bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Combining Anticoagulant and Antiplatelet Agents in COVID-19 Treatment: A Rapid Review
Authors: Matli Kamal , Farah Raymond , Maalouf Mario , Costanian Christy , Chamoun Nibal , Ghanem Georges
Published: March 2021

Although primarily affecting the respiratory system, COVID-19 causes multiple organ damage. One of its grave consequences is a prothrombotic state that manifests as thrombotic, microthrombotic, and thromboembolic events.Therefore, understanding the effect of antiplatelet and anticoagulation therapy in the context of COVID-19 treatment is important. The aim of this rapid review is to highlight the role of thrombosis in COVID-19 and provide new insights on the use of antithrombotic therapy in its management. A rapid systematic review was performed using preferred reporting items for systematic reviews. Papers published in English on antithrombotic agent use and COVID-19 complications were eligible. Results showed that the use of anticoagulants increased survival and reduced thromboembolic events in patients. However, despite the use of anticoagulants, patients still suffered thrombotic events likely due to heparin resistance. Data on antiplatelet use in combination with anticoagulants in the setting of COVID-19 is quite scarce. Current side effects of anticoagulation therapy emphasize the need to update treatment guidelines. In this rapid review, we address a possible modulatory role of antiplatelet and anticoagulant combination against COVID□19 pathogenesis. This combination may be an effective form of adjuvant therapy against COVID□19 infection. However, further studies are needed to elucidate potential risks and benefits associated with this combination.

It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research
How to incentivise doctor attendance in Bangladesh: a latent class analysis of a discrete choice experiment
Authors: Angell Blake , Khan Mushtaq , Islam Mir Raihanul , Mandeville Kate , Naher Nahitun , Hutchinson Eleanor , McKee Martin , Ahmed Syed Masud , Balabanova Dina
Published: March 2021

Objective

To elicit preferences of doctors over interventions to address doctor absenteeism in rural facilities in Bangladesh, a pervasive form of corruption across the country.

Methods

We conducted a discrete choice experiment with 308 doctors across four tertiary hospitals in Dhaka, Bangladesh. Four attributes of rural postings were included based on a literature review, qualitative research and a consensus-building workshop with policymakers and key health-system stakeholders: relationship with the community, security measures, attendance-based policies, and incentive payments. Respondents’ choices were analysed with mixed multinomial logistic and latent class models and were used to simulate the likely uptake of jobs under different policy packages.

Results

All attributes significantly impacted doctor choices (p<0.01). Doctors strongly preferred jobs at rural facilities where there was a supportive relationship with the community (β=0.93), considered good attendance in education and training (0.77) or promotion decisions (0.67), with functional security (0.67) and higher incentive payments (0.5 per 10% increase of base salary). Jobs with disciplinary action for poor attendance were disliked by respondents (-.63). Latent class analysis identified three groups of doctors that differed in their uptake of jobs. Scenario modelling identified intervention packages that differentially impacted doctor behaciour and combinations that could feasibly improve doctors’ attendance.

Conclusion

Bangladeshi doctors have strong but varied preferences over interventions to overcome absenteeism. Some were unresponsive to intervention but a substantial number appear amenable to change. Designing policy packages that consider these differences and target particular doctors could begin to generate sustainable solutions to doctor absenteeism in rural Bangladesh.
Computational modeling of C-terminal tails to predict the calcium-dependent secretion of ER resident proteins
Authors: Trychta Kathleen A. , Xie Bing , Verma Ravi Kumar , Xu Min , Shi Lei , Harvey Brandon K.
Published: March 2021

The lumen of the endoplasmic reticulum (ER) has resident proteins that are critical to perform the various tasks of the ER such as protein maturation and lipid metabolism. These ER resident proteins typically have a carboxy-terminal ER retention sequence (ERS). The canonical ERS is Lys-Asp-Glu-Leu (KDEL) and when an ER resident protein moves from the ER to the Golgi, KDEL receptors (KDELRs) in the Golgi recognize the ERS and return the protein to the ER lumen. Depletion of ER calcium leads to the mass departure of ER resident proteins in a process termed exodosis, which is also regulated by KDELRs. Here, by combining computational prediction with machine learning-based models and experimental validation, we identify carboxy tail sequences of ER resident proteins divergent from the canonical “KDEL” ERS. Using molecular modeling and simulations, we demonstrated that two representative non-canonical ERS can stably bind to the KDELR. Collectively, we developed a method to predict whether a carboxy-terminal sequence acts as a putative ERS that would undergo secretion in response to ER calcium depletion and interact with the KDELRs. Identification of proteins that undergo exodosis will further our understanding of changes in ER proteostasis under physiological and pathological conditions where ER calcium is depleted.
Optical Nanosensors for Real-time Feedback on Insulin Secretion by β-Cells
Authors: Ehrlich Roni , Hendler-Neumark Adi , Wulf Verena , Amir Dean , Bisker Gili
Published: March 2021

