bluuebunny/crossref_metadata_2025 huggingface dataset:
Common cuckoo females remove more conspicuous eggs during parasitism
Authors: Wang Longwu , Zhang Yuhan , Liang Wei , Møller Anders Pape
Published: January 2021

Avian obligate brood parasites gain an advantage by removing the eggs of the cuckoos who have already visited the nest, which can increase the chances of survival for their offspring. Conversely, to prevent their eggs from being picked up by the next parasitic cuckoo, they need to take some precautions. Egg mimicry and egg crypsis are two alternative strategies to prevent the parasitized egg from being picked up by another parasitic cuckoo. Here, we tested whether the egg crypsis hypothesis has a preventative effect when common cuckoos (
Cuculus canorus
) parasitize their Oriental reed warbler (
Acrocephalus orientalis
) hosts. We designed two experimental groups with different crypsis effects to induce common cuckoos to lay eggs and observed whether the cuckoos selectively picked up the experimental eggs with low crypsis levels in the process of parasitism. Our results supported the egg crypsis hypothesis; the observed cuckoos significantly preferred to select the more obvious white model eggs. This shows that even in an open nest, eggs that are adequately hidden can also be protected from being picked up by cuckoo females during parasitism so as to increase the survival chance of their own parasitic eggs.
Crowdsourcing snake identification with online communities of professional herpetologists and avocational snake enthusiasts
Authors: Durso A. M. , Bolon I. , Kleinhesselink A. R. , Mondardini M. R. , Fernandez-Marquez J. L. , Gutsche-Jones F. , Gwilliams C. , Tanner M. , Smith C. E. , Wüster W. , Grey F. , Ruiz de Castañeda R.
Published: January 2021

Species identification can be challenging for biologists, healthcare practitioners and members of the general public. Snakes are no exception, and the potential medical consequences of venomous snake misidentification can be significant. Here, we collected data on identification of 100 snake species by building a week-long online citizen science challenge which attracted more than 1000 participants from around the world. We show that a large community including both professional herpetologists and skilled avocational snake enthusiasts with the potential to quickly (less than 2 min) and accurately (69–90%; see text) identify snakes is active online around the clock, but that only a small fraction of community members are proficient at identifying snakes to the species level, even when provided with the snake's geographical origin. Nevertheless, participants showed great enthusiasm and engagement, and our study provides evidence that innovative citizen science/crowdsourcing approaches can play significant roles in training and building capacity. Although identification by an expert familiar with the local snake fauna will always be the gold standard, we suggest that healthcare workers, clinicians, epidemiologists and other parties interested in snakebite could become more connected to these communities, and that professional herpetologists and skilled avocational snake enthusiasts could organize ways to help connect medical professionals to crowdsourcing platforms. Involving skilled avocational snake enthusiasts in decision making could build the capacity of healthcare workers to identify snakes more quickly, specifically and accurately, and ultimately improve snakebite treatment data and outcomes.
Study on pharmacological properties and cell absorption metabolism of novel daidzein napsylates
Authors: Jiao Yanxiao , Peng Jing , Ye Xinglin , Hu Huanan , Gan Lijun , Yang Jianyuan , Peng You
Published: January 2021

Novel daidzein napsylates (DD4 and DD5) were synthesized by microwave irradiation, according to structural modification of daidzein (DAI) using the principle of pharmacokinetic transformation. The pharmacological properties of DD4 and DD5 were evaluated via high performance liquid chromatography (HPLC) and calculated based on the drug design software ChemAxon16.1.18. The cell uptake changes of DD4 and DD5 were investigated to analyse the structure–property relationship. The metabolisms of DD4 and DD5 were analysed by HPLC-mass spectrometry in human aortic vascular smooth muscle cells (HAVSMCs) and their possible metabolic pathways were inferredin vivo. The results showed that the solubility of DD4 and DD5 was increased by 2.79 × 105and 2.16 × 105times compared to that of DAI, separately, in ethyl acetate. The maximum absorption rates of DD4 and DD5 were enhanced by 4.3–4.5 times relative to DAI. Preliminary studies on metabolites of DD4 and DD5 in HAVSMCs showed that DD4 and DD5 were hydrolysed into DAI under the action of intracellular hydrolase in two ways, ester hydrolysis or ether hydrolysis. Then, DAI was combined with glucuronic acid to form daidzein monoglucuronate under the action of uridine diphosphate (UDP)-glucuronidase. Meanwhile, it was also found that metabolite M5 of DD5 could undergo glucuronidation under the action of UDP-glucuronosyltransferase and competitive sulphation under the action of sulphotransferase to produce its sulfate conjugate M7. Analysis of structure–property relationships indicated that the absorption and utilization of drugs is closely relative to the physical properties and could be improved by adjusting the liposolubility. The pharmaceutical properties were optimized comprehensively after DAI was modified by naphthalene sulphonate esterification. This indicates that this kind of derivatives may have relatively good absorption and transport characteristics and biological activitiesin vivo. The research on biological activities of the new derivatives (DD4 and DD5) is ongoing in our laboratory.
Flickering body temperature anticipates criticality in hibernation dynamics
Authors: Oro Daniel , Freixas Lídia
Published: January 2021

