bluuebunny/crossref_metadata_2025 huggingface dataset:
Applicability of Neighborhood and Building Scale Wastewater-Based Genomic Epidemiology to Track the SARS-CoV-2 Pandemic and other Pathogens
Authors: Spurbeck Rachel R. , Minard-Smith Angela T. , Catlin Lindsay A.
Published: February 2021

The benefits of wastewater-based epidemiology (WBE) for tracking the viral load of SARS-CoV-2, the causative agent of COVID-19, have become apparent since the start of the pandemic. However, most sampling occurs at the wastewater treatment plant influent and therefore can only monitor SARS-CoV-2 concentration and spread within the entire catchment, which can encompass multiple municipalities. Furthermore, most WBE only quantifies the virus, and therefore miss crucial information that can be gained by sequencing SARS-CoV-2. Here we demonstrate feasibility of sampling at the neighborhood or building complex level using a mix of quantitative polymerase chain reaction (qPCR) and targeted sequencing to provide a more refined understanding of the local dynamics of SARS-CoV-2 strains. When coupled with the higher-level treatment plant samples, this creates an opportunity for health officials to monitor the spread of the virus at different spatial and temporal scales to inform policy decisions.

Here we demonstrate the feasibility of tracking SARS-CoV-2 at the neighborhood, hospital, and nursing home level with the ability to detect one COVID-19 positive out of 60 nursing home residents. The viral load obtained was correlative with the number of COVID-19 patients being treated in the hospital. Sequencing of the samples over time demonstrated that nonsynonymous mutations fluctuate in the viral population, and wastewater-based sequencing could be an efficient approach to monitor for vaccine or convalescent plasma escape mutants, as well as mutations that could reduce the efficacy of diagnostics. Furthermore, while SARS-CoV-2 was detected by untargeted RNA sequencing, qPCR and targeted whole genome amplicon sequencing were more reliable methods for tracking the pandemic. From our sequencing data, clades and shifts in mutation profiles within the community were traceable and could be used to determine if vaccine or diagnostics need to be adapted to ensure continued efficacy.

Graphical Abstract

Highlights

Neighborhood or building level wastewater analysis accurately detects SARS-CoV-2

SARS-CoV-2 was detected in wastewater from one infected person out of 60 residents

Total RNAseq did not accurately detect SARS-CoV-2 in wastewater samples.

Targeted whole genome sequencing of wastewater samples identified Spike mutations.
A glomerular transcriptomic landscape of APOL1 in Black patients with focal segmental glomerulosclerosis
Authors: McNulty Michelle M. , Fermin Damian , Eichinger Felix , Jang Dongkeun , Kretzler Matthias , Burtt Noel , Pollak Martin R. , Flannick Jason , Friedman David J. ,   Nephrotic Syndrome Study Network (NEPTUNE), Sampson Matthew G.
Published: February 2021

Apolipoprotein L1 (APOL1)-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black people. There are no targeted therapies for this condition, in part because the molecular mechanisms underlying APOL1’s pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease. With the hypothesis that the pathology driven by the high-risk (HR) APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black FSGS patients with a HR vs 14 with a low-risk (“LR”) APOL1 genotype. Expression data from APOL1-inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways illuminated in these studies.

We discovered (1) increased expression of APOL1 in HR and nine other significant differentially expressed genes, including stanniocalcin (STC1), which has a role in mitochondrial and calcium-related processes, (2) differential correlations between HR and LR APOL1 and metabolism pathway genes, but similar correlations with extracellular matrix- and immune-related genes, (3) significant loss of co-expression of mitochondrial genes in HR FSGS, and (4) an NF-κB -down-regulating gene, NKIRAS1, as the most significant hub gene with strong differential correlations with NDUF family and immune-related genes. Overall, differences in mitochondrial gene regulation appear to underlie many differences observed between HR and LR FSGS. All data are available for secondary analysis through the “APOL1 Portal” (http://APOL1portal.org).
Cognitive, emotional, and social functioning of preschoolers with attention deficit hyperactivity problems
Authors: Biele Guido , Overgaard Kristin R. , Friis Svein , Zeiner Pal , Aase Heidi
Published: February 2021

Attention Deficit Hyperactivity Disorder (ADHD) is associated with deficits in a number of functional domains, which have been described both as causes and effects of ADHD. It remains unclear if deficits in different domains are equally strong in early childhood, and which deficits are specific to ADHD. Here, we describe functional domains in preschoolers and assess deficits in children with ADHD problems, by comparing them to preschoolers who have other mental health problems or who develop typically. The ADHD Study assessed 1195 ca. 3.5 years old preschoolers through a semi-structured parent interview, parent questionnaires, and with neuropsychological tests. We determined functional domains by applying factor analytic methods to a broad set of questionnaire- and test-scales. Using resulting factor scores, we employed a Bayesian hierarchical regression to estimate functional deficits in children with ADHD. We found that preschoolers’ functioning could be described along the seven relatively independent dimensions activity level and regulation, executive function, cognition, language, emotion regulation, introversion, and sociability. Compared to typically developing preschoolers, those with ADHD had deficits in all domains except introversion and sociability. Only deficits in activity level and regulation and executive functions were larger than 0.5 standardized mean deviations and larger than deficits of children with other mental health problems. Preschoolers with ADHD have deficits in multiple functional domains, but only impairments in activity level and regulation and executive functions are specific for ADHD and large enough to be clinically significant. Research on functioning in these domains will likely be central for understanding the development of ADHD in later the childhood, and for improving treatment and prevention approaches.
Association between Psychotropic Medications Functionally Inhibiting Acid Sphingomyelinase and reduced risk of Intubation or Death among Individuals with Mental Disorder and Severe COVID-19: an Observational Study
Authors: Hoertel Nicolas , Sánchez-Rico Marina , Gulbins Erich , Kornhuber Johannes , Carpinteiro Alexander , Abellán Miriam , de la Muela Pedro , Vernet Raphaël , Beeker Nathanaël , Neuraz Antoine , Delcuze Aude , Alvarado Jesús M. , Meneton Pierre , Limosin Frédéric
Published: February 2021

