bluuebunny/crossref_metadata_2025 huggingface dataset:
Bundling and segregation affects “liking”, but not “wanting”, in an insect
Authors: De Agrò Massimo , Matschunas Chiara , Czaczkes Tomer J.
Published: May 2022

Behavioural economists have identified many psychological manipulations which affect perceived value, although value in humans is not a unitary experience, with “liking” and “wanting” being neurologically separate processes. A prominent example of this is bundling, in which several small gains (or costs) are experienced as more valuable (or costly) than if the same total amount is presented together. While extensively demonstrated in humans, to our knowledge this effect has never been investigated in an animal, let alone an invertebrate. We trained individual Lasius niger workers to two of three conditions in which either costs (travel distance), gains (sucrose reward), or both were either bundled or segregated: A) both costs and gains bundled, B) both segregated, and C) only gains segregated. We recorded pheromone deposition on the ants’ return trips to the nest as measure of “liking”. After training, we offer the ants a binary choice between odours associated with the treatments, as a measure of “wanting”. While bundling treatment did not affect choice, i.e. “wanting”, it strongly influenced pheromone deposition, i.e. “liking”. Ants deposited c. 80% more pheromone when rewards were segregated but costs bundled as compared with both costs and rewards being bundled. This pattern is further complicated by the pairwise experience each animal made, and which of the treatments it experiences first during training. The current study is the first to demonstrate a bundling effect in an animal, and the first to report a dichotomy between “liking” and “wanting” in an insect. We propose that the deviation between “wanting” and “liking” in this case is due to the unique nature of distance perception in ants, which is recorded linearly, while almost all other sensory perception in animals is logarithmic.
Negative Control Exposures: Causal effect Identifiability and Use in Probabilistic-Bias and Bayesian Analyses with Unmeasured Confounders
Authors: Flanders WD , Waller LA , Zhang Q , Getahun D , Silverberg M , Goodman M
Published: May 2022

Probabilistic bias and Bayesian analyses are important tools for bias correction, particularly if required parameters are nonidentifiable. Negative controls are another tool; they can detect confounding and correct for confounders. Our goals are to present conditions that assure identifiability of certain causal effects and to describe and illustrate a probabilistic bias analysis and related Bayesian analysis that use a negative control exposure.

Using potential-outcome models, we characterize assumptions needed for identification of causal effects using a dichotomous, negative control exposure when residual confounding exists. We define bias parameters, characterize their relationships with the negative control and with specified causal effects, and describe the corresponding probabilistic-bias and Bayesian analyses.

We exemplify analyses using data on hormone therapy and suicide attempts among transgender people. To address possible confounding by healthcare utilization, we used prior TdaP (tetanus-diphtheria-pertussis) vaccination as a negative control exposure. Hormone therapy was weakly associated with risk (risk ratio (RR) = 0.9). The negative control exposure was associated with risk (RR = 1.7), suggesting confounding. Based on an assumed prior distribution for the bias parameter, the 95% simulation interval for the distribution of confounding-adjusted RR was (0.17, 1.64), with median 0.5; the 95% credibility interval was similar.

A dichotomous negative control exposure can be used to identify causal effects when a confounder is unmeasured under strong assumptions. More realistically, assumptions can be relaxed and the negative control exposure may prove helpful for probabilistic bias analyses and Bayesian analyses.
Joint engagement is associated with greater development of language and sensory awareness in children with autism
Authors: Vyshedskiy Andrey , Khokhlovich Edward
Published: May 2022

The effect of joint engagement in 2- to 6-year-old children with ASD was investigated in the largest and the longest observational study to-date. Parents assessed the development of 12081 children quarterly for three years on five subscales: receptive language, expressive language, sociability, sensory awareness, and health. Longer duration of time spent with an adult actively involved in the same activity was associated with improved trajectory of receptive language, expressive language, and sensory awareness. On the annualized basis, the high-joint-engagement group (3 hours or more of joint engagement per day) improved their combinatorial receptive language 1.4-times faster (p=0.0019), expressive language 1.5-times faster (p<0.0001), and sensory awareness 1.5-times faster (p=0.0248) than the low-joint-engagement group (1 hour or less joint engagement per day). The difference in the sociability and the health scores at the end of 3-year study was insignificant. This study confirms the importance of ASD children spending more time with adults actively involved in the same activity and highlights the need to include joint engagement as a target for intervention with this population.