Quantification of insulin is essential for diabetes research in general, and for the study of pancreatic β-cell function in particular. Herein, fluorescent single-walled carbon nanotubes (SWCNT) are used for the recognition and real-time quantification of insulin. Two approaches for rendering the SWCNT sensors for insulin are compared, using surface functionalization with either a natural insulin aptamer with known affinity to insulin, or a synthetic PEGylated-lipid (C16-PEG(2000Da)-Ceramide), both of which show a modulation of the emitted fluorescence in response to insulin. Although the PEGylated-lipid has no prior affinity to insulin, the response of C16-PEG(2000Da)-Ceramide-SWCNTs to insulin is more stable and reproducible compared to the insulin aptamer-SWCNTs. The C16-PEG(2000Da)-Ceramide-SWCNTs optical response is excitation-wavelength dependent, where resonant excitation leads to a larger fluorescence decrease in response to insulin. The SWCNT sensors successfully detect insulin secreted by β-cells within the complex environment of the conditioned media. The insulin is quantified by comparing the SWCNTs fluorescence response to a standard calibration curve, and the results are found to be in agreement with an enzyme-linked immunosorbent assay (ELISA). This novel analytical tool for real time quantification of insulin secreted by β-cells provides new opportunities for rapid assessment of β-cell function, with the ability to push forward many aspects of diabetes research.
Dram1 confers resistance toSalmonellainfection
Authors: Masud Samrah , Zhang Rui , Prajsnar Tomasz K. , Meijer Annemarie H.
Published: March 2021

Dram1 is a stress and infection inducible autophagy modulator that functions downstream of transcription factors p53 and NFκB. Using a zebrafish embryo infection model, we have previously shown that Dram1 provides protection against the intracellular pathogenMycobacterium marinumby promoting the p62-dependent xenophagy of bacteria that have escaped into the cytosol. However, the possible interplay between Dram1 and other anti-bacterial autophagic mechanisms remains unknown. Recently, LC3-associated phagocytosis (LAP) has emerged as an important host defense mechanism that requires components of the autophagy machinery and targets bacteria directly in phagosomes. Our previous work established LAP as the main autophagic mechanism by which macrophages restrict growth ofSalmonellaTyphimurium in a systemically infected zebrafish host. We therefore employed this infection model to investigate the possible role of Dram1 in LAP. Morpholino knockdown or CRISPR/Cas9-mediated mutation of Dram1 led to reduced host survival and increased bacterial burden duringS. Typhimurium infections. In contrast, overexpression ofdram1by mRNA injection curtailedSalmonellareplication and reduced mortality of the infected host. During the early response to infection, GFP-Lc3 levels in transgenic zebrafish larvae correlated with thedram1expression level, showing over two-fold reduction of GFP-Lc3-Salmonellaassociation indram1knockdown or mutant embryos and an approximately 30% increase bydram1overexpression. Since LAP is known to require the activity of the phagosomal NADPH oxidase, we used aSalmonellabiosensor strain to detect bacterial exposure to reactive oxygen species (ROS) and found that the ROS response was largely abolished in the absence ofdram1. Together, these results demonstrate the host protective role of Dram1 duringS. Typhimurium infection and suggest a functional link between Dram1 and the induction of LAP.
Mechanosensory input during circuit formation shapes Drosophila motor behavior through Patterned Spontaneous Network Activity
Authors: Carreira-Rosario Arnaldo , York Ryan A. , Choi Minseung , Doe Chris Q. , Clandinin Thomas R.
Published: March 2021

Neural activity sculpts circuit wiring in many animals. In vertebrates, patterned spontaneous network activity (PaSNA) generates sensory maps and establishes local circuits1–3. However, it remains unclear how PaSNA might shape neuronal circuits and behavior in invertebrates. Previous work in the developingDrosophilaembryo discovered spontaneous muscle activity that did not require synaptic transmission, and hence was myogenic, preceding PaSNA4–6. These studies, however, monitored muscle movement, not neural activity, and were therefore unable to observe how myogenic activity might relate to subsequent neural network engagement. Here we use calcium imaging to directly record neural activity and characterize the emergence of PaSNA. We demonstrate that the spatiotemporal properties of PaSNA are highly stereotyped across embryos, arguing for genetic programming. Consistent with previous observations, we observe neural activity well before it becomes patterned, initially emerging during the myogenic stage. Remarkably, inhibition of mechanosensory input as well as inhibition of muscle contractions results in premature and excessive PaSNA, demonstrating that muscle movement serves as a brake on this process. Finally, using an optogenetic strategy to selectively disrupt mechanosensory inputs during PaSNA, followed by quantitative modeling of larval behavior, we demonstrate that mechanosensory modulation during development is required for proper larval foraging. This work thus provides a foundation for using theDrosophilaembryo to study the role of PaSNA in circuit formation, provides mechanistic insight into how PaSNA is entrained by motor activity, and demonstrates that spontaneous network activity is essential for locomotor behavior. These studies argue that sensory feedback during the earliest stages of circuit formation can sculpt locomotor behaviors through innate motor learning.