Prior preclinical and clinical evidence suggests that the acid sphingomyelinase (ASM)/ceramide system may provide a useful framework for better understanding SARS-CoV-2 infection and the repurposing of psychotropic medications with functional inhibition of acid sphingomyelinase, called FIASMA psychotropic medications, against COVID-19. We examined the potential usefulness of FIASMA psychotropic medication use among patients with mental disorder hospitalized for severe COVID-19, in an observational multicenter retrospective study conducted at AP-HP Greater Paris University hospitals. Of 545 adult patients with mental disorder hospitalized for severe COVID-19, 164 (30.1%) received a psychotropic FIASMA medication at study baseline, which was defined as the date of hospital admission for COVID-19. The primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received a psychotropic FIASMA medication at baseline and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, psychiatric and other medical comorbidity, and psychotropic and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW). There was a significant association between FIASMA psychotropic medication use at baseline and reduced risk of intubation or death both in the crude analysis (HR=0.42; 95%CI=0.31-0.57; p<0.01) and in the primary IPW analysis (HR=0.50; 95%CI=0.37-0.67; p<0.01). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggested that this association was not specific to one FIASMA psychotropic class or medication. These results suggest the usefulness of the ASM/ceramide system framework in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.
Predicted epitope binding core motifs and common amino acid polymorphisms distinguish protective- from susceptibility-associated HLA alleles in leishmaniasis
Authors: de Vrij Nicky , Meysman Pieter , Gielis Sofie , Adriaensen Wim , Laukens Kris , Cuypers Bart
Published: February 2021

Susceptibility for leishmaniasis is largely dependent on genetic- and immune factors of the host. Despite the previously described association of human leukocyte antigen (HLA) gene cluster variants as genetic susceptibility factors, little is known on the mechanisms that mediate these associations. To characterize the functionality underpinning these associations between HLA and disease, we predicted the epitope binding repertoires for all known leishmaniasis-associated HLA variants collected in a thorough literature review. We identified several amino acid polymorphisms in the HLA sequences that distinguished protective-from risk-associated HLA-DRB1 alleles. Proteome-wide and multi-species T cell epitope binding predictions were carried out across these alleles, enabling us to map the effects on the epitope binding repertoires. The protective-associated HLA-DRB1 alleles were characterized by common binding core motifs, which map to the identified amino acid polymorphisms. These results strongly suggest that polymorphism in the HLA region, resulting in differential antigen presentation, affects the association between HLA and leishmaniasis disease development. Finally, we established a valuable open-access resource of putative epitopes, of which a set of 14 HLA-unrestricted strong-binding epitopes, conserved across species, were prioritized for further epitope discovery in the search for novel subunit-based vaccines.
Determining the pathogenicity of MUT gene variant by mini-gene splicing assay
Authors: Wang Yanyun , Sun Yun , Jiang Tao
Published: February 2021

Objective

To perform gene mutation splicing analysis on 12 suspected pathogenic MMUT/MUT gene mutation sites to verify the pathogenicity of the mutation.

Methods

Wild-type and mutant minigenes were inserted into pcMINI vector, and total 5 wild-type recombinant vectors and 12 mutant recombinant vectors were constructed. The total RNA in 293T cells was extracted after the recombinant vectors were transfected into 293T cell line. Then PCR products were detected by agarose gel electrophoresis and analyzed by sequencing.

Results

RT-PCR and sequencing results showed that among 12 mutations, 9 mutations (c.419T>C, 469G>T, c.470T>A, c.626dupC, c.693C>G, c.976A>G, c.1009T>C, c.1777G>T and c.1874A>C) did not affect the gene splicing, and the other 3 mutations (c.454C>T, c.421G>A and c.2125-3C>G) all affected mRNA splicing.

Conclusion

In recent case reports of MMUT/MUT gene mutation sites, variant of uncertain significance (VUS) variation is very common. In this study, the pathogenicity of three mutation sites is confirmed by the mini-gene method.
Distinguishing dopamine and calcium responses using XNA-nanotube sensors for improved neurochemical sensing
Authors: Gillen Alice J. , Antonucci Alessandra , Reggente Melania , Morales Daniel , Boghossian Ardemis A.
Published: February 2021

To date, the engineering of single-stranded DNA-SWCNT (DNA-SWCNT) optical biosensors have largely focused on creating sensors for new applications with little focus on optimising existing sensors for in vitro and in vivo conditions. Recent studies have shown that nanotube fluorescence can be severely impacted by changes in local cation concentrations. This is particularly problematic for neurotransmitter sensing applications as spatial and temporal fluctuations in the concentration of cations, such as Na+, K+, or Ca2+, play a central role in neuromodulation. This can lead to inaccuracies in the determination of neurotransmitter concentrations using DNA-SWCNT sensors, which limits their use for detecting and treating neurological diseases.