Lay summary

Parents of 2- to 6-year-old children with ASD assessed the development of 12081 children quarterly for three years. Longer duration of time spent with an adult actively involved in the same activity was associated with improved developmental trajectory. This study confirms the importance of ASD children spending more time with adults actively involved in the same activity and highlights the need to include joint engagement as a target for intervention with this population.
Basal forebrain cholinergic circuits orchestrate diverse cell types in the adult dentate gyrus to support neural stem cell function and spatial memory
Authors: Quintanilla Luis , Su Yijing , Simon Jeremy M. , Luo Yan-Jia , Asrican Brent , Tart Seth , Sheehy Ryan N. , Li Ya-Dong , Ming Guo-li , Song Hongjun , Song Juan
Published: May 2022

Dentate gyrus (DG) is a critical structure involved in spatial memory and adult neurogenesis, two distinct processes dynamically regulated by local circuits comprising diverse populations of DG cells. It remains unknown how these DG cells are orchestrated to regulate these distinct hippocampal functions. Here we report activation of a cholinergic circuit from the Diagonal Band of Broca to DG promotes quiescent radial neural stem cell (rNSC) activation and spatial memory. Furthermore, single-nucleus RNA-sequencing reveals broad transcriptomic changes across DG mature and adult-born cells in response to cholinergic-circuit activation. Notably, neuronal populations exhibit cholinergic-activity-induced molecular changes related to synaptic functions crucial for spatial memory; while rNSCs exhibit changes related to structural remodeling and neurogenic proliferation crucial for hippocampal neurogenesis. Electrophysiology and NicheNet analyses reveal granule cells, endothelial cells, and astrocytes as potential intermediaries for cholinergic regulation of rNSCs. Our findings reveal cell-type-specific signaling mechanisms underlying cholinergic regulation of distinct DG functions.
AlphaFold2-RAVE: From sequence to Boltzmann ensemble
Authors: Vani Bodhi P. , Aranganathan Akashnathan , Wang Dedi , Tiwary Pratyush
Published: May 2022

While AlphaFold2 is rapidly being adopted as a new standard in protein structure predictions, it is limited to single structure prediction. This can be insufficient for the inherently dynamic world of biomolecules. Even with recent modifications towards conformational diversity, AlphaFold2 is devoid of providing thermodynamically ranked conformations. AlphaFold2-RAVE is an efficient protocol using the structural outputs from AlphaFold2 as initializations for AI augmented molecular dynamics. These simulations result in Boltzmann ranked ensembles, which we demonstrate on different proteins.
Bayesian analyses of radiocarbon dates on rice reveal geographic variations in the rate of agricultural dispersal in prehistoric Japan
Authors: Crema Enrico R. , Stevens Chris J. , Shoda Shinya
Published: May 2022

The adoption of rice farming during the 1st millennium BC was a turning point in Japanese prehistory, defining the subsequent cultural, linguistic, genetic variation in the archipelago. Here we employ a suite of novel Bayesian techniques to estimate the regional rates of dispersal and arrival time of rice farming using radiocarbon dates on charred rice remains. Our results indicate substantial variations in the pace of agricultural adoption within the Japanese islands, hinting at the presence of a mixture of demic and cultural diffusion, geographic variations in the suitability of rice cultivation, as well as the possible role of existing social networks in facilitating or hindering the adoption of the new subsistence economy.

Teaser

The adoption of rice farming in prehistoric Japan was characterised by regional episodes of slowdowns and accelerations.
Integrative metabolomics reveal the organisation of alkaloid biosynthesis in Daphniphyllum macropodum
Authors: Eljounaidi Kaouthar , Radzikowska Barbara , Whitehead Caragh , Conde Susana , Davis William , Dowle Adam , Langer Swen , Larson Tony , Unsworth William P. , Ezer Daphne , Lichman Benjamin R.
Published: May 2022

Daphniphyllum alkaloids are structurally diverse nitrogen-containing compounds with polycyclic, stereochemically rich carbon skeletons. Understanding how plants biosynthesise these compounds may lead to greater access to allow exploration of bioactivities; however, very little is known about their biosynthetic origins. Here, we integrated metabolomics approaches to map alkaloid distribution across Daphniphyllum macropodum plants and tissues. We generated a novel untargeted metabolomics workflow to highlight trends in alkaloid distribution across tissues, using a holistic approach that does not rely on ambiguous peak annotations. Both liquid-chromatography-mass spectrometry and mass-spectrometry imaging analyses independently revealed that alkaloids have a pattern of spatial distribution based on their skeletal subtypes. The distinct alkaloid subtype localisation suggests the biosynthetic pathway is controlled spatially with intermediates transported from the phloem to the epidermis where they undergo additional derivatization. This study sets the stage for the future work on Daphniphyllum alkaloid biosynthesis and highlights how integrating different metabolomics strategies can reveal valuable insights on these compounds’ distribution within the plant.
ADOPT: intrinsic protein disorder prediction through deep bidirectional transformers
Authors: Redl Istvan , Fisicaro Carlo , Dutton Oliver , Hoffmann Falk , Henderson Louie , Owens Benjamin M.J. , Heberling Matthew , Paci Emanuele , Tamiola Kamil
Published: May 2022

