bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic Rapamycin
Authors: Xu Cheng , Shen Wei-Bin , Reece E. Albert , Hasuwa Hidetoshi , Harman Christopher , Kaushal Sunjay , Yang Peixin
Published: September 2020

Neural tube defects (NTDs) are the second most common structural birth defects. Senescence, a state of permanent cell cyle arrest, only occurs after neural tube closure. Maternal diabetes-induced NTDs, severe diabetic complications leading to infant mortality or lifelong morbidity, may be linked to premature senescence. Here we report that premature senescence occurs in the mouse neuroepithelium and disrupts neurulation, leading to NTDs in diabetic pregnancy. Premature senescence and NTDs were abolished by deleting the transcription factorFoxo3a, themiR-200cgene, the cell cycle inhibitorsp21orp27, or by transgenic expression of the dominant-negative FoxO3a mutant or by the senomorphic rapamycin. Double transgenic expression of p21 and p27 mimicked maternal diabetes in inducing premature neuroepithelium senescence and NTDs. These findings integrate transcription- and epigenome-regulated miRNAs and cell cycle regulators in premature neruoepithelium senescence, and provide a mechanistic basis for targeting premature senescence and NTDs using senomorphs.
Metabolic effects of the schizophrenia-associated 3q29 deletion are sex-specific and uncoupled from behavioral phenotypes
Authors: Pollak Rebecca M , Purcell Ryan H , Rutkowski Timothy P , Malone Tamika , Pachura Kimberly J , Bassell Gary J , Epstein Michael P , Dawson Paul A , Smith Matthew R , Jones Dean P , Zwick Michael E ,   the Emory 3q29 Project, Warren Stephen T , Caspary Tamara , Weinshenker David , Mulle Jennifer G
Published: September 2020

The 1.6 Mb 3q29 deletion is associated with developmental and psychiatric phenotypes. Reduced birthweight and a high prevalence of feeding disorders in patients suggest underlying metabolic dysregulation. We investigated 3q29 deletion-induced metabolic changes using the B6.Del16+/Bdh1-Tfrcmouse model. We found that B6.Del16+/Bdh1-Tfrcanimals preferentially use dietary lipids as an energy source. Untargeted metabolomics showed a strong sex-dependent effect of the 3q29 deletion on fat metabolism. A high-fat diet (HFD) partially rescued the 3q29 deletion-associated weight deficit in females, but not males. Untargeted metabolomics after HFD revealed persistent fat metabolism alterations in females. The HFD did not affect B6.Del16+/Bdh1-Tfrcbehavioral phenotypes, suggesting that 3q29 deletion-associated metabolic and behavioral outcomes are uncoupled. Our data indicate a HFD intervention in 3q29 deletion syndrome may improve weight phenotypes without exacerbating behavioral manifestations. Our study also highlights the importance of assessing sex in metabolic studies and suggests mechanisms underlying 3q29 deletion-associated metabolic phenotypes are sex-specific.
Carbamazepine Causes Changes in Maternal Reproductive Performance and Fetal Growth Retardation in Rats
Authors: Nunes Marina , de Sousa Felipe Duarte Coelho , Andretta Rhaiza Roberta , Miraglia Sandra Maria , de Oliva Samara Urban
Published: September 2020

Purpose

Carbamazepine (CBZ) is widely used in the treatment of trigeminal neuralgia, affective disorders, and mainly as an anticonvulsant, specially by fertile women, due to their need to continuously use CBZ during pregnancy and the lactation period. CBZ crosses the placenta barrier and may impair pregnancy and the embryonic development. The aim of this study was to determine the effect of CBZ on maternal reproductive outcome, besides fetal growth and development in Wistar rats.

Methods

Rat dams received CBZ (20mg/Kg/day) or propylene glycol (vehicle) via intraperitoneal (i.p.) injection throughout the gestational period. On the 19thday of gestation, the ovary and uterine contents were examined, and the placenta and fetuses were analyzed.

Results

The CBZ exposure during pregnancy caused a reduction in fetal weight, fetal weight classification, and crown-rump distance. CBZ also decreased the implantation index, average number of corpora lutea, fetal weights and crown-rump length and increased the pre and post-implantation loss rate. The CBZ-exposed fetus also presented external congenital malformations.

