bluuebunny/crossref_metadata_2025 huggingface dataset:
Definition, modeling and detection of saccades in the face of post-saccadic oscillations
Authors: Schweitzer Richard , Rolfs Martin
Published: March 2021

When analyzing eye tracking data, one of the central tasks is the detection of saccades. Although many automatic saccade detection algorithms exist, the field still debates how to deal with brief periods of instability around saccade offset, so-called post-saccadic oscillations (PSOs), which are especially prominent in today’s widely used video-based eye tracking techniques. There is good evidence that PSOs are caused by inertial forces that act on the elastic components of the eye, such as the iris or the lens. As this relative movement can greatly distort estimates of saccade metrics, especially saccade duration and peak velocity, video-based eye tracking has recurrently been considered unsuitable for measuring saccade kinematics. In this chapter, we review recent biophysical models that describe the relationship between pupil motion and eyeball motion. We found that these models were well capable of accurately reproducing saccade trajectories and implemented a framework for the simulation of saccades, PSOs, and fixations, which can be used – just like datasets hand-labelled by human experts – to evaluate detection algorithms and train statistical models. Moreover, as only pupil and corneal-reflection signals are observable in video-based eye tracking, one may also be able to use these models to predict the unobservable motion of the eyeball. Testing these predictions by analyzing saccade data that was registered with video-based and search-coil eye tracking techniques revealed strong relationships between the two types of measurements, especially when saccade offset is defined as the onset of the PSO. To enable eye tracking researchers to make use of this definition, we present and evaluate two novel algorithms – one based on eye-movement direction inversion, one based on linear classifiers previously trained on simulation data. These algorithms allow for the detection of PSO onset with high fidelity. Even though PSOs may still pose problems for a range of eye tracking applications, the techniques described here may help to alleviate these.
Building alternative consensus trees and supertrees usingk-means and Robinson and Foulds distance
Authors: Tahiri Nadia , Fichet Bernard , Makarenkov Vladimir
Published: March 2021

Each gene has its own evolutionary history which can substantially differ from the evolutionary histories of other genes. For example, some individual genes or operons can be affected by specific horizontal gene transfer and recombination events. Thus, the evolutionary history of each gene should be represented by its own phylogenetic tree which may display different evolutionary patterns from the species tree that accounts for the main patterns of vertical descent. The output of traditional consensus tree or supertree inference methods is a unique consensus tree or supertree. Here, we describe a new efficient method for inferring multiple alternative consensus trees and supertrees to best represent the most important evolutionary patterns of a given set of phylogenetic trees (i.e. additive trees orX-trees). We show how a specific version of the populark-means clustering algorithm, based on some interesting properties of the Robinson and Foulds topological distance, can be used to partition a given set of trees into one (when the data are homogeneous) or multiple (when the data are heterogeneous) cluster(s) of trees. We adapt the popular Caliński-Harabasz, Silhouette, Ball and Hall, and Gap cluster validity indices to tree clustering withk-means. A special attention is paid to the relevant but very challenging problem of inferring alternative supertrees, built from phylogenies constructed for different, but mutually overlapping, sets of taxa. The use of the Euclidean approximation in the objective function of the method makes it faster than the existing tree clustering techniques, and thus perfectly suitable for the analysis of large genomic datasets. In this study, we apply it to discover alternative supertrees characterizing the main patterns of evolution of SARS-CoV-2 and the related betacoronaviruses.
Tradeoffs for a viral mutant with enhanced replication speed
Authors: Lanahan Matthew R. , Pfeiffer Julie K.
Published: March 2021

RNA viruses exist as genetically heterogeneous populations due to high mutation rates and many of these mutations reduce fitness and/or replication speed. However, it is unknown whether mutations can increase replication speed of a virus already well adapted to replication in cultured cells. By sequentially passaging coxsackievirus B3 in cultured cells and collecting the very earliest progeny, we selected for increased replication speed. We found that a single mutation in a viral capsid protein, VP1-F106L, was sufficient for the fast-replication phenotype. Characterization of this mutant revealed quicker genome release during entry compared to wild-type virus, highlighting a previously unappreciated infection barrier. However, this mutation also reduced capsid stabilityin vitroand reduced replication and pathogenesis in mice. These results reveal a tradeoff between overall replication speed and fitness. Importantly, this approach— selecting for the earliest viral progeny—could be applied to a variety of viral systems and has the potential to reveal unanticipated inefficiencies in viral replication cycles.

