bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexually dimorphic dorsal coloration in a jumping spider: testing a potential case of sex-specific mimicry
Authors: Cook Collette , Powell Erin C. , McGraw Kevin J. , Taylor Lisa A.
Published: June 2021

To avoid predation, many animals mimic behaviours and/or coloration of dangerous prey. Here we examine potential sex-specific mimicry in the jumping spiderHabronattus pyrrithrix. Previous work proposed that males' conspicuous dorsal coloration paired with characteristic leg-waving (i.e. false antennation) imperfectly mimics hymenopteran insects (e.g. wasps and bees), affording protection to males during mate-searching and courtship. By contrast, less active females are cryptic and display less leg-waving. Here we test the hypothesis that sexually dimorphic dorsal colour patterns inH. pyrrithrixare most effective when paired with sex-specific behaviours. We manipulated spider dorsal coloration with makeup to model the opposite sex and exposed them to a larger salticid predator (Phidippus californicus). We predicted that males painted like females should suffer higher predation rates than sham-control males. Likewise, females painted like males should suffer higher predation rates than sham-control females. Contrary to expectations, spiders with male-like coloration were attacked more than those with female-like coloration, regardless of their actual sex. Moreover, males were more likely to be captured, and were captured sooner, than females (regardless of colour pattern). With these unexpected negative results, we discuss alternative functional hypotheses forH. pyrrithrixcolours, as well as the evolution of defensive coloration generally.
Differential invariant method for seeking nonlocally related systems and nonlocal symmetries. I: General theory and examples
Authors: Bluman George W. , de la Rosa Rafael , Santos Bruzón María , Luz Gandarias María
Published: June 2021

Nonlocally related systems, obtained through conservation law and symmetry-based methods, have proved to be useful for determining nonlocal symmetries, nonlocal conservation laws, non-invertible mappings and new exact solutions of a given partial differential equation (PDE) system. In this paper, it is shown that the symmetry-based method is a differential invariant-based method. It is shown that this allows one to naturally extend the symmetry-based method to ordinary differential equation (ODE) systems and to PDE systems with at least three independent variables. In particular, we present the situations for ODE systems, PDE systems with two independent variables and PDE systems with three or more independent variables, separately, and show that these three situations are directly connected. Examples are exhibited for each of the three situations.
A highly conserved ontogenetic limb allometry and its evolutionary significance in the adaptive radiation of
Anolis
lizards
Authors: Feiner Nathalie , Jackson Illiam S. C. , Van der Cruyssen Eliane , Uller Tobias
Published: June 2021

Diversifications often proceed along highly conserved, evolutionary trajectories. These patterns of covariation arise in ontogeny, which raises the possibility that adaptive morphologies are biased towards trait covariations that resemble growth trajectories. Here, we test this prediction in the diverse clade of
Anolis
lizards by investigating the covariation of embryonic growth of 13 fore- and hindlimb bones in 15 species, and compare these to the evolutionary covariation of these limb bones across 267
Anolis
species. Our results demonstrate that species differences in relative limb length are established already at hatching, and are resulting from both differential growth and differential sizes of cartilaginous anlagen. Multivariate analysis revealed that Antillean
Anolis
share a common ontogenetic allometry that is characterized by positive allometric growth of the long bones relative to metapodial and phalangeal bones. This major axis of ontogenetic allometry in limb bones deviated from the major axis of evolutionary allometry of the Antillean
Anolis
and the two clades of mainland
Anolis
lizards. These results demonstrate that the remarkable diversification of locomotor specialists in
Anolis
lizards are accessible through changes that are largely independent from ontogenetic growth trajectories, and therefore likely to be the result of modifications that manifest at the earliest stages of limb development.
Seed dispersers shape the pulp nutrients of fleshy-fruited plants
Authors: Lei Boyu , Cui Jifa , Newman Chris , Buesching Christina D. , Xie Zongqiang , Macdonald David W. , Zhou Youbing
Published: June 2021

The dispersal-syndrome hypothesis posits that fruit traits are a product of selection by frugivores. Although criticized as adaptationist, recent studies have suggested that traits such as fruit or seed size, colour and odour exhibit signatures that imply selection by animal mutualists. These traits imply nutritional rewards (e.g. lipid, carbohydrate), attracting frugivores; however, this remains incompletely resolved. Here, we investigated whether fruit nutrients (lipid, sugar, protein, vitamin C, water content) moderate the co-adaptation of key disperser-group mutualisms. Multivariate techniques revealed that fruit nutrients assembled non-randomly and grouped according to key dispersal modes. Bird-dispersed fruits were richer in lipids than mammal-dispersed fruits. Mixed-dispersed fruits had significantly higher vitamin C than did mammal- or bird-dispersed fruits separately. Sugar and water content were consistently high irrespective of dispersal modes, suggesting that these traits appeal to both avian and mammalian frugivores to match high-energy requirements. Similarly, protein content was low irrespective of dispersal modes, corroborating that birds and mammals avoid protein-rich fruits, which are often associated with toxic levels of nitrogenous secondary compounds. Our results provide substantial over-arching evidence that seed disperser assemblages co-exert fundamental selection pressures on fruit nutrient trait adaptation, with broad implications for structuring fruit–frugivore mutualism and maintaining fruit trait diversity.
Reduction in left frontal alpha oscillations by transcranial alternating current stimulation in major depressive disorder is context-dependent in a randomized-clinical trial
Authors: Riddle Justin , Alexander Morgan L. , Schiller Crystal Edler , Rubinow David R. , Frohlich Flavio
Published: June 2021

Background

Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial.