Conclusion

The results suggest that maternal exposure to CBZ interfered on several maternal reproductive outcomes and can cause severe fetal intrauterine growth restriction (IUGR).
Stochasticity explains differences in the number ofde novomutations between families
Authors: Goldmann Jakob M. , Hampstead Juliet , Wong Wendy S.W. , Wilfert Amy B. , Turner Tychele , Jonker Marianne A. , Bernier Raphael , Huynen Martijn A. , Eichler Evan E. , Veltman Joris A. , Maxwell George L. , Gilissen Christian
Published: September 2020

The number of de novo mutations (DNMs) in the human germline is correlated with parental age at conception, but this explains only part of the observed variation. We investigated whether there is a family-specific contribution to the number of DNMs in offspring. The analysis of DNMs in 111 dizygotic twin pairs did not identify a significant family-specific contribution. This result was corroborated by comparing DNMs of 1669 siblings to those of age-matched unrelated offspring. In addition, by modeling DNM data from 1714 multi-offspring families we estimated that the family specific contribution explains approximately 5.2% of the variation in DNM number. Furthermore, we found no significant difference between the observed number of DNMs and those based on a stochastic Poisson process. We conclude that a family-specific contribution to DNMs is small and that stochasticity explains a large proportion of variation in DNM counts.
Expression of a membrane-targeted fluorescent reporter disrupts auditory hair cell mechanoelectrical transduction and causes profound deafness
Authors: Ballesteros Angela , Fitzgerald Tracy S. , Swartz Kenton J.
Published: September 2020

The reporter mT/mG mice expressing a membrane-targeted fluorescent protein are becoming widely used to study the auditory and vestibular system due to its versatility. Here we show that high expression levels of the fluorescent mtdTomato reporter affect the function of the sensory hair cells and the auditory performance of mT/mG transgenic mice. Auditory brainstem responses and distortion product otoacoustic emissions revealed that adult mT/mG homozygous mice are profoundly deaf, whereas heterozygous mice present high frequency loss. We explore whether this line would be useful for studying and visualizing the membrane of auditory hair cells by airyscan super-resolution confocal microscopy. Membrane localization of the reporter was observed in hair cells of the cochlea, facilitating imaging of both cell bodies and stereocilia bundles without altering cellular architecture or the expression of the integral membrane motor protein prestin. Remarkably, hair cells from mT/mG homozygous mice failed to uptake the FM1-43 dye and to locate TMC1 at the stereocilia, indicating defective mechanoelectrical transduction machinery. Our work emphasizes that precautions must be considered when working with reporter mice and highlights the potential role of the cellular membrane in maintaining functional hair cells and ensuring proper hearing.
A sexual dimorphism in the spatial vision of band-winged grasshoppers
Authors: Duncan Alex B. , Salazar Brae A. , Garcia Sara R. , Brandley Nicholas C.
Published: September 2020

Visual acuity (VA) --- a measurement of the fineness or coarseness of vision --- correlates with the size of an animal, with larger species often possessing sharper vision. However, it is unknown whether the same relationship between visual acuity and size holds within a species when individuals differ consistently and substantially in size, such as through a sexual size dimorphism. Here we examine the visual acuity of three species of sexually dimorphic band-winged grasshoppers, in which females are the larger sex (Arphia pseudonietana, Dissosteira carolina, andSpharagemon equale;total n = 98). Using a radius of curvature estimation method, we find that females have ∼21% finer vision in the most acute region and axis of the eye than do males. Further explorations of the eyes of the species showing the greatest size dimorphism (D. carolina) suggest that this VA dimorphism is driven by females having larger eyes with more ommatidia. In contrast to many flying insects where males have finer vision to acquire mates, our study is one of the first to demonstrate a female-biased sexual dimorphism in acuity. Given the number of species in which females are larger than males, our results suggest that differences in VA between the sexes may be more common than currently appreciated.
Orchestrating and sharing large multimodal data for transparent and reproducible research
Authors: Mammoliti Anthony , Smirnov Petr , Nakano Minoru , Safikhani Zhaleh , Eeles Christopher , Seo Heewon , Nair Sisira Kadambat , Mer Arvind S. , Ho Chantal , Beri Gangesh , Kusko Rebecca ,   MAQC Society, Haibe-Kains Benjamin
Published: September 2020

Reproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA (orcestra.ca), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.
Cell type-selective secretome profiling in vivo
Authors: Wei Wei , Riley Nicholas M. , Yang Andrew C. , Kim Joon T. , Terrell Stephanie M. , Li Veronica L. , Garcia-Contreras Marta , Bertozzi Carolyn R. , Long Jonathan Z.
Published: September 2020

Secreted polypeptides are a fundamental biochemical axis of intercellular and endocrine communication. However, a global understanding of composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection, and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte, and myeloid cell secretomes by direct purification of biotinylated secreted polypeptides from blood. Our secretome atlas validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types, and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by increased unconventional secretion of the cytosolic enzyme BHMT. This secretome profiling strategy enables dynamic and cell-type dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.
A unique multi-synaptic mechanism regulates dopamine release in the nucleus accumbens during adolescence
Authors: Pitts Elizabeth G. , Stowe Taylor A. , Ferris Mark J.
Published: September 2020

Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry to examine differences in regulation of dopamine release in the nucleus accumbens core of adolescent and adult male rats. We found that differences between adolescent and adult stimulated dopamine release is driven by a unique multisynaptic mechanism in early adolescence involving acetylcholine acting at α6-containing nicotinic acetylcholine receptors to mediate inhibition of dopamine via GABA release. These changes in dopamine regulation across adolescence provides a springboard for our understanding of basic brain development and targeted therapy for a range of psychiatric conditions that emerge in adolescence.
Structural determinants of calcium binding beyond the EF-hand binding site: a study of alpha parvalbumins
Authors: Immadisetty Kalyan , Sun Bin , Kekenes-Huskey Peter
Published: September 2020

1

Parvalbumin (PV) is a calcium binding protein expressed in humans, fish and avian species. In these organisms, the calcium (Ca2+) affinities of specific PV isoforms can vary by orders of magnitude. Despite the availability of high resolution structural data for many PV isoforms, the structural bases for how such proteins confer widely-varying divalent Ca2+affinities and selectivities against common ions like magnesium (Mg2+) has been difficult to rationalize. We therefore conducted molecular simulations of severalα-pavalbumin (α-parvalbumin (αPV)) constructs with Ca2+affinities in the micromolar to nanomolar ranges to identify properties of conformations that contribute to their wide-ranging binding constants and selectivities against Mg2+. Specifically, we examined a D94S/G98E construct with a reported lower Ca2+affinity (≈ −18.2 kcal/mol) relative to the WT (≈ −22 kcal/mol), an S55D/E59D variant with enhanced affinity (≈ −24 kcal/mol), and a truncated variant ofαPV with weak affinity (≈ −12.6 kcal/mol). We performed molecular dynamics simulations of these constructs and assessed their Ca2+and Mg2+binding properties using scores from molecular mechanics generalized Born approximation (MM/GBSA), ion/oxygen coordination patterns and thermodynamics via mean spherical approximation (MSA) theory, as well as via metrics of protein structure and hydration. Our key findings are that although MM/GBSA and MSA scores successfully rank-ordered the variants according to their previously-published affinities and Mg2+selectivity, importantly, properties of Ca2+loops in CBPs such as coordination, and charge are alone insufficient to rationalize their binding properties. Rather, Ca2+affinity and selectivity against Mg2+are emergent properties stemming from both local effects within the proteins’ ion binding sites as well as non-local contributions from protein folding and solubility. Our findings broaden our understanding of the molecular bases governingαPV ion binding that are likely shared by many Ca2+binding proteins.
Coupled social-land dynamics and the future of sustainable consumption
Authors: Pal Saptarshi , Bauch Chris T. , Anand Madhur
Published: September 2020

Dietary patterns have long been a driver of global land use. Increasingly, they also respond to it, in part because of social forces that support adoption of sustainable diets. Here we develop a coupled social-land use dynamics model parameterised for 164 countries. We project global land use under 20 scenarios for future population, income, and agricultural yield. When future yields are low and/or population size is high, coupled social-land feedbacks can reduce the peak global land use by up to 2 billion hectares, if socio-economic barriers to adopting a sustainable diet are sufficiently low. In contrast, when population growth is low or yield is high, reductions in income elasticity can increase peak land use by 100 million hectares. The model also exhibits a regime of synergistic effects whereby simultaneous changes to multiple social and economic parameters are required to change land use projections. This research demonstrates the value of including coupled social-land feedbacks in land use projections.
Exogenous Sex Hormone Effects on Brain Microstructure in Women: A diffusion MRI Study in the UK Biobank
Authors: Nabulsi Leila , Lawrence Katherine E. , Santhalingam Vigneshwaran , Abaryan Zvart , Boyle Christina P. , Villalon-Reina Julio E. , Nir Talia M. , Gari Iyad Ba , Zhu Alyssa H. , Haddad Elizabeth , Muir Alexandra M. , Jahanshad Neda , Thompson Paul M.
Published: September 2020

Changes in estrogen levels in women have been associated with increased risk for age-related neurodegenerative diseases, including Alzheimer’s disease, but the impact of exogenous estrogen exposure on the brain is poorly understood. Oral contraceptives (OC) and hormone therapy (HT) and are both common sources of exogenous estrogen for women in reproductive and post-menopausal years, respectively. Here we examined the association of exogenous sex hormone exposure with the brain’s white matter (WM) aging trajectories in postmenopausal women using and not using OC and HT (HT users: n=3,033, non-users n=5,093; OC users: n=6,964; non-users n=1,156), while also investigating multiple dMRI models. Cross-sectional brain dMRI data was analyzed from the UK Biobank using conventional diffusion tensor imaging (DTI), the tensor distribution function (TDF), and neurite orientation dispersion and density imaging (NODDI). Mean skeletonized diffusivity measures were extracted across the whole brain, and fractional polynomial regressions were used to characterize age-related trajectories for WM microstructural measures. Advanced dMRI model NODDI revealed a steeper WM aging trajectory in HT users relative to non-users, and for those using unopposed estrogens relative to combined estrogens treatment. By contrast, no interaction was detected between OC status and age effects on the diffusivity measures we examined. Exogenous sex hormone exposure may negatively impact WM microstructure aging in postmenopausal women. We also present normative reference curves for white matter microarchitectural parameters in women, to help identify individuals with microstructural anomalies.
Proficiency Testing for bacterial whole genome sequencing in assuring the quality of microbiology diagnostics in clinical and public health laboratories
Authors: Lau Katherine A. , da Silva Anders Gonçalves , Theis Torsten , Gray Joanna , Ballard Susan A , Rawlinson William D.
Published: September 2020