Intrinsically disordered proteins (IDP) are important for a broad range of biological functions and are involved in many diseases. An understanding of intrinsic disorder is key to develop compounds that target IDPs. Experimental characterization of IDPs is hindered by the very fact that they are highly dynamic. Computational methods that predict disorder from the amino acid sequence have been proposed. Here, we present ADOPT, a new predictor of protein disorder. ADOPT is composed of a self-supervised encoder and a supervised disorder predictor. The former is based on a deep bidirectional transformer, which extracts dense residue level representations from Facebook’s Evolutionary Scale Modeling (ESM) library. The latter uses a database of NMR chemical shifts, constructed to ensure balanced amounts of disordered and ordered residues, as a training and test dataset for protein disorder. ADOPT predicts whether a protein or a specific region is disordered with better performance than the best existing predictors and faster than most other proposed methods (a few seconds per sequence). We identify the features which are relevant for the prediction performance and show that good performance can already gained with less than 100 features. ADOPT is available as a standalone package athttps://github.com/PeptoneLtd/ADOPT.
Rapid and precise genome engineering in a naturally short-lived vertebrate
Authors: Nath Ravi D. , Bedbrook Claire N. , Nagvekar Rahul , Deisseroth Karl , Brunet Anne
Published: May 2022

The African turquoise killifish is a powerful vertebrate system to study complex phenotypes at scale, including aging and age-related disease. Here we develop a rapid and precise CRISPR/Cas9-mediated knock-in approach in the killifish. We show its efficient application to precisely insert fluorescent reporters of different sizes at various genomic loci, to drive cell-type- and tissue-specific expression. This knock-in method should allow the establishment of humanized disease models and the development of cell-type-specific molecular probes for studying complex vertebrate biology.
Obesity-Associated Alterations in Lung Function in Mice Measured with Head-Out Plethysmography
Authors: Bruggink Stephanie M , Pederson William P , Kentch Kyle P , Kronenfeld Jason M , Ledford Julie G , Renquist Benjamin J
Published: May 2022

Declines in lung function worsen quality of life and increase the risk of mortality. Obesity and non-alcoholic fatty liver disease are associated with worsened lung function. To investigate this association, we assessed lung function in lean and diet-induced obese conscious mice using our newly developed leak-free head-out plethysmography system. Obesity was associated with increased volume (P<0.0001), minute ventilation (volume per minute; P<0.0001), mid-expiratory flow (flow rate at 50% expiratory volume; P<0.0001), end-inspiratory pause (pause at end of inspiration; P<0.0001) and decreased expiratory time (P<0.0001). We next compared the response to methacholine (0, 25, 50, 100 mg/ml in PBS flow 0.2ml/30sec) measured using our head-out plethysmography system with forced oscillation technique (using the standard flexiVent system) measures taken in the same mice. Many of the measures gathered using head-out plethysmography were associated with measures collected using the forced oscillation technique. Minute ventilation was most significantly associated with maximal airway resistance, maximal airway elastance, tissue damping, and tissue elastance (r=-0.59 P<0.0001; r=-0.54 P<0.005; r=-0.48 P<0.005; r=-0.40 P<0.005 respectively). Volume, corrected for energy expenditure, was most significantly associated with maximal resistance of the conducting airways (r=-0.57 P<0.0001). Although fatty liver is associated with changes in lung function, we found neither hepatic vagotomy nor knocking down obesity-induced hepatic GABA production improved lung function in obese mice. Still, our head-out plethysmography system is ideal for assessing the response to interventions aimed at improving obesity-associated declines in lung function.
UNDESRTANDING MESENCHYMAL STEM CELL IMMUNE POTENCY: A MORPHOLOMIC AND LIPIDOMIC PERSPECTIVE
Authors: Priyadarshani Priyanka , DeVeaux S’Dravious , Leitmann Bobby , Rui Kejie , Botchwey Edward A , Mortensen Luke J.
Published: May 2022

Interest in human mesenchymal stem cells (MSCs) as an immune therapy has been on the rise for the past two decades with cutting edge research yielding promising results, but there are currently no MSC therapies approved by the food and drug administration (FDA). Failure of MSCs to translate as a therapy has been reported by the National Cell Manufacturing Consortium (NCMC) to be due to a lack of reliable potency metrics and sufficient understanding of the mechanism of action. Here we show that cell membrane components are a good candidate to interrogate the MSC immunomodulatory mechanism of action and provide a method to increase MSC potency through the sphingolipid pathway. We found that high and low indolamine-2,3-deoxygenase (IDO) potency cells have distinct morphological signatures that is also reflected in the sphingolipid activity, with low IDO potency cell lines having low sphingomyelinase activity and high IDO potency cell lines having high sphingomyelinase activity. Perturbation of the salvage pathway with the addition of exogenous neutral sphingomyelinase not only shifted morphological signatures to a high potency profile, but also significantly increased IDO activity within both high and low IDO potency donors. These results provide a proof of concept for the engineering of MSC immunomodulation and provides further evidence for the role sphingolipids in MSC immunomodulation that can enable further investigation.
PervasiveListeria monocytogenesare common in the Norwegian food system and associated with increased prevalence of stress survival and resistance determinants
Authors: Fagerlund Annette , Wagner Eva , Møretrø Trond , Heir Even , Moen Birgitte , Rychli Kathrin , Langsrud Solveig
Published: May 2022