Methods

In this current study, we aimed to replicate such successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence.

Results

In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants.

Conclusion

Together these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD.

National Clinical Trial

NCT03449979, “Single Session of tACS in a Depressive Episode (SSDE)”https://www.clinicaltrials.gov/ct2/show/NCT03449979
Big Data Analysis of Electronic Health Records: Clinically interpretable representations of older adult inpatient trajectories using time-series numerical data and Hidden Markov Models
Authors: Herrero-Zazo Maria , Fitzgerald Tomas , Taylor Vince , Street Helen , Chaudhry Afzal N , Bradley John , Birney Ewan , Keevil Victoria L
Published: June 2021

The implementation of Electronic Health Records (EHR) in UK hospitals provides new opportunities for clinical ‘big data’ analysis. The representation of observations routinely recorded in clinical practice is the first step to use these data in several research tasks. Anonymised data were extracted from 11 158 first emergency admission episodes (AE) in older adults. Irregular records from 23 laboratory blood tests and vital signs were normalized and regularised into daily bins and represented as numerical multivariate time-series (MVTS). Unsupervised Hidden Markov Models (HMM) were trained to represent each day of each AE as one of 17 state spaces. The visual clinical interpretation of these states showed remarkable differences between patients who died at the end of the AE and those who were discharged. All states had marked features that allowed their clinical interpretation and differentiation between those associated with the patients’ disease burden, their physiological response to this burden or the stage of admission. The most evident relationships with hold-out clinical information were also confirmed by Chi-square tests, with two states strongly associated with inpatient mortality (IM) and 12 states (71%) associated with at least one admission diagnosis. The potential of these data representations on prediction of hospital outcomes was also explored using Logistic Regression (LR) and Random Forest (RF) models, with higher prediction performance observed when models were trained with MVTS data compared to HMM state spaces. However, the outputs of generative and discriminative analyses were complementary. For example, highest ranking features of the best performing RF model for IM (ROC-AUC 0.85) resembled the laboratory blood test and vital sign variables characterising the ‘Early Inflammatory Response-like’ state, itself strongly associated with IM. These results provide evidence of the capability of generative models to extract biological signals from routinely collected clinical data and their potential to represent interpretable patients’ trajectories for future research in hypothesis generation or prediction modelling.
Insights on Genetic and Environmental Factors in Parkinson’s Disease from a regional Swedish Case-Control Cohort
Authors: Brolin Kajsa , Bandres-Ciga Sara , Blauwendraat Cornelis , Widner Håkan , Odin Per , Hansson Oskar , Puschmann Andreas , Swanberg Maria
Published: June 2021

BACKGROUND

Risk factors for Parkinson’s disease (PD) can be more or less relevant to a population due to population-specific genetic architecture, local lifestyle habits, and environmental exposures. Therefore, it is essential to study PD at a local, regional, and continental scale in order to increase the knowledge on disease etiology.

OBJECTIVE

We aimed to investigate the contribution of genetic and environmental factors to PD in a new Swedish case-control cohort.

METHODS

PD patients (n=929) and matched population-based controls (n=935) from the southernmost county in Sweden were included in the cohort. Information on environmental exposures was obtained using questionnaires at inclusion. Genetic analyses included a genome-wide association study (GWAS), haplotype assessment, and a risk profile analysis using cumulative genetic risk scores.

RESULTS

The cohort is a representative PD case-control cohort (64% men, mean age at diagnosis=67 years, median Hoehn and Yahr score=2.0), in which previously reported associations between PD and environmental factors, such as tobacco, could be confirmed. We describe the first GWAS of PD solely composed of PD patients from Sweden, and confirm associations to well-established risk alleles inSNCA. In addition, we nominate an unconfirmed and potentially population-specific genome-wide significant association in thePLPP4locus (rs12771445).