Significance

Viruses have characteristic replication speeds within a given cell type. Many factors can slow the rate of viral replication, including attenuating mutations and host antiviral responses. However, it has been unclear whether it would be possible to “speed up” a virus that already replicates efficiently in a specific cell type. Here, we selected for a mutant coxsackievirus with enhanced replication speed by sequentially harvesting the very earliest progeny in multiple rounds of selection. A single mutation conferred the fast replication phenotype. While this mutant virus has enhanced replication in cultured cells due to faster genome uncoating, it was attenuated in mice. These results highlight selective pressures that shape viral populations in different environments.
Lateralized deficits in arousal processing after insula lesions: behavioral and autonomic evidence
Authors: Holtmann Olga , Franz Marcel , Moenig Constanze , Tenberge Jan-Gerd , Schloßmacher Insa , Ivanova Iskrena , Preul Christoph , Schwindt Wolfram , Melzer Nico , Miltner Wolfgang H.R. , Straube Thomas
Published: March 2021

A large body of evidence ascribes a pivotal role in emotion processing to the insular cortex. However, the complex structure and lateralization of emotional deficits following insular damage are not understood. Here, we investigated emotional ratings of valence and arousal and skin conductance responses (SCR) to a graded series of emotionally arousing scenes in patients with left (n= 10) or right (n= 9) insular damage and in healthy controls (n= 18). We found a significant reduction in overall SCRs, arousal ratings and valence extremity scores in right-lesioned patients, as compared to left-lesioned patients and healthy controls. Additional analyses of correlations between subjective arousal ratings resp. SCR and normative arousal ratings revealed that both lesion groups had evaluative and physiological difficulties to discover changes in stimulus arousal. Although no group differences emerged on overall ratings of valence, analysis of correlations between subjective and normative valence ratings displayed markedly reduced accuracy in right-lesioned patients, as compared to left-lesioned patients and healthy controls. Our findings support the hypothesis that the left and right insulae subserve different functions in emotion processing, potentially due to asymmetrical representations of autonomic information in the left and right human forebrain. The right insula may serve as integral node for sympathetic arousal and cognitive affective processing.
Development of an integrated structural biology platform specialized for sub-100 kDa protein complexes to support biologics discovery and rational engineering
Authors: Iozzo Yuri , Qiu Yu , Xu Albert , Park Anna , Wendt Maria , Zhou Yanfeng
Published: March 2021

Developing a biologic medicine requires successful decision making at each step of selection, optimization, and/or combination of the right candidates at early research stages. Knowing the structural information and binding pattern between drug target and discovery candidates greatly increases the possibility of success. With the cryo-EM resolution revolution and rapid development of computational software, we have evaluated and integrated different tools in structural biology and the computation field and established a highly cost-effective platform, which allows us to obtain fast and accurate structural information for biologics projects with a close to 100% success rate and as fast as weeks turn-around time. Here we report four case studies selected from over 40 different protein structures and share how we integrate cryo-EM structure determination, computational structure modeling, and molecular dynamics simulation. With proper decision making and strategic planning, the platform allows us to obtain quality results within days to weeks, including sub-100 kDa complexes which are usually considered as a challenge due to their small size. Our utilization of this differential approach and use of multiple software packages, allows to manage priorities and resources to achieve goals quickly and efficiently. We demonstrate how to effectively overcome particle orientation bias by altering complex composition. In several of our examples, we use glycan density to facilitate interpretation of low-resolution 3D reconstruction and epitope mapping. Protein information plays an important role in our cryo-EM projects, especially in cases where we see significant challenges in obtaining high-resolution 3D maps.
Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation
Authors: Orlowska Karina , Fling Russ R. , Nault Rance , Sink Warren J. , Schilmiller Anthony L. , Zacharewski Tim
Published: March 2021

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which induces diverse biological and toxic effects, including the reprograming of intermediate metabolism, mediated by the aryl hydrocarbon receptor (AHR). Targeted LC-MS analysis of hepatic extracts from mice gavaged with TCDD every 4 days for 28 days detected an increase in S-(2-carboxyethyl)-L-cysteine, a conjugate produced following the spontaneous reaction between the sulfhydryl group of cysteine and highly reactive acrylyl-CoA, an intermediate in the cobalamin (Cbl)-independent β–oxidation-like metabolism of propionyl-CoA. In addition to repressing genes in both the canonical Cbl-dependent carboxylase and the alternate Cbl-independent β–oxidation-like pathways at 30 μg/kg TCDD, methylmalonyl-CoA mutase (MUT) activity was inhibited at lower doses. Moreover, TCDD decreased serum Cbl levels and hepatic cobalt levels while eliciting negligible effects on gene expression associated with Cbl absorption, transport, trafficking, or the derivatization to 5’-deoxy-adenosylcobalamin (AdoCbl), the required MUT cofactor. In addition to inducingAcod1that encodes for aconitate decarboxylase 1, the enzyme responsible for the decarboxylation cis-aconitate to itaconate, TCDD also dose-dependently increased itaconate levels in hepatic extracts. MUT inhibition is consistent with itaconate activation to itaconyl-CoA, a MUT suicide inactivator that adducts AdoCbl, that in turn, inhibits MUT activity and reduces Cbl levels. Collectively, these results suggest the decrease in MUT activity is due to Cbl depletion following TCDD treatment that redirected propionyl-CoA metabolism to the alternate Cbl-independent β–oxidation-like pathway. The resulting hepatic accumulation of acrylyl-CoA likely contributes to TCDD-elicited hepatotoxicity and the multi-hit progression of steatosis to steatohepatitis with fibrosis.
PyDamage: automated ancient damage identification and estimation for contigs in ancient DNAde novoassembly
Authors: Borry Maxime , Hübner Alexander , Rohrlach A.B. , Warinner Christina
Published: March 2021

