bluuebunny/crossref_metadata_2025 huggingface dataset:
GIVE Statistic for Goodness of Fit in Instrumental Variables Models with Application to COVID Data
Authors: Dhar Subhra Sankar , Shalabh
Published: April 2021

Since COVID-19 outbreak, scientists have been interested to know whether there is any impact of the Bacillus Calmette-Guerin (BCG) vaccine against COVID-19 mortality or not. It becomes more relevant as a large population in the world may have latent tuberculosis infection (LTBI), for which a person may not have active tuberculosis but persistent immune responses stimulated by Mycobacterium tuberculosis antigens, and that means, both LTBI and BCG generate immunity against COVID-19. In order to understand the relationship between LTBI and COVID-19 mortality, this article proposes a measure of goodness of fit, viz.,Goodness ofInstrumentalVariableEstimates (GIVE) statistic, of a model obtained by Instrumental Variables estimation. The GIVE helps in finding the appropriate choice of instruments, which provides a better fitted model. In the course of study, the large sample properties of the GIVE statistic are investigated. As indicated before, the COVID-19 data is analysed using the GIVE statistic, and moreover, simulation studies are also conducted to show the usefulness of the GIVE statistic.
Clarivate listed nursing journals in 2020: what they publish and how they measure use of social media
Authors: Watson Roger , Younas Ahtisham , Rehman Salma Abdul , Ali Parveen Azam
Published: April 2021

Objectives

To investigate what the most common types of articles that nursing journals purport to publish are and what they actually publish? And to investigate the extent to which academic nursing journals listed by Clarivate track alternative metrics?

Methods

Journals included in the nursing Journal Citation Report journal category in 2019 described as nursing were identified and considered suitable for inclusion in the analysis. Instructions for authors were reviewed online and mention of each type of article identified. The tables of contents of each issue of each journal published during 2019 was examined and the types of articles published were extracted to a spreadsheet into permitted article types and published articles. Likewise, the use of alternative metrics by each journal was extracted to a spreadsheet. Pearson’s and Spearman’s correlation analysis was applied to investigate the relationship between articles permitted and articles published.

Results

In the 2020 Journal Citation Report, 123 journals were listed. The most common article type permitted was original research (n=117), followed by review papers (n=116) and discussion papers (n=63). Original research (n=7045); review papers (n=1268); discussion papers (n=1225); editorials (n=793) and commentaries (n=776) were the most commonly published categories of article. Of journals examined, 108 (96.8%) tracked mentions on social media and the Altmetric score was the most commonly use (75%). There was a strong correlation (r=0.73; p=0,002) between the numbers of article permitted and published and a strong correlation (rho=0.86; p<0.001) in terms of the rankings of the permitted and published articles.

Conclusions

There is a relationship between the most frequently permitted article types and those published, especially for the most frequent categories of both. Original articles, review papers and discussion papers are the backbone of academic publishing in nursing with original articles vastly outweighing review and discussion papers. Most Clarivate listed journals now use some method of tracking alternative metrics indicating how seriously publishers take their social media profiles.
Study of knowledge and practices of local anaesthetic systemic toxicity among Doctors in Sri Lanka
Authors: Munasinghe B.M. , Arambepola AG. , Subramaniam N. , Nimalan S. , Gunathilake KUIS. , Nissankaarachchi RD. , Karunathilake S K. , Jayamanne BDW.
Published: April 2021

Background

Local anaesthetic systemic toxicity (LAST) could be potentially life threatening. This study focused on describing the knowledge and practices of use of local anaesthetics (LA) among the doctors in Sri Lanka and the ability to detect and manage an event of LAST.

Materials and methods

A descriptive cross-sectional study was conducted among doctors in Sri Lanka using an online self-administered questionnaire based on AAGBI guidelines (2010). Descriptive statistics were analyzed by cross-tabulations and presented as numbers and percentages using IBM-SPSS 25.

Results

The response rate was 60% out of 600. Majority were males (58%) while 45% of the respondents were anesthetists. Ultrasound was used by 47.4% during LA. The majority considered total body weight for dose calculations. Around 50% of respondents identified bupivacaine as the most cardiotoxic. The majority utilized some form of monitoring and were knowledgeable on identification, prevention and initial management of LAST. Approximately 45% identified Intralipid (ILE) as the definitive treatment of LAST, out of which, 66.8% knew the correct dose and 77.2% and 26.5%, the availability and location of storage, respectively.