The adoption of whole genome sequencing (WGS) data over the past decade for pathogen surveillance, and decision-making for infectious diseases has rapidly transformed the landscape of clinical microbiology and public health. However, for successful transition to routine use of these techniques, it is crucial to ensure the WGS data generated meet defined quality standards for pathogen identification, typing, antimicrobial resistance detection and surveillance. Further, the ongoing development of these standards will ensure that the bioinformatic processes are capable of accurately identifying and characterising organisms of interest, and thereby facilitate the integration of WGS into routine clinical and public health laboratory setting. A pilot proficiency testing (PT) program for WGS of infectious agents was developed to facilitate widely applicable standardisation and benchmarking standards for WGS across a range of laboratories. The PT participating laboratories were required to generate WGS data from two bacterial isolates, and submit the raw data for independent bioinformatics analysis, as well as analyse the data with their own processes and answer relevant questions about the data. Overall, laboratories used a diverse range of bioinformatics tools and could generate and analyse high-quality data, either meeting or exceeding the minimum requirements. This pilot has provided valuable insight into the current state of genomics in clinical microbiology and public health laboratories across Australia. It will provide a baseline guide for the standardisation of WGS and enable the development of a PT program that allows an ongoing performance benchmark for accreditation of WGS-based test processes.
How super-spreader cities, highways, hospital bed availability, and dengue fever influenced the COVID-19 epidemic in Brazil
Authors: Nicolelis Miguel A.L. , Raimundo Rafael L. G. , Peixoto Pedro S. , de Andreazzi Cecília S.
Published: September 2020

Although its international airports served as the country’s main entry points for SARS-CoV-2, the factors driving the uneven geographic spread of COVID-19 cases and deaths in Brazil remain largely unknown. Here we show that four major factors likely accounted for the entire dynamics of COVID-19 in Brazil. Mathematical modeling revealed that, initially, the “super-spreading city” of São Paulo accounted for roughly 80% of the case spread in the entire country. During the first 3 months of the epidemic, by adding only 16 other spreading cities, we accounted for 98-99% of the cases reported in Brazil at the time. Moreover, 26 of the major Brazilian federal highways accounted for about 30% of SARS-CoV-2’s case spread. As cases accumulated rapidly in the Brazilian countryside, the distribution of COVID-19 deaths began to correlate with a third parameter: the geographic distribution of the country’s hospital intensive care unit (ICU) beds, which is highly skewed towards state capitals where the epidemic began. That meant that severely ill patients living in the countryside had to be transported to state capitals to access ICU beds where they often died, creating a “boomerang effect” that contributed to the skew of the geographic distribution of COVID-19 deaths. Finally, we discovered that the geographic distribution of dengue fever, amounting to more than 3.5 million cases from January 2019 to July 2020, was highly complementary to that of COVID-19. This was confirmed by the identification of significant negative correlations between COVID-19’s incidence, infection growth rate, and mortality to the percentage of people with antibody (IgM) levels for dengue fever in each of the country’s states. No such correlations were observed when IgM data for chikungunya virus, which is transmitted by the same mosquito vector as dengue, was used. Thus, states in which a large fraction of the population had contracted dengue fever in 2019-2020 reported lower COVID-19 cases and deaths, and took longer to reach exponential community transmission, due to slower SARS-CoV-2 infection growth rates. This inverse correlation between COVID-19 and dengue fever was further observed in a sample of countries around Asia and Latin America, as well as in islands in the Pacific and Indian Oceans. This striking finding raises the intriguing possibility of an immunological cross-reactivity between DENV serotypes and SARS-CoV-2. If proven correct, this hypothesis could mean that dengue infection or immunization with an efficacious and safe dengue vaccine could produce some level of immunological protection for SARS-CoV-2, before a vaccine for SARS-CoV-2 becomes available.
Novel rRNA-depletion methods for total RNA sequencing and ribosome profiling developed for avian species
Authors: Gu Hanwen , Sun Yu H. , Li Xin Zhiguo
Published: September 2020