CONCLUSIONS

This work provides an in-depth description of a new PD case-control cohort from southern Sweden, giving insights into environmental and genetic risk factors of PD in the Swedish population.
Threshold concepts in medical education: A scoping review protocol
Authors: Jones Helen , Hammond Lucy
Published: June 2021

Threshold concepts are attracting increasing attention as a framework for improving medical education practice. A growing number of studies in recent years have explored the role of threshold concepts in knowledge and skill acquisition amongst medical students and physicians. However, no review has utilised a systematic approach to examine the literature in this area. The author therefore proposes to undertake a scoping review to explore and describe the current research regarding threshold concepts in medical education and identify gaps in the existing literature. Medical and education databases will be searched for studies exploring threshold concepts in undergraduate, graduate and continuing medical education contexts. The findings will be presented in the form of a descriptive numerical summary and a narrative synthesis. The review will provide a comprehensive overview of how the threshold concept framework is currently being utilised and applied, and provide recommendations for how medical educators can employ the framework in their own practice. Exploration of the research approaches being used, and identification of gaps in the literature, will help inform future research, including determining focus for future systematic reviews.
A multimodal iPSC platform for cystic fibrosis drug testing
Authors: Berical Andrew , Lee Rhianna E. , Lu Junjie , Beermann Mary Lou , LeSeur Jake A. , Mithal Aditya , Thomas Dylan , Ranallo Nicole , Peasley Megan , Stuffer Alex , Harrington Jan , Coote Kevin , Hurley Killian , McNally Paul , Mostovslavsky Gustavo , Mahoney John , Randell Scott H. , Hawkins Finn J.
Published: June 2021

Cystic fibrosis (CF) is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane regulator (CFTR) anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of the CFTR channel using established animal and cell-based models led to the recent discovery of effective CFTR modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we assembled a panel of iPSCs derived from individuals with common or rare variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function in patient-specific iPSCs we adapted two establishedin vitroassays of CFTR function to iPSC-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we quantified CFTR baseline function and response to CFTR modulators and detected genotype-specific differences. Our results demonstrate the potential of the human iPSC platform as a research tool to study cystic fibrosis and in particular accelerate therapeutic development for CF caused by rare mutations.
Protective role of the Atg8 homologue Gabarapl1 in regulating cardiomyocyte glycophagy in diabetic heart disease
Authors: Mellor Kimberley M. , Varma Upasna , Koutsifeli Parisa , Curl Claire L. , Janssens Johannes V. , Daniels Lorna J. , Bernasochi Gabriel B. , Raaijmakers Antonia J.A. , Benson Victoria L. , Chan Eleia J. , Annandale Marco , Li Xun , Nursalim Yohanes , Ip Wendy T.K. , Taylor David J. , Raedschelders Koen , Stotland Aleksandr , Robinson Aaron E. , Mills Richard J. , Lamberts Regis R. , Powell Kim L. , O’Brien Terence J. , Katare Rajesh , Chandramouli Chanchal , Ritchie Rebecca H. , Lim Shiang Y. , Parton Robert G. , Hu Xinli , Bell James R. , Porrello Enzo R. , Hudson James E. , Xiao Rui-Ping , Van Eyk Jennifer E. , Gottlieb Roberta A. , Delbridge Lea M.D.
Published: June 2021

Diabetic heart disease is highly prevalent and characterized by diastolic dysfunction. The mechanisms of diabetic heart disease are poorly understood and no targeted therapies are available. Here we show that the diabetic myocardium (type 1 and type 2) is characterized by marked glycogen elevation and ectopic cellular localization - a paradoxical metabolic pathology given suppressed cardiomyocyte glucose uptake in diabetes. We demonstrate involvement of a glycogen-selective autophagy pathway (‘glycophagy’) defect in mediating this pathology. Genetically manipulated deficiency of Gabarapl1, an Atg8 autophagy homologue, induces cardiac glycogen accumulation and diastolic dysfunction. Stbd1, the Gabarapl1 cognate autophagosome partner is identified as a unique component of the early glycoproteome response to hyperglycemia in cardiac, but not skeletal muscle. Cardiac-targeted in vivo Gabarapl1 gene delivery normalizes glycogen levels, diastolic function and cardiomyocyte mechanics. These findings reveal that cardiac glycophagy is a key metabolic homeostatic process perturbed in diabetes that can be remediated by Gabarapl1 intervention.
Structure of the human FERRY Rab5 effector complex
Authors: Quentin Dennis , Schuhmacher Jan S. , Klink Björn U. , Lauer Jeni , Shaikh Tanvir R. , Huis in ’t Veld Pim J. , Welp Luisa M. , Urlaub Henning , Zerial Marino , Raunser Stefan
Published: June 2021

Long-range mRNA transport is crucial for the spatio-temporal regulation of gene expression, and its malfunction leads to neurological disorders. The pentameric FERRY Rab5 effector complex is the molecular link between mRNA and early endosomes in mRNA intracellular distribution. Here, we determine the cryo-EM structure of the human FERRY complex, composed of Fy-1 to Fy-5. The structure reveals a clamp-like architecture, where two arm-like appendages of Fy-2 and a Fy-5 dimer, protrude from the central Fy-4 dimer. The coiled-coil domains of Fy-2 are flexible and project into opposite directions from the core. While the Fy-2 C-terminal coiled-coil acts as binding region for Fy-1/3 and Rab5, both coiled-coils and Fy-5 concur to bind mRNA. Mutations causing truncations of Fy-2 in patients with neurological disorders impair Rab5 binding or FERRY complex assembly. Thus, Fy-2 serves as a binding hub connecting all five complex subunits and mediating the binding to mRNA and early endosomes via Rab5. The FERRY structure provides novel mechanistic insights into long-distance mRNA transport.
The interplay between host biogeography and phylogeny in structuring diversification of the feather louse genusPenenirmus
Authors: Johnson Kevin P. , Weckstein Jason D. , Herrera Stephany Virrueta , Doña Jorge
Published: June 2021