Highlights

PaSNA in theDrosophilaembryonic CNS is spatiotemporally stereotyped

Mechanosensory neurons negatively modulate PaSNA

Embryonic PaSNA is required for larval locomotor behavior
The Geometry of Concept Learning
Authors: Sorscher Ben , Ganguli Surya , Sompolinsky Haim
Published: March 2021

Understanding the neural basis of the remarkable human cognitive capacity to learn novel concepts from just one or a few sensory experiences constitutes a fundamental problem. We propose a simple, biologically plausible, mathematically tractable, and computationally powerful neural mechanism for few-shot learning of naturalistic concepts. We posit that the concepts that can be learnt from few examples are defined by tightly circumscribed manifolds in the neural firing rate space of higher order sensory areas. We further posit that a single plastic downstream readout neuron learns to discriminate new concepts based on few examples using a simple plasticity rule. We demonstrate the computational power of our proposal by showing it can achieve high few-shot learning accuracy on natural visual concepts using both macaque inferotemporal cortex representations and deep neural network models of these representations, and can even learn novel visual concepts specified only through linguistic descriptors. Moreover, we develop a mathematical theory of few-shot learning that links neurophysiology to behavior by delineating several fundamental and measurable geometric properties of high-dimensional neural representations that can accurately predict the few-shot learning performance of naturalistic concepts across all our numerical simulations. We discuss testable predictions of our theory for psychophysics and neurophysiological experiments.
Effect of Aqueous Extract of Antiaris Africana Stem Bark on Phagocytic Activities of Human Neutrophil Ex-Vivo
Authors: Bello Ibrahim O. , Adedeji Adebayo L.
Published: March 2021

The immune system is one of the most complex biological systems in the body. During infection, the immune system is under attack by a large number of viruses, bacteria, fungi and parasites. Immune response firstly involves, recognition of the pathogen or foreign object and secondly, a reaction to eliminate it. Aqueous extract ofAntiaris africanais used to study their immune modulator activity. This plant has its various parts used in folk medicines. The mechanism of action has not been fully elucidated. Therefore, this research work studies the effect of aqueous extract ofAntiaris Africanastem bark on phagocytic activities of neutrophil isolated from apparently healthy individual using a non-subjective commercial colourimetric assay kit obtained from Cell-Biolab Inc., USA. The purity and viability of isolated neutrophils were >90% and >95% respectively. The extract enhances neutrophil phagocytosis at 1.0, 5.0, 10.0, 15.0, 20.0 and 25 μg/ml by 2.5%, 11.6%, 18.4%, 24.4%, 31.2% and 38.2% respectively, compared to the control (100%). Hence, it was observed that neutrophil phagocytosis increases with increased extract concentrations. It can be concluded from the study that enhancement of phagocytosis may be the possible mechanism of action of the plant as an immune modulator.
Predicting potentially permissive substitutions that improve the fitness of A(H1N1)pdm09 viruses bearing the H275Y NA substitution
Authors: Farrukee Rubaiyea , Gunalan Vithiagaran , Maurer-Stroh Sebastian , Reading Patrick C. , Hurt Aeron C.
Published: March 2021

Oseltamivir-resistant influenza viruses arise due to amino-acid mutations in key residues, but these changes often reduce their replicative and transmission fitness. Widespread oseltamivir-resistance has not yet been observed in A(H1N1)pdm09 viruses. However, it is known that permissive mutations in the neuraminidase (NA) of former seasonal A(H1N1) viruses from 2007-2009 buffered the detrimental effect of the NA H275Y mutation, resulting in fit oseltamivir-resistant viruses that circulated widely. This study explored two approaches to predict permissive mutations that may enable a fit H275Y A(H1N1)pdm09 variant to arise.

A computational approach used phylogenetic andin silicoprotein stability analyses to predict potentially permissive mutations, which were then evaluated byin vitroNA enzyme activity and expression analysis, followed byin vitroreplication. The second approach involved the generation of a virus library which encompassed all possible individual 2.9 × 104codon mutations in the NA whilst keeping H275Y fixed. To select for variant viruses with the greatest fitness, the virus library was serially passaged in ferrets (via contact and aerosol transmission) and resultant viruses were deep sequenced.

The computational approach predicted three NA permissive mutations, and even though they only offset thein vitroimpact of H275Y on NA enzyme expression by 10%, they could restore replication fitness of the H275Y variant in A549 cells. In our experimental approach, a diverse virus library (97% of 8911 possible single amino-acid substitutions were sampled) was successfully transmitted through ferrets, and sequence analysis of resulting virus pools in nasal washes identified three mutations that improved virus transmissibility. Of these, one NA mutation, I188T, has been increasing in frequency since 2017 and is now present in 90% of all circulating A(H1N1)pdm09 viruses.