Herein, we present new approaches using locked nucleic acid (LNA) to engineer SWCNT sensors with improved stability towards cation-induced fluorescence changes. By incorporating LNA bases into the (GT)15-DNA sequence, we create sensors that are not only more resistant towards undesirable fluorescence modulation in the presence of Ca2+ but that also retain their capabilities for the label-free detection of dopamine. The synthetic biology approach presented in this work therefore serves as a complementary means for enhancing nanotube optoelectronic behavior, unlocking previously unexplored possibilities for developing nano-bioengineered sensors with augmented capabilities.
Early embryogenesis and organogenesis in the annelidOwenia fusiformis
Authors: Carrillo-Baltodano Allan Martín , Seudre Océane , Guynes Kero , Martín-Durán José María
Published: February 2021

Background

Annelids are a diverse group of segmented worms within Spiralia, whose embryos exhibit spiral cleavage and a variety of larval forms. While most modern embryological studies focus on species with unequal spiral cleavage nested in Pleistoannelida (Sedentaria + Errantia), a few recent studies looked intoOwenia fusiformis, a member of the sister group to all remaining annelids and thus a key lineage to understand annelid and spiralian evolution and development. However, the timing of early cleavage and detailed morphogenetic events leading to the formation of the idiosyncratic mitraria larva ofO. fusiformisremain largely unexplored.

Results

O. fusiformisundergoes equal spiral cleavage where the first quartet of animal micromeres are slightly larger than the vegetal macromeres. Cleavage results in a coeloblastula approximately five hours post fertilization (hpf) at 19 °C. Gastrulation occurs via invagination and completes four hours later, with putative mesodermal precursors and the chaetoblasts appearing 10 hpf at the dorsoposterior side. Soon after, at 11 hpf, the apical tuft emerges, followed by the first neurons (as revealed by the expression ofelav1andsynaptotagmin1) in the apical organ and the prototroch by 13 hpf. Muscles connecting the chaetal sac to various larval tissues develop around 18 hpf and by the time the mitraria is fully formed at 22 hpf, there are FMRFamide+neurons in the apical organ and prototroch, the latter forming a prototrochal ring. As the mitraria feeds, it grows in size and the prototroch expands through active proliferation. The larva becomes competent after ∼3 weeks post fertilization at 15 °C, when a conspicuous juvenile rudiment has formed ventrally.

Conclusions

O. fusiformisembryogenesis is similar to that of other equal spiral cleaving annelids, supporting that equal cleavage is associated with the formation of a coeloblastula, gastrulation via invagination, and a feeding trochophore-like larva in Annelida. The nervous system of the mitraria larva forms earlier and is more complex than previously recognised and develops from anterior to posterior, which is likely an ancestral condition to Annelida. Altogether, our study identifies the major developmental events duringO. fusiformisontogeny, defining a conceptual framework for future investigations.
A neural circuit basis for binasal input-enhanced chemosensory avoidance
Authors: Sy Samuel K. H. , Chan Danny C. W. , Chan Roy C. H. , Lyu Jing , Li Zhongqi , Wong Kenneth K. Y. , Choi Chung Hang Jonathan , Mok Vincent C. T. , Lai Hei-Ming , Hu Yu , Ko Ho
Published: February 2021

Our understanding of how bilaterian animals utilize parallel input channels from paired sensory organs to optimize chemosensory behavior and the underlying neural circuit mechanisms are limited. Here we developed microfluidics-based behavioral and brainwide imaging platforms to study the neural integration of binasal inputs and chemosensory avoidance in larval zebrafish. We show that larval zebrafish efficiently escape from cadaverine-carrying streams by making more frequent swim bouts and larger undirected turns. Binasal inputs are strictly required for the nasal input-dependent component of klinokinesis, while each nasal input additively enhances angular orthokinesis. Throughout brain regions, including those along the olfactory processing pathways, a distributed neural representation with a wide spectrum of ipsilateral-contralateral nasal stimulus selectivity is maintained. Nonlinear sensory information gain with bilateral signal convergence is especially prominent in neurons weakly encoding unilateral cadaverine stimulus, and associated with stronger activation of sensorimotor neurons in the downstream brain regions. Collectively, these results provide insights into how the vertebrate model sums parallel input signals to guide chemosensory avoidance behavior.
Unraveling micro-architectural modulations in neural tissue upon ischemia by Correlation Tensor MRI
Authors: Alves Rita , Henriques Rafael Neto , Kerkelä Leevi , Chavarrías Cristina , Jespersen Sune N , Shemesh Noam
Published: February 2021

