bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythroid spectrin binding modulates peroxidase and catalase activity of heme proteins
Authors: Bose Dipayan , Aggarwal Shantanu , Das Debashree , Narayana Chandrabhas , Chakrabarti Abhijit 
Published: September 2021

ABSTRACTHemoglobin oxidation due to oxidative stress and disease conditions leads to generation of ROS (reactive oxygen species) and membrane attachment of hemoglobin in-vivo, where its redox activity leads to peroxidative damage of membrane lipids and proteins. Spectrin, the major component of the RBC membrane skeleton, is known to interact with hemoglobin and, here this interaction is shown to increase hemoglobin peroxidase activity in the presence of reducing substrate ABTS (2’, 2’-Azino-Bis-3-Ethylbenzothiazoline-6-Sulfonic Acid). It is also shown that in the absence of reducing substrate, spectrin forms covalently cross-linked aggregates with hemoglobin which display no peroxidase activity. This may have implications in the clearance of ROS and limiting peroxidative damage. Spectrin is found to modulate the peroxidase activity of different hemoglobin variants like A, E, and S, and of isolated globin chains from each of these variants. This may be of importance in disease states like sickle cell disease and HbE-β-thalassemia, where increased oxidative damage and free globin subunits are present due to the defects inherent in the hemoglobin variants associated with these diseases. This hypothesis is corroborated by lipid peroxidation experiments. The modulatory role of spectrin is shown to extend to other heme proteins, namely catalase and cytochrome-c. Experiments with free heme and Raman spectroscopy of heme proteins in the presence of spectrin show that structural alterations occur in the heme moiety of the heme proteins on spectrin binding, which may be the structural basis of increased enzyme activity.
Oxytocin neurons mediates the effect of social isolation via the VTA circuits
Authors: Musardo Stefano , Contestabile Alessandro , Mairesse Jerome , Baud Olivier , Bellone Camilla 
Published: September 2021

AbstractSocial interaction during adolescence strongly influences brain function and behaviour, and the recent pandemic has emphasized the devastating effect of social distancing on mental health. While accumulating evidences have shown the importance of the reward system in encoding specific aspects of social interaction, the consequences of social isolation on the reward system and the development of social skills later in adulthood are still largely unknown. Here, we found that one week of social isolation during adolescence in mice increased social interaction at the expense of social habituation and social novelty preference. Behavioural changes were accompanied by the acute hyperexcitability of dopamine (DA) neurons in the ventral segmental area (VTA) and long-lasting expression of GluA2-lacking AMPARs at excitatory inputs onto DA neurons that project to the prefrontal cortex (PFC). Social isolation-dependent behavioural deficits and changes in neural activity and synaptic plasticity were reversed by chemogenetic inhibition of oxytocin neurons in the paraventricular nucleus (PVN) of the hypothalamus. These results demonstrate that social isolation has acute and long-lasting effects on social interaction and suggest that these effects are mediated by homeostatic adaptations within the reward circuit.
Experimental evolution of a pheromone signal
Authors: Blankers Thomas , Fruitet Elise , Burdfield-Steel Emily , Groot Astrid T. 
Published: September 2021

ABSTRACTSexual signals are important in speciation, but understanding their evolution is complex as these signals are often composed of multiple, genetically interdependent components. To understand how signals evolve, we thus need to consider selection responses in multiple components and account for the genetic correlations among components. One intriguing possibility is that selection changes the genetic covariance structure of a multicomponent signal in a way that facilitates a response to selection. However, this hypothesis remains largely untested empirically. In this study, we investigate the evolutionary response of the multicomponent female sex pheromone blend of the moth Heliothis subflexa to 10 generations of artificial selection. We observed a selection response of about 3/4s of a phenotypic standard deviation in the components under selection. Interestingly, other pheromone components that are biochemically and genetically linked to the components under selection did not change. We also found that after the onset of selection, the genetic covariance structure diverged, resulting in the disassociation of components under selection and components not under selection across the first two genetic principle components. Our findings provide rare empirical support for an intriguing mechanism by which a sexual signal can respond to selection without possible constraints from indirect selection responses.
An unconventional GABAergic circuit differently controls pyramidal neuron activity in two visual cortical areas via endocannabinoids
Authors: Montmerle Martin , Koukouli Fani , Aguirre Andrea , Peixoto Jérémy , Choudhary Vikash , De Brito Van Velze Marcel , Varilh Marjorie , Julio-Kalajzic Francisca , Allene Camille , Mendéz Pablo , Marsicano Giovanni , Schlüter Oliver M. , Rebola Nelson , Bacci Alberto , Lourenço Joana 
Published: September 2021