Hibernation has been selected for increasing survival in harsh climatic environments. Seasonal variability in temperature may push the body temperatures of hibernating animals across boundaries of alternative states between euthermic temperature and torpor temperature, typical of either hibernation or summer dormancy. Nowadays, wearable electronics present a promising avenue to assess the occurrence of criticality in physiological systems, such as body temperature fluctuating between attractors of activity and hibernation. For this purpose, we deployed temperature loggers on two hibernating edible dormice for an entire year and under Mediterranean climate conditions. Highly stochastic body temperatures with sudden switches over time allowed us to assess the reliability of statistical leading indicators to anticipate tipping points when approaching a critical transition. Hibernation dynamics showed flickering, a phenomenon occurring when a system rapidly moves back and forth between two alternative attractors preceding the upcoming major regime shift. Flickering of body temperature increased when the system approached bifurcations, which were also anticipated by several metric- and model-based statistical indicators. Nevertheless, some indicators did not show a pattern in their response, which suggests that their performance varies with the dynamics of the biological system studied. Gradual changes in air temperature drove transient between states of hibernation and activity, and also drove hysteresis. For hibernating animals, hysteresis may increase resilience when ending hibernation earlier than the optimal time, which may occur in regions where temperatures are sharply rising, especially during winter. Temporal changes in early indicators of critical transitions in hibernation dynamics may help to understand the effects of climate on evolutionary life histories and the plasticity of hibernating organisms to cope with shortened hibernation due to global warming.
Bipartite network analysis of ant-task associations reveals task groups and absence of colonial daily activity
Authors: Fujioka Haruna , Okada Yasukazu , Abe Masato S.
Published: January 2021

Social insects are one of the best examples of complex self-organized systems exhibiting task allocation. How task allocation is achieved is the most fascinating question in behavioural ecology and complex systems science. However, it is difficult to comprehensively characterize task allocation patterns due to behavioural complexity, such as the individual variation, context dependency and chronological variation. Thus, it is imperative to quantify individual behaviours and integrate them into colony levels. Here, we applied bipartite network analyses to characterize individual-behaviour relationships. We recorded the behaviours of all individuals with verified age in ant colonies and analysed the individual-behaviour relationship at the individual, module and network levels. Bipartite network analysis successfully detected the module structures, illustrating that certain individuals performed a subset of behaviours (i.e. task groups). We confirmed age polyethism by comparing age between modules. Additionally, to test the daily rhythm of the executed tasks, the data were partitioned between daytime and nighttime, and a bipartite network was re-constructed. This analysis supported that there was no daily rhythm in the tasks performed. These findings suggested that bipartite network analyses could untangle complex task allocation patterns and provide insights into understanding the division of labour.
High-resolution thickness maps of corrosion using SH1 guided wave tomography
Authors: Zimmermann Andreas A. E. , Huthwaite Peter , Pavlakovic Brian
Published: January 2021

Quantifying corrosion damage is vital for the petrochemical industry, and guided wave tomography can provide thickness maps of such regions by transmitting guided waves through these areas and capturing the scattering information using arrays. The dispersive nature of the guided waves enables a reconstruction of wave velocity to be converted into thickness. However, existing approaches have been shown to be limited in in-plane resolution, significantly short of that required to accurately image a defect target of three times the wall thickness (i.e. 3 T) in each in-plane direction. This is largely due to the long wavelengths of the fundamental modes commonly used, being around 4 T for both A0 and S0 at the typical operation points. In this work, the suitability of the first-order shear-horizontal guided wave mode, SH1, has been investigated to improve the resolution limit. The wavelength at the desired operating point is significantly shorter, enabling an improvement in resolution of around 2.4 times. This is first verified by realistic finite-element simulations and then validated by experimental results, confirming the improved resolution limit can now allow defects of maximum extent 3T-by-3T to be reliably detected and sized, i.e. a long-pursued goal of guided wave tomography has been achieved.
Numerical calculation ofN-periodic wave solutions to coupled KdV–Toda-type equations
Authors: Zhang Yingnan , Hu Xingbiao , Sun Jianqing
Published: January 2021

In this paper, we study theN-periodic wave solutions of coupled Korteweg–de Vries (KdV)–Toda-type equations. We present a numerical process to calculate theN-periodic waves based on the direct method of calculating periodic wave solutions proposed by Akira Nakamura. Particularly, in the case ofN = 3, we give some detailed examples to show theN-periodic wave solutions to the coupled Ramani equation, the Hirota–Satsuma coupled KdV equation, the coupled Ito equation, the Blaszak–Marciniak lattice, the semi-discrete KdV equation, the Leznov lattice and a relativistic Toda lattice.
Anomalous invasion dynamics due to dispersal polymorphism and dispersal–reproduction trade-offs
Authors: Keenan Vincent A. , Cornell Stephen J.
Published: January 2021

Dispersal polymorphism and mutation play significant roles during biological invasions, potentially leading to evolution and complex behaviour such as accelerating or decelerating invasion fronts. However, life-history theory predicts that reproductive fitness—another key determinant of invasion dynamics—may be lower for more dispersive strains. Here, we use a mathematical model to show that unexpected invasion dynamics emerge from the combination of heritable dispersal polymorphism, dispersal-fitness trade-offs, and mutation between strains. We show that the invasion dynamics are determined by the trade-off relationship between dispersal and population growth rates of the constituent strains. We find that invasion dynamics can be ‘anomalous’ (i.e. faster than any of the strains in isolation), but that the ultimate invasion speed is determined by the traits of, at most, two strains. The model is simple but generic, so we expect the predictions to apply to a wide range of ecological, evolutionary, or epidemiological invasions.
Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes
Authors: Lim Chun Shen , Sozzi Vitina , Littlejohn Margaret , Yuen Lilly K.W. , Warner Nadia , Betz-Stablein Brigid , Luciani Fabio , Revill Peter A. , Brown Chris M.
Published: January 2021