DNAde novoassembly can be used to reconstruct longer stretches of DNA (contigs), including genes and even genomes, from short DNA sequencing reads. Applying this technique to metagenomic data derived from archaeological remains, such as paleofeces and dental calculus, we can investigate past microbiome functional diversity that may be absent or underrepresented in the modern microbiome gene catalogue. However, compared to modern samples, ancient samples are often burdened with environmental contamination, resulting in metagenomic datasets that represent mixtures of ancient and modern DNA. The ability to rapidly and reliably establish the authenticity and integrity of ancient samples is essential for ancient DNA studies, and the ability to distinguish between ancient and modern sequences is particularly important for ancient microbiome studies. Characteristic patterns of ancient DNA damage, namely DNA fragmentation and cytosine deamination (observed as C-to-T transitions) are typically used to authenticate ancient samples and sequences. However, existing tools for inspecting and filtering aDNA damage either compute it at the read level, which leads to high data loss and lower quality when used in combination with de novo assembly, or require manual inspection, which is impractical for ancient assemblies that typically contain tens to hundreds of thousands of contigs. To address these challenges, we designed PyDamage, a robust, automated approach for aDNA damage estimation and authentication ofde novoassembled aDNA. PyDamage uses a likelihood ratio based approach to discriminate between truly ancient contigs and contigs originating from modern contamination. We test PyDamage on both simulated, and empirical aDNA data from archaeological paleofeces, and we demonstrate its ability to reliably and automatically identify contigs bearing DNA damage characteristic of aDNA. Coupled with aDNAde novoassembly, PyDamage opens up new doors to explore functional diversity in ancient metagenomic datasets.
The Hippo pathway transcriptional co-activator YAP is involved in head regeneration and bud development inHydra
Authors: Unni Manu , Reddy Puli Chandramouli , Galande Sanjeev
Published: March 2021

The Hippo signaling pathway has been shown to be involved in the regulation of cellular identity, cell/tissue size maintenance and mechanotransduction. The Hippo pathway consists of a kinase cascade which determines the nucleo-cytoplasmic localization of YAP in the cell. YAP is the effector protein in the Hippo pathway which acts as a transcriptional cofactor for TEAD. Phosphorylation of YAP upon activation of the Hippo pathway prevents it from entering the nucleus and hence abrogates its function in transcription of target genes. In Cnidaria, the information on the regulatory roles of the Hippo pathway is virtually lacking. Here, we report for the first time the existence of a complete set of Hippo pathway core components inHydra. By studying their phylogeny and domain organization, we report evolutionary conservation of the components of the Hippo pathway. Protein modelling suggested conservation of YAP-TEAD interaction inHydra. We also characterized the expression pattern of the homologs ofyap, hippo, mobandsavinHydrausing whole mount RNA in situ hybridization and report their possible role in stem cell maintenance. Immunofluorescence assay revealed thatHvul_YAP expressing cells occur in clusters in the body column and are excluded in the terminally differentiated regions. The YAP expressing cells are recruited early during head regeneration and budding implicating the Hippo pathway in early response to injury or establishment of oral fate. These cells exhibit a non-clustered existence at the site of regeneration and budding, indicating the involvement of a new population of YAP expressing cells during oral fate specification. Collectively, we posit that the Hippo pathway is an important signaling system inHydra, its components are ubiquitously expressed in theHydrabody column, and may play crucial role inHydraoral fate specification.
Weak effect ofGypsyretrotransposon bursts onSonneratia albasalt stress gene expression
Authors: Wang Yushuai , Dai Aimei , Tang Tian
Published: March 2021

Background and Aims

Transposable elements (TEs) are an important source of genetic diversity and can be co-opted for the regulation of host genes. However, to what extent the pervasive TE colonization of plant genomes has contributed to stress adaptation remains controversial. Plants inhabiting harsh environments in nature provide a unique opportunity to answer this question.

Methods

We compared TE compositions and their evolutionary dynamics in the genomes of two mangrove species: the pioneerSonneratia albaand its less salt-tolerant relativeS. caseolaris. Age distribution, strength of purifying selection and the removal rate of LTR (long terminal repeat) retrotransposons were estimated. Phylogenetic analysis of LTR retrotransposons and their distribution in the genome ofS. albawere surveyed. Small RNA sequencing and whole-genome bisulfite sequencing was conducted using leaves ofS. alba. Expression pattern of LTR retrotransposons and their nearby genes were examined using RNA-seq data ofS. albaunder different salt treatments.

Key Results

S. albapossesses more TEs thanS. caseolaris. Particularly, many more youngGypsyLTR retrotransposons have accumulated inS. albathan inS. caseolarisdespite an increase in purifying selection against TE insertions. The top two most abundantGypsyfamilies inS. albapreferentially insert in gene-poor regions. They are under relaxed epigenetic repression, probably due to the presence of CHROMO domains in their 3’-ends. Although a considerable number of TEs inS. albashowed differential expression under salt stress, only four copies were significantly correlated with their nearby genes in expression levels. One such TE-gene pair involvesAbscisic acid 8’-hydroxylase 3functioning in abscisic acid catabolism.