SummaryPerisomatic inhibition of neocortical pyramidal neurons (PNs) coordinates cortical network activity during sensory processing, and it has been mainly attributed to parvalbumin-expressing basket cells (BCs). However, cannabinoid receptor type 1 (CB1)-expressing interneurons also inhibit the perisomatic region of PNs but the connectivity and function of these elusive – yet prominent – neocortical GABAergic cells is unknown. We found that the connectivity pattern of CB1-positive BCs strongly differs between primary and high-order cortical visual areas. Moreover, persistently active CB1 signaling suppresses GABA release from CB1 BCs in the medial secondary visual cortex (V2M), but not in the primary (V1) visual area. Accordingly, in vivo, tonic CB1 signaling is responsible for higher but less coordinated PN activity in V2M than in V1. Our results indicate a differential CB1-mediated mechanism controlling PN activity, and suggest an alternative connectivity schemes of a specific GABAergic circuit in different cortical areas
Unscheduled DNA replication in G1 causes genome instability through head-to-tail replication fork collisions
Authors: Reusswig Karl-Uwe , Bittmann Julia , Peritore Martina , Wierer Michael , Mann Matthias , Pfander Boris 
Published: September 2021

SummaryDNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineered genetic systems in budding yeast to induce unscheduled replication in the G1-phase of the cell cycle. Unscheduled G1 replication initiated at canonical S-phase origins across the genome. We quantified differences in replisomes in G1- and S-phase and identified firing factors, polymerase α, and histone supply as factors that limit replication outside S-phase. G1 replication per se did not trigger cellular checkpoints. Subsequent replication during S-phase, however, resulted in over-replication and led to chromosome breaks via head-to-tail replication fork collisions that are marked by chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA. Low-level, sporadic induction of G1 replication induced an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation by G1/S deregulation.
Enzyme Catalysis Enhances Lateral Lipid Motility and Directional Particle Transport on Membranes
Authors: Somasundar Ambika , Mandal Niladri Sekhar , Sen Ayusman 
Published: September 2021

AbstractThe dynamic interplay between the composition of lipid membranes and the behavior of membrane-bound enzymes is critical to the understanding of cellular function and viability, and the design of membrane-based biosensing platforms. While there is a significant body of knowledge on how lipid composition and dynamics affect membrane-bound enzymes, little is known about how enzyme catalysis influences the motility and lateral transport in lipid membranes. Using enzymes-attached lipids in supported bilayers (SLB), we show catalysis-induced enhanced lateral diffusion of lipids in the bilayer. Enhancing the membrane viscosity by increasing the cholesterol content in the bilayer suppresses the overall diffusion but not the relative diffusion enhancement of the enzyme-attached lipids. We also provide direct evidence of catalysis-induced membrane fluctuations leading to the enhanced diffusion of passive tracers resting on the SLB. Additionally, by using active enzyme patches, we demonstrate the directional transport of tracers on SLBs. These are first steps in understanding diffusion and transport in lipid membranes due to active, out-of-equilibrium processes that are the hallmark of living systems. In general, our study demonstrates how active enzymes can be used to control diffusion and transport in confined 2-D environments.
tascCODA: Bayesian tree-aggregated analysis of compositional amplicon and single-cell data
Authors: Ostner Johannes , Carcy Salomé , Müller Christian L. 
Published: September 2021