To investigate the diversity, distribution, persistence, and prevalence of stress survival and resistance genes ofListeria monocytogenesclones dominating in food processing environments in Norway, genome sequences from 769L. monocytogenesisolates from food industry environments, foods, and raw materials (of which 512 were sequenced in the present study) were subjected to wgMLST, SNP, and comparative genomic analyses. The dataset comprised isolates from nine meat and six salmon processing facilities in Norway collected over a period of three decades. The most prevalent clonal complex (CC) was CC121, found in ten factories, followed by CC7, CC8, and CC9, found in seven factories each. Overall, 72% of the isolates were classified as persistent, showing 20 or fewer wgMLST allelic differences towards an isolate found in the same factory in a different calendar year. Moreover, over half of the isolates (56%) showed this level of genetic similarity towards an isolate collected from a different food processing facility. These were designated as pervasive strains, defined as clusters with the same level of genetic similarity as persistent strains but isolated from different factories. The prevalence of genetic determinants associated with increased survival in food processing environments, including heavy metal and biocide resistance determinants, stress response genes andinlAtruncation mutations, showed a highly significant increase among pervasive isolates, but not among persistent isolates. Furthermore, these genes were significantly more prevalent among the isolates from food processing environments compared to in isolates from natural and rural environments (n=218) and clinical isolates (n=111) from Norway.

Importance

Listeria monocytogenescan persist in food processing environments for months to decades and spread through the food system by e.g., contaminated raw materials. Knowledge about the distribution and diversity ofL. monocytogenesis of importance in outbreak investigations and essential to effectively track and control this pathogen in the food system. The current study presents a comprehensive overview of the prevalence of persistent clones and of the diversity ofL. monocytogenesin Norwegian food processing facilities. The results demonstrate extensive spread of highly similar strains throughout the Norwegian food system, in that 56% of the 769 collected isolates from food processing factories belonged to clusters ofL. monocytogenesidentified in more than one facility. These strains were associated with an overall increase in the prevalence of plasmids and determinants of heavy metal and biocide resistance as well as other genetic elements associated with stress survival mechanisms and persistence.
Shared within-host SARS-CoV-2 variation in households
Authors: Walter Katharine S. , Kim Eugene , Verma Renu , Altamirano Jonathan , Leary Sean , Carrington Yuan J. , Jagannathan Prasanna , Singh Upinder , Holubar Marisa , Subramanian Aruna , Khosla Chaitan , Maldonado Yvonne , Andrews Jason R.
Published: May 2022

Background

The limited variation observed among SARS-CoV-2 consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference.

Methods

We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples from four prospective studies and combined sequence data with household membership data, a proxy for transmission linkage.

Results

Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 SNPs; range, 0-40). Most (83.1%, 255/307) samples harbored at least one intrahost single nucleotide variant (iSNV; median: 117; IQR: 17-208), when applying a liberal minor allele frequency of 0.5% and prior to filtering. A mean of 15.4% of within-host iSNVs were recovered one day later. Pairs in the same household shared significantly more iSNVs (mean: 1.20 iSNVs; 95% CI: 1.02-1.39) than did pairs in different households infected with the same viral clade (mean: 0.31 iSNVs; 95% CI: 0.28-0.34), a signal that increases with increasingly liberal thresholds.

Conclusions

Although only a subset of within-host variation is consistently shared across likely transmission pairs, shared iSNVs may augment the information in consensus sequences for predicting transmission linkages.
High Intelligence is not a Risk Factor for Mental Health Disorders
Authors: Michèle Williams Camille , Peyre Hugo , Labouret Ghislaine , Fassaya Judicael , Guzmán García Adoración , Gauvrit Nicolas , Ramus Franck
Published: May 2022

Objective

Studies reporting that highly intelligent individuals have more mental health disorders often have sampling bias, no or inadequate control group, or insufficient sample size. We addressed these caveats by examining the difference in the prevalence of mental health disorders between individuals with high and average general intelligence (g-factor) in the UK Biobank.

Methods

Participants with general intelligence (g-factor) scores standardized relative to the same-age UK population, were divided into 2 groups: a high g-factor group (g-factor 2 SD above the UK mean; N=16,137) and an average g-factor group (g-factor within 2 SD of the UK mean; N=236,273). Using self-report questionnaires and medical diagnoses, we examined group differences in prevalence across 32 phenotypes, including mental health disorders, trauma, allergies, and other traits.

Results

High and average g-factor groups differed across 15/32 phenotypes and did not depend on sex and/or age. Individuals with high g-factors had less general anxiety (OR=0.69) and PTSD (OR=0.67), were less neurotic (β=-0.12), less socially isolated (OR=0.85), and were less likely to have experienced childhood stressors and abuse, adulthood stressors, or catastrophic trauma (OR=0.69-0.90). They did not differ in any other mental health disorder or trait. However, they generally had more allergies (e.g., eczema; OR=1.13-1.33).

Conclusions

The present study provides robust evidence that highly intelligent individuals have no more mental health disorders than the average population. High intelligence even appears as a protective factor for general anxiety and PTSD.

Key Points

Question

Are high IQ individuals at increased risk of mental health disorders?