Hepatitis B virus (HBV) is a major human pathogen that causes liver diseases. The main HBV RNAs are unspliced transcripts that encode the key viral proteins. Recent studies have shown that some of the HBV spliced transcript isoforms are predictive of liver cancer, yet the roles of these spliced transcripts remain elusive. Furthermore, there are nine major HBV genotypes common in different regions of the world, these genotypes may express different spliced transcript isoforms. To systematically study the HBV splice variants, we transfected human hepatoma cells, Huh7, with four HBV genotypes (A2, B2, C2 and D3), followed by deep RNA-sequencing. We found that 13–28 % of HBV RNAs were splice variants, which were reproducibly detected across independent biological replicates. These comprised 6 novel and 10 previously identified splice variants. In particular, a novel, singly spliced transcript was detected in genotypes A2 and D3 at high levels. The biological relevance of these splice variants was supported by their identification in HBV-positive liver biopsy and serum samples, and in HBV-infected primary human hepatocytes. Interestingly the levels of HBV splice variants varied across the genotypes, but the spliced pregenomic RNA SP1 and SP9 were the two most abundant splice variants. Counterintuitively, these singly spliced SP1 and SP9 variants had a suboptimal 5′ splice site, supporting the idea that splicing of HBV RNAs is tightly controlled by the viral post-transcriptional regulatory RNA element.
Comparative genomics of Staphylococcus epidermidis from prosthetic-joint infections and nares highlights genetic traits associated with antimicrobial resistance, not virulence
Authors: Månsson Emeli , Bech Johannesen Thor , Nilsdotter-Augustinsson Åsa , Söderquist Bo , Stegger Marc
Published: January 2021

There is increased awareness of the worldwide spread of specific epidemic multidrug-resistant (MDR) lineages of the human commensal

Staphylococcus epidermidis

. Here, using bioinformatic analyses accounting for population structure, we determined genomic traits (genes, SNPs and k-mers) that distinguish

S. epidermidis

causing prosthetic-joint infections (PJIs) from commensal isolates from nares, by analysing whole-genome sequencing data from

S. epidermidis

from PJIs prospectively collected over 10 years in Sweden, and contemporary

S. epidermidis

from the nares of patients scheduled for arthroplasty surgery. Previously suggested virulence determinants and the presence of genes and mutations linked to antimicrobial resistance (AMR) were also investigated. Publicly available

S. epidermidis

sequences were used for international extrapolation and validation of findings. Our data show that

S. epidermidis

causing PJIs differed from nasal isolates not by virulence but by traits associated with resistance to compounds used in prevention of PJIs: β-lactams, aminoglycosides and chlorhexidine. Almost a quarter of the PJI isolates did not belong to any of the previously described major nosocomial lineages, but the AMR-related traits were also over-represented in these isolates, as well as in international

S. epidermidis

isolates originating from PJIs. Genes previously associated with virulence in

S. epidermidis

were over-represented in individual lineages, but failed to reach statistical significance when adjusted for population structure. Our findings suggest that the current strategies for prevention of PJIs select for nosocomial MDR

S. epidermidis

lineages that have arisen from horizontal gene transfer of AMR-related traits into multiple genetic backgrounds.
A Multiple Linear Regression Analysis of Rural-Urban COVID-19 Risk Disparities in Texas
Authors: Luo Amber K. , Zhong Sophia , Sun Charles , Wang Jasmine , White Alexander
Published: January 2021

As the number of COVID-19 cases in the U.S. rises, the differential impact of the pandemic in urban and rural regions becomes more pronounced, and the major factors relating to this difference remain unclear. Using the 254 counties of Texas as units of analysis, we utilized multiple linear regression to investigate the influence of 83 county-level predictor variables including race demographics, age demographics, healthcare and financial status, and prevalence of and mortality rate from COVID-19 risk factors on the incidence rate and case fatality rate from COVID-19 in Texas on September 15, 2020. Here, we report that urban counties experience, on average, 41.1% higher incidence rates from COVID-19 than rural counties and 34.7% lower case fatality rates. Through comparisons between our models, we found that this difference was largely attributable to four major predictor variables: namely, the proportion of elderly residents, African American residents, and Hispanic residents, and the presence of large nursing homes. According to our models, counties with high incidence rates of COVID-19 are predicted to have high proportions of African American residents and Hispanic residents coupled with low proportions of elderly residents. Furthermore, we found that counties with the highest case fatality rates are predicted to have high proportions of elderly residents, obese residents, and Hispanic residents, coupled with low proportions of residents ages 20-39 and residents who report smoking cigarettes. In our study, major variables and their effects on COVID-19 risk are quantified, highlighting the most vulnerable populations and regions of Texas.
Cohesin-mediated loop anchors confine the location of human replication origins
Authors: Emerson Daniel , Zhao Peiyao A , Klein Kyle , Ge Chunmin , Zhou Linda , Sasaki Takayo , Yang Liyan , Venvev Sergey V. , Gibcus Johan H. , Dekker Job , Gilbert David M. , Phillips-Cremins Jennifer E.
Published: January 2021

DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability across dividing cells in metazoans. It is currently unknown how the location of replication origins and the timing of their activation is determined in the human genome. Here, we dissect the role for G1 phase topologically associating domains (TADs), subTADs, and loops in the activation of replication initiation zones (IZs). We identify twelve subtypes of self-interacting chromatin domains distinguished by their degree of nesting, the presence of corner dot structures indicative of loops, and their co-localization with A/B compartments. Early replicating IZs localize to boundaries of nested corner-dot TAD/subTADs anchored by high density arrays of co-occupied CTCF+cohesin binding sites with divergently oriented motifs. By contrast, late replicating IZs localize to weak TADs/subTAD boundaries devoid of corner dots and most often anchored by singlet CTCF+cohesin sites. Upon global knock-down of cohesin-mediated loops in G1, early wave focal IZs replicate later in S phase and convert to diffuse placement along the genome. Moreover, IZs in mid-late S phase are delayed to the final minutes before entry into G2 when cohesin-mediated dot-less boundaries are ablated. We also delete a specific loop anchor and observe a sharp local delay of an early wave IZ to replication in late S phase. Our data demonstrate that cohesin-mediated loops at genetically-encoded TAD/subTAD boundaries in G1 phase are an essential determinant of the precise genomic placement of human replication origins in S phase.
Brain connectivity at rest predicts individual differences in normative activity during movie watching
Authors: Gruskin David C. , Patel Gaurav H.
Published: January 2021

When multiple individuals are exposed to the same sensory event, some are bound to have less typical experiences than others. These atypical experiences are underpinned by atypical stimulus-evoked brain activity, the extent of which is often indexed by intersubject correlation (ISC). Previous research has attributed individual differences in ISC to variation in trait-like behavioral phenotypes. Here, we extend this line of work by showing that an individual’s degree and spatial distribution of ISC are closely related to their brain’s intrinsic functional architecture. Using resting state and movie watching fMRI data from 176 Human Connectome Project participants, we reveal that resting state functional connectivity (RSFC) profiles can be used to predict cortex-wide ISC with considerable accuracy. Similar region-level analyses demonstrate that the amount of ISC a brain region exhibits during movie watching is associated with its connectivity to others at rest, and that the nature of these connectivity-activity relationships varies as a function of the region’s role in sensory information processing. Finally, we show that an individual’s unique spatial distribution of ISC, independent of its magnitude, is also related to their RSFC profile. These findings suggest that the brain’s ability to process complex sensory information is tightly linked to its baseline functional organization and motivate a more comprehensive understanding of individual responses to naturalistic stimuli.
The local topological free energy of proteins
Authors: Baldwin Quenisha , Panagiotou Eleni
Published: January 2021

Protein folding, the process by which proteins attain a 3-dimensional conformation necessary for their function, remains an important unsolved problem in biology. A major gap in our understanding is how local properties of proteins relate to their global properties. In this manuscript, we use the Writhe and Torsion to introduce a new local topological/geometrical free energy that can be associated to 4 consecutive residues along protein backbone. By analyzing a culled protein dataset from the PDB, our results show that high local topological free energy conformations are independent of sequence and may be involved in the rate limiting step in protein folding. By analyzing a set of 2-state single domain proteins, we find that the total local topological free energy of these proteins correlates with the experimentally observed folding rates reported in [29].
Utilizing Multimodal Imaging to Visualize Potential Mechanism for Sudden Death in Epilepsy
Authors: Mandal Ranajay , Budde Ryan , Lawlor Georgia L. , Irazoqui Pedro
Published: January 2021

Sudden death in epilepsy, or SUDEP, is a fatal condition that accounts for more than 4000 deaths each year. Limited clinical and preclinical data on sudden death suggests critical contributions from autonomic, cardiac, and respiratory pathways. Recent animal (rat) studies on kainic acid induced seizure models explored a potential mechanism for such sudden and severe cardiorespiratory dysregulation being linked to acid reflux induced laryngospasm. Here, we expand on those previous investigations and utilize a multimodal approach to provide visual evidence of acid reflux-initiated laryngospasm and subsequent fatal cardiorespiratory distress in seizing rats.

We used systemic kainic acid to acutely induce seizure activity in Long Evans rats, under urethane anesthesia. We recorded electroencephalography (EEG), electrocardiography (ECG), chest plethysmography and esophageal pH signals during simultaneous fast MRI scans of the rat stomach and esophagus. MRI images, in conjunction with electrophysiology data were used to identify seizure progression, stomach acid movement up the esophagus, cardiorespiratory changes, and sudden death.