Parasite diversification is influenced by many of the same factors that affect speciation of free-living organisms, such as biogeographic barriers. However, the ecology and evolution of the host lineage also has a major impact on parasite speciation. Here we explore the interplay between biogeography and host-association on the pattern of diversification in a group of ectoparasitic lice (Insecta: Phthiraptera:Penenirmus) that feeds on the feathers of woodpeckers, barbets, and honeyguides (Piciformes) and some songbirds (Passeriformes). We use whole genome sequencing of 41 ingroup and 12 outgroup samples to develop a phylogenomic dataset of DNA sequences from a reference set of 2,395 single copy ortholog genes, for a total of nearly four million aligned base positions. The phylogenetic trees resulting from both concatenated and gene-tree/species-tree coalescent analyses were nearly identical and highly supported. These trees recovered the genusPenenirmusas monophyletic and identified several major clades, which tended to be associated with one major host group. However, cophylogenetic analysis revealed that host-switching was a prominent process in the diversification of this group. This host-switching generally occurred within single major biogeographic regions. We did, however, find one case in which it appears that a rare dispersal event by a woodpecker lineage from North America to Africa allowed its associated louse to colonize a woodpecker in Africa, even though the woodpecker lineage from North America never became established there.
SRF-CLICAL: an approach for patient risk stratification using random forest models
Authors: Simao Felipe A. , Hieta Reija , Pulman Jane A. , Madonna Gabriele , Ascierto Paolo Antonio , Lewensohn Rolf , Masucci Giuseppe V.
Published: June 2021

An important part of good clinical care is identifying which patients have a high likelihood of experiencing adverse outcomes. Similarly, due to the significant impact cancer treatment can have on a patient’s quality of life, it is also important to properly identify which patients are likely to benefit from more aggressive treatment options. As such, models for predictive risk stratification can be extremely useful in clinical decision making. In this paper, we present, Survival Random Forest-Clinical Categorization Algorithm (SRF-CLICAL), a new method for patient risk stratification using random forests for survival, regression and classification. As a proof of concept, we demonstrate this method on two different cohorts of cancer patients.
Super.Complex: A supervised machine learning pipeline for molecular complex detection in protein-interaction networks
Authors: Palukuri Meghana V. , Marcotte Edward M.
Published: June 2021

Characterization of protein complexes, i.e. sets of proteins assembling into a single larger physical entity, is important, as such assemblies play many essential roles in cells such as gene regulation. From networks of protein-protein interactions, potential protein complexes can be identified computationally through the application of community detection methods, which flag groups of entities interacting with each other in certain patterns. Most community detection algorithms tend to be unsupervised and assume that communities are dense network subgraphs, which is not always true, as protein complexes can exhibit diverse network topologies. The few existing supervised machine learning methods are serial and can potentially be improved in terms of accuracy and scalability by using better-suited machine learning models and parallel algorithms. Here, we present Super.Complex, a distributed, supervised AutoML-based pipeline for overlapping community detection in weighted networks. We also propose three new evaluation measures for the outstanding issue of comparing sets of learned and known communities satisfactorily. Super.Complex learns a community fitness function from known communities using an AutoML method and applies this fitness function to detect new communities. A heuristic local search algorithm finds maximally scoring communities, and a parallel implementation can be run on a computer cluster for scaling to large networks. On a yeast protein-interaction network, Super.Complex outperforms 6 other supervised and 4 unsupervised methods. Application of Super.Complex to a human protein-interaction network with ~8k nodes and ~60k edges yields 1,028 protein complexes, with 234 complexes linked to SARS-CoV-2, the COVID-19 virus, with 111 uncharacterized proteins present in 103 learned complexes. Super.Complex is generalizable with the ability to improve results by incorporating domain-specific features. Learned community characteristics can also be transferred from existing applications to detect communities in a new application with no known communities. Code and interactive visualizations of learned human protein complexes are freely available at: https://sites.google.com/view/supercomplex/super-complex-v3-0.
Probing interplays between human XBP1u translational arrest peptide and 80S ribosome
Authors: Palma Francesco Di , Decherchi Sergio , Pardo-Avila Fátima , Succi Sauro , Levitt Michael , Heijne Gunnar von , Cavalli Andrea
Published: June 2021