Noninvasively detecting and characterizing modulations in cellular scale micro-architecture is a desideratum for contemporary neuroimaging. Diffusion MRI (dMRI) has become the mainstay methodology for probing microstructure, and, in ischemia, its contrasts have revolutionized stroke management. However, the biological underpinnings of the contrasts observed in conventional dMRI in general and in ischemia in particular are still highly debated since the markers only indirectly reporter on microstructure. Here, we present Correlation Tensor MRI (CTI), a method that rather than measuring diffusion, harnesses diffusion correlations as its source of contrast. We show that CTI can resolve the sources of diffusional kurtosis, which in turn, provide dramatically enhanced specificity and sensitivity towards ischemia. In particular, the sensitivity towards ischemia nearly doubles, both in grey matter (GM) and white matter (WM), and unique signatures for neurite beading, cell swelling, and edema are inferred from CTI. The enhanced sensitivity and specificity endowed by CTI bodes well for future applications in biomedicine, basic neuroscience, and in the clinic.
Preprints in motion: tracking changes between preprint posting and journal publication during a pandemic
Authors: Brierley Liam , Nanni Federico , Polka Jessica K , Dey Gautam , Pálfy Máté , Fraser Nicholas , Coates Jonathon Alexis
Published: February 2021

Amidst the COVID-19 pandemic, preprints in the biomedical sciences are being posted and accessed at unprecedented rates, drawing widespread attention from the general public, press and policymakers for the first time. This phenomenon has sharpened longstanding questions about the reliability of information shared prior to journal peer review. Does the information shared in preprints typically withstand the scrutiny of peer review, or are conclusions likely to change in the version of record? We assessed preprints from bioRxiv and medRxiv that had been posted and subsequently published in a journal through 30th April 2020, representing the initial phase of the pandemic response. We utilised a combination of automatic and manual annotations to quantify how an article changed between the preprinted and published version. We found that the total number of figure panels and tables changed little between preprint and published articles. Moreover, the conclusions of 7.2% of non-COVID-19-related and 17.2% of COVID-19-related abstracts undergo a discrete change by the time of publication, but the majority of these changes do not qualitatively change the conclusions of the paper.
Daily orexinergic modulation of the rat superficial layers of the superior colliculus – implications for intrinsic clock activities in the visual system
Authors: Chrobok Lukasz , Jeczmien-Lazur Jagoda Stanislawa , Bubka Monika , Pradel Kamil , Klekocinska Aleksandra , Klich Jasmin Daniela , Rahim Amalia Ridla , Myung Jihwan , Kepczynski Mariusz , Lewandowski Marian Henryk
Published: February 2021

The orexinergic system delivers excitation for multiple brain centres to facilitate behavioural arousal, with its malfunction resulting in narcolepsy, somnolence, and notably, visual hallucinations. Since the circadian clock underlies the daily arousal, a timed coordination is expected between the orexin system and its target subcortical visual system, including the superior colliculus (SC). Here, we use a combination of electrophysiological, immunohistochemical, and molecular approaches across 24 h, together with the neuronal tract tracing methods in rodents to elucidate the daily coordination between the orexin system and the superficial layers of the SC. We find the daily orexinergic innervation onto the SC, coinciding with the daily silencing of spontaneous firing in this visual brain area. We identify autonomous daily and circadian expression of clock genes in the SC, which may underlie these day-night changes. Additionally, we establish the lateral hypothalamic origin of orexin innervation to the SC and that the SC neurons robustly respond to orexin A via OX2 receptor in both excitatory and GABAA receptor-dependent inhibitory manners. Together, our evidence supports that the clock coordination between the orexinergic input and its response in the SC provides arousal-related excitation needed to detect sparse visual information during the behaviourally active phase.
Multiple PDZ Domain Protein Maintains Patterning of the Apical Cytoskeleton in Sensory Hair Cells
Authors: Jarysta Amandine , Tarchini Basile
Published: February 2021

Sound transduction occurs in the hair bundle, the apical compartment of sensory hair cells in the inner ear. The hair bundle is formed of stereocilia aligned in rows of graded heights. It was previously shown that the GNAI-GPSM2 complex is part of a developmental blueprint that defines the polarized organization of the apical cytoskeleton in hair cells, including stereocilia distribution and elongation. Here we report a novel and critical role for Multiple PDZ domain (MPDZ) protein during apical hair cell morphogenesis. We show that MPDZ is enriched at the hair cell apical membrane, and required there to maintain the proper segregation of apical blueprints proteins, including GNAI-GPSM2. Loss of the blueprint coincides with misaligned stereocilia inMpdzmutants, and results in permanently misshapen hair bundles. Graded molecular and structural defects along the cochlea can explain the profile of hearing loss inMpdzmutants, where deficits are most severe at high frequencies.
DNA-Encoded Multivalent Display of Protein Tetramers on Phage: Synthesis and In Vivo Aplications
Authors: Lima Guilherme M. , Atrazhev Alexey , Sarkar Susmita , Sojitra Mirat , Reddy Revathi , Macauley Matthew S. , Monteiro Gisele , Derda Ratmir
Published: February 2021