Conclusions

This study sheds light on the evolutionary dynamics and potential function of TEs in an extremophile. Our results suggest that the conclusion on co-option of TEs should be cautious even though activation of TEs by stress might be prevalent.
Computational prediction of the effect of amino acid changes on the binding affinity between SARS-CoV-2 spike protein and the human ACE2 receptor
Authors: Chen Chen , Boorla Veda Sheersh , Banerjee Deepro , Chowdhury Ratul , Cavener Victoria S , Nissly Ruth H , Gontu Abhinay , Boyle Nina R , Vandergrift Kurt , Nair Meera Surendran , Kuchipudi Suresh V , Maranas Costas D.
Published: March 2021

The association of the receptor binding domain (RBD) of SARS-CoV-2 viral spike with human angiotensin converting enzyme (hACE2) represents the first required step for viral entry. Amino acid changes in the RBD have been implicated with increased infectivity and potential for immune evasion. Reliably predicting the effect of amino acid changes in the ability of the RBD to interact more strongly with the hACE2 receptor can help assess the public health implications and the potential for spillover and adaptation into other animals. Here, we introduce a two-step framework that first relies on 48 independent 4-ns molecular dynamics (MD) trajectories of RBD-hACE2 variants to collect binding energy terms decomposed into Coulombic, covalent, van der Waals, lipophilic, generalized Born electrostatic solvation, hydrogen-bonding, π-π packing and self-contact correction terms. The second step implements a neural network to classify and quantitatively predict binding affinity using the decomposed energy terms as descriptors. The computational base achieves an accuracy of 82.2% in terms of correctly classifying single amino-acid substitution variants of the RBD as worsening or improving binding affinity for hACE2 and a correlation coefficient r of 0.69 between predicted and experimentally calculated binding affinities. Both metrics are calculated using a 5-fold cross validation test. Our method thus sets up a framework for effectively screening binding affinity change with unknown single and multiple amino-acid changes. This can be a very valuable tool to predict host adaptation and zoonotic spillover of current and future SARS-CoV-2 variants.
Neurogenesis mediated plasticity is associated with reduced neuronal activity in CA1 during context fear memory retrieval
Authors: Evans Alexandria , Terstege Dylan J. , Scott Gavin A. , Tsutsui Mio , Epp Jonathan R.
Published: March 2021

Adult hippocampal neurogenesis has been demonstrated to affect learning and memory in numerous ways. Several studies have now demonstrated that increased neurogenesis can induce forgetting of memories acquired prior to the manipulation of neurogenesis and, as a result of this forgetting can also facilitate new learning. However, the mechanisms mediating neurogenesis-induced forgetting are not well understood. Here, we used a subregion-based analysis of the immediate early gene c-Fos as well as in vivo fiber photometry to determine changes in activity corresponding with neurogenesis induced forgetting. We found that increasing neurogenesis led to reduced CA1 activity during context memory retrieval. We also demonstrate here that perineuronal net expression in areas CA1 is bidirectionally altered by the levels or activity of adult generated neurons in the dentate gyrus. These results suggest that neurogenesis may induce forgetting by disrupting perineuronal nets in CA1 which may otherwise protect memories from degradation.
Biofilm-forming capacity of Escherichia coli isolated from cattle and beef packing plants: relation to virulence attributes, stage of processing, antimicrobial interventions, and heat tolerance
Authors: Stanford Kim , Tran Frances , Zhang Peipei , Yang Xianqin
Published: March 2021

Despite the importance of biofilm formation in contamination of meat by pathogenic Escherichia coli at slaughter plants, drivers for biofilm have been unclear. To identify selection pressures for biofilm, we evaluated 745 ‘Top 7’ from cattle and 700 generic E. coli from two beef slaughter plants for motility, expression of curli and cellulose, and biofilm-forming potential. Top 7 were also screened for serogroup, stx1, stx2, eae and rpoS. Generic E. coli were compared by source (hide of carcass, hide-off carcass, processing equipment) before and after implementation of antimicrobial hurdles. The proportion of E. coli capable of forming biofilms was lowest (7.1%; P < 0.05) for cattle isolates and highest (87.3%; P < 0.05) from equipment. Only one enterohemorrhagic E. coli (EHEC) was an extremely-strong biofilm-former, in contrast to 73.4% of E. coli from equipment. Isolates from equipment after sanitation had a greater biofilm-forming capacity (P < 0.001) than those before sanitation. Most Top 7 were motile and expressed curli, although these traits along with expression of cellulose and presence of rpoS were not necessary for biofilm formation. In contrast, isolates capable of forming biofilms on equipment were almost exclusively motile and able to express curli. Results of the present study indicate that cattle would rarely carry EHEC capable of making strong biofilms to slaughter plants. However, if biofilm-forming EHEC contaminated equipment, current antimicrobial hurdles would inadvertently perpetuate the most robust biofilm-forming strains. Accordingly, new and effective anti-biofilm hurdles are required for meat-processing equipment, to reduce future instances of food-borne disease.