The ribosome stalling mechanism is a crucial biological process; yet its atomistic underpinning is still elusive. In this framework, the XBP1u translational arrest peptide (AP) plays a central role in regulating the Unfolded Protein Response (UPR) in eukaryotic cells. Here, we report multi-microseconds all atom molecular dynamics simulations designed to probe the interactions between the XBP1u AP and the mammalian ribosome exit tunnel, both for the wild type AP and for four mutant variants of different arrest potency. Enhanced sampling simulations allow investigating the AP release process of the different variants shedding light on this complex mechanism. The present outcomes are in qualitative/quantitative agreement with available experimental data. In conclusion, we provide an unprecedented atomistic picture of this biological process and clear-cut insights into the key AP-ribosome interactions.
Spatial transcriptomics using combinatorial fluorescence spectral and lifetime encoding, imaging and analysis
Authors: Vu Tam , Vallmitjana Alexander , Gu Joshua , La Kieu , Xu Qi , Flores Jesus , Zimak Jan , Shiu Jessica , Hosohama Linzi , Wu Jie , Douglas Christopher , Waterman Marian , Ganesan Anand , Hedde Per Niklas , Gratton Enrico , Zhao Weian
Published: June 2021

Multiplexed mRNA profiling in the spatial context provides important new information enabling basic research and clinical applications. Unfortunately, most existing spatial transcriptomics methods are limited due to either low multiplexing or assay complexity. Here, we introduce a new spatialomics technology, termed Multi Omic Single-scan Assay with Integrated Combinatorial Analysis (MOSAICA), that integrates in situ labeling of mRNA and protein markers in cells or tissues with combinatorial fluorescence spectral and lifetime encoded probes, spectral and time-resolved fluorescence imaging, and machine learning-based target decoding. This technology is the first application combining the biophotonic techniques, Spectral and Fluorescence Lifetime Imaging and Microscopy (FLIM), to the field of spatial transcriptomics. By integrating the time dimension with conventional spectrum-based measurements, MOSAICA enables direct and highly-multiplexed in situ spatial biomarker profiling in a single round of staining and imaging while providing error correction removal of background autofluorescence. We demonstrate mRNA encoding using combinatorial spectral and lifetime labeling and target decoding and quantification using a phasor-based image segmentation and machine learning clustering technique. We then showcase MOSAICA’s multiplexing scalability in detecting 10-plex targets in fixed colorectal cancer cells using combinatorial labeling of only five fluorophores with facile error-correction and removal of autofluorescent moieties. MOSAICA’s analysis is strongly correlated with sequencing data (Pearson’s r = 0.9) and was further benchmarked using RNAscope™and LGC Stellaris™. We further apply MOSAICA for multiplexed analysis of clinical melanoma Formalin-Fixed Paraffin-Embedded (FFPE) tissues that have a high degree of tissue scattering and intrinsic autofluorescence, demonstrating the robustness of the approach. We then demonstrate simultaneous co-detection of protein and mRNA in colorectal cancer cells. MOSAICA represents a simple, versatile, and scalable tool for targeted spatial transcriptomics analysis that can find broad utility in constructing human cell atlases, elucidating biological and disease processes in the spatial context, and serving as companion diagnostics for stratified patient care.
Single-cell Chromatin Accessibility and Lipid Profiling Reveals a Metabolic Shift in Adipocytes Induced by Bariatric Surgery
Authors: Harlan Blaine , Park Hui Gyu , Spektor Roman , Cummings Bethany , Thomas Brenna J. , Soloway Paul D.
Published: June 2021

Obesity promotes type 2 diabetes and cardiometabolic pathologies. Vertical sleeve gastrectomy (VSG) is used to treat obesity resulting in long-term weight loss and health improvements that precede weight loss; however, the mechanisms underlying the immediate benefits remain incompletely understood. Because adipose plays a crucial role in energy homeostasis and utilization, we hypothesized that VSG exerts its influences, in part, by modulating adipose functional states. We applied single-cell ATAC sequencing and lipid profiling to inguinal and epididymal adipose depots from mice that received sham surgery or VSG. We observed depot-specific cellular composition and chromatin accessibility patterns that were altered by VSG. Specifically, accessibility at Scd1, a fatty acid desaturase, was substantially reduced after VSG in mature adipocytes of inguinal but not epididymal depots. This was accompanied by reduced accumulation of SCD1-produced unsaturated fatty acids. Given these findings and reports that reductions in Scd1 attenuate obesity and insulin resistance and that unsaturated fatty acids stimulate glucose uptake, storage, and oxidation, our results suggest VSG exerts its beneficial effects through modifications of fatty acid profiles mediated by Scd1.
Regulatory approved monoclonal antibodies contain framework mutations predicted from human antibody repertoires
Authors: Petersen Brian M. , Ulmer Sophia A. , Rhodes Emily R. , Gutierrez Gonzalez Matias F , Dekosky Brandon J , Sprenger Kayla G , Whitehead Timothy A.
Published: June 2021