Overall, this study provides valuable insights into the evolution of the influenza NA protein and identified several mutations that may potentially facilitate the emergence of a fit H275Y A(H1N1)pdm09 variant.
Kupeantha yabassi(Coffeeae- Rubiaceae), a new Critically Endangered shrub species of the Ebo Forest area, Littoral Region, Cameroon
Authors: Alvarez-Aguirre Maria G. , Cheek Martin , Sonké Bonaventure
Published: March 2021

A new species to science of evergreen forest shrub,Kupeantha yabassi(Coffeeae - Rubiaceae), is described, illustrated, mapped, and compared morphologically with the closely similar speciesK. pentamera. Restricted so far to a single site in evergreen lowland forest near the Ebo Forest, Yabassi, Littoral Region, Cameroon, this species is Critically Endangered using the IUCN 2012 standard due to habitat clearance driven mainly by agriculture, adding to the growing list of threatened species resulting from anthropogenic pressure on Cameroon forests. A revised key to the six species ofKupeanthais presented. Two distinct geographical and ecological species groupings within the genus are identified and discussed. Notes are given on other narrowly endemic and threatened species in the Ebo forest area, a threatened centre of diversity important for conservation in Littoral Region.
The E3 ubiquitin ligase RNF216/TRIAD3 is a central regulator of the hypothalamic-pituitary-gonadal axis
Authors: George Arlene J. , Hoffiz Yarely C. , Ware Christopher , Dong Bin , Fang Ning , Hrabovszky Erik , Mabb Angela M.
Published: March 2021

RNF216/TRIAD3 is an E3 ligase that ubiquitinates substrates in the nervous system. Recessive mutations inRNF216/TRIAD3cause Gordon Holmes syndrome (GHS), where hypogonadotropic hypogonadism is a core phenotype. However, the functions of RNF216/TRIAD3 within the neuroendocrine system are not well-understood. Here, we used the CRISPR-Cas9 system to knock outRnf216/Triad3in GT1-7 cells, a GnRH immortalized cell line derived from mouse hypothalamus.Rnf216/Triad3knockout cells had decreased steady stateGnrhand reduced calcium transient frequency. To address functions of RNF216/TRIAD3in vivo, we generated aRnf216/Triad3constitutive knockout (KO) mouse. KO mice of both sexes showed reductions in GnRH and soma size. Furthermore, KO mice exhibited sex-specific phenotypes with males showing gonadal impairment and derangements in gonadotropin release compared to KO females, which only had irregular estrous cyclicity. Our work shows that dysfunction of RNF216/TRIAD3 affects the HPG axis in a sex-dependent manner, implicating sex-specific therapeutic interventions for GHS.

Highlights

Rnf216/Triad3controlsGnrhand intrinsic hypothalamic cell activity

Rnf216/Triad3knockout male mice have greater reproductive impairments than females

Rnf216/Triad3controls the HPG axis at multiple levels
Minimal clustering and species delimitation based on multi-locus alignments vs SNPs: the case of theSeriphium plumosumL. complex (Gnaphalieae: Asteraceae)
Authors: Shaik Zaynab , Bergh Nicola G , Oxelman Bengt , Verboom G Anthony
Published: March 2021

We applied species delimitation methods based on the Multi-Species Coalescent (MSC) model to 500+ loci derived from genotyping-by-sequencing on the South AfricanSeriphium plumosum(Asteraceae) species complex. The loci were represented either as multiple sequence alignments or single nucleotide polymorphisms (SNPs), and analysed by the STACEY and Bayes Factor Delimitation (BFD)/SNAPP methods, respectively. Both methods supported species taxonomies where virtually all of the 32 sampled individuals, each representing its own geographical population, were identified as separate species. Computational efforts required to achieve adequate mixing of MCMC chains were considerable, and the species/minimal cluster trees identified similar strongly supported clades in replicate runs. The resolution was, however, higher in the STACEY trees than in the SNAPP trees, which is consistent with the higher information content of full sequences. The computational efficiency, measured as effective sample sizes of likelihood and posterior estimates per time unit, was consistently higher for STACEY. A random subset of 56 alignments had similar resolution to the 524-locus SNP data set. The STRUCTURE-like sparse Non-negative Matrix Factorisation (sNMF) method was applied to six individuals from each of 48 geographical populations and 28023 SNPs. Significantly fewer (13) clusters were identified as optimal by this analysis compared to the MSC methods. The sNMF clusters correspond closely to clades consistently supported by MSC methods, and showed evidence of admixture, especially in the western Cape Floristic Region. We discuss the significance of these findings, and conclude that it is important toa prioriconsider the kind of species one wants to identify when using genome-scale data, the assumptions behind the parametric models applied, and the potential consequences of model violations may have.
Gastruloids asin vitromodels of embryonic blood development with spatial and temporal resolution
Authors: Rossi Giuliana , Giger Sonja , Hübscher Tania , Lutolf Matthias P.
Published: March 2021

Gastruloids are three-dimensional embryonic organoids that reproduce key features of early mammalian developmentin vitrowith unique scalability, accessibility, and spatiotemporal similarity to real embryos. Recently, we adapted gastruloid culture conditions to promote cardiovascular development. In this work, we extended these conditions to capture features of embryonic blood development through a combination of immunophenotyping, detailed transcriptomics analysis, and identification of blood stem/progenitor cell potency. We uncovered the emergence of blood progenitor and erythroid-like cell populations in late gastruloids and showed the multipotent clonogenic capacity of these cells, bothin vitroand after transplantation into irradiated mice. We also identified the spatial localization near a vessel-like plexus in the anterior of gastruloids with similarities to the emergence of blood stem cells in the embryo. These results highlight the potential and applicability of gastruloids to thein vitrostudy of complex processes in embryonic blood development with spatiotemporal fidelity.
Identification of biomarkers and candidate regulators for multiple myeloma under the knockout of AURKA
Authors: Gu Hanming , Wang Wei , Yuan Gongsheng
Published: March 2021