Phage display links phenotype of displayed polypeptides with DNA sequence in phage genome and offers a universal method for discovery of proteins with novel properties. Injection of phage-displayed libraries in living organisms further provides a unique and powerful approach to optimize biochemical, pharmacological and biological properties of the displayed peptides, antibodies and other proteins in vivo. However, over 60% of the proteome is comprised of multi-domain proteins, and display of large multi-subunit proteins on phages remains a challenge. Majority of protein display systems are based on monovalent phagemid constructs but methods for robust display of multiple copies of large proteins are scarce. Here, we describe a DNA-encoded display of a ∼200 kDa tetrameric protein tetrameric L-asparaginase on M13 phage produced by ligation of SpyCatcher-Asparaginase fusion (ScA) to prospectively barcoded phage clones displaying SpyTag peptide. Starting from the SpyTag display on p3 minor coat protein or p8 major coat protein yielded constructs with five copies of ScA displayed on p3 (ScA5-phage) and 50 copies of ScA on p8 protein (ScA50-phage). ScA remained active after conjugation. It could be easily produced directly from lysates of bacteria that express ScA. Display constructs of different valency can be injected into mice and analyzed by deep-sequencing of the DNA barcodes associated phage clones. In these multiplexed studies, we observed a density-dependent clearance rate in vivo. A known clearance mechanism of L-asparaginase is endocytosis by phagocytic cells. Our observations, thus, link the increase in density of the displayed protein with the increased rate of the endocytosis by cells in vivo. In conclusion, we demonstrate that a multivalent display of L-asparaginase on phage could be used to study the circulation life of this protein in vivo and such approach opens the possibility to use DNA sequencing to investigate multiplexed libraries of other multi-subunit proteins in vivo.

Abstract Graphic
Kinetic Interval Measurement: A Tool to Characterize Thermal Reversion Dynamics of Light-switchable Fluorescent Proteins
Authors: von Trotha Tassilo , Jöhr Res , Fischer Jonas , Schendel Leonard C. , Gaub Hermann E. , Kluger Carleen
Published: February 2021

Light-switchable proteins like Light-Oxygen-Voltage (LOV) domains can be used to control protein interactions and have been applied in vivo to manipulate cell behavior. The switching between dark and light state of LOV domains depends on temperature or their chemical microenvironment and can be tuned by point mutations. Here, we present a method called Kinetic Interval Measurement (KIM) to quantify the thermal reversion dynamics of light-switchable proteins by using a custom microplate reader. We show that this versatile method can be used to determine the reversion half-life of the excited state of LOV proteins in a reproducible, fast and simple manner consuming only small amounts of protein. The sensitivity of the method allows to report on changes in temperature and imidazole concentration as well as the photoswitching dynamics of LOV proteins in living cells.
Antigenic waves of virus-immune co-evolution
Authors: Marchi Jacopo , Lässig Michael , Walczak Aleksandra M. , Mora Thierry
Published: February 2021

The evolution of many microbes and pathogens, including circulating viruses such as seasonal influenza, is driven by immune pressure from the host population. In turn, the immune systems of infected populations get updated, chasing viruses even further away. Quantitatively understanding how these dynamics result in observed patterns of rapid pathogen and immune adaptation is instrumental to epidemiological and evolutionary forecasting. Here we present a mathematical theory of co-evolution between immune systems and viruses in a finite-dimensional antigenic space, which describes the cross-reactivity of viral strains and immune systems primed by previous infections. We show the emergence of an antigenic wave that is pushed forward and canalized by cross-reactivity. We obtain analytical results for shape, speed, and angular diffusion of the wave. In particular, we show that viral-immune co-evolution generates a new emergent timescale, the persistence time of the wave’s direction in antigenic space, which can be much longer than the coalescence time of the viral population. We compare these dynamics to the observed antigenic turnover of influenza strains, and we discuss how the dimensionality of antigenic space impacts on the predictability of the evolutionary dynamics. Our results provide a concrete and tractable framework to describe pathogen-host co-evolution.
A Ratio-Dependent Model of Replicator-Genetic Parasite Coevolution Demonstrates Instability of the Parasite-Free State
Authors: Berezovskaya Faina , Karev Georgy P. , Koonin Eugene V.
Published: February 2021

Nearly all organisms on earth are hosts to diverse genetic parasites including viruses and various types of mobile genetic elements. The emergence and persistence of genetic parasites was hypothesized to be an intrinsic feature of biological evolution. Here we examine this proposition by analysis of a ratio-dependent Lotka-Volterra type model of replicator(host)-parasite coevolution where the evolutionary outcome depends on the ratio of the host and parasite numbers. In a large, unbounded domain of the space of the model parameters, which include the replicator carrying capacity, the damage inflicted by the parasite, the replicative advantage of the parasites, and its mortality rate, the parasite-free equilibrium takes the form of a saddle and accordingly is unstable. Therefore, the evolutionary outcome is either the stable coexistence of the replicator and the parasite or extinction of both. Thus, the results of ratio-dependent model analysis are compatible with the hypothesis that genetic parasites are inherent to life.
Unraveling the role of MADS transcription factor complexes in apple tree dormancy using sequential DAP-seq
Authors: Falavigna Vítor da Silveira , Severing Edouard , Lai Xuelei , Estevan Joan , Farrera Isabelle , Hugouvieux Véronique , Revers Luís Fernando , Zubieta Chloe , Coupland George , Costes Evelyne , Andrés Fernando
Published: February 2021

Background

The effect of global warming on dormancy and flowering patterns of crop trees threatens world-wide fruit production and food security. In Rosaceous tree species, it is believed that a group of genes encoding MADS transcription factors (TFs) controls temperature-mediated dormancy cycle. These genes are similar toSHORT VEGETATIVE PHASE(SVP) fromArabidopsis thalianaand referred asDORMANCY-ASSOCIATED MADS-BOX(DAM) genes.