Monoclonal antibodies (mAbs) are an important class of therapeutics used to treat cancer, inflammation, and infectious diseases. Identifying highly developable mAb sequences in silico could greatly reduce the time and cost required for therapeutic mAb development. Here, we present position-specific scoring matrices (PSSMs) for antibody framework mutations developed using natural human antibody repertoire sequences. Our analysis shows that natural human antibody repertoire-based PSSMs are consistent across individuals and demonstrate high correlations between related germlines. We show that mutations in existing therapeutic antibodies can be accurately predicted solely from natural human antibody sequence data. mAbs developed using humanized mice had more human-like FR mutations than mAbs originally developed by hybridoma technology. A quantitative assessment of entire framework regions of therapeutic antibodies revealed that there may be potential for improving the properties of existing therapeutic antibodies by incorporating additional mutations of high frequency in natural human antibody repertoires. In addition, high frequency mutations in natural human antibody repertoires were predicted in silico to reduce immunogenicity in therapeutic mAbs due to the removal of T cell epitopes. Several therapeutic mAbs were identified to have common, universally high-scoring framework mutations, and molecular dynamics simulations revealed the mechanistic basis for the evolutionary selection of these mutations. Our results suggest that natural human antibody repertoires may be useful as predictive tools to guide mAb development in the future.
Witnessing the structural evolution of an RNA enzyme
Authors: Portillo Xavier , Huang Yu-Ting , Breaker Ronald R , Horning David P , Joyce Gerald F
Published: June 2021

An RNA polymerase ribozyme that has been the subject of extensive directed evolution efforts has attained the ability to synthesize complex functional RNAs, including a full-length copy of its own evolutionary ancestor. During the course of evolution, the catalytic core of the ribozyme has undergone a major structural rearrangement, resulting in a novel tertiary structural element that lies in close proximity to the active site. Through a combination of site-directed mutagenesis, structural probing, and deep sequencing analysis, the trajectory of evolution was seen to involve the progressive stabilization of the new structure, which provides the basis for improved catalytic activity of the ribozyme. Multiple paths to the new structure were explored by the evolving population, converging upon a common solution. Tertiary structural remodeling of RNA is known to occur in nature, as evidenced by the phylogenetic analysis of extant organisms, but this type of structural innovation had not previously been observed in an experimental setting. Despite prior speculation that the catalytic core of the ribozyme had become trapped in a narrow local fitness optimum, the evolving population has broken through to a new fitness locale, suggesting that further improvement of polymerase activity may be achievable.
SNAREs and Synaptotagmin cooperatively determine the Ca2+ sensitivity of neurotransmitter release in fixed stoichiometry modules
Authors: McDargh Zachary A. , O’Shaughnessy Ben
Published: June 2021

Neurotransmitter release is accomplished by a multi-component machinery including the membrane-fusing SNARE proteins and Ca2+-sensing Synaptotagmin molecules. However, the Ca2+ sensitivity of release was found to increase or decrease with more or fewer SNARE complexes at the release site, respectively, while the cooperativity is unaffected (Acuna et al., 2014; Arancillo et al., 2013), suggesting that there is no simple division of labor between these two components. To examine the mechanisms underlying these findings, we developed molecular dynamics simulations of the neurotransmitter release machinery, with variable numbers of Synaptotagmin molecules and assembled SNARE complexes at the release site. Ca2+ uncaging simulations showed that increasing the number of SNARE complexes at fixed stoichiometric ratio of Synaptotagmin to SNAREs increased the Ca2+ sensitivity without affecting the cooperativity. The physiological cooperativity of ~4-5 was reproduced with 2-3 Synaptotagmin molecules per SNARE complex, suggesting that Synaptotagmin and SNAREs cooperate in fixed stoichiometry modules. In simulations of action potential-evoked release, increased numbers of Synaptotagmin-SNARE modules increased release probability, consistent with experiment. Our simulations suggest that the final membrane fusion step is driven by SNARE complex-mediated entropic forces, and by vesicle-tethering forces mediated by the long Synaptotagmin linker domains. In consequence, release rates are increased when more SNARE complexes and Synaptotagmin monomers are present at the fusion site.
Profiling Myxococcus xanthus swarming phenotypes through mutation and environmental variation
Authors: Ritchie Linnea J. , Curtis Erin M. , Murphy Kimberly A. , Welch Roy D.
Published: June 2021

Myxococcus xanthus is a bacterium that lives on surfaces as a predatory biofilm called a swarm.As a growing swarm feeds on prey and expands, it displays dynamic multicellular patterns such as traveling waves called ripples and branching protrusions called flares. The rate at which a swarm expands across a surface, and the emergence of the coexisting patterns, are all controlled through coordinated cell movement. M. xanthus cells move using two motility systems known as Adventurous (A) and Social (S). Both are involved in swarm expansion and pattern formation. In this study, we describe a set of M. xanthus swarming genotype-to-phenotype associations that include both genetic and environmental perturbations. We identified new features of the swarming phenotype; recorded and measured swarm expansion using time-lapse microscopy; and compared the impact of mutation on different surfaces. These observations and analyses have increased our ability to discriminate between swarming phenotypes and provided context that allowed us to identify some phenotypes as improbable ‘outliers’ within the M. xanthus swarming phenome.