Deep sequencing of RNAs has greatly aided the study of the transcriptome, enabling comprehensive gene expression profiling and the identification of novel transcripts. While mRNAs are of the greatest interest in gene expression studies as they encode for proteins, mRNAs make up only 3-5% of total RNAs, with the majority comprising ribosomal RNAs (rRNAs). Therefore, applications of deep sequencing to RNA face the challenge of how to efficiently enrich mRNA species prior to library construction. Traditional methods extract mRNAs using oligo-dT primers targeting the poly-A tail on mRNAs; however, this approach is not comprehensive as it does not account for mRNAs lacking the poly-A tail or other lncRNAs that we may be interested in. Alternative methods deplete rRNAs, but such approaches require species-specific probes and the commercially available kits are costly and have only been developed for a limited number of model organisms. Here we describe a quick, cost-effective method for depleting rRNAs using custom-designed oligos. We use chickens as an example species for probe design, and the same approach also apply to mice. Using this protocol, we have not only removed the rRNAs from total RNAs for RNA-seq library construction but also depleted rRNA fragments from ribosome-protected fragments for ribosome profiling. Currently, this is the only rRNA depletion-based method for avian species; this method thus provides a valuable resource for both the scientific community and the poultry industry.
Chromogranin A regulates gut permeabilityviathe antagonistic actions of its proteolytic peptides
Authors: Muntjewerff Elke M. , Tang Kechun , Lutter Lisanne , Christoffersson Gustaf , Nicolasen Mara J.T. , Gao Hong , Katkar Gajanan D. , Das Soumita , Beest Martin ter , Ying Wei , Ghosh Pradipta , Aidy Sahar El , Oldenburg Bas , van den Bogaart Geert , Mahata Sushil K.
Published: September 2020

Aim

A ‘leaky’ gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we show how pro-hormone Chromogranin A (CgA), produced by the enteroendocrine cells, and Catestatin (CST: hCgA352-372), the most abundant CgA-derived proteolytic peptide, affect the gut barrier.

Methods

Colon tissues from region-specific CST-knockout (CST-KO) mice, CgA-knockout (CgA-KO) and WT mice were analyzed by immunohistochemistry, ultrastructural and flowcytometry studies. FITC-dextran assays were used to measure intestinal barrier function. Mice were supplemented with CST or CgA fragment pancreastatin (PST: CgA250-301). The microbial composition of cecum was determined. CgA and CST levels were measured in blood of IBD patients.

Results

CST-KO mice displayed (i) elongated tight, adherens junctions and desmosomes similar to IBD patients, and (ii) gut inflammation. Consistently, plasma FITC-dextran measurements showed increased intestinal paracellular permeability in the CST-knockout mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST-knockout mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA-knockout mice supplementation with CST and/or PST in CgA-KO mice showed that intestinal paracellular permeability is regulated by the antagonistic roles of these two peptides: CST reduces and PST increases permeability.

Conclusion

The pro-hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts via antagonizing the effects of PST.
>Corna - An Open Source Python Tool For Natural Abundance Correction In Isotope Tracer Experiments
Authors: Raaisa Raaisa , Lathwal Shefali , Chubukov Victor , Kibbey Richard G. , Jha Abhishek K.
Published: September 2020

Background

Stable isotope-based approaches are used in the field of metabolomics for quantification and identification of metabolites, discovery of new pathways and measurement of intracellular fluxes. In these experiments, often performed with mass spectrometry (MS), data must be corrected for natural abundance of isotopes. Various stand-alone tools with their own separate data formats and learning curves exist for correction of data collected at different resolutions, for tandem MS, and for different number of tracer elements.

Results

We present a Python package, Corna, that combines natural abundance correction workflows for several experimental conditions and can be used as a one-stop-shop for stable isotope labeled experiments. We validate the algorithms in Corna with published tools, where available, and include new features, such as correction of two tracer elements, that are not yet implemented in any existing software application as per our knowledge. We also present the integration of Corna with an existing open source peak integration software. The integrated workflow can reduce processing times for a typical stable isotope based workflow from days to hours for a familiar user.

Conclusions

Algorithmic advancements have been keeping up with the developments in mass spectrometry technologies and have been the focus of most existing tools for natural abundance correction. However, in this high throughput era, it is also important to recognize user experience, and integrated and reproducible workflows. Corna has been written in Python and is designed for users who have access to large amounts of data from different kinds of experiments and want to integrate a natural abundance correction tool seamlessly in their pipelines. The latest version of Corna can be accessed athttps://github.com/raaisakuk/NA_Correction.
scLink: Inferring Sparse Gene Co-expression Networks from Single-cell Expression Data
Authors: Li Wei Vivian , Li Yanzeng
Published: September 2020

A system-level understanding of the regulation and coordination mechanisms of gene expression is essential to understanding the complexity of biological processes in health and disease. With the rapid development of single-cell RNA sequencing technologies, it is now possible to investigate gene interactions in a cell-type-specific manner. Here we propose the scLink method, which uses statistical network modeling to understand the co-expression relationships among genes and to construct sparse gene co-expression networks from single-cell gene expression data. We use both simulation and real data studies to demonstrate the advantages of scLink and its ability to improve single-cell gene network analysis. The source code used in this article is available athttps://github.com/Vivianstats/scLink.
Structure of autosynthetic models of balanced cell growth and numerical optimization of their growth rate
Authors: Sezer Deniz , Schubert Peter , Lercher Martin J.
Published: September 2020