In all cases of sudden death, esophageal pH recordings alongside MRI images visualized stomach acid movement up the esophagus. Severe cardiac (ST segment elevation), respiratory (intermittent apnea) and brain activity (EEG narrowing due to hypoxia) changes were observed only after acid reached the larynx, which strongly suggests onset of laryngospasm following acid reflux. Additionally, absence of stomach acid in the esophagus of animals that survived acute seizure, provided evidence of a causal relationship between acid reflux and sudden death. The complimentary information coming from electrophysiology and fast MRI scans provided insight into the mechanism of esophageal reflux, laryngospasm, obstructive apnea, and subsequent sudden death in seizing animals. The results carry clinical significance as they outline a potential mechanism that may be relevant to SUDEP in humans.
Using genomic prediction to detect microevolutionary change of a quantitative trait
Authors: Hunter DC , Ashraf B , Bérénos C , Ellis PA , Johnston SE , Wilson AJ , Pilkington JG , Pemberton JM , Slate J
Published: January 2021

Detecting microevolutionary responses to natural selection by observing temporal changes in individual breeding values is challenging. The collection of suitable datasets can take many years and disentangling the contributions of the environment and genetics to phenotypic change is not trivial. Furthermore, pedigree-based methods of obtaining individual breeding values have known biases. Here, we apply a genomic prediction approach to estimate breeding values of adult weight in a 35-year dataset of Soay sheep (Ovis aries). During the study period adult body weight decreased, but the underlying genetic component of body weight increased, at a rate that is unlikely to be attributable to genetic drift. Thus cryptic microevolution of greater adult body weight has probably occurred. Using genomic prediction to study microevolution in wild populations can remove the requirement for pedigree data, potentially opening up new study systems for similar research.
Fibronectin-mediated inflammatory signaling through integrin α5 in vascular remodeling
Authors: Budatha Madhusudhan , Zhang Jiasheng , Schwartz Martin A.
Published: January 2021

Adhesion of vascular endothelial cells (ECs) to the underlying basement membrane potently modulates EC inflammatory activation. The normal basement membrane proteins laminin and collagen IV attenuate inflammatory signaling in part through integrin α2β1. In contrast, fibronectin, the provisional matrix protein found in injured, remodeling or inflamed vessels, sensitizes ECs to inflammatory stimuli through integrins α5β1and and αvβ3. A chimeric integrin in which the cytoplasmic domain of α5 is replaced with that of α2 pairs with β1 and binds fibronectin but signals like α2β1. Here, we examined mice in which integrin α5 is replaced with the α5/2 chimera, using the transverse aortic constriction (TAC) and partial carotid ligation (PCL) models of vessel remodeling. Following TAC and PCL surgery, WT mice showed increased fibronectin deposition and expression of inflammatory markers, which were strongly attenuated in a5/2 mice. α5/2 mice also showed reduced artery wall hypertrophy in the TAC model and diminished inward remodeling in the PCL model. Acute atherosclerosis after PCL in hyperlipidemic ApoE−/− mice on a high fat diet was dramatically decreased in α5/2 mice. These results underscore the key role for integrin α5 signaling in pathological vascular remodeling and support its potential as a therapeutic target.
Immature olfactory sensory neurons provide behaviourally relevant sensory input to the olfactory bulb
Authors: Huang Jane S. , Kunkhyen Tenzin , Rangel Alexander N. , Brechbill Taryn R. , Gregory Jordan D. , Winson-Bushby Emily D. , Liu Beichen , Avon Jonathan T. , Muggleton Ryan J. , Cheetham Claire E.J.
Published: January 2021

Postnatal neurogenesis provides an opportunity to understand how newborn neurons integrate into circuits to restore function. Newborn olfactory sensory neurons (OSNs) wire into highly organized olfactory bulb (OB) circuits throughout life, enabling lifelong plasticity and regeneration. Immature OSNs form functional synapses capable of evoking firing in OB projection neurons but what contribution, if any, they make to odor processing is unknown. Here, we show that immature OSNs provide odor input to the OB, where they form monosynaptic connections with excitatory neurons. Importantly, immature OSNs respond as selectively to odorants as mature OSNs and provide information about high odorant concentrations at which mature OSN responses are already maximal, suggesting that immature and mature OSNs provide distinct odor input streams. Furthermore, mice can successfully perform odor detection and discrimination tasks using sensory input from immature OSNs alone. Together, our findings suggest that immature OSNs play a previously unappreciated role in olfactory-guided behavior.
Evaluating the efficacy of Optoα1AR activation in astrocytes in modulating basal hippocampal synaptic excitation and inhibition
Authors: Courtney Connor D. , Sobieski Courtney , Ramakrishnan Charu , Ingram Robbie J. , Wojnowski Natalia M. , DeFazio R. Anthony , Deisseroth Karl , Christian-Hinman Catherine A.
Published: January 2021

Astrocytes play active roles at synapses and can monitor, respond, and adapt to local synaptic activity. To investigate this relationship, more tools that can selectively activate native G protein signaling pathways in astrocytes with both spatial and temporal precision are needed. Here, we tested AAV8-GFAP-Optoα1AR-eYFP (Optoα1AR), a viral vector to enable activation of Gqsignaling in astrocytes via light-sensitive α1-adrenergic receptors. To determine if stimulating astrocytic Optoα1AR modulates hippocampal synaptic transmission, recordings were made in CA1 pyramidal cells with surrounding astrocytes expressing Optoα1AR, channelrhodopsin (ChR2), or GFP. Both high-frequency (20 Hz, 45-ms light pulses, 5 mW, 5 min) and low-frequency (0.5 Hz, 1-s pulses at increasing 1, 5, and 10 mW intensities, 90 s per intensity) blue light stimulation were tested. 20 Hz Optoα1AR stimulation increased both inhibitory and excitatory postsynaptic current (IPSC and EPSC) frequency, and the mIPSC effect was largely reversible within 20 min. By contrast, low-frequency stimulation of Optoα1AR did not modulate either IPSCs or EPSCs, whereas the same stimulation of astrocytic ChR2 was effective. These data demonstrate that Optoα1AR activation in astrocytes changes synaptic excitation and inhibition in a stimulation-sensitive manner, demonstrating the efficacy and utility of GFAP-Optoα1AR as a tool in studying astrocyte-neuron interactions.
Dissociating the effect of reward uncertainty and timing uncertainty on neural indices of reward prediction errors: A reward positivity (RewP) event-related potential (ERP) study
Authors: Muir Alexandra M. , Eberhard Addison C. , Walker Megan S. , Bennion Angus , South Mikle , Larson Michael J.
Published: January 2021