Results

By making use of apple tree (Malusxdomestica) as a model for Rosaceous species, we have investigated the function of MADS TFs during the dormancy cycle. We found that MdDAM and other dormancy related MADS TFs form multimeric complexes with MdSVPa, and that MdSVPa is essential for the transcriptional complex activity. Then, for the first time in non-model plant species, we performed sequential DNA Affinity Purification sequencing (seq-DAP-seq) to define the genome-wide binding sites of these MADS TF complexes. Target genes associated with the binding sites were identified by combining seq-DAP-seq data with transcriptomics datasets obtained by the inducible glucocorticoid receptor expression system, and reanalyzing preexisting data related to dormancy cycle in apple trees.

Conclusion

We have determined a gene regulatory network formed by MdSVPa-containing complexes that regulate the dormancy cycle in apple trees in response to environmental cues. Key genes identified with our genomic approach and the elucidated regulatory relationships provide leads for breeding fruit trees better adapted to changing climate conditions. Moreover, we provide novel molecular evidence on the evolutionary functional segregation between DAM and SVP proteins in the Rosaceae family.
Finding Druggable Sites in Proteins using TACTICS
Authors: Evans Daniel J. , Yovanno Remy A. , Rahman Sanim , Cao David W. , Beckett Morgan Q. , Patel Milan H. , Bandak Afif F. , Lau Albert Y.
Published: February 2021

Structure-based drug discovery efforts require knowledge of where drug-binding sites are located on target proteins. To address the challenge of finding druggable sites, we developed a machine-learning algorithm called TACTICS (Trajectory-based Analysis of Conformations To Identify Cryptic Sites), which uses an ensemble of molecular structures (such as molecular dynamics simulation data) as input. First, TACTICS uses k-means clustering to select a small number of conformations that represent the overall conformational heterogeneity of the data. Then, TACTICS uses a random forest model to identify potentially bindable residues in each selected conformation, based on protein motion and geometry. Lastly, residues in possible binding pockets are scored using fragment docking. As proof-of-principle, TACTICS was applied to the analysis of simulations of the SARS-CoV-2 main protease and methyltransferase and theYersinia pestisaryl carrier protein. Our approach recapitulates known small-molecule binding sites and predicts the locations of sites not previously observed in experimentally determined structures. The TACTICS code is available athttps://github.com/Albert-Lau-Lab/tactics_protein_analysis.
Causal approach to environmental risks of seabed mining
Authors: Kaikkonen Laura , Helle Inari , Kostamo Kirsi , Kuikka Sakari , Törnroos Anna , Nygård Henrik , Venesjärvi Riikka , Uusitalo Laura
Published: February 2021

Seabed mining is approaching the commercial mining phase across the world’s oceans. This rapid industrialization of seabed resource use is introducing new pressures to marine environments. The environmental impacts of such pressures should be carefully evaluated prior to permitting new activities, yet observational data is mostly missing. Here, we examine the environmental risks of seabed mining using a causal, probabilistic network approach. Drawing on a series of interviews with a multidisciplinary group of experts, we outline the cause-effect pathways related to seabed mining activities to inform quantitative risk assessments. The approach consists of (1) iterative model building with experts to identify the causal connections between seabed mining activities and the affected ecosystem components, and (2) quantitative probabilistic modelling to provide estimates of mortality of benthic fauna in the Baltic Sea. The model is used to evaluate alternative mining scenarios, offering a quantitative means to highlight the uncertainties around the impacts of mining. We further outline requirements for operationalizing quantitative risk assessments, highlighting the importance of a cross-disciplinary approach to risk identification. The model can be used to support permitting processes by providing a more comprehensive description of the potential environmental impacts of seabed resource use, allowing iterative updating of the model as new information becomes available.
Money stock determination process and money multiplier: case of South Korea
Authors: Ongan Serdar , Gocer Ismet
Published: February 2021

Purpose

This study aims to re-examine the money stock determination process for South Korea under the assumption of the existence of potential asymmetric (non-linear) relations (a mechanism) between the money stock and the monetary base. Because, the true and detailed diagnosis of this mechanism is crucially important for the Bank of Korea’s (BOK)’ monetary policy, as this country has been adopting an inflation targeting policy (ITP) for a long-time.

Design/methodology/approach

This paper applies the non-linear autoregressive distributed lag model by Shinet al.(2014). This model separates the original series of the monetary base into their increases (+) and decreases (−). The increases (+) and decreases (−) done by the BOK correspond to expansionary and contractionary monetary policies, respectively, in this study.

Findings

The empirical findings are two-fold. First, the money stock determination process in Korea has a non-linear (asymmetric) structure. This means that increases (+) and decreases (−) in the monetary base have asymmetric (different) impacts on money stock. Second, the BOK’s only expansionary monetary policy exhibits exogenous nature money stock determination with an almost stable money multiplier. These findings may help the BOK to take preventive precautions in its monetary policy implementations.