Findings

In the UK Biobank (N ≃ 7,266 - 252,249), highly intelligent individuals (2SD above the population mean) were less likely to suffer from general anxiety and PTSD, and no more likely to have depression, social anxiety, a drug use disorder, eating disorders, obsessive-compulsive disorder, bipolar disorder, and schizophrenia.

Meaning

Contrary to popular belief, high intelligence is not a risk factor for psychiatric disorders and even serves as a protective factor for general anxiety and PTSD.
The relationship between the prevalence and severity of Non-suicidal self-injury (NSSI) and personality traits among Chinese junior high school students
Authors: Jiang Zhongliang , Wang Zhiyi , Zhao Miao , He Long , He Qiang , Cheng Xiaojing , Chen Jie , Tian Geng , Li Xianbin , Haider Muhammad Imran , Liu Jintong
Published: May 2022

Background

Non-suicidal self-injury (NSSI) is more common in adolescents and its occurrence may be influenced by personality traits. Children and adolescents are a high-risk group for NSSI. Although there are some studies on the prevalence of NSSI, however, there are fewer studies on the factors associated with the severity of NSSI and the specific causes of the influence of NSSI and personality traits.

Methods

Participants of this study were junior high school students enrolled in three different schools of a Chinese province. NSSI was evaluated using the Adolescents Self-Harm Scale and their personality traits were assessed using the Neuroticism Extraversion Openness Five-factor Inventory (NEO-FFI).

Results

2376 junior high school students participated, and the annual incidence of NSSI was 37.1% (n=881). The mean age of the NSSI-detected individuals was 13.61 years (SD=1.017). Out of total number of detections, 56.6% (n=499) were female and 67.4% (n=594) were individuals who self-injured using multiple means. Hair pulling, scratching the skin, and whacking harder objects with the hand were the most common modes of NSSI, with incidences of 51.0%, 43.0%, and 42.8% respectively in the NSSI-detected population. There was a negative association between grade and NSSI severity (p < 0.05), and NSSI was more severe in females. The scores in the Neuroticism dimension were higher in the group with NSSI than in the group without NSSI, while the scores in the extraversion, openness, agreeableness and conscientiousness dimensions were lower than in the group without NSSI (p < 0.01). Neuroticism and openness were significantly positively correlated with NSSI severity, and extraversion, agreeableness, conscientiousness were significantly negatively correlated with NSSI severity (p < 0.01).

Conclusion

The severity of NSSI was relatively higher in lower grades among junior grades and females, and the number of self-injury using multiple means was significantly higher; hair pulling, skin scratching and whacking harder objects with hands were the most common NSSI modalities. Among the personality traits, for the incidence of NSSI, high neuroticism was a risk factor, and high extraversion, openness, agreeableness, and conscientiousness were protective factors. For the severity of NSSI, high neuroticism and high openness were risk factors, and high extraversion, high agreeableness, and high conscientiousness were protective factors.
Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance
Authors: Fazakerley Daniel J. , van Gerwen Julian , Cooke Kristen C. , Duan Xiaowen , Needham Elise J. , Madsen Søren , Norris Dougall M. , Shun-Shion Amber S. , Krycer James R. , Burchfield James G. , Yang Pengyi , Wade Mark R. , Brozinick Joseph T. , James David E. , Humphrey Sean J.
Published: May 2022

The failure of metabolic tissues to appropriately respond to insulin (“insulin resistance”) is an early marker in the pathogenesis of type 2 diabetes. Protein phosphorylation is central to the adipocyte insulin response, but how adipocyte signaling networks are dysregulated upon insulin resistance is unknown. Here we employed phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults triggering insulin resistance, we observed marked rewiring of the insulin signaling network. This included both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying signaling changes common to multiple insults revealed subnetworks likely containing causal drivers of insulin resistance. Focusing on defective GSK3 signaling initially observed in a relatively small subset of well-characterized substrates, we employed a pipeline for identifying context-specific kinase substrates. This facilitated robust identification of widespread dysregulated GSK3 signaling. Pharmacological inhibition of GSK3 partially reversed insulin resistance in cells and tissue explants. These data highlight that insulin resistance is a multi-nodal signaling defect that encompasses dysregulated GSK3 activity.
Development of Non-invasive ABPP-BRET Platform Technology Enable Real-Time Detection of Post-Translational Modification and Target Engagement with Absolute Specificity in Living Systems
Authors: Bathla Punita , Mujawar Aaiyas , De Abhijit , Sandanaraj Britto S
Published: May 2022

Non-invasive, real-time, longitudinal imaging of protein functions in living systems with unprecedented specificity is one of the critical challenges of modern biomedical research. Despite several advancements, it is estimated that nearly 35% of the human proteome is not completely characterized. Therefore, the development of new technologies is imperative for shining more light on so-called “dark proteomes”. Towards that goal, here we report a platform fusion technology called activity-based protein profiling-bioluminescence resonance energy transfer (ABPP-BRET). This method provides an opportunity to study the post-translational modification of a target protein in real-time in living systems in a longitudinal manner with a high spatio-temporal resolution. This semi-synthetic BRET biosensor method is used for target engagement studies and further for inhibitor profiling in live cells. The simplicity of this method coupled with the critical physical distance dependent BRET read-out turned out to be a powerful method, thus pushing the activity-based protein profiling technology to the next level.
Discovering and prioritizing candidate resistance genes against soybean pests by integrating GWAS and gene coexpression networks
Authors: Almeida-Silva Fabricio , Venancio Thiago M.
Published: May 2022