ABSTRACTAccurate generative statistical modeling of count data is of critical relevance for the analysis of biological datasets from high-throughput sequencing technologies. Important instances include the modeling of microbiome compositions from amplicon sequencing surveys and the analysis of cell type compositions derived from single-cell RNA sequencing. Microbial and cell type abundance data share remarkably similar statistical features, including their inherent compositionality and a natural hierarchical ordering of the individual components from taxonomic or cell lineage tree information, respectively. To this end, we introduce a Bayesian model fortree-aggregatedamplicon andsingle-cellcompositionaldataanalysis (tascCODA) that seamlessly integrates hierarchical information and experimental covariate data into the generative modeling of compositional count data. By combining latent parameters based on the tree structure with spike-and-slab Lasso penalization,tascCODAcan determine covariate effects across different levels of the population hierarchy in a data-driven parsimonious way. In the context of differential abundance testing, we validatetascCODA’s excellent performance on a comprehensive set of synthetic benchmark scenarios. Our analyses on human single-cell RNA-seq data from ulcerative colitis patients and amplicon data from patients with irritable bowel syndrome, respectively, identified aggregated cell type and taxon compositional changes that were more predictive and parsimonious than those proposed by other schemes. We posit that tascCODA1constitutes a valuable addition to the growing statistical toolbox for generative modeling and analysis of compositional changes in microbial or cell population data.
Iron promotes Slc7a11-deficient valvular interstitial cell osteogenic differentiation: A possible mechanism by which ferroptosis participates in intraleaflet hemorrhage-induced calcification
Authors: Xu Ran , Zhu Dan , Guo Jianghong , Huang Ying 
Published: September 2021

AbstractBackgroundCalcific aortic valve disease (CAVD) is the most frequent pathogeny of aortic valve replacement in developed countries. Iron deposits are found in the intraleaflet hemorrhage (IH) areas of calcific aortic valves. Ferroptosis is a form of regulated cell death that involves metabolic dysfunction resulting from iron overload-dependent excessive lipid peroxidation. In this research, we attempted to clarify the role of ferroptosis in CAVD.MethodsThe level of ferroptosis in tissue and valvular interstitial cells (VICs) was assessed by the contents of 4-HNE, NADPH, ROS, and GSH, lipid peroxidation and mitochondrial morphology. The levels of calcification, iron accumulation and Slc7a11 expression in surgical aortic valve specimens were detected by Alizarin red or Von Kossa, Perl’s blue and immunohistochemical staining. The osteogenic differentiation of VICs was assessed by PCR and western blot analyses. Furthermore, RNA sequencing was used to detect potential differentially expressed genes between normal and osteogenic medium-treated (OM-treated) VICs.ResultsOur experiments demonstrated that ferroptosis occurred in the IH areas of calcific aortic valves. We also found that Slc7a11 was expressed at low levels in OM-treated VICs and IH areas. Finally, we demonstrated that iron promoted Slc7a11-deficient VICs osteogenic differentiation by aggravating ferroptosis in vitro.ConclusionIn conclusion, iron promotes Slc7a11-deficient VIC osteogenic differentiation by aggravating ferroptosis in vitro, thereby accelerating the progression of aortic valve calcification.StatementStatements and opinions expressed in the articles and communications herein are those of the author(s) and not necessarily those of the Editor(s), Society, or publisher, and the Editor(s), Society, and publisher disclaim any responsibility or liability for such material.Brief SummaryIn this work, two novel notions have been proposed. First, we reported that ferroptosis participated in the progression of CAVD. Second, this is the first cytology experiment of valvular interstitial cells (VICs) to clarify the mechanism by which intraleaflet hemorrhage aggravates calve calcification. This research provides new ideas and targets for alleviating the progression of CAVD, especially in patients who have calcified aortic valves without severe stenosis.
CRISPR/Cas9 mediated editing of the Quorn fungus Fusarium venenatum A3/5 by transient expression of Cas9 and sgRNAs targeting endogenous marker gene PKS12
Authors: Wilson Fiona M , Harrison Richard J 
Published: September 2021