Multiple myeloma (MM) is a plasma cell malignancy that is characterized by the overabundance of monoclonal paraprotein. Aurora kinase A (AURKA) was upregulated in patients with high-risk MM. AURKA inhibitors were used to inhibit MM cell proliferation by inducing cell apoptosis and injury. In our study, we aim to identify biological processes and pathways of MM cells under the knockout of AURKA (AURKA KO) by using a bioinformatics method to elucidate their potential pathogenesis. The gene expression profiles of the GSE163589 dataset were originally produced by using the high-throughput BGISEQ-500 (Homo sapiens). The biological categories and pathways were analyzed by the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), Gene Ontology (GO), and Reactom enrichment. KEGG and GO results indicated the biological pathways related to the immune responses and cancer activities were mostly affected in the development of MM with AURKA KO. Moreover, we identified several genes including GNG5, UBE2D1, and BUB1B were involved in the regulation of cancer genesis. We further predicted novel regulators that had the ability to affect the progression of MM with AURKA KO based on the L1000fwd analysis. Therefore, this study provides further insights into the mechanism of MM under AURKA inhibitor treatments.
The effects of experimental floral resource removal on plant-pollinator interactions
Authors: Bain Justin A. , Dickson Rachel G. , Gruver Andrea M. , CaraDonna Paul J.
Published: March 2021

Pollination is essential for ecosystem functioning, yet our understanding of the empirical consequences of species loss for plant-pollinator interactions remains limited. It is hypothesized that the loss of abundant and generalized (well-connected) species from a pollination network will have a large effect on the remaining species and their interactions. However, to date, relatively few studies have experimentally removed species from their natural setting to address this hypothesis. We investigated the consequences of losing an abundant, well-linked species from a series of plant-pollinator networks by experimentally removing the flowers ofHelianthella quinquenervis(Asteraceae) from half of a series of 10 paired plots (15 m diameter) within a subalpine ecosystem. We then asked how the localized loss of this species influenced pollinator visitation patterns, floral visitor composition, and interaction network structure. The experimental removal ofHelianthellaflowers led to an overall decline in plot-level pollinator visitation rates and shifts in pollinator composition. Species-level responses to floral removal differed between the two other abundant, co-flowering plants in our experiment:Potentilla pulcherrimareceived higher visitation rates, whereasErigeron speciosusvisitation rates did not change. Experimental floral removal altered the structural properties of the localized plant-pollinator networks such that they were more specialized, less nested, and less robust to further species loss. Such changes to interaction structure were consistently driven more by species turnover than by interaction rewiring. Our findings suggest that the local loss of an abundant, well-linked, generalist plant can bring about diverse responses within pollination networks, including potential competitive and facilitative effects for individual species, changes to network structure that may render them more sensitive to future change, but also numerous changes to interactions that may also suggest flexibility in response to species loss.
Origin of diversity in spatial social dilemmas
Authors: Hauert Christoph , Doebeli Michael
Published: March 2021

Cooperative investments in social dilemmas can spontaneously diversify into stably co-existing high and low contributors in well-mixed populations. Here we extend the analysis to emerging diversity in (spatially) structured populations. Using pair approximation we derive analytical expressions for the invasion fitness of rare mutants in structured populations, which then yields a spatial adaptive dynamics framework. This allows us to predict changes arising from population structures in terms of existence and location of singular strategies, as well as their convergence and evolutionary stability as compared to well-mixed populations. Based on spatial adaptive dynamics and extensive individual based simulations, we find that spatial structure has significant and varied impacts on evolutionary diversification in continuous social dilemmas. More specifically, spatial adaptive dynamics suggests that spontaneous diversification through evolutionary branching is suppressed, but simulations show that spatial dimensions offer new modes of diversification that are driven by an interplay of finite-size mutations and population structures. Even though spatial adaptive dynamics is unable to capture these new modes, they can still be under-stood based on an invasion analysis. In particular, population structures alter invasion fitness and can open up new regions in trait space where mutants can invade, but that may not be accessible to small mutational steps. Instead, stochastically appearing larger mutations or sequences of smaller mutations in a particular direction are required to bridge regions of unfavourable traits. The net effect is that spatial structure tends to promote diversification, especially when selection is strong.
A Hierarchy of Biomolecular Proportional-Integral-Derivative Feedback Controllers for Robust Perfect Adaptation and Dynamic Performance
Authors: Filo Maurice , Kumar Sant , Khammash Mustafa
Published: March 2021

