The results confirm that naturalistic tasks capture cognitive deficits beyond those measured by fluid intelligence. We suggest, however, that these deficits may not arise from specific control operations required by complex behaviour. Instead, like everyday activities, complex tasks combine a rich variety of interacting cognitive components, bringing many opportunities for processing to be disturbed.
Common neural bases for processing speech prosody and music: An integrated model
Authors: Proverbio Alice Mado , Piotti Elisabetta
Published: May 2021

It is shared notion that speech and music processing share some commonalities. Brain bioelectrical activity was recorded in healthy participants listening to music obtained by digitally transforming real speech into melodies played by viola. Sentences were originally pronounced with a positive or negative affective prosody. The research’s aim was to investigate if the emotional content of music was extracted similarly to how the affective prosody of speech is processed.

EEG was recorded from 128 electrodes in 20 healthy students. Participants had to detect rare neutral piano sounds while ignoring viola melodies. Stimulus negative valence increased the amplitude of frontal P300 and N400 ERP components while a late inferior frontal positivity was enhanced in response to positive melodies. Similar ERP markers were previously found for processing positive and negative music, vocalizations and speech. Source reconstruction applied to N400 showed that negative melodies engaged the right superior temporal gyrus and right anterior cingulate cortex, while positive melodies engaged the left middle and inferior temporal gyrus and the inferior frontal cortex. An integrated model is proposed depicting a possible common circuit for processing the emotional content of music, vocalizations and speech, which might explain some universal and relatively innate brain reaction to music.
A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia
Authors: Azpurua Jorge , El-Karim Enas Gad , Tranquille Marvel , Dubnau Josh
Published: May 2021

Cytoplasmic aggregation of Tar-DNA/RNA binding protein 43 (TDP-43) occurs in 97 percent of amyotrophic lateral sclerosis (ALS), about 40 percent of frontotemporal dementia (FTD) and in many cases of Alzheimer’s disease (AD). Cytoplasmic TDP-43 inclusions are seen in both sporadic and familial forms of these disorders, including those cases that are caused by repeat expansion mutations in the C9orf72 gene. To identify downstream mediators of TDP-43 toxicity, we expressed human TDP-43 in a subset of Drosophila motor neurons. Such expression causes age-dependent deficits in negative geotaxis behavior. Using this behavioral readout of locomotion, we conducted an shRNA suppressor screen and identified 32 transcripts whose knockdown was sufficient to ameliorate the neurological phenotype. The majority of these suppressors also substantially suppressed the negative effects on lifespan seen with glial TDP-43 expression. In addition to identification of a number of genes whose roles in neurodegeneration were not previously known, our screen also yielded genes involved in chromatin regulation and nuclear/import export-pathways that were previously identified in the context of cell based or neurodevelopmental suppressor screens. A notable example is SF2, a conserved orthologue of mammalian SRSF1, an RNA binding protein with roles in splicing and nuclear export. Our identification SF2/SRSF1 as a potent suppressor of both neuronal and glial TDP-43 toxicity also provides a convergence with C9orf72 expansion repeat mediated neurodegeneration, where this gene also acts as a downstream mediator.

Author Summary

Loss of nuclear function of TDP-43 and its mislocalization into cytoplasmic inclusions are central features to a suite of neurodegenerative disorders. We screened 2700 Drosophila genes to identify downstream mediators that suppress an age-dependent motor dysfunction phenotype when they are knocked down by RNA interference. We identified both previously implicated pathways and several novel genes whose knock down is sufficient to dramatically and robustly rescue TDP-43 toxicity both in neuronal and glial contexts. Notably, we report that SF2/SRSF1, which was previously reported as a suppressor of C9orf72 hexanucleotide expansion repeat toxicity, also is a potent suppressor of TDP-43 mediated neurodegeneration.