Importance

As the majority of enterohemorrhagic E. coli (EHEC) are not capable of forming biofilms, sources were undetermined of the biofilm-forming EHEC isolated from ‘high-event periods’ in beef slaughter plants. This study demonstrated that sanitation procedures used on beef-processing equipment inadvertently select for survival of the most robust biofilm-forming strains of E. coli. Cattle only rarely carry EHEC capable of forming strong biofilms (1/745 isolates evaluated), but sanitation of equipment markedly increased (P < 0.001) biofilm-forming capacity of E. coli. In contrast, chilling carcasses for 3 days at 0°C reduced (P < 0.05) biofilm-forming capacity of E. coli. Consequently, an additional anti-biofilm hurdle for meat-processing equipment, perhaps involving cold exposure, is necessary to further reduce the risk of food-borne disease.
Neural circuitry for maternal oxytocin release induced by infant cries
Authors: Valtcheva Silvana , Issa Habon A. , Bair-Marshall Chloe J. , Martin Kathleen A. , Jung Kanghoon , Zhang Yiyao , Kwon Hyung-Bae , Froemke Robert C.
Published: March 2021

Oxytocin is a neuropeptide important for maternal physiology and childcare, including parturition and milk ejection during nursing1–8. Suckling triggers oxytocin release, but other sensory cues- specifically infant cries- can elevate oxytocin levels in new human mothers9–11indicating that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit routing auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not pure tones, via input from the posterior intralaminar thalamus, and repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behavior in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.
Identifying Brain Regions Related to Word Prediction During Listening to Japanese Speech by Combining a LSTM Language Model and MEG
Authors: Takahashi Yuta , Oseki Yohei , Sakai Hiromu , Makuuchi Michiru , Osu Rieko
Published: March 2021

Recently, a neuroscientific approach has revealed that humans understand language while subconsciously predicting the next word from the preceding context. Most studies on human word prediction have investigated the correlations between brain activity while reading or listening to sentences on functional magnetic resonance imaging (fMRI) and the predictive difficulty of each word in a sentence calculated by the N-gram language model. However, because of its low temporal resolution, fMRI is not optimal for identifying the changes in brain activity that accompany language comprehension. In addition, the N-gram language model is a simple computational structure that does not account for the structure of the human brain. Furthermore, it is necessary for humans to retain information prior to the N-1 word in order to form a contextual understanding of a presented story. Therefore, in the present study, we measured brain activity using magnetoencephalography (MEG), which has a higher temporal resolution than fMRI, and calculated the prediction difficulty of words using a long short-term memory language model (LSTMLM), which is based on a neural network inspired by the structure of the human brain and has longer information retention than the N-gram language model. We then identified the brain regions involved in language prediction during Japanese-language speech listening using encoding and decoding analyses. In addition to surprisal-related regions revealed in previous studies, such as the superior temporal gyrus, fusiform gyrus, and temporal pole, we also found relationships between surprisal and brain activity in other regions, including the insula, superior temporal sulcus, and middle temporal gyrus, which are believed to be involved in longer-term, sentence-level cognitive processing.
Effect of temperature and loading frequency on the performance of vertical subsurface flow constructed wetlands: Modelling study using HYDRUS
Authors: Jayswal Nikita , Rodríguez Jorge
Published: March 2021

Constructed wetlands are used in wastewater treatment for the removal of organic matter, nutrients, pathogens and other pollutants from water. The diversity of chemical, physical and biological processes taking place inside constructed wetlands (CWs) make them difficult systems for accurate quantitative description through conventional modelling approaches. However, existing modelling tools can bring valuable insight into important phenomena and interactions that might remain otherwise neglected. In this study the CW2D module under HYDRUS – 2D is used to identify the possible mechanisms by which temperature and loading frequency impacts the performance of the vertical subsurface flow constructed wetlands (VSSFCWs). An improvement on CWs design and operation guidelines in warm regions is intended. Case studies of a VSSFCW at 10°C, 20°C and 30°C treating septic tank effluent are simulated with parameters adjusted for high temperature conditions. The simulation results suggest oxygen limitation as possibly constraining nitrification capacity at high temperatures. Simulations also suggest that higher loading frequencies enhance performance and capacity. This detailed mechanistic modelling study aims at bringing insight into possible non trivial interactions and mechanisms in CWs such that in conjunction with a necessary experimental validation, should lead to enhanced operation and design in warm regions.
Lotka-Volterra Equations in the Presence of Mimicry
Authors: Enaganti Inavamsi , Mishra Bud
Published: March 2021

This paper studies a novel framework for understanding toxicity and nutritional value of a prey to a predator with utility. Furthermore, it introduces a novel notion of prey mimicry in a multi predator - multi prey system. In addition, the paper also analyzes the dynamics and the stability of equilibrium that arise as a result of the one or more predators’ inability to distinguish between certain prey. The paper is motivated by the mimicry in the context of adversarial chase involved in the evolution of multiple viral variants in the presence of multiple vaccines – possibly, in a population stratified by a diverse HLA background.
The Nestin neural enhancer is essential for normal levels of endogenous Nestin in neuroprogenitors but is not required for embryo development
Authors: Thomson Ella , Dawson Ruby , H’ng Chee Ho , Adikusuma Fatwa , Piltz Sandra , Thomas Paul Q
Published: March 2021