Conclusion

The basic knowledge on LAST was satisfactory among the respondents. A statistically significant difference on knowledge on maximum safe doses of LA, ILE in established LAST, its dosage and the availability was identified between anaesthetic and non-anaesthetic doctors and post graduate trainees and the rest of the doctors. Overall, significant lapses were noted with regard to the use of total body weight for dose calculations, use of ultrasound during LA administration and dosage, availability and storage of the definitive therapy, ILE, suggesting updates in these key areas.
Evidence for a multicellular symplasmic water pumping mechanism across vascular plant roots
Authors: Couvreur Valentin , Heymans Adrien , Lobet Guillaume , Draye Xavier
Published: April 2021

With global warming, climate zones are projected to shift poleward, and the frequency and intensity of droughts to increase, driving threats to crop production and ecosystems. Plant hydraulic traits play major roles in coping with such droughts, and process-based plant hydraulics (water flowing alongdecreasing pressure Ψpor total water potential Ψtotgradients) has newly been implemented in land surface models.

An enigma reported for the past 35 years is the observation of water flowing alongincreasing water potential gradientsacross roots. By combining the most advanced modelling tool from the emerging field of plant micro-hydrology with pioneering cell solute mapping data, we found thatthe current paradigm of water flow across roots ofall vascular plantsis incomplete: it lacks the impact of solute concentration (and thus negative osmotic potential Ψo) gradients acrosslivingcells. This gradient acts as a water pump as it reduces water tension without loading solutes in plant vasculature (xylem). Importantly, water tension adjustments in roots may have large impacts in leaves due to the tension-cavitation feedback along stems.

Here, we mathematically demonstrate the water pumping mechanism by solving water flow equations analytically on a triple-cell system. Then we show that the simplistic upscaled equations hold in 2- and 3-D maize, grapevine and Arabidopsis complex hydraulic anatomies, and that water may flow “uphill” of water potential gradients toward xylem as observed experimentally.

Besides its contribution to the fundamental understanding of plant water relations, this study lays new foundations for future multidisciplinary research encompassing plant physiology and ecohydrology, and has the ambition to mathematically capture a keystone process for the accurate forecasting of plant water status in crop models and LSMs.

Graphical Abstract

Highlights

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We provide a scale-consistent solution of water flow equations across root tissues

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Symplasmic osmotic potential gradients are missing in the current theory of root water uptake

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The model solves the empirical enigma of root water uptake uphill of water potential gradients
Real-Time EEG Neurofeedback as a Tool to Improve Neural Entrainment to Speech
Authors: Carrera Arias Francisco Javier , Molinaro Nicola , Lizarazu Mikel
Published: April 2021

Neurofeedback represents a particular type of biofeedback whose aim is to teach self-control of brain function by measuring brain activity and presenting a feedback signal in real-time. Traditionally, neurofeedback has been used to complement interventions for various neuropsychological disorders through techniques like frequency training, which attempts to change the power ratio of certain EEG frequency bands. However, to date, there are no neurofeedback approaches that look directly into modulating the neural entrainment to speech. Speech-brain entrainment, which stands for the alignment of the neural activity to the envelope of the speech input, has been shown to be key to speech comprehension. In fact, atypical neural entrainment to speech seems to be consistently found in language development disorders such as dyslexia. Thus, making speech entrainment neurofeedback a promising technique to obtain behavioral improvements. In this work, we present the first open-source brain-computer interface system that can be reliably used to provide speech entrainment neurofeedback while still being flexible enough to deliver more traditional coherence-based neurofeedback. In addition, it has the potential of being an open-source alternative to deliver other types of neurofeedback if configured to do so.
Refining the evolutionary time machine: an assessment of whole genome amplification using single historicalDaphniaeggs
Authors: O’Grady Christopher James , Dhandapani Vignesh , Colbourne John K. , Frisch Dagmar
Published: April 2021

Whole genome sequencing is instrumental for the study of genome variation in natural populations, delivering important knowledge on genomic modifications and potential targets of natural selection at the population level. Large dormant eggbanks of aquatic invertebrates such as the keystone herbivoreDaphnia, a microcrustacean widespread in freshwater ecosystems, provide detailed sedimentary archives to study genomic processes over centuries. To overcome the problem of limited DNA amounts in singleDaphniadormant eggs, we developed an optimised workflow for whole genome amplification (WGA), yielding sufficient amounts of DNA for downstream whole genome sequencing of individual historical eggs, including polyploid lineages. We compare two WGA kits, applied to recently producedDaphnia magnadormant eggs from laboratory cultures, and to historical dormant eggs ofDaphnia pulicariacollected from Arctic lake sediment between 10y and 300y old. Resulting genome coverage breadth in most samples was ~70%, including those from >100y old isolates. Sequence read distribution was highly correlated among samples amplified with the same kit, but less correlated between kits. Despite this, a high percentage of genomic positions with SNPs in one or more samples (maximum of 74% between kits, and 97% within kits) were recovered at a depth required for genotyping. As a by-product of sequencing we obtained 100% coverage of the mitochondrial genomes even from the oldest isolates (~300y). The mtDNA provides an additional source for evolutionary studies of these populations. We provide an optimised workflow for WGA followed by whole genome sequencing including steps to minimise exogenous DNA.
Deformation of membrane vesicles due to chiral surface proteins
Authors: Behera Arabinda , Kumar Gaurav , Akram Sk Ashif , Sain Anirban
Published: April 2021