Genome-scale reaction network models are available for many prokaryotic organisms. Yet, to predict the proteome and metabolome of the cell from them, additional information about (i) the nonlinear enzyme kinetics and (ii) the regulation of protein expression by metabolic signals is necessary. Knowledge about the latter could be sidestepped by assuming that expression regulation has evolved to achieve the protein composition that maximizes cellular growth rate. A general mathematical framework for optimizing the growth rate of models comprising an arbitrarily complex metabolic network and a relatively simple protein-synthesis network was recently formulated independently by two research groups [de Groot et al., PLoS Comput. Biol.16, e1007559 (2020); Dourado & Lercher, Nature Commun.11, 1226 (2020)]. Here, this formalism is further developed with particular focus on carrying out the optimization numerically. To this end, we identify the concentrations of the enzymes as the independent variables of the optimization problem and propose novel multiplicative updates for the iterative calculation of the dependent metabolite concentrations. The reduced gradient method, with analytical derivatives, is employed for the numerical optimization. Additionally, the roles of the dilution of the metabolite concentrations by growth and the commonly invoked constraint on the cell dry mass density are clarified. These developments should lay the basis for the practical optimization of large-scale kinetic models, thus formally connecting the physiological “macrostate” of the cell, characterized by its growth rate, to its “microstate”, described by the cell proteome and metabolome.

Author summary

An evolving population of non-interacting, unicellular organisms in a constant environment will maximize its growth rate. By expressing the growth rate as a mathematical function of the cellular composition, it becomes possible to formulate an optimization problem whose solution yields the cell proteome and metabolome at the maximal growth rate. The formulation and solution of such an optimization problem has the potential to elucidate fundamental optimality principles in living cells and to enable the engineering of complex biological systems. Building on previous work, here we address the task of solving this optimization problem numerically. In the process, we elucidate the mathematical role of some common simplifying approximations. This allows us to organize many of the existing formulations of the optimization problem into a hierarchy, whose lower levels are reached by invoking these approximations.
Mapping the impacts of hurricanes Maria and Irma on banana production area in the Dominican Republic
Authors: Varma Varun , Thompson William , Duarte Solhanlle Bonilla , Krütli Pius , Six Johan , Bebber Daniel P
Published: September 2020

Extreme weather events can have devastating impacts on agricultural systems, and the livelihoods that depend on them. Tools for rapid, comprehensive and cost-effective assessment of impacts, especially if carried out remotely, can be of great value in planning systematic recovery of production, as well as assessing risks from future events. Here, we use openly available remote sensing data to quantify the impacts of hurricanes Irma and Maria in 2017 on banana production area in the Dominican Republic — the world’s largest producer of organic bananas. Further, we assess the risk to current production area if a similar extreme event were to re-occur. Hurricane associated damage was mapped using a simple change detection algorithm applied to Synthetic Aperture Radar (SAR) data over the three main banana growing provinces of northern Dominican Republic, i.e. Monte Cristi, Valverde and Santiago. The map of hurricane affected area was overlaid with banana plantation distributions for 2017 and 2019 that were mapped (accuracy = 99.8%) using a random forest classifier, and a combination of SAR and multi-spectral satellite data. Our results show that 11.35% of banana plantation area was affected by hurricane damage in 2017. Between 2017 and 2019, there was a high turnover of plantation area, but with a net gain of 10.8%. However, over a quarter (26.9%) of new plantation area spatially overlapped with regions which had seen flooding or damage from hurricanes in 2017. Our results indicate that banana production systems in northern Dominican Republic saw extensive damage in the aftermath of hurricanes Irma and Maria. While production area has recovered since then, a substantial proportion of new plantations, and a greater fraction of production area in general, occur at locations at risk from future extreme events.
Genomic comparison of non-photosynthetic plants from the family Balanophoraceae with their photosynthetic relatives
Authors: Schelkunov Mikhail I. , Nuraliev Maxim S. , Logacheva Maria D.
Published: September 2020

The plant family Balanophoraceae consists entirely of species that have lost the ability to photosynthesize. Instead, they obtain nutrients by parasitizing other plants. Recent studies have shown that plastid genomes of Balanophoraceae have a number of interesting features, one of the most prominent of those being a tremendous AT content close to 90%. Also, the nucleotide substitution rate in the plastid genomes of Balanophoraceae is greater by an order of magnitude compared to photosynthetic relatives, without signs of relaxed selection. All these features have no definite explanations.