Soybean is one of the most important legume crops worldwide. Soybean pests have considerable impact on crop yield. Here, we integrated publicly available genome-wide association studies and transcriptomic data to prioritize candidate resistance genes against the insects Aphis glycines and Spodoptera litura, and the nematode Heterodera glycines. We identified 171, 7, and 228 high-confidence candidate resistance genes against A. glycines, S. litura, and H. glycines, respectively. We found some overlap of candidate genes between insect species, but not between insects and H. glycines. Although 15% of the prioritized candidate genes encode proteins of unknown function, the vast majority of the candidates are related to plant immunity processes, such as transcriptional regulation, signaling, oxidative stress, recognition, and physical defense. Based on the number of resistance alleles, we selected the ten most promising accessions against each pest species in the soybean USDA germplasm. The most resistant accessions do not reach the maximum theoretical resistance potential, indicating that they might be further improved to increase resistance in breeding programs or through genetic engineering. Finally, the coexpression networks generated here are available in a user-friendly web application (https://soypestgcn.venanciogroup.uenf.br/) and an R/Shiny package (https://github.com/almeidasilvaf/SoyPestGCN) that serve as a public resource to explore soybean-pest interactions at the transcriptional level.
Comparative Insilco functional, structural and phylogenetic characterization of plant Mn-Superoxide Dismutase
Authors: Gangwar Rashmi
Published: May 2022

The environmental stress is jeopardizing the production as well as the survival of plants. This stress leads to the emergence of ROS, a toxic byproduct of several metabolic processes. To combat the ROS plant possess definite defense machinery, superoxide dismutase is one of the antioxidant enzymes responsible for effectively eradicating these ROS. Amongst several SOD, MnSOD is specialized in eliminating the ROS from mitochondria, a site for cellular energy production. In this study, the MnSOD from 16 plants was considered, and its physiochemical and structural properties were predicted using various computational tools. The physiochemical characterization reveals protein properties such as Mw, PI, AI, GRAVY, and II. The secondary structure and the motif analysis revealed these proteins’ functional characteristics. The 3D structure of several proteins was not available, so the SWISS model was used for the homology modeling. The quality of the predicted protein structures was verified using the Ramachandran Plot, VERIFY 3D, and PROCHECK under the SAVES server. These data would provide a foundation for structural and functional characterization of potential MnSOD yet to be characterized, which is expected to enhance the knowledge about its metal binding and catalytic efficiency for future applications.
Ventral forebrain organoids derived from individuals with schizophrenia recapitulate perturbed striatal gene expression dynamics of the donor’s brains
Authors: Sawada Tomoyo , Barbosa André , Araujo Bruno , McCord Alejandra E. , D’Ignazio Laura , Benjamin Kynon J. M. , Feltrin Arthur , Arora Ria , Brandtjen Anna C. , Kleinman Joel E. , Hyde Thomas M. , Weinberger Daniel R. , Paquola Apuā C. M. , Erwin Jennifer A.
Published: May 2022

Schizophrenia (SCZ) is a brain disorder originating during neurodevelopment with complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, its cellular and molecular underpinnings remain unclear. Here, to explore neurodevelopmental alterations in the striatum associated with SCZ, we established a method for the differentiation of iPS cells into ventral forebrain organoids. Given substantial genetic heterogeneity among individuals, which can obscure disease-associated phenotypes, we generated organoids from postmortem dural fibroblast-derived iPS cells of 3 patients and 4 healthy control individuals with nonoverlapping polygenic risk score (PRS) for SCZ and whose genotype and postmortem caudate transcriptomic data were profiled in the Brainseq neurogenomics consortium. Single cell RNA sequencing (scRNA-seq) analyses of the organoids revealed differences in developmental trajectory between SCZ cases and controls in which inhibitory neurons from patients exhibited accelerated maturation. Furthermore, we found a significant overlap of genes upregulated in the inhibitory neurons in SCZ organoids with upregulated genes in postmortem caudate tissues from patients with SCZ compared with control individuals, including the donors of our iPS cell cohort. Our findings suggest that striatal neurons in the patients with SCZ carry abnormalities that originated during early brain development and a ventral forebrain striatal organoid model can recapitulate those neurodevelopmental phenotypes in a dish.
Genomic correlates for migratory direction in a free-ranging cervid
Authors: Bonar Maegwin , Anderson Spencer J. , Anderson Charles R. , Wittemyer George , Northrup Joseph M. , Shafer Aaron B. A.
Published: May 2022