Proportional-Integral-Derivative (PID) feedback controllers have been the most widely used controllers in industry for almost a century due to their good performance, simplicity, and ease of tuning. Motivated by their success in various engineering disciplines, PID controllers recently found their way into synthetic biology, where the design of feedback molecular control systems has been identified as an important goal. In this paper, we consider the mathematical realization of PID controllers via biomolecular interactions. We propose an array of topologies that offer a compromise between simplicity and high performance. We first demonstrate that different Proportional-Integral (PI) controllers exhibit different capabilities for enhancing the dynamics and reducing variance (cell-to-cell variability). Next, we introduce several derivative controllers that are realized based on incoherent feedforward loops acting in a feedback configuration. Alternatively, we show that differentiators can be realized by placing molecular integrators in a negative feedback loop—an arrangement that can then be augmented by PI components to yield PID feedback controllers. We demonstrate that the derivative component can be exploited for enhancing system stability, dramatically increasing the molecular control system’s dynamic performance, and for reducing the noise effect on the output of interest. The PID controller features are established through various deterministic and stochastic analyses as well as numerical simulations. Finally, we provide an experimental demonstration using a recently developed hybrid setup, the cyberloop, where the controller is implementedin silicoto control a biological genetic circuitin vivo. The large array of novel biomolecular PID controllers introduced here forms a basis for the design and construction of advanced high-performance biomolecular control systems that robustly regulate the dynamics of living systems.
MAAPER: model-based analysis of alternative polyadenylation using 3’ end-linked reads
Authors: Li Wei Vivian , Zheng Dinghai , Wang Ruijia , Tian Bin
Published: March 2021

Most eukaryotic genes harbor multiple cleavage and polyadenylation sites (PASs), leading to expression of alternative polyadenylation (APA) isoforms. APA regulation has been implicated in a diverse array of physiological and pathological conditions. While RNA sequencing tools that generate reads containing the PAS, namedonSitereads, have been instrumental in identifying PASs, they have not been widely used. By contrast, a growing number of methods generate reads that are close to the PAS, namednearSitereads, including the 3’ end counting strategy commonly used in single cell analysis. How these nearSite reads can be used for APA analysis, however, is poorly studied. Here, we present a computational method, named model-based analysis of alternative polyadenylation using 3’ end-linked reads (MAAPER), to examine APA using nearSite reads. MAAPER uses a probabilistic model to predict PASs for nearSite reads with high accuracy and sensitivity, and examines different types of APA events, including those in 3’UTRs and introns, with robust statistics. We show MAAPER’s accuracy with data from both bulk and single cell RNA samples and its applicability in unpaired or paired experimental designs. Our result also highlights the importance of using well annotated PASs for nearSite read analysis.
Drosophilaprimary microRNA-8 encodes a microRNA encoded peptide acting in parallel ofmiR-8
Authors: Montigny Audrey , Tavormina Patrizia , Duboe Carine , San Clémente Hélène , Aguilar Marielle , Valenti Philippe , Lauressergues Dominique , Combier Jean-Philippe , Plaza Serge
Published: March 2021

Background

Recent genome-wide studies of many species reveal the existence of a myriad of RNAs differing in size, coding potential and function. Among these are the long non-coding RNAs, some of them producing functional small peptides via the translation of short ORFs. It now appears that any kind of RNA presumably has a potential to encode small peptides. Accordingly, our team recently discovered that plant primary transcripts of microRNAs (pri-miRNAs) produce small regulatory peptides (miPEPs) involved in auto-regulatory feedback loops enhancing their cognate microRNA expression which in turn controls plant development. Here we investigate whether this regulatory feedback loop is present inDrosophila melanogaster.

Results

We perform a survey of ribosome profiling data and reveal that many pri-miRNAs exhibit ribosome translation marks. Focusing on miR-8, we show thatpri-miR-8can produce a miPEP-8. Functional assays performed in Drosophila reveal that miPEP-8 affects development when overexpressed or knocked down. Combining genetic and molecular approaches as well as genome-wide transcriptomic analyses, we show thatmiR-8expression is independent of miPEP-8 activity and that miPEP-8 acts in parallel tomiR-8to regulate the expression of hundreds of genes.

Conclusion

Taken together, these results reveal that severalDrosophila pri-miRNAsexhibit translation potential. Contrasting with the mechanism described in plants, these data shed light on the function of yet un-describedpri-microRNAencoded peptides inDrosophilaand their regulatory potential on genome expression.
Principles of RNA recruitment to viral ribonucleoprotein condensates in a segmented dsRNA virus
Authors: Strauss Sebastian , Borodavka Alexander , Papa Guido , Desiró Daniel , Schueder Florian , Jungmann Ralf
Published: March 2021

Rotaviruses transcribe eleven distinct protein-coding RNAs that must be stoichiometrically co-packaged prior to their replication to make an infectious virion. During infection, rotavirus transcripts accumulate in cytoplasmic ribonucleoprotein (RNP) condensates, termed viroplasms. Understanding the mechanisms of viroplasm assembly and RNA enrichment within is crucial to gaining greater insight into their function and stoichiometric assortment of individual transcripts. We analysed the subcellular distribution of individual RV transcripts and viroplasm transcriptome by combining multiplexed DNA-barcoded single-molecule RNA FISH of infected cells. Using DNA-PAINT microscopy, we provide evidence of the early onset of viral transcript oligomerisation that occurs prior to the formation of viroplasms. We demonstrate that viral sequences lacking the conserved terminal regions fail to undergo enrichment in rotavirus RNP condensates. We show that individual viral transcripts exhibit variable propensities to partition into viroplasms, irrespective of their absolute numbers in cells, suggesting a selective RNA enrichment mechanism distinct from other known cellular RNP granules. We suggest that rotavirus replication factories represent unique RNP condensates enriched in eleven types of cognate transcripts that may facilitate the assembly of a multi-segmented RNA genome.
Two-stage Linked Component Analysis for Joint Decomposition of Multiple Biologically Related Data Sets
Authors: Chen Huan , Caffo Brian , Stein-O’Brien Genevieve , Liu Jinrui , Langmead Ben , Colantuoni Carlo , Xiao Luo
Published: March 2021