Originality/value

This study with its methodology may help the BOK to take preventive measures in its ongoing ITP proactively.
Covid-19, out-of-pocket medical expenses and consumption
Authors: Leightner Jonathan E.
Published: February 2021

Purpose

Based upon estimates of the change in consumption due to a change in out-of-pocket-health expenses (dC/dOOPHE) for 43 countries, this paper aims to argue for a reevaluation of what constitutes OOPHE when determining health insurance especially in the wake of Covid-19.

Design/methodology/approach

Reiterative truncated projected least squares (RTPLS), a statistical technique designed to handle the omitted variables problem of regression analysis.

Findings

If budgets are binding than dC/dOOPHE should be 0; if OOPHE merely adds to current consumption than dC/dOOPHE should be 1. However, merely plotting consumption versus OOPHE for the 43 countries for which organization for economic cooperation and development has the required data clearly shows a dC/dOOPHE much greater than one. This paper’s estimates of dC/dOOPHE for 2000 to 2017 range from 15.6 for Switzerland (in 2016) to 225.2 for Columbia (in 2003).

Research limitations/implications

RTPLS cannot determine what part of the results are due to an increase in income causing both consumption and OOPHE to increase and what part is because of actual OOPHE far exceeding official OOPHE. However, the latter is involved.

Practical implications

As Covid-19 sickens millions while depriving millions of their normal means of generating income, what constitutes OOPHE should be expanded when determining health insurance. This paper’s results imply that even prior to Covid-19 health insurance covered much less than the optimal amount of actual OOPHE.

Originality/value

This is the first paper to use RTPLS to estimate dC/dOOPHE.
Evaluation of bioequivalence of two flurbiprofen axetil injections: A randomized, open‐label, double‐cycle, and crossover study
Authors: Wang Jin , Dong Liuhan , Wang Rui , Cai Yun
Published: February 2021

Flurbiprofen is a non‐steroidal anti‐inflammatory drug. We evaluated the bioequivalence of a new formulation of flurbiprofen axetil for injection and the reference drug ROPION (another kind of flurbiprofen axetil injection marketed for use) in healthy Chinese subjects. This is a single‐centre, randomized, open‐label, single‐dose, two period crossover bioequivalence study. Each subject received a single intravenous injection at the dose of 50 mg under fasting. The drug was dissolved in 100 mL normal saline, and the injection was completed in 15 minutes. There was a 7‐day washout period between the two administrations. The plasma concentrations of flurbiprofen were measured by LC‐MS/MS, and descriptive statistics were used to describe the safety outcomes including adverse events (AEs) and adverse drug reactions (ADRs). Twenty‐four subjects were enrolled in this study. Mean values of primary PK parameters (Tmax, Cmax, AUC0‐t, AUC0‐∞, λz, T1/2) were similar (P > 0.05). Tmax for both products is 0.3 hours. The 90% confidence intervals (CIs) for peak concentration Cmax ranged between 96.87% and 100.42%, and the area under curve AUC0‐t and AUC0‐∞ ranged between 99.09% and 104.29% and 98.97% and 104.29%, respectively. The 90% CIs for the geometric means and ratios of primary PK endpoints of flurbiprofen axetil injection to reference drug ranged between 98.97% and 104.29%. The adverse event rate of the test product was 8.3% and no serious adverse events (SAE) occurred in this clinical study. We concluded that the test product and the reference drug were bioequivalent and the safety was high in healthy Chinese subjects.
Indian dye yielding plants: Efforts and opportunities
Authors: Aggarwal Shilpi
Published: February 2021

The present review article deals with the information on the dye‐yielding plants of India. Dyes are intensively coloured compounds that are applied to a substrate such as fibre, paper, cosmetics, hair, etc. to give colours and can be extracted from the roots, fruits/berries, bark, leaves, flowers, and stem/wood, fungi, and lichens by various processes of extractions. In addition to their dye‐yielding characteristics, many of these plants possess medicinal values and can be used for multiple other purposes. Plant derived‐colours have an important role in human life because of their safe and eco‐friendly nature. But due to the availability of economically cheaper synthetic dyes, the indigenous knowledge of extraction, processing, and proper utilisation has been diminished. Nowadays, the demand for natural dyes has been increased worldwide due to awareness about their beneficial properties. It has been essential that proper documentation and measure of conservation should be undertaken to preserve these natural dye‐yielding plants. This review article is an aid to a collective inquiry into Indian dye plants.
The evolving role of EUS‐guided tissue acquisition
Authors: Ang Tiing Leong , Wang Lai Mun
Published: February 2021

The introduction of endoscopic ultrasound‐guided fine‐needle aspiration into clinical practice was a pivotal moment for diagnostic gastrointestinal endoscopy. It facilitates the ease of tissue acquisition from previously inaccessible sites. The performance characteristics of cytological diagnosis are excellent. However, there remain areas of inadequacies. These include procedural inefficiencies such as the need for rapid on‐site cytological evaluation or macroscopic on‐site evaluation, the crucial role of histology for diagnosis in specific conditions, the issue of sampling errors and the need for repeat procedures, and the shift towards personalized medicine, which requires histology, immunohistochemical studies, and molecular analysis. The original Trucut biopsy needle had been cumbersome to use, but the recent introduction of newer‐generation biopsy needles has transformed the landscape, such that there is now a greater focus on tissue acquisition for histological assessment. Concomitant technological advances of endoscopic ultrasound processors enabled higher‐resolution imaging, and facilitated image enhancement using contrast harmonic endoscopic ultrasound and endoscopic ultrasound elastography. These techniques can be used as an adjunct to guide tissue acquisition in challenging situations. There is ongoing research on the use of artificial intelligence to complement diagnostic endoscopic ultrasound and the early data are promising. Artificial intelligence may be especially important to guide clinical decision‐making if biopsy results are nondiagnostic.
Epigenetics of ankylosing spondylitis: Recent developments
Authors: Yang Hui , Chen Yuting , Xu Wei , Shao Ming , Deng Jixiang , Xu Shanshan , Gao Xing , Guan Shiyang , Wang Jinian , Xu Shengqian , Shuai Zongwen , Pan Faming
Published: February 2021