Given these unusual features, we supposed that it would be interesting to gain insight into the characteristics ofnucleargenomes of Balanophoraceae. To do this, in the present study we analysed transcriptomes of two species from Balanophoraceae, namelyRhopalocnemis phalloidesandBalanophora fungosa, and compared them with transcriptomes of their close photosynthetic relativesDaenikerasp.,Dendropemon caribaeus, Malania oleifera.

The analysis showed that the AT content of nuclear genes of Balanophoraceae does not markedly differ from that of photosynthetic relatives. The nucleotide substitution rate in genes of Balanophoraceae is for an unknown reason several times larger than in genes of photosynthetic Santalales, though the negative selection in Balanophoraceae is likely stronger.

We observed an extensive loss of photosynthesis-related genes in Balanophoraceae. Also, for Balanophoraceae we did not see transcripts of several genes whose products participate in plastid genome repair. This implies their loss or very low expression, which may explain the increased nucleotide substitution rate and AT content of the plastid genomes.
Coarse-grained implicit solvent lipid force field with a compatible resolution to the Cα protein representation
Authors: La Torre Diego Ugarte , Takada Shoji
Published: September 2020

Biological membranes have been prominent targets for coarse-grained (CG) molecular dynamics (MD) simulations. While minimal CG lipid models with three-beads per lipid and quantitative CG lipid models with >10-beads per lipid have been well studied, in between them, CG lipid models with a compatible resolution to residue-level CG protein models are much less developed. Here, we extended a previously developed three-bead lipid model into a five-bead model and parametrized it for two phospholipids, POPC and DPPC. The developed model, iSoLF, reproduced the area per lipid, hydrophobic thickness, and phase behaviors of the target phospholipid bilayer membranes at the physiological temperature. The model POPC and DPPC membranes were in liquid and gel phases, respectively, in accordance with experiments. We further examined the spontaneous formation of a membrane bilayer, the temperature dependence of physical properties, vesicle dynamics, and the POPC/DPPC two-component membrane dynamics of the CG lipid model, showing some promise. Once combined with standard Cα protein models, the iSoLF model will be a powerful tool to simulate large biological membrane systems made of lipids and proteins.
Neuroglia Infection by Rabies Virus after Anterograde Virus Spread in Peripheral Neurons
Authors: Potratz Madlin , Zaeck Luca M. , Weigel Carlotta , Klein Antonia , Freuling Conrad M. , Müller Thomas , Finke Stefan
Published: September 2020

The highly neurotropic rabies virus (RABV) enters peripheral neurons at axon termini and requires long distance axonal transport and trans-synaptic spread between neurons for the infection of the central nervous system (CNS). Whereas laboratory strains are almost exclusively detected in neurons, recent 3D imaging of field RABV-infected brains revealed an remarkably high proportion of infected astroglia, indicating that in contrast to attenuated lab strains highly virulent field viruses are able to suppress astrocyte mediated innate immune responses and virus elimination pathways. While fundamental for CNS invasion,in vivofield RABV spread and tropism in peripheral tissues is understudied. Here, we used three-dimensional light sheet and confocal laser scanning microscopy to investigate thein vivodistribution patterns of a field RABV clone in cleared high-volume tissue samples after infection via a natural (intramuscular; hind leg) and an artificial (intracranial) inoculation route. Immunostaining of virus and host markers provided a comprehensive overview of RABV infection in the CNS and peripheral nerves after centripetal and centrifugal virus spread. Importantly, we identified non-neuronal,axon-ensheathing neuroglia (Schwann cells, SCs) in peripheral nerves of the hind leg and facial regions as a target cell population of field RABV. This suggest that virus release from axons and infected SCs is part of the RABVin vivocycle and may affect RABV-related demyelination of peripheral neurons and local innate immune responses. Detection of RABV in axon surrounding myelinating SCs after i.c. infection further provided evidence for anterograde spread of RABV, highlighting that RABV axonal transport and spread of infectious virus in peripheral nerves is not exclusively retrograde. Our data support a new model in which, comparable to CNS neuroglia, SC infection in peripheral nerves suppresses glia-mediated innate immunity and delays antiviral host responses required for successful transport from the peripheral infection sites to the brain.
Filopodia rotate and coil by actively generating twist in their actin shaft
Authors: Leijnse Natascha , Barooji Younes Farhangi , Verhagen Bram , Wullkopf Lena , Erler Janine Terra , Semsey Szabolcs , Nylandsted Jesper , Doostmohammadi Amin , Oddershede Lene Broeng , Bendix Poul Martin
Published: September 2020