Summary

Integrative analysis of multiple data sets has the potential of fully leveraging the vast amount of high throughput biological data being generated. In particular such analysis will be powerful in making inference from publicly available collections of genetic, transcriptomic and epigenetic data sets which are designed to study shared biological processes, but which vary in their target measurements, biological variation, unwanted noise, and batch variation. Thus, methods that enable the joint analysis of multiple data sets are needed to gain insights into shared biological processes that would otherwise be hidden by unwanted intra-data set variation. Here, we propose a method called two-stage linked component analysis (2s-LCA) to jointly decompose multiple biologically related experimental data sets with biological and technological relationships that can be structured into the decomposition. The consistency of the proposed method is established and its empirical performance is evaluated via simulation studies. We apply 2s-LCA to jointly analyze four data sets focused on human brain development and identify meaningful patterns of gene expression in human neurogenesis that have shared structure across these data sets.
CVnCoV protects human ACE2 transgenic mice from ancestral B BavPat1 and emerging B.1.351 SARS-CoV-2
Authors: Hoffmann Donata , Corleis Björn , Rauch Susanne , Roth Nicole , Mühe Janine , Halwe Nico Joel , Ulrich Lorenz , Fricke Charlie , Schön Jacob , Kraft Anna , Breithaupt Angele , Wernike Kerstin , Michelitsch Anna , Sick Franziska , Wylezich Claudia , Müller Stefan O. , Mettenleiter Thomas C. , Petsch Benjamin , Dorhoi Anca , Beer Martin
Published: March 2021

The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic necessitates the fast development of vaccines as the primary control option. Recently, viral mutants termed “variants of concern” (VOC) have emerged with the potential to escape host immunity. VOC B.1.351 was first discovered in South Africa in late 2020, and causes global concern due to poor neutralization with propensity to evade preexisting immunity from ancestral strains. We tested the efficacy of a spike encoding mRNA vaccine (CVnCoV) against the ancestral strain BavPat1 and the novel VOC B.1.351 in a K18-hACE2 transgenic mouse model. Naive mice and mice immunized with formalin-inactivated SARS-CoV-2 preparation were used as controls. mRNA-immunized mice developed elevated SARS-CoV-2 RBD-specific antibody as well as neutralization titers against the ancestral strain BavPat1. Neutralization titers against VOC B.1.351 were readily detectable but significantly reduced compared to BavPat1. VOC B.1.351-infected control animals experienced a delayed course of disease, yet nearly all SARS-CoV-2 challenged naïve mice succumbed with virus dissemination and high viral loads. CVnCoV vaccine completely protected the animals from disease and mortality caused by either viral strain. Moreover, SARS-CoV-2 was not detected in oral swabs, lung, or brain in these groups. Only partial protection was observed in mice receiving the formalin-inactivated virus preparation. Despite lower neutralizing antibody titers compared to the ancestral strain BavPat1, CVnCoV shows complete disease protection against the novel VOC B.1.351 in our studies.
Naked mole-rats (Heterocephalus glaber) do not specialise on cooperative tasks
Authors: Siegmann Susanne , Feitsch Romana , Hart Daniel W. , Bennett Nigel C. , Penn Dustin J. , Zöttl Markus
Published: March 2021

It has been proposed that naked mole-rat (Heterocephalus glaber) societies resemble those of eusocial insects by showing a division of labour among non-breeding individuals. Earlier studies suggested that non-breeders belong to distinct castes that specialise permanently or temporarily on specific cooperative tasks. In contrast, recent research on naked mole-rats has shown that behavioural phenotypes are continuously distributed across non-breeders and that mole-rats exhibit considerable behavioural plasticity suggesting that individuals may not specialise permanently on work tasks. However, it is currently unclear whether individuals specialise temporarily and whether there is a sex bias in cooperative behaviour among non-breeders. Here we show that non-breeding individuals vary in overall cooperative investment, but do not specialise on specific work tasks. Within individuals, investment into specific cooperative tasks such as nest building, food carrying and burrowing are positively correlated, and there is no evidence that individuals show trade-offs between these cooperative behaviours. Non-breeding males and females do not differ in their investment in cooperative behaviours and show broadly similar age and body mass related differences in cooperative behaviours. Our results suggest that non-breeding naked mole-rats vary in their overall contribution to cooperative behaviours and that some of this variation may be explained by differences in age and body mass. Our data provide no evidence for temporary specialisation, as found among some eusocial insects, and suggests that the behavioural organisation of naked mole-rats resembles that of other cooperatively breeding vertebrates more than that of eusocial insect species.
Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin
Authors: Wang Jialiang S. , Kamath Tushar , Mirzamohammadi Fatemeh , Rotter Daniel , Hojo Hironori , Castro Christian D. , Patel Rushi , Govea Nicolas , Enishi Tetsuya , Wu Yunshu , da Silva Martins Janaina , Bruce Michael , Brooks Daniel J. , Bouxsein Mary L. , Tokarz Danielle , Lin Charles P. , Abdul Abdul , Macosko Evan Z. , Fiscaletti Melissa , Munns Craig F. , Fujiwara Makoto , Kronenberg Henry M. , Wein Marc N.
Published: March 2021