Ankylosing spondylitis (AS) is a chronic inflammatory autoimmune disease which mainly affects the spine, sacroiliac joint and peripheral joints. To date, the exact causes and pathogenesis of AS still remain unknown. It is considered that the pathogenesis of AS is associated with genetic, infection, environment, immunity and other factors. Among them, the role of genetic factors in the pathogenesis of AS has been studied most deeply. However, over the past few years, the function of environmental predisposition and epigenetic modification in the pathogenesis of AS has received extensive attention. This paper summarizes the recent progress in the epigenetics of AS, including abnormal epigenetic modifications at AS‐associated genomic loci, such as DNA methylation, histone modification, microRNA, and so on. In summary, the findings of this review attempt to explain the role of epigenetic modification in the occurrence and development of AS. Nevertheless, there are still unknown and complicated aspects worth exploring to deepen our understanding of the pathogenesis of AS.
Antisense‐Induced Downregulation of Clock Genes in the Shell Region of the Nucleus Accumbens Reduces Binge Drinking in Mice
Authors: Sharma Rishi , Puckett Hunter , Kemerling Micaela , Parikh Meet , Sahota Pradeep , Thakkar Mahesh
Published: February 2021

Introductions

Binge drinking is a deadly pattern of alcohol consumption. Evidence suggests that genetic variation in clock genes is strongly associated with alcohol misuse; however, the neuroanatomical basis for such a relationship is unknown. The shell region of the nucleus accumbens (NAcSh) is well known to play a role in binge drinking. Hence, we examined whether clock genes in the NAcSh regulate binge drinking.

Methods

To address this question, 2 experiments were performed on male C57BL/6J mice. In the first experiment, mice exposed to alcohol or sucrose under the 4‐day drinking‐in‐the‐dark (DID) paradigm were euthanized at 2 different time points on day 4 [7 hours after light (pre–binge drinking) or dark (post–binge drinking) onset]. The brains were processed for RT–PCR to examine the expression of circadian clock genes (Clock, Per1, and Per2) in the NAcSh and suprachiasmatic nucleus (SCN). In the second experiment, mice were exposed to alcohol, sucrose, or water as described above. On day 4, 1 hour prior to the onset of alcohol exposure, mice were bilaterally infused with either a mixture of circadian clock gene antisense oligodeoxynucleotides (AS‐ODNs; antisense group) or nonsense/random ODNs (R‐ODNs; control group) through surgically implanted cannulas above the NAcSh. Alcohol/sucrose/water consumption was measured for 4 hours. Blood alcohol concentration was measured to confirm binge drinking. Microinfusion sites were histologically verified using cresyl violet staining.

Results

As compared to sucrose, mice euthanized post–binge drinking (not pre–binge drinking) on day 4 displayed a greater expression of circadian genes in the NAcSh but not in the SCN. Knockdown of clock genes in the NAcSh caused a significantly lower volume of alcohol to be consumed on day 4 than in the control treatment. No differences were found in sucrose or water consumption.

Conclusions

Our results suggest that clock genes in the NAcSh play a crucial role in binge drinking.
Growth and competition between a native leguminous forb and an alien grass from the Cerrado under elevated CO2
Authors: de Oliveira Amanda Cristina Gonçalves , Rios Patrick Moreira , Pereira Eduardo Gusmão , Souza João Paulo
Published: February 2021

The increase in atmospheric CO2 concentration ([CO2]) due to climate change may alter the composition of communities and the functioning of ecosystems. Owing to greater nitrogen use efficiency, leguminous plants present more effective responses to increasing [CO2] than non‐legumes. The objective of this study was to evaluate the morphophysiological and growth responses of two species from the Cerrado, a native C3 herbaceous legume (Stylosanthes capitata Vogel.) and an invasive C4 grass (Melinis minutiflora P. Beauv) growing alone or in competition, in ambient (350 ppm) and high (1000 ppm) [CO2]. Competition with S. capitata reduced leaf development and dry matter production in M. minutiflora individuals, regardless of [CO2]. Stylosanthes capitata increased root system growth under high [CO2] and competition. This change allows greater soil exploitation, decreasing nutrient limitation to S. capitata development. The leguminous species S. capitata showed advantages in the competition for resources under high [CO2] concerning the invasive grass. Although invasive C4 species are initially better in the colonisation of the invaded areas, the C3 native species of Cerrado may adjust morphophysiological traits when growing at high [CO2] and develop strategies that enable it to more effectively compete for resources.