Importance

Myxococcus xanthus grows on surfaces as a predatory biofilm called a swarm. A feeding swarm expands by moving over and consuming prey bacteria. In the laboratory, a swarm is created by spotting cell suspension onto nutrient agar in lieu of prey. The cells quickly settle on the surface and the new swarm then expands radially. An assay that measures the expansion rate of a swarm of mutant cells is the first, and sometimes only, measurement used to decide whether a particular mutation impacts swarm motility. We have broadened the scope of this assay by increasing the accuracy of measurements and reintroducing prey, resulting in new identifiable and quantifiable features that can be used to improve genotype-to-phenotype associations.
Deep learning assessment of cultural ecosystem services from social media images
Authors: Cardoso Ana Sofia , Renna Francesco , Moreno-Llorca Ricardo , Alcaraz-Segura Domingo , Tabik Siham , Ladle Richard J. , Vaz Ana Sofia
Published: June 2021

Crowdsourced social media data has become popular in the assessment of cultural ecosystem services (CES). Advances in deep learning show great potential for the timely assessment of CES at large scales. Here, we describe a procedure for automating the assessment of image elements pertaining to CES from social media. We focus on a binary (natural, human) and a multiclass (posing, species, nature, landscape, human activities, human structures) classification of those elements using two Convolutional Neural Networks (CNNs; VGG16 and ResNet152) with the weights from two large datasets - Places365 and ImageNet -, and our own dataset. We train those CNNs over Flickr and Wikiloc images from the Peneda-Gerês region (Portugal) and evaluate their transferability to wider areas, using Sierra Nevada (Spain) as test. CNNs trained for Peneda-Gerês performed well, with results for the binary classification (F1-score > 80%) exceeding those for the multiclass classification (> 60%). CNNs pre-trained with Places365 and ImageNet data performed significantly better than with our data. Model performance decreased when transferred to Sierra Nevada, but their performances were satisfactory (> 60%). The combination of manual annotations, freely available CNNs and pre-trained local datasets thereby show great relevance to support automated CES assessments from social media.
CHARMM-GUI Membrane Builder for Lipid Nanoparticles with Ionizable Cationic Lipids and PEGylated Lipids
Authors: Park Soohyung , Choi Yeol Kyo , Kim Seonghoon , Lee Jumin , Im Wonpil
Published: June 2021

A lipid nanoparticle (LNP) formulation is a state-of-the-art delivery system for genetic drugs such as DNA, mRNA, and siRNA, which is successfully applied to COVID-19 vaccines and gains tremendous interest in therapeutic applications. Despite its importance, a molecular-level understanding of the LNP structures and dynamics is still lacking, which makes a rational LNP design almost impossible. In this work, we present an extension of CHARMM-GUI Membrane Builder to model and simulate all-atom LNPs with various (ionizable) cationic lipids and PEGylated lipids (PEG-lipids). These new lipid types can be mixed with any existing lipid types with or without a biomolecule of interest, and the generated systems can be simulated using various molecular dynamics engines. As a first illustration, we considered model LNP membranes with DLin-KC2-DMA (KC2) or DLin-MC3-DMA (MC3) without PEG-lipids. The results from these model membranes are consistent with those from the two previous studies albeit with mild accumulation of neutral MC3 in the bilayer center. To demonstrate Membrane Builder’s capability of building a realistic LNP patch, we generated KC2- or MC3-containing LNP membranes with high concentrations of cholesterol and ionizable cationic lipids together with 2 mol% PEG-lipids. We observe that PEG-chains are flexible, which can be more preferentially extended laterally in the presence of cationic lipids due to the attractive interactions between their head groups and PEG oxygen. The presence of PEG-lipids also relaxes the lateral packing in LNP membranes, and the area compressibility modulus (KA) of LNP membranes with cationic lipids fit into typical KA of fluid-phase membranes. Interestingly, the interactions between PEG oxygen and head group of ionizable cationic lipids induce a negative curvature. We hope that this LNP capability in Membrane Builder can be useful to better characterize various LNPs with or without genetic drugs for a rational LNP design.
Identification of PAX6 and NFAT4 as the transcriptional regulators of lncRNA Mrhl in neuronal progenitors
Authors: Pal Debosree , Dutta Sangeeta , Iyer Dhanur P , Bhaduri Utsa , Rao M.R.S
Published: June 2021

LncRNA Mrhl has been shown to be involved in regulating meiotic commitment of mouse spermatogonial progenitors and coordinating differentiation events in mouse embryonic stem cells. Here we have characterized the interplay of Mrhl with lineage-specific transcription factors during mouse neuronal lineage development. Our results demonstrate that Mrhl is predominantly expressed in the neuronal progenitor populations in mouse embryonic brains and in retinoic acid derived radial-glia like neuronal progenitor cells. Mrhl levels are significantly down regulated in postnatal brains and in maturing neurons. In neuronal progenitors, a master transcription factor, PAX6, acts to regulate the expression of Mrhl through direct physical binding at a major site in the distal promoter, located at 2.9kb usptream of the TSS of Mrhl. Furthermore, NFAT4 occupies the Mrhl proximal promoter at two sites, at 437bp and 143bp upstream of the TSS. ChIP studies reveal that PAX6 and NFAT4 interact with each other, suggesting co-regulation of lncRNA Mrhl expression in neuronal progenitors. Our studies herewith are crucial towards understanding how lncRNAs are regulated by major lineage-specific TFs towards defining specific development and differentiation events.