Animal migrations are some of the most ubiquitous and one of the most threatened ecological processes. A wide range of migratory behaviours occur in nature, and this behaviour is not uniform between and within species, where even individuals in the same population can exhibit differentiation. While the environment largely drives migratory behaviour, it is necessary to understand the genetic mechanisms influencing migration to elucidate the adaptive potential of migratory species to cope with novel conditions and adapt to environmental change. In this study, we identified genes associated with migratory traits by undertaking pooled genome-wide scans on a natural population of a facultatively migrating ungulate. We identified genomic regions associated with variation in migratory direction in the study population, including FTM1, a gene linked to the formation of lipids, and DPPA3, a gene linked to epigenetic modifications of the maternal line. Such a genetic basis for migratory traits can have implications on heritability of behaviour and the flexibility of individuals to change their behaviour in the face of stochastic changes in their environment.
p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression
Authors: Ghosh Monisankar , Saha Suchandrima , Li Jinyu , Montrose David C , Martinez Luis A.
Published: May 2022

Tumor suppression by p53 is known to involve cell autonomous and non-cell autonomous mechanisms. p53 has been shown to suppress tumor growth by modulating immune system functions, however, the mechanistic basis for this activity is not well understood. Here we report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 ubiquitin-dependent degradation. The accumulation of cytosolic DNA due to p53’s suppression of TREX1 activates the cytosolic DNA sensor, cGAS and its downstream effectors STING/TBK1/IRF3 resulting in induction of Type I interferons. TREX1 overexpression sufficed to block WTp53 activation of the cGAS/STING pathway. WTp53 mediated induction of type I interferon (IFNB1) response could be suppressed by cGAS/STING knockout. We find that p53’s tumor suppressor activities are compromised by loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell intrinsic and cell extrinsic tumor suppressor activities.
Developmental heterogeneity of embryonic neuroendocrine chromaffin cells and their maturation dynamics
Authors: Akkuratova Natalia , Faure Louis , Kameneva Polina , Kastriti Maria Eleni , Adameyko Igor
Published: May 2022

During embryonic development, nerve-associated Schwann cell precursors (SCPs) give rise to chromaffin cells of the adrenal gland via the “bridge” transient stage, according to recent functional experiments and single cell transcriptomics data from humans and mice. However, currently existing data do not resolve the finest heterogeneity of developing chromaffin populations. Here we took advantage of deep SmartSeq2 transcriptomics sequencing to expand our collection of individual cells from developing murine sympatho-adrenal anlage and uncover the microheterogeneity of embryonic chromaffin cells and corresponding developmental paths. After improving our atlas of sympatho-adrenal development and performing experimental validations, we discovered that SCPs in the local nerve show high degree of microheterogeneity corresponding to early biases towards either Schwann or chromaffin terminal fates. Furthermore, we found that a post-”bridge” population of developing chromaffin cells gives rise to persisting immature chromaffin cells and the two terminal populations (adrenergic and noradrenergic) via diverging differentiation paths. Taken together, we provide a thorough identification of novel markers of adrenergic and noradrenergic populations in developing adrenal glands and report novel differentiation micro-paths leading to them.
ALDH9A1 Deficiency as a Source of Endogenous DNA Damage that Requires Repair by the Fanconi Anemia Pathway
Authors: Jung Moonjung , Ilyashov Isaac , Park Yeji , Donovan Frank X. , Ramanagoudr-Bhojappa Ramanagouda , Keahi Danielle , Durmaz Jordan A. , Choijilsuren Haruna B. , Goldfarb Audrey , Stein Mia , Kim Jungwoo , White Ryan R. , Sridhar Sunandini , Noonan Raymond , Wiley Tom , Carroll Thomas S. , Lach Francis P. , Auerbach Arleen D. , Miranda Ileana , Chandrasekharappa Settara C. , Smogorzewska Agata
Published: May 2022

Fanconi anemia (FA) pathway is required for the repair of DNA interstrand crosslinks (ICL). ICLs are caused by genotoxins, such as chemotherapeutic agents or reactive aldehydes. Inappropriately repaired ICLs contribute to hematopoietic stem cell (HSC) failure and tumorigenesis. While endogenous acetaldehyde and formaldehyde are known to induce HSC failure and leukemia in humans with FA, the effects of other toxic metabolites in FA pathogenesis have not been systematically investigated. Using a metabolism-focused CRISPR screen, we found that ALDH9A1 deficiency causes synthetic lethality in FA pathway-deficient cells. Combined deficiency of ALDH9A1 and FANCD2 causes genomic instability, apoptosis, and decreased hematopoietic colony formation.Fanca−/−Aldh9a1−/−mice exhibited an increased incidence of ovarian tumors. A suppressor CRISPR screen revealed that the loss of ATP13A3, a polyamine transporter, resulted in improved survival ofFANCD2−/−ALDH9A1−/−cells. These findings implicate high intracellular polyamines and the resulting 3-aminopropanal or acrolein in the pathogenesis of FA. In addition, we find that ALDH9A1 variants may be modifying disease onset in FA patients.