AbstractBackgroundGene editing using CRISPR/Cas9 is a widely used tool for precise gene modification, modulating gene expression and introducing novel proteins, and its use has been reported in a number of filamentous fungi including the genus Fusarium. The aim of this study was to optimise gene editing efficiency using AMA1 replicator vectors for transient expression of CRISPR constituents in Fusarium venenatum (A3/5), used commercially in the production of mycoprotein (Quorn™).ResultsWe present evidence of CRISPR/Cas9 mediated gene editing in Fusarium venenatum, by targeting the endogenous visible marker gene PKS12, which encodes a polyketide synthase responsible for the synthesis of the pigment aurofusarin. Constructs for expression of single guide RNAs (sgRNAs) were cloned into an AMA1 replicator vector incorporating a construct for constitutive expression of cas9 codon-optimised for Aspergillus niger or F. venenatum. Vectors were maintained under selection for transient expression of sgRNAs and cas9 in transformed protoplasts. 100% gene editing efficiency of protoplast-derived isolates was obtained using A. niger cas9 when sgRNA transcription was regulated by the F. venenatum 5SrRNA promoter. In comparison, expression of sgRNAs using a PgdpA-ribozyme construct was much less effective, generating mutant phenotypes in 0-40% of isolates, with evidence of off-target editing. Viable isolates were not obtained from protoplasts transformed with an AMA1 vector expressing cas9 codon-optimised for F. venenatum.ConclusionsUsing an AMA1 replicator vector for transient expression of A. niger cas9 and sgRNAs transcribed from the native 5SrRNA promoter, we demonstrate efficient gene editing of an endogenous marker gene in F. venenatum, resulting in knockout of gene function and a visible mutant phenotype in 100% of isolates. This establishes a platform for further development of CRISPR/Cas technology in F. venenatum, such as modulation of gene expression, gene insertion, base editing and prime editing. These tools will facilitate an understanding of the controls of secondary metabolism and hyphal development during fermentation of F. venenatum for mycoprotein production and may be used to validate prototypes of strains for improvement using classical means, enabling more cost-effective and sustainable production of this industrially important fungus.
Patterns of selection in the evolution of a transposable element
Authors: Dazenière Julie , Bousios Alexandros , Eyre-Walker Adam 
Published: September 2021

AbstractTransposable elements (TEs) are a major component of most eukaryotic genomes. Here, we present a new approach which allows us to study patterns of natural selection in the evolution of TEs over short time scales. The method uses the alignment of all elements with intact gag/pol genes of a TE family from a single genome. We predict that the ratio of non-synonymous to synonymous variants (vN/vS) in the alignment should decrease as a function of the frequency of the variants, because elements with non-synonymous variants that reduce transposition will have fewer progeny. We apply our method to Sirevirus LTR retrotransposons that are abundant in maize and other plant species and show that vN/vS declines as variant frequency increases, indicating that negative selection is acting strongly on the Sirevirus genome. The asymptotic value of vN/vS suggests that at least 85% of all non-synonymous mutations in the TE reduce transposition. Crucially, these patterns in vN/vS are only predicted to occur if the gene products from a particular TE insertion preferentially promote the transposition of the same insertion. Overall, this study is the first to use large numbers of intact elements to shed new light on the selective processes that act on TEs.
Simulations on the efficacy of radiotherapy with different time schemes of antiangiogenic therapy
Authors: Tuzer Mert , Yilmaz Defne , Unlu Mehmet Burcin 
Published: September 2021

ABSTRACTThe combination of radiotherapy and antiangiogenic agents has been suggested to be potent in tumor growth control compared to the application of antiangiogenic therapy or radiotherapy alone. Since radiotherapy is highly dependent on the oxygen level of the tumor area, antiangiogenic agents are utilized for the reoxygenation of tumor vasculature. We present a mathematical framework to investigate the efficacy of radiotherapy combined with antiangiogenic treatment. The framework consists of tumor cells, vasculature, and oxygenation levels evolving with time to mimic a tumor microenvironment. Non-linear partial differential equations (PDEs) are employed to simulate each component of the framework. Different treatment schemes are investigated to see the changes in tumor growth and oxygenation. To test combination schedules, radiation monotherapy, neoadjuvant, adjuvant, and concurrent cases are simulated. The efficiency of each therapy scheme on tumor growth control, the changes in tumor cell density, and oxygen levels shared by tumor cells are represented. The simulation results indicate that the application of radiotherapy after antiangiogenic treatment is more efficient in tumor growth control compared to other therapy schemes. The present study gives an insight into the possible interaction and timing of the combination of radiotherapy and antiangiogenic drug treatment.
A DCL3 dicing code within Pol IV-RDR2 transcripts diversifies the siRNA pool guiding RNA-directed DNA methylation
Authors: Loffer Andrew , Singh Jasleen , Fukudome Akihito , Mishra Vibhor , Wang Feng , Pikaard Craig S. 
Published: September 2021