Accurate reward predictions include forecasting bothwhata reward will be andwhena reward will occur. We tested how variations in the certainty of reward outcome and certainty in timing of feedback presentation modulate neural indices of reward prediction errors using the reward positivity (RewP) component of the scalp-recorded brain event-related potential (ERP). In a within-subjects design, seventy-three healthy individuals completed two versions of a cued doors task; one cued the probability of a reward outcome while the other cued the probability of a delay before feedback. Replicating previous results, RewP amplitude was larger for uncertain feedback compared to certain feedback. Additionally, RewP amplitude was differentially associated with uncertainty of presence/absence of reward, but not uncertainty of feedback timing. Findings suggest a dissociation in that RewP amplitude is modulated by reward prediction certainty but is less affected by certainty surrounding timing of feedback.
The female pheromone (Z)-4-undecenal mediates flight attraction and courtship in Drosophila melanogaster
Authors: Borrero-Echeverry Felipe , Solum Marit , Trona Federica , Wallin Erika A. , Bengtsson Marie , Witzgall Peter , Lebreton Sebastien
Published: January 2021

Specific mate communication and recognition underlies reproduction and hence speciation. Mate communication evolves during adaptation to ecological niches and makes use of social signals and habitat cues.

Our study provides new insights in Drosophila melanogaster premating olfactory communication, showing that female pheromone (Z)-4-undecenal (Z4-11Al) and male pheromone cVA interact with food odour in a sex-specific manner. Furthermore, Z4-11Al, which mediates upwind flight attraction in both sexes, also elicits courtship in experienced males.

Twin variants of the olfactory receptor Or69a are co-expressed in the same olfactory sensory neurons, and feed into the same glomerulus in the antennal lobe. Z4-11Al is perceived via Or69aB, while the food odorant (R)-linalool is a main ligand for the other variant, Or69aA. That Z4-11Al mediates courtship in experienced males, not (R)- linalool, is probably due to courtship learning. Behavioural discrimination is reflected by calcium imaging of the antennal lobe, showing distinct glomerular activation patterns by these two compounds.

Male sex pheromone cVA is known to affect male and female courtship at close range, but does not elicit upwind flight attraction as a single compound, in to contrast to Z4-11Al. A blend of cVA and the food odour vinegar attracted females, while a blend of female pheromone Z4-11Al and vinegar attracted males instead.

Sex-specific upwind flight attraction to blends of food volatiles and male and female pheromone, respectively, adds a new element to Drosophila olfactory premating communication and is an unambiguous paradigm for identifying the behaviourally active components, towards a more complete concept of food-pheromone odour objects.

The female-produced, species-specific volatile pheromone of D. melanogaster attracts both sexes from a distance, alone and in concert with food odorants, and elicits courtship in experienced males.
Enhanced detection of nucleotide repeat mRNA with hybridization chain reaction
Authors: Glineburg M. Rebecca , Zhang Yuan , Tank Elizabeth , Barmada Sami , Todd Peter K
Published: January 2021

RNAs derived from expanded nucleotide repeats form detectable foci in patient cells and these foci are thought to contribute to disease pathogenesis. The most widely used method for detecting RNA foci is fluorescence in situ hybridization (FISH). However, FISH is prone to low sensitivity and photo-bleaching that can complicate data interpretation. Here we applied hybridization chain reaction (HCR) as an alternative approach to repeat RNA foci detection of GC-rich repeats in two neurodegenerative disorders: GGGGCC (G4C2) hexanucleotide repeat expansions inC9orf72that cause amyotrophic lateral sclerosis and frontotemporal dementia (C9 ALS/FTD) and CGG repeat expansions inFMR1that cause Fragile X-associated tremor/ataxia syndrome. We found that HCR of both G4C2and CGG repeats has comparable specificity to traditional FISH, but is >40x more sensitive and shows repeat-length dependence in its intensity. HCR is better than FISH at detecting both nuclear and cytoplasmic foci in human C9 ALS/FTD fibroblasts, patient iPSC derived neurons, and patient brain samples. We used HCR to determine the impact of integrated stress response (ISR) activation on RNA foci number and distribution. G4C2repeat RNA did not readily co-localize with the stress granule marker G3BP1, but ISR induction increased both the number of detectible nuclear RNA foci and the nuclear/cytoplasmic foci ratio in patient fibroblasts and patient derived neurons. Taken together, these data suggest that HCR can be a useful tool for detecting repeat expansion mRNA in C9 ALS/FTD and other repeat expansion disorders.
Optimized antibody humanization by intra and inter VH-VL binding energy sorting
Authors: Zhong Qiang
Published: January 2021