Enhancers are vitally important during embryonic development to control the spatial and temporal expression of genes. Recently, large scale genome projects have identified a vast number of putative developmental regulatory elements. However, the proportion of these that have been functionally assessed is relatively low. While enhancers have traditionally been studied using reporter assays, this approach does not characterise their contribution to endogenous gene expression. We have studied the murine Nestin (Nes)intron 2 enhancer, which is widely used to direct exogenous gene expression within neural progenitor cells in cultured cells andin vivo. We generated CRISPR deletions of the enhancer region in mice and assessed their impact onNesexpression during embryonic development. Loss of theNesneural enhancer significantly reducedNesexpression in the developing CNS by as much as 82%. By assessing NES protein localization, we also show that this enhancer region contains repressor element(s) that inhibitNesexpression within the vasculature. Previous reports have stated thatNesis an essential gene, and its loss causes embryonic lethality. We also generated 2 independentNesnull lines and show that both develop without any obvious phenotypic effects. Finally, through crossing of null and enhancer deletion mice we provide evidence oftrans-chromosomal interaction of theNesenhancer and promoter.
Astrocytes render memory flexible
Authors: Koh Wuhyun , Park Mijeong , Chun Ye Eun , Lee Jaekwang , Shim Hyun Soo , Park Mingu Gordon , Kim Sunpil , Kang Hyunji , Oh Soo-Jin , Woo Junsung , Chun Heejung , Lee Seungeun , Hong Jinpyo , Feng Jiesi , Li Yulong , Ryu Hoon , Cho Jeiwon , Lee C. Justin
Published: March 2021

Cognitive flexibility is an essential ability to adapt to changing environment and circumstances. NMDAR has long been implicated in cognitive flexibility, but the precise molecular and cellular mechanism is not well understood. Here, we report that astrocytes regulate NMDAR tone through Best1-mediated glutamate and D-serine release, which is critical for cognitive flexibility. Co-release of D-serine and glutamate is required for not only homosynaptic LTD but also heterosynaptic LTD, which is induced at unstimulated synapses upon release of norepinephrine and activation of astrocytic α1-AR during homosynaptic LTP. Remarkably, heterosynaptic LTD at unstimulated synapses during memory acquisition is required for later repotentiation LTP during reversal learning, laying a foundation for flexible memory and cognitive flexibility. Our study sheds light on the pivotal role of astrocytes in orchestrating multiple synapses during memory formation and determining the fate of consolidated memory to be retained as a flexible memory.

Highlights

Astrocytes regulate NMDAR tone via Best1-mediated glutamate and D-serine release

Activation of astrocytic α1-AR induces heterosynaptic LTD via NMDAR tone

Heterosynaptic LTD is required for repotentiation LTP and spatial reversal learning

Astrocytic regulation of NMDAR tone is critical for metaplasticity and flexible memory
Spatiotemporal patterns in Golden-cheeked Warbler breeding habitat quality and quantity
Authors: Dreiss Lindsay M. , Sanchez-Navarro Paul , Bird Bryan
Published: March 2021

The Golden-cheeked Warbler,Setophaga chrysoparia, is a migratory songbird listed as endangered under the federal Endangered Species Act that breeds exclusively in central Texas and is heavily impacted by habitat conversion. The species relies on mixed Ashe-juniper and oak woodlands for nest-building and shelter during spring and early summer months. Using land cover data spanning the last 25 years, we conduct a geospatial analysis to quantify changes and\ identify shifts in breeding habitat quantity and quality. Since 1985, 13% of all forests within the warbler’s breeding range were disturbed, with greater incidences near San Antonio (32%) and Austin (24%) metropolitan areas. Additionally, data show a 45% decrease in high-quality habitat (i.e., intact mixed or evergreen core forests) and a decrease in patch size. Habitats within protected areas see a less sharp decline in habitat quality and large increases in warbler sightings, but these only represent 10% of all highest-quality habitat in the breeding range. Drastic declines in habitat quality suggest that generalized metrics of conversion may underestimate true habitat loss as degradation may impact the ecological viability of remaining forests for warbler nesting. Further evidence suggests that the few protected areas within the Texas range continue to play a significant role in warbler breeding. This information will assist researchers and managers prioritizing conservation action and will inform upcoming species status determinations.
Unsupervised temporal consistency improvement for microscopy video segmentation with Siamese networks
Authors: Shabanov Akhmedkhan , Schichler Daja , Pape Constantin , Cuylen-Haering Sara , Kreshuk Anna
Published: March 2021