Statement of Significance

ALDH9A1 deficiency is a previously unrecognized source of endogenous DNA damage. If not repaired by the Fanconi anemia pathway, such damage leads to increased genomic instability and tumorigenesis. Limiting substrates that accumulate when ALDH9A1 is absent can reduce aldehyde production and rescue synthetic lethality in the combined deficiency of ALDH9A1/FANCD2.
Effect of chemical modifications of tannins on their antibiofilm effect against Gram-negative and Gram-positive bacteria
Authors: Villanueva Xabier , Zhen Lili , Nunez Ares José , Vackier Thijs , Lange Heiko , Crestini Claudia , Steenackers Hans
Published: May 2022

(1)

Background

Tannins have demonstrated antibacterial and antibiofilm activity, but the mechanisms of action are not completely elucidated. We are interested in understanding how to modulate the antibiofilm activity of tannins and in delineating the relationship between chemical determinants and antibiofilm activity.

(2)

Materials and methods

the effect of five different naturally acquired tannins and their chemical derivatives on biofilm formation and planktonic growth of Salmonella Typhimurium, Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus was determined in the Calgary biofilm device.

(3)

Results

most of the unmodified tannins exhibited specific antibiofilm activity against the assayed bacteria. The chemical modifications were found to alter the antibiofilm activity level and spectrum of the tannins, with the positive charge introducing C3NMe3Cl-0.5 derivatization shifting the anti-biofilm spectrum towards Gram-negative bacteria and C3NMe3Cl-0.1 and the acidifying CH3COOH derivatization shifting the spectrum towards Gram-positive bacteria. Also, the quantity of phenolic-OH groups per molecule has a weak impact on the anti-biofilm activity of the tannins.

(4)

Conclusions

we were able to modulate the antibiofilm activity of several tannins by specific chemical modifications, providing a first approach for fine tuning of their activity and spectrum.
Bacterial growth-promoting properties of pooled urine and individual urines from post-menopausal women with or without a urinary tract infection can vary substantially
Authors: Hogins Jacob , Fan Ethan , Seyan Zheyar , Kusin Sam , Christie Alana L. , Zimmern Philippe E. , Reitzer Larry
Published: May 2022

Urinary tract infections (UTIs), mostly caused by uropathogenic E. coli (UPEC), are common bacterial infections that affect a majority of women and often recur. Genomic and transcriptomic analyses have not identified a common set of virulence genes which has suggested conserved virulence functions instead of virulence genes, multiple virulence mechanisms, and complex host-pathogen interactions. One aspect of the host-pathogen interaction is rapid UPEC growth in urine in vivo. When bacteria are grown in pooled urine, an averaged urine is assumed to diminish individual variation. We grew a non-pathogenic and pathogenic E. coli strains in urine from individuals who never had a UTI, had a UTI history but no current infection, and had a UTI history with a current infection. Bacterial growth showed large variations in individual urines and pooled urine supported significantly more growth than predicted for never and history groups but not the current group. UPEC strains, but not the non-pathogenic strain, were resistant to urinary inhibitory factors e.g., antimicrobial peptides based on an indirect inoculation-density effect assay. Total nutrient content tended to be higher in current group urine than never and history group urine. We propose that pooling optimizes a nutrient mixture in never and history group urines, which are often studied, whereas urine from current group individuals appear to have a more optimal nutrient mixture. We conclude that pooled urine is not “an average urine”, and that the best comparisons of results between labs using pooled urine would also include results with a standardized synthetic urine.
Antigen testing for COVID-19 using image-based assessment of oral specimens
Authors: Shimozono Satoshi , Sugiyama Mayu , Kurokawa Hiroshi , Hama Hiroshi , Sato Masae , Morikawa Satoru , Kuwana Kumiko , Haga Kei , Takai-Todaka Reiko , Inaura Shunsuke , Matsumura Yuta , Masaki Hidekazu , Nemoto Naoto , Ando Ryoko , Kogure Takako , Tosaki Asako , Fukuyama Hidehiro , Saya Hideyuki , Nakagawa Taneaki , Morimoto Takuya , Nishihara Hiroshi , Katayama Kazuhiko , Miyawaki Atsushi
Published: May 2022

While numerous diagnostic tests for COVID-19 have been developed for clinical and public health use, most of them provide binary or one-dimensional information on SARS-CoV-2 infection in pursuit of speed and ease of use. As their readouts are largely dependent on the specimen collection procedure, reliable diagnosis is still difficult. Here we report the development of a prototypical method for the immunocytochemical diagnosis of SARS-CoV-2 infection using oral specimens and fluorescent nanobodies against the viral spike and nucleocapsid proteins. Our cytological approach for the detection of SARS-CoV-2 infection was validated by our finding that at least half of SARS-CoV-2 RNAs in oral specimens were localized in the cellular fraction. Mapping antigens on sampled cells provided qualitative image data to which appropriate statistical texture analysis could be applied for the quantitative assessment of SARS-CoV-2 infectious status. A comprehensive comparative analysis revealed that oral cavity swabbing by medical workers provides specimens for COVID-19 diagnosis that yield comparable diagnostic accuracy as self-collected saliva specimens. Our diagnostic strategy may enable medical workers to acquire a wealth of information on virus–human cell interactions for multifaceted insight into COVID-19.