Summary statement

Transcriptional regulation of lncRNA Mrhl by multiple lineage-specific transcription factors in neuronal progenitors highlights context-dependent regulation important for lineage specification.
Bifurcation drives the evolution of assembly-line biosynthesis
Authors: Booth Thomas J. , Bozhüyük Kenan A. J. , Liston Jonathon D. , Lacey Ernest , Wilkinson Barrie
Published: June 2021

Reprogramming biosynthetic assembly-lines is a topic of intense interest. This is unsurprising as the scaffolds of most antibiotics in current clinical use are produced by such pathways. The modular nature of assembly-lines provides a direct relationship between the sequence of enzymatic domains and the chemical structure of the product, but rational reprogramming efforts have been met with limited success. To gain greater insight into the design process, we wanted to examine how Nature creates assembly-lines and searched for biosynthetic pathways that might represent evolutionary transitions. By examining the biosynthesis of the anti-tubercular wollamides, we show how whole gene duplication and neofunctionalization can result in pathway bifurcation. Importantly, we show that neofunctionalization occurs primarily through intragenomic recombination. This pathway bifurcation leads to redundancy, providing the genetic robustness required to enable large structural changes during the evolution of antibiotic structures. Should the new product be none-functional, gene loss can restore the original genotype. However, if the new product confers an advantage, depreciation and eventual loss of the original gene creates a new linear pathway. This provides the blind watchmaker equivalent to the ‘design, build, test’ cycle of synthetic biology.
Dynamics of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes
Authors: Belhocine Mohamed , Simonin Mathieu , Abad Flores José David , Cieslak Agata , Manosalva Iris , Pradel Lydie , Smith Charlotte , Mathieu Eve-Lyne , Charbonnier Guillaume , Martens Joost H.A. , Stunnenberg Hendrik G. , Maqbool Muhammad Ahmad , Mikulasova Aneta , Russell Lisa J. , Rico Daniel , Puthier Denis , Ferrier Pierre , Asnafi Vahid , Spicuglia Salvatore
Published: June 2021

Broad domains of H3K4 methylation have been associated with consistent expression of tissue-specific, cell identity, and tumor suppressor genes. Here, we identified broad domain–associated genes in healthy human thymic T cell populations and a collection of T cell acute lymphoblastic leukemia (T-ALL) primary samples and cell lines. We found that broad domains are highly dynamic throughout T cell differentiation, and their varying breadth allows the distinction between normal and neoplastic cells. Although broad domains preferentially associate with cell identity and tumor suppressor genes in normal thymocytes, they flag key oncogenes in T-ALL samples. Moreover, the expression of broad domain–associated genes, both coding and noncoding, is frequently deregulated in T-ALL. Using two distinct leukemic models, we showed that the ectopic expression of T-ALL oncogenic transcription factor preferentially impacts the expression of broad domain–associated genes in preleukemic cells. Finally, an H3K4me3 demethylase inhibitor differentially targets T-ALL cell lines depending on the extent and number of broad domains. Our results show that the regulation of broad H3K4me3 domains is associated with leukemogenesis, and suggest that the presence of these structures might be used for epigenetic prioritization of cancer-relevant genes, including long noncoding RNAs.
Organizational performance and capabilities to analyze big data: do the ambidexterity and business value of big data analytics matter?
Authors: Aljumah Ahmad Ibrahim , Nuseir Mohammed T. , Alam Md. Mahmudul
Published: June 2021

Purpose

The aim of the study is to examine the impact of the big data analytics capabilities (BDAC) on the organizational performance. The study also examines the mediating role of ambidexterity and the moderating role of business value of big data (BVBD) analytics in the relationship between the big data analytics capabilities and the organizational performance.

Design/methodology/approach

This study collected primary data based on a questionnaire survey among the large manufacturing firms operating in UAE. A total of 650 questionnaires were distributed among the manufacturing firms and 295 samples were used for final data analysis. The survey was conducted from September to November in 2019, and data were analyzed based on partial least squares structural equation modeling (PLS-SEM).

Findings

The big data analysis (BDA) scalability is supported by the findings on the performance of firm and its determinants such as system, value of business and quality of information. The roles of business value as a moderator and ambidexterity as mediator are found significant. The results reveal that there is a need for managers to consider the business value and quality dynamics as crucial strategic objectives to achieve high performance of the firm.

Research limitations/implications

The study has significant policy implication for practitioners and researchers for understanding the issues related to big data analytics.

Originality/value

This is an original study based on primary data from UAE manufacturing firms.