Humanization of non-human derived antibody is necessary to reduce the immunogenicity of antibody drug. In recent years, computer aided antibody humanization became an efficient and rapid routine process. We report here a new computational humanization pipeline which includes CDR grafting onto the crystal structures of homologous antibody and CDR grafted humanized antibody structures. Then, the intra and inter VH-VL binding energies are calculated and sorted for optimized humanized antibody. The resulted humanized antibodies are ranked and compared to experimental dataset, which confirms the validity of humanized antibody design by intra and inter VH-VL binding energy.
T cell stiffness is enhanced upon formation of immunological synapse
Authors: Jung Philipp , Zhou Xiangda , Bischoff Markus , Qu Bin
Published: January 2021

T cells are activated by cognate target cells via an intimate contact, termed immunological synapse (IS). Cellular mechanical properties, especially stiffness, are essential to regulate cell functions, T cell stiffness at a subcellular level at the IS still remains largely elusive. In this work, we established an atomic force microscopy (AFM)-based elasticity mapping method on whole T cells to obtain an overview of the stiffness with a resolution of ~ 60 nm. Using Jurkat T-cells and primary human CD4+T cells, we show that in the T cells in contact with functionalized surfaces, the lamellipodia are stiffer than the cell body. Upon IS formation, T cell stiffness is substantially enhanced both at the lamellipodia and in cell body. Chelation of intracellular Ca2+abolishes IS-induced stiffening at the lamellipodia but has no influence on cell body-stiffening, suggesting different regulatory mechanism of IS-induced stiffening between the lamellipodia and the cell body.
A single- and paired-pulse TMS-EEG investigation of the N100 and long interval cortical inhibition in autism spectrum disorder
Authors: Kirkovski Melissa , Hill Aron T. , Rogasch Nigel C , Saeki Takashi , Fitzgibbon Bernadette M. , Yang Joel , Do Michael , Donaldson Peter H , Albein-Urios Natalia , Fitzgerald Paul B , Enticott Peter G
Published: January 2021

Background

There is evidence to suggest a disruption of gamma-aminobutyric acid (GABA) in autism spectrum disorder (ASD), but findings are mixed. Concurrent electroencephalography and transcranial magnetic stimulation (TMS-EEG) provides a novel method by which to probe GABA-mediated cortical inhibition.

Methods

With a particular focus on GABAB-ergic mechanisms, we investigated the N100 peak of the TMS evoked potential (TEP), as well as long interval cortical inhibition (LICIEEG) in adults with ASD (n = 23; 12 female) without intellectual disability, and a neurotypical comparison group (n =22; 12 female) matched for age, sex, and IQ. Seventy-five single-(spTMS) and 75 paired-(ppTMS; 100 ms inter-stimulus-interval) pulses were applied to the right primary motor cortex (M1), right temporoparietal junction (TPJ), and right dorsolateral prefrontal cortex (DLPFC) while EEG was recorded from 20 scalp electrodes. Additionally, electromyography (EMG) was used to investigate corticospinal inhibition following ppTMS to M1 (LICIEMG).

Results

There were no group differences in the N100 amplitude or latency following spTMS. LICI outcomes following ppTMS, as measured by either EEG or EMG, also did not differ between groups. These findings were further supported by Bayesian analyses, which provided weak-moderate support for the null hypothesis.

Limitations

Data presented here reflect adults without intellectual disability, and the generalisability of these results is therefore limited.

Conclusions

The findings of this study argue against GABAB-ergic impairment in adults with ASD without intellectual disability, at least at the cortical regions examined. Further research investigating these mechanisms in ASD at various ages, with varying degrees of symptomatology, and at different brain sites is an important factor in understating the role of GABA in the neuropathophysiology of ASD.
Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons
Authors: Biane Célia , Rückerl Florian , Abrahamsson Therese , Saint-Cloment Cécile , Mariani Jean , Shigemoto Ryuichi , DiGregorio David A. , Sherrard Rachel M. , Cathala Laurence
Published: January 2021

Synaptic transmission, connectivity, and dendritic morphology mature in parallel during brain development and are often disrupted in neurodevelopmental disorders. Yet how these changes influence the neuronal computations necessary for normal brain function are not well understood. To identify cellular mechanisms underlying the maturation of synaptic integration in interneurons, we combined patch-clamp recordings of excitatory inputs in cerebellar stellate cells (SCs), 3D-reconstruction of SC morphology with excitatory synapse location, and biophysical modeling. We found that, during development, synaptic strength was homogeneously reduced along the somato-dendritic axis, but that dendritic integration was always sublinear. However, dendritic branching increased without changes in synapse density, leading to a substantial gain in distal inputs. Thus, changes in synapse distribution, rather than dendrite cable properties, are the dominant mechanism underlying the maturation of neuronal computation. These mechanisms favor the emergence of a spatially compartmentalized two-stage integration model promoting location-dependent integration within dendritic subunits.
IRGM/Irgm1 Aggravates Progression of Atherosclerosis by Inducing Macrophage Apoptosis through the MAPK Signaling Pathway
Authors: Fang Shaohong , Sun Song , Cai Hengxuan , Hao Xinran , Zou Xiaoyi , Wan Xin , Tian Jiangtian , Li Zhaoying , Wang Shanjie , He Zhongze , Huang Wei , Liang Chenchen , Zhang Zhenming , Yang Liming , Tian Jinwei , Yu Bo , Sun Bo
Published: January 2021

Aims

Atherosclerosis underlies most cardiovascular diseases, among which acute coronary syndrome (ACS) caused by plaque rupture (PR) often leads to death. Immune-related GTPases (IRGM/Irgm1) have been extensively studied in inflammatory diseases, but their role in atherosclerosis is unclear. Determining how IRGM/Irgm1 promotes atherosclerotic plaque vulnerability will provide information for new biomarkers and/or therapeutic targets.