Filopodia are actin-rich structures, present on the surface of practically every known eukaryotic cell. These structures play a pivotal role in specific cell-cell and cell-matrix interactions by allowing cells to explore their environment, generate mechanical forces, perform chemical signaling, or convey signals via intercellular tunneling nano-bridges. The dynamics of filopodia appear quite complex as they exhibit a rich behavior of buckling, pulling, length and shape changes. Here, we find that filopodia additionally explore their 3D extracellular space by combining growth and shrinking with axial twisting and buckling of their actin rich core. Importantly, we show the rotational dynamics of the filamentous actin inside filopodia for a range of highly distinct and cognate cell types spanning from earliest development to highly differentiated tissue cells. Non-equilibrium physical modeling of actin and myosin confirm that twist, and hence rotation, is an emergent phenomenon of active filaments confined in a narrow channel which points to a generic mechanism present in all cells. Our measurements confirm that filopodia exert traction forces and form helical buckles in a range of different cell types that can be ascribed to accumulation of sufficient twist. These results lead us to conclude that activity induced twisting of the actin shaft is a general mechanism underlying fundamental functions of filopodia.
HillTau: A fast, compact abstraction for model reduction in biochemical signaling networks
Authors: Bhalla Upinder S.
Published: September 2020

Signaling networks mediate many aspects of cellular function. The conventional, mechanistically motivated approach to modeling such networks is through mass-action chemistry, which maps directly to biological entities and facilitates experimental tests and predictions. However such models are complex, need many parameters, and are computationally costly. Here we introduce the HillTau form for signaling models. HillTau retains the direct mapping to biological observables, but it uses far fewer parameters, and is 100 to over 1000 times faster than ODE-based methods. In the HillTau formalism, the steady-state concentration of signaling molecules is approximated by the Hill equation, and the dynamics by a time-coursetau. We demonstrate its use in implementing several biochemical motifs, including association, inhibition, feedforward and feedback inhibition, bistability, oscillations, and a synaptic switch obeying the BCM rule. The major use-cases for HillTau are system abstraction, model reduction, scaffolds for data-driven optimization, and fast approximations to complex cellular signaling.

Author summary

Chemical signals mediate many computations in cells, from housekeeping functions in all cells to memory and pattern selectivity in neurons. These signals form complex networks of interactions. Computer models are a powerful way to study how such networks behave, but it is hard to get all the chemical details for typical models, and it is slow to run them with standard numerical approaches to chemical kinetics. We introduce HillTau as a simplified way to model complex chemical networks. HillTau models condense multiple reaction steps into single steps defined by a small number of parameters for activation and settling time. As a result the models are simple, easy to find values for, and they run quickly. Remarkably, they fit the full chemical formulations rather well. We illustrate the utility of HillTau for modeling several signaling network functions, and for fitting complicated signaling networks.
Cardiniumsymbiosis as a potential confounder of mtDNA based phylogeographic inference inCulicoides imicola(Diptera: Ceratopogonidae), a vector of veterinary viruses
Authors: Pilgrim Jack , Siozios Stefanos , Baylis Matthew , Venter Gert , Garros Claire , Hurst Gregory D. D.
Published: September 2020

Culicoides imicola(Diptera: Ceratopogonidae) is an important Afrotropical and Palearctic vector of disease, transmitting viruses of animal health and economic significance. The apparent incursions ofC. imicolainto mainland Europe via wind-movement events has made it important to trace this species to better predict new areas of arbovirus outbreaks. A widely used method for tracking dispersal patterns ofC. imicolaemploys a phylogeographic approach anchored on the mtDNA markerCOI(cytochrome c oxidase subunit I). However, a problem with this approach is that maternally-inherited symbiotic bacteria can alter the frequency ofCOImitochondrial haplotypes (mitotypes), masking the true patterns of movement and gene flow. In this study, we investigate possible associations of the symbiontCardiniumwithC. imicolamitotype distribution. Haplotype network analysis indicates the concordance of specific mitotypes withCardiniuminfection status inC. imicolapopulations from the Mediterranean basin and South Africa. This observation urges caution on the single usage of theCOImarker to determine population structure and movement inC. imicola, and instead suggests the complementary utilisation of additional molecular markers (e.g. microsatellites and nuclear markers).
DNA-Origami-Based Fluorescence Brightness Standards for Convenient and Fast Protein Counting in Live Cells
Authors: Williams Nathan D. , Landajuela Ane , Kasula Ravi Kiran , Zhou Wenjiao , Powell John T. , Xi Zhiqun , Isaacs Farren J. , Berro Julien , Toomre Derek , Karatekin Erdem , Lin Chenxiang
Published: September 2020

Fluorescence microscopy has been one of the most discovery-rich methods in biology. In the digital age, the discipline is becoming increasingly quantitative. Virtually all biological laboratories have access to fluorescence microscopes, but abilities to quantify biomolecule copy numbers are limited by the complexity and sophistication associated with current quantification methods. Here, we present DNA-origami-based fluorescence brightness standards for counting 5–300 copies of proteins in mammalian and bacterial cells, tagged with fluorescent proteins or organic dyes. Compared to conventional quantification techniques, our brightness standards are robust, straightforward to use, and compatible with nearly all fluorescence imaging applications, thereby providing a practical and versatile tool to quantify biomoleculesviafluorescence microscopy.