Osteocytes use an elaborate network of dendritic connections to control bone remodeling. Some osteoblasts embed within mineralized bone matrix, change shape, and become osteocytes. The molecular circuitry that drives dendrite formation during “osteocytogenesis” is poorly understood. Here we show that deletion ofSp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites. Unbiased profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation.Osteocrinis a Sp7 target gene that promotes osteocyte dendrite formation and rescues phenotypic and molecular defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates overt defects in osteocyte maturationin vivoin the absence of Sp7. Sp7-dependent gene networks enriched in developing osteocytes are associated with rare and common human skeletal traits. Moreover, humans homozygous for the osteogenesis imperfecta-causingSP7R316Cmutation show dramatic defects in osteocyte morphology. Genes that mark osteocytesin vivoand that are regulated by Sp7in vitroare highly enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. Taken together, these findings reveal a crucial role for Sp7 and its target geneOsteocrinin osteocytogenesis, demonstrating that pathways that control osteocyte development influence human bone diseases.
From temporal network data to the dynamics of social relationships
Authors: Gelardi Valeria , Barrat Alain , Claidiere Nicolas
Published: March 2021

Networks are well-established representations of social systems, and temporal networks are widely used to study their dynamics. Temporal network data often consist in a succession of static networks over consecutive time windows whose length, however, is arbitrary, not necessarily corresponding to any intrinsic timescale of the system. Moreover, the resulting view of social network evolution is unsatisfactory: short time windows contain little information, whereas aggregating over large time windows blurs the dynamics. Going from a temporal network to a meaningful evolving representation of a social network therefore remains a challenge. Here we introduce a framework to that purpose: transforming temporal network data into an evolving weighted network where the weights of the links between individuals are updated at every interaction. Most importantly, this transformation takes into account the interdependence of social relationships due to the finite attention capacities of individuals: each interaction between two individuals not only reinforces their mutual relationship but also weakens their relationships with others. We study a concrete example of such a transformation and apply it to several data sets of social interactions. Using temporal contact data collected in schools, we show how our framework highlights specificities in their structure and temporal organization. We then introduce a synthetic perturbation into a data set of interactions in a group of baboons to show that it is possible to detect a perturbation in a social group on a wide range of timescales and parameters. Our framework brings new perspectives to the analysis of temporal social networks.
α1-COP delivers sphingolipid modifiers and controls plasmodesmal callose deposition in Arabidopsis
Authors: Iswanto Arya Bagus Boedi , Vu Minh Huy , Kumar Ritesh , Shon Jong Cheol , Wu Shuwei , Kim Da-Ran , Sik Kwak Yeon , Hui Son Geon , Kang Hobin , Kim Woe Yoen , Kim Sang Hee , Liu Kwang Hyeon , Kim Jae-Yean
Published: March 2021

Callose is a plant cell wall polymer in the form of β-1,3-glucan, which regulates symplasmic channel size at plasmodesmata (PD). It plays a crucial role in a variety of processes in plants through the regulation of intercelluar symplasmic continuity. However, how to maintain callose homeostasis at PD in the molecular levels is poorly understood. To further elucidate the mechanism of PD callose homeostasis, we screened and identified an Arabidopsis mutant plant that exhibited excessive callose deposition at PD. Based on the Next-generation sequencing (NGS)-based mapping, other mutant allele analysis, and complementation assay, the mutated gene was shown to beα1-COP, which encodes a member of the COPI coatomer complex comprised of α, β, β′, γ, δ, ε, and ζ subunits. Since there is no report on the link between COPI and callose/PD, it was extremely curious to know the roles ofα1-COPor COPI in PD regulation through callose deposition. Here, we report that loss-of-function ofα1-COPdirectly elevates the callose accumulation at PD by affecting subcellular protein localization of callose degradation enzyme PdBG2. This process is linked to ERH1, an inositol phosphoryl ceramide synthase (IPCS), and glucosylceramide synthase (GCS) functions through physical interactions with the α1-COP protein. In addition, the loss-of-function ofα1-COPalso alters the subcellular localization of ERH1 and GCS proteins, results in a reduction of GlcCers and GlcHCers molecules, which are the key SL species for lipid raft formation. According to our findings, we propose that α1-COP protein, together with the SL modifiers controlling lipid raft compositions, regulates the function of GPI-anchored PD proteins and hence the callose turnover at PD and symplastic movement of biomolecules. Our findings provide the first key clue to link the COPI-mediated intracellular trafficking pathway to the callose-mediated intercellular signaling pathway through PD.

One-sentence summary

Plant-specific coatomer protein functions as a negative regulator of callose accumulation by regulating the translocation of sphingolipid enzymes.