Methods and results

We identified ruptured and unruptured plaques by optical coherence tomography, and found that serum IRGM was highly expressed in patients with ST-segment elevation myocardial infarction in PR. We used ApoE-/-Irgm1+/+, ApoE-/-Irgm1+/-mice and chimeric mice to establish a model of advanced atherosclerosis. The results of pathological experiments showed that Irgm1 caused plaque necrosis. The ratio of neutral lipids and cholesterol crystals increases, while the content of collagen fibers decreases, aggravating the destabilization of atherosclerotic plaques. In vitro, we used multiple approaches to confirm that Irgm1 promotes macrophage apoptosis by promoting the production of reactive oxygen species and activating the MAPK signaling pathway.

Conclusions

IRGM may be a potential risk factor for PR. Mechanistic studies have shown that IRGM/Irgm1 contributes to the formation and rupture of fragile plaques. This is partly mediated by the induction of macrophage apoptosis via the MAPK signaling pathway. IRGM may offer new strategies for early treatment of ACS.

Translation view

Our findings indicate that IRGM/Irgm1 contributes to formation and rupture of vulnerable plaques. It suggests that IRGM may provide a new target for the early treatment of ACS.
Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy
Authors: Pérez Malena M. , Pimentel Vinícius E. , Fuzo Carlos A. , da Silva-Neto Pedro V. , Toro Diana M. , Souza Camila O. S. , Fraga-Silva Thais F. C. , Gardinassi Luiz Gustavo , de Carvalho Jonatan C. S. , Neto Nicola T. , Carmona-Garcia Ingryd , Oliveira Camilla N. S. , Milanezi Cristiane M. , Takahashi Viviani Nardini , De Leo Thais Canassa , Rodrigues Lilian C. , Dias Cassia F. S. L. , Xavier Ana C. , Porcel Giovanna S. , Guarneri Isabelle C. , Zaparoli Kamila , Garbato Caroline T. , Argolo Jamille G. M. , Júnior Ângelo A. F. , Feitosa Marley R. , Parra Rogerio S. , da Rocha José J. R. , Feres Omar , Vilar Fernando C. , Gaspar Gilberto G. , da Silva Rafael C. , Constant Leticia F. , Ostini Fátima M. , de Amorim Alessandro P. , Degiovani Augusto M. , da Silva Dayane P. , Nepomuceno Debora C. , Barbieri Rita C. C. , Santos Isabel K. F. M. , Maruyama Sandra R. C. , Russo Elisa M. S. , Viana Angelina L. , Fernandes Ana P. M. , Bonato Vânia L. D. , Cardoso Cristina R. B. , Sorgi Carlos A. , Dias-Baruffi Marcelo , Faccioli Lúcia H.
Published: January 2021

Cytokine storms and hyperinflammation, potentially controlled by glucocorticoids, occur in COVID-19; the roles of lipid mediators and acetylcholine (ACh) and how glucocorticoid therapy affects their release in Covid-19 remain unclear. Blood and bronchoalveolar lavage (BAL) samples from SARS-CoV-2- and non-SARS-CoV-2-infected subjects were collected for metabolomic/lipidomic, cytokines, soluble CD14 (sCD14), and ACh, and CD14 and CD36-expressing monocyte/macrophage subpopulation analyses. Transcriptome reanalysis of pulmonary biopsies was performed by assessing coexpression, differential expression, and biological networks. Correlations of lipid mediators, sCD14, and ACh with glucocorticoid treatment were evaluated. This study enrolled 190 participants with Covid-19 at different disease stages, 13 hospitalized non-Covid-19 patients, and 39 healthy-participants. SARS-CoV-2 infection increased blood levels of arachidonic acid (AA), 5-HETE, 11-HETE, sCD14, and ACh but decreased monocyte CD14 and CD36 expression. 5-HETE, 11-HETE, cytokines, ACh, and neutrophils were higher in BAL than in circulation (fold-change for 5-HETE 389.0; 11-HETE 13.6; ACh 18.7, neutrophil 177.5, respectively). Only AA was higher in circulation than in BAL samples (fold-change 7.7). Results were considered significant at P<0.05, 95%CI. Transcriptome data revealed a unique gene expression profile associated with AA, 5-HETE, 11-HETE, ACh, and their receptors in Covid-19. Glucocorticoid treatment in severe/critical cases lowered ACh without impacting disease outcome. We first report that pulmonary inflammation and the worst outcomes in Covid-19 are associated with high levels of ACh and lipid mediators. Glucocorticoid therapy only reduced ACh, and we suggest that treatment may be started early, in combination with AA metabolism inhibitors, to better benefit severe/critical patients.