Chiral, rod-like molecules can self-assemble into cylindrical membrane tubules and helical ribbons. They have been successfully modeled using the theory of chiral nematics. Models have also predicted the role of chiral lipids in forming nanometer-sized membrane buds in the cell. However, in most theoretical studies, the membrane shapes are considered fixed (cylinder, sphere, saddle, etc.), and their optimum radius of curvatures are found variationally by minimizing the energy of the composite system consisting of membrane and chiral nematics. Numerical simulations have only recently started to consider membrane deformation and chiral orientation simultaneously. Here we examine how deformable, closed membrane vesicles and chiral nematic rods mutually influence each other’s shape and orientation, respectively, using Monte-Carlo (MC) simulation on a closed triangulated surface. For this, we adopt a discrete form of chiral interaction between rods, originally proposed by Van der Meer et al. (1976) for off-lattice simulations. In our simulation, both conical and short cylindrical tubules emerge, depending on the strength of the chiral interaction and the intrinsic chirality of the molecules. We show that the Helfrich-Prost term, which couple nematic tilt with local membrane curvature in continuum models, can account for most of the observations in the simulation. At higher chirality, our theory also predicts chiral tweed phase on cones, with varying bandwidths.

PACS numbers: PACS : 87.16.-b, 87.15.Aa, 81.40.Jj, 87.15.Rn
Enhanced longitudinal differential expression detection in proteomics with robust reproducibility optimization regression
Authors: Välikangas Tommi , Suomi Tomi , Chandler Courtney E. , Scott Alison J , Tran Bao Q. , Ernst Robert K. , Goodlett David R. , Elo Laura L.
Published: April 2021

Quantitative proteomics has matured into an established tool and longitudinal proteomic experiments have begun to emerge. However, no effective, simple-to-use differential expression method for longitudinal proteomics data has been released. Typically, such data is noisy, contains missing values, has only few time points and biological replicates. To address this need, we provide a comprehensive evaluation of several existing differential expression methods for high-throughput longitudinal omics data and introduce a new method, Robust longitudinal Differential Expression (RolDE). The methods were evaluated using nearly 2000 semi-simulated spike-in proteomic datasets and a large experimental dataset. The RolDE method performed overall best; it was most tolerant to missing values, displayed good reproducibility and was the top method in ranking the results in a biologically meaningful way. Furthermore, contrary to many approaches, the open source RolDE does not require prior knowledge concerning the types of differences searched, but can easily be applied even by non-experienced users.
Prostaglandin E2directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling
Authors: Goepp Marie , Crittenden Siobhan , Zhou You , Rossi Adriano G , Narumiya Shuh , Yao Chengcan
Published: April 2021

Background and Purpose

Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing Th1 and Th17 cells. The bioactive lipid mediator prostaglandin E2(PGE2) promotes inflammatory Th1 and Th17 cells and exacerbates T cell-mediated autoimmune diseases. However, the actions of PGE2on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we examined whether PGE2had a direct action on T cells to modulatede novodifferentiation of Treg cells.

Experimental Approach

We employed anin vitroT cell culture system of TGF-β-dependent Treg induction from naïve T cells. PGE2and selective agonists for its receptors, and other small molecular inhibitors were used. Mice with specific lack of EP4 receptors in T cells were used to assess Treg cell differentiationin vivo. Human peripheral blood T cells from healthy individuals were used to induce differentiation of inducible Treg cells.

Key Results

TGF-β-induced Foxp3 expression and Treg cell differentiationin vitrowas markedly inhibited by PGE2, which was due to interrupting TGF-β signalling. EP2 or EP4 agonism mimicked suppression of Foxp3 expression in WT T cells, but not in T cells deficient in EP2 or EP4, respectively. Moreover, deficiency of EP4 in T cells impaired iTreg cell differentiationin vivo. PGE2also appeared to inhibit the conversion of human iTreg cells.

Conclusion and Implications

Our results show a direct, negative regulation of iTreg cell differentiation by PGE2, highlighting the potential for selectively targeting the PGE2-EP2/EP4 pathway to control T cell-mediated inflammation.

What is already known

PGE2promotes inflammatory Th1 and Th17 cells and facilitates T cell-mediated immune inflammation, but the action of PGE2on Treg cells is debated.

What does this study add

PGE2directly acts on T cells to inhibit inducible Treg cell differentiationin vitroandin vivothrough its receptors EP2 and EP4 and by antagonising TGF-β signalling.