We introduce a simple mechanism by which a CNN trained to perform semantic segmentation of individual images can be re-trained - with no additional annotations - to improve its performance for segmentation of videos. We put the segmentation CNN in a Siamese setup with shared weights and train both for segmentation accuracy on annotated images and for segmentation similarity on unlabelled consecutive video frames. Our main application is live microscopy imaging of membrane-less organelles where the fluorescent groundtruth for virtual staining can only be acquired for individual frames. The method is directly applicable to other microscopy modalities, as we demonstrate by experiments on the Cell Segmentation Benchmark. Our code is available athttps://github.com/kreshuklab/learning-temporal-consistency.
The influence of sex, hormone status, and growth rate on dietary isotope fractionation: a case study with laboratory rats
Authors: Kim Sora L. , Jones Caroline , Santollo Jessica
Published: March 2021

Stable isotope analysis is increasingly used to discern ecological differences within and among species, especially those difficult to observe. In applied ecological studies, variations in stable isotope composition are often attributed to foraging behavior or trophic ecology rather than fractionation during metabolic processes. One physiological difference among individuals is gonadal hormone levels, which affects food intake, metabolism, and locomotor activity. However, it is unclear how these effects– isolated from ecology– affect metabolic dynamics and expression in stable isotope analysis. Here, we test the linkage between gonadal hormones and isotopic heterogeneity among individuals with captive rats. We found that sex and removal of gonadal hormones are factors either individually or interactive for δ15N and δ13C values in serum and blood as well as δ15N values of muscle and liver. Furthermore, the degree of fractionation in these tissues is related to growth rate. Gonadectomization also affected isotopic composition for liver δ13C values and kidney δ15N values, but fat δ13C values were affected only by sex. The pattern of differentiation between groups was most different for kidney δ15N and δ13C values, which also had the largest isotopic variability among groups. Overall, isotopic variation within one tissue for the four groups demonstrated up to 1‰ difference in δ13C and δ15N values suggesting that sex based within population variations should into consideration these potential physiological effects.

What is already known

There are isotopic differences between diet and various consumer tissues with variability among individuals, which is often characterized based on captive feeding studies. Effects of protein quality and quantity, variable growth rate based on ontogeny, and differences between sexes have been tested thus far in experiments. Furthermore, it is known that gonadal hormones affect energy regulation with difference in weight gain, which suggest differences in extent and rate of biochemical processes.

What this study adds

This study demonstrates effects of gonadal hormone status with metabolic biochemistry by using stable isotopes of carbon and nitrogen as dietary tracers. We find that gonadal hormone status accounts for some isotopic heterogeneity among individuals, which should be considered when interpreting stable isotope data from wild specimens. Rather than attributing isotopic differences to ecological factors, such as foraging preference, there may be underlying physiological processes that differentiate groups based on ontogeny and sex.
Gene Conversion Facilitates the Adaptive Evolution of Self-Resistance in Highly Toxic Newts
Authors: Gendreau Kerry L. , Hornsby Angela D. , Hague Michael T. J. , McGlothlin Joel W.
Published: March 2021

Reconstructing the histories of complex adaptations and identifying the evolutionary mechanisms underlying their origins are two of the primary goals of evolutionary biology.Tarichanewts, which contain high concentrations of the deadly toxin tetrodotoxin (TTX) as an antipredator defense, have evolved resistance to self-intoxication, which is a complex adaptation requiring changes in six paralogs of the voltage-gated sodium channel (Nav) gene family, the physiological target of TTX. Here, we reconstruct the origins of TTX self-resistance by sequencing the entire Navgene family in newts and related salamanders. We show that moderate TTX resistance evolved early in the salamander lineage in three of the six Navparalogs, preceding the proposed appearance of tetrodotoxic newts by ∼100 million years. TTX-bearing newts possess additional unique substitutions across the entire Navgene family that provide physiological TTX resistance. These substitutions coincide with signatures of positive selection and relaxed purifying selection, as well as gene conversion events, that together likely facilitated their evolution. We also identify a novel exon duplication within Nav1.4 encoding an expressed TTX-binding site. Two resistance-conferring changes within newts appear to have spread via nonallelic gene conversion: in one case, one codon was copied between paralogs, and in the second, multiple substitutions were homogenized between the duplicate exons of Nav1.4. Our results demonstrate that gene conversion can accelerate the coordinated evolution of gene families in response to a common selection pressure.
Higher-order interactions among coinfecting parasites and a microbial mutualist impact disease progression
Authors: O’Keeffe Kayleigh R. , Simha Anita , Mitchell Charles E.
Published: March 2021