SummaryIn plants, selfish genetic elements including retrotransposons and DNA viruses are transcriptionally silenced by RNA-directed DNA methylation. Guiding the process are short interfering RNAs (siRNAs) cut by DICER-LIKE 3 (DCL3) from double-stranded precursors of ∼30 bp synthesized by NUCLEAR RNA POLYMERASE IV (Pol IV) and RNA-DEPENDENT RNA POLYMERASE 2 (RDR2). We show that Pol IV initiating nucleotide choice, RDR2 initiation 1-2 nt internal to Pol IV transcript ends and RDR2 terminal transferase activity collectively yield a code that influences which end of the precursor is diced and whether 24 or 23 nt siRNAs are generated from the Pol IV or RDR2-transcribed strands. By diversifying the size, sequence, and strand polarity of siRNAs derived from a given precursor, alternative patterns of DCL3 dicing allow maximal siRNA coverage at methylated target loci.
Spatial modeling of extinct Southeast Asian Hobbit Homo floresiensis habitat suitability based on its diet availability and climatic parameters as a proxy
Authors: Wibowo Andri 
Published: September 2021

AbstractThe discovery of a new prehistoric species of the genus Homo remains a significant matter of intense interest. One of significant discovery recently is the Homo floresiensis, representing a small-bodied and small-brained hominin, excavated, and found in Liang Bua Cave in Flores Island, East Nusa Tenggara, Indonesia. This species height was only about 106 cm (3’6“) and the weight was 30-40 kg (66-86 lbs). H. floresiensis was known consumed extant murine rodents as its diets as this was evidence found in Liang Bua Cave. Then this study aims to model the H. floresiensis suitable habitat using maximum entropy method and 2 extant murine rodents, Rattus exulans and R. rattus as a proxy. The results show that the most suitable habitats for H. floresiensis indicated by suitable habitat values close to 1 were concentrated in the central of Flores Island that was overlapped with mountainous areas with elevation ranging from 1500 to 2000 m. These suitable habitats were also overlapped with dense vegetation covers, volcanic rock, and Kiro rock formation. Climatic parameters that limit the distributions of H. floresiensis were annual mean temperature, isothermality, minimum temperature of coldest period, and precipitation seasonality. Parts of Flores Island with the low temperature below 20 °C were favorable for H. floresiensis while an increase in isothermality limits the H. floresiensis distributions.
Reduced metabolic activity in established Gardnerella spp. biofilms contributes to protection from the bactericidal effects of metronidazole
Authors: Khan Salahuddin , Hill Janet E. 
Published: September 2021

AbstractGardnerella spp. can form biofilm and it has been suggested that failure of antibiotic treatment of bacterial vaginosis and recurrent vaginosis are linked to this property, however no specific mechanisms have been identified. Here, we performed broth microdilution assays to measure the minimum inhibitory concentration (MIC) of metronidazole for thirty-five Gardnerella isolates in one medium in which Gardnerella spp. grow primarily as biofilm and another in which growth is primarily planktonic. The MIC of isolates in the two conditions were highly correlated (R2= 0.69, p <0.001). No significant reduction in viable cell count of 7/9 isolates was observed when established biofilms were exposed to metronidazole at levels double the MIC. Subsequent measurements of metabolic activity in established biofilms formed by a larger collection of 31 isolates showed reduced metabolic activity following treatment with 128 μg/ml of metronidazole relative to untreated controls in 27/31 cases. The amount of biofilm produced by Gardnerella isolates was not enhanced by metronidazole exposure, even at sub-MIC levels. Our results suggest that reduced metabolic activity in Gardnerella spp. growing in established biofilms may be a mechanism of protection from the bactericidal effects of metronidazole.