Interactions among parasites and other microbes within hosts can impact disease progression, yet study of such interactions has been mostly limited to pairwise combinations of microbes. Given the diversity of microbes within hosts, higher-order interactions among more than two microbial species may also impact disease. To test this hypothesis, we performed inoculation experiments that investigated interactions among two fungal parasites,Rhizoctonia solaniandColletotrichum cereale, and a systemic fungal endophyte,Epichloë coenophiala, within a grass host. Both pairwise and higher-order interactions impacted disease progression. While the endophyte did not directly influenceR. solanigrowth orC. cerealesymptom development, the endophyte modified the interaction between the two parasites. The magnitude of the facilitative effect ofC. cerealeon the growth ofR. solanitended to be greater when the endophyte was present. Moreover, this interaction modification strongly affected leaf mortality. For plants lacking the endophyte, parasite co-inoculation did not increase leaf mortality compared to single-parasite inoculations. In contrast, for endophyte-infected plants, parasite co-inoculation increased leaf mortality compared to inoculation withR. solaniorC. cerealealone by 1.9 or 4.9 times, respectively. Together, these results show that disease progression can be strongly impacted by higher-order interactions among microbial symbionts.
Differential effects of loss ofpark7activity on Iron Responsive Element (IRE) gene sets: Implications for the role of iron dyshomeostasis in the pathophysiology of Parkinson’s disease
Authors: Chin Hui Yung , Lardelli Michael , Collins-Praino Lyndsey , Barthelson Karissa
Published: March 2021

Mutation of the genePARK7(DJ1) causes monogenic autosomal recessive Parkinson’s disease (PD) in humans. Subsequent alterations of PARK7 protein function lead to mitochondrial dysfunction, a major element in PD pathology. Homozygous mutants for thePARK7-orthologous genes in zebrafish,park7, show changes to gene expression in the oxidative phosphorylation pathway, supporting that disruption of energy production is a key feature of neurodegeneration in PD. Iron is critical for normal mitochondrial function, and we have previously used bioinformatic analysis of IRE-bearing transcripts in brain transcriptomes to find evidence supporting the existence of iron dyshomeostasis in Alzheimer’s disease. Here, we analysed IRE-bearing transcripts in the transcriptome data from homozygouspark7−/−mutant zebrafish brains. We found that the set of genes with “high quality” IREs in their 5’ untranslated regions (UTRs, the HQ5’IRE gene set) was significantly altered in these 4-month-oldpark7−/−brains. However, sets of genes with IREs in their 3’ UTRs appeared unaffected. The effects on HQ5’IRE genes are possibly driven by iron dyshomeostasis and/or oxidative stress, but illuminate the existence of currently unknown mechanisms with differential overall effects on 5’ and 3’ IREs.
Sex disparities in influenza: a multiscale network analysis
Authors: Wang Chang , Lashua Lauren P. , Carter Chalise E. , Johnson Scott K. , Wang Minghui , Ross Ted M. , Ghedin Elodie , Zhang Bin , Forst Christian V.
Published: March 2021

Sex differences in the pathogenesis of infectious diseases due to differential immune responses between females and males have been well documented for multiple pathogens. However, the molecular mechanism underlying the observed sex differences in influenza virus infection remains poorly understood. In this study, we used a network-based approach to characterize the blood transcriptome collected over the course of infection with influenza A virus from female and male ferrets to dissect sex-biased gene expression. We identified significant differences in the temporal dynamics and regulation of immune responses between females and males. Our results elucidate sex-differentiated pathways involved in the unfolded protein response (UPR), lipid metabolism, and inflammatory responses, including a female-biased IRE1/XBP1 activation and male-biased crosstalk between metabolic reprogramming and IL-1 and AP-1 pathways. Overall, our study provides molecular insights into sex differences in transcriptional regulation of immune responses and contributes to a better understanding of sex bias in influenza pathogenesis.
Epithelial Regeneration Ability of Crohn’s Disease Assessed Using Patient-Derived Intestinal Organoids
Authors: Lee Chnasu , Hong Sung Noh , Kim Eun Ran , Chang Dong Kyung , Kim Young-Ho
Published: March 2021

Background

The intrinsic limitation of cell lines and animal models limits our understanding of epithelial regeneration capability in Crohn’s disease (CD). Therefore, we aimed to study epithelial regeneration ability in CD using an intestinal organoid model. Further, since tumor necrosis factor alpha (TNFα) is a major proinflammatory effector during CD pathogenesis, we also investigated TNFα-induced alteration of regeneration ability in CD patient-derived intestinal organoids.

Methods

Human intestinal organoids were constructed in a three-dimensional intestinal crypt culture of enteroscopic biopsy samples from control subjects and patients with CD. The epithelial regeneration ability of intestinal organoids was assessed using organoid reconstitution, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2′-deoxyuridine (EdU), and wound healing assays.

Results

Ex vivocultures of ileal crypt cells revealed that organoid formation rate of CD patients were reduced compared with that of control subjects (p<.001). CD patient-derived organoids sub-cultured for more than 6 passages showed stable organoid reconstitution and identical morphological features. The organoid constitution and MTT assay revealed that the viability of TNFα-treated CD patient-derived organoids were significantly lower than that of TNFα-treated control organoids (p<.05 for each). The number of EdU+ proliferative cells was significantly lower in TNFα-treated CD patient-derived organoids than in TNFα-treated control organoids (p<.05). The wound-healing ability of TNFα-treated CD patient-derived organoids was significantly lower than that of TNFα-treated control organoids (p<.001).

Conclusions

The clinical trials are disabled to settle this issue, our results indicated that the epithelial regenerative ability is impaired in patients with CD, especially in TNFα-enriched condition.