What is the clinical significance

Therapeutically blocking the EP4 receptor may be beneficial for management of T cell-mediated autoimmune inflammation.
Independent information from PET, CSF and plasma biomarkers of tau pathology in Alzheimer’s disease
Authors: Ossenkoppele Rik , Reimand Juhan , Smith Ruben , Leuzy Antoine , Strandberg Olof , Palmqvist Sebastian , Stomrud Erik , Zetterberg Henrik ,   the Alzheimer’s Disease Neuroimaging Initiative, Scheltens Philip , Dage Jeffrey L. , Bouwman Femke , Blennow Kaj , Mattsson-Carlgren Niklas , Janelidze Shorena , Hansson Oskar
Published: April 2021

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer’s disease (AD) related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n=400) and ADNI (n=371). All had tau-PET ([18F]RO948 in BioFINDER-2, [18F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66% and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, andAPOEε4-carriership and Aβ-positivity, while increased tau-PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially Aβ pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.
Individualized VDJ recombination predisposes the available Ig sequence space
Authors: Slabodkin Andrei , Chernigovskaya Maria , Mikocziova Ivana , Akbar Rahmad , Scheffer Lonneke , Pavlović Milena , Bashour Habib , Snapkov Igor , Mehta Brij Bhushan , Weber Cédric R. , Gutierrez-Marcos Jose , Sollid Ludvig M. , Haff Ingrid Hobæk , Sandve Geir Kjetil , Robert Philippe A. , Greiff Victor
Published: April 2021

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual’s naïve Ig repertoire, and consequently (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual-specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also non-genetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor-based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.
Scalable Batch Fabrication of Ultrathin Flexible Neural Probes using Bioresorbable Silk Layer
Authors: Cointe Clement , Laborde Adrian , Nowak Lionel G , Bourrier David , Bergaud Christian , Maziz Ali
Published: April 2021

Flexible deep brain probes have been the focus of many research works and aims at achieving better compliance with the surrounding brain tissue while maintaining minimal rejection. Strategies have been explored to find the best way to implant a flexible probe in the brain, while maintaining its flexibility once positioned in the cortex. Here, we present a novel and versatile scalable batch fabrication approach to deliver ultra-thin and flexible penetrating neural probe consisting of a silk-parylene bilayer. The biodegradable silk layer provides a temporary and programmable stiffener to ensure ease of insertion of the ultrathin parylene-based flexible devices. The innovative and yet robust batch fabrication technology allows complete design freedom of the neural probe in terms of materials, size, shape and thickness. These results provide a novel technological solution for implanting ultra-flexible and ultrathin devices, which possesses great potential for brain research.
Nuclear retention of pre-mRNA involving Cajal bodies during meiotic prophase in plants
Authors: Rudzka Magda , Hyjek-Składanowska Malwina , Wróblewska-Ankiewicz Patrycja , Majewska Karolina , Gołębiewski Marcin , Sikora Marcin , Smoliński Dariusz Jan , Kołowerzo-Lubnau Agnieszka
Published: April 2021

Gene regulation ensures that the appropriate genes are expressed at the proper times. Nuclear retention of incompletely spliced or mature mRNAs emerges as a novel, previously underappreciated layer of post-transcriptional gene regulation. Studies on this phenomenon indicated that it exerted significant impact on the regulation of gene expression by regulating export and translation delay, which allows synthesis of specific proteins in response to a stimulus, e.g. under stress conditions or at strictly controlled time points, e.g. during cell differentiation or development. Here, we found that transcription in microsporocytes, during prophase of the first meiotic division, occurs in pulsatile manner. After each pulse, the transcriptional activity is silenced, but the transcripts synthesized at this time are not exported immediately to the cytoplasm, but are retained in the nucleoplasm and Cajal bodies (CBs). In contrast to nucleoplasm, mature transcripts were not found in CBs. Only non-fully-spliced transcripts with retained introns were stored in the CBs. Retained introns are spliced at precisely defined times, and fully mature mRNAs are released into the cytoplasm, where the proteins are produced. These proteins are necessary for further cell development during meiotic prophase. Our findings provide new insight into the regulatory mechanisms of gene expression based on mRNA retention in the nucleus during the development of generative cells in plants. Similar processes were observed during spermatogenesis in animals. This indicates the existence of an evolutionarily conserved mechanism of gene expression regulation during generative cells development in Eukaryota.
The forest avifauna of Arabuko Sokoke Forest and adjacent modified habitats
Authors: Chiawo David O. , Kombe Wellington N. , Craig Adrian J.F.K.
Published: April 2021

Arabuko Sokoke Forest (ASF) is the largest area of coastal forest remaining in East Africa and a major Important Bird Area in mainland Kenya. The study analysed data from point count surveys over 15 months in three land use types; primary forest (PF), plantation forest (PL), and farmlands (FM), and compared these to the first comprehensive bird checklist for the forest, as well as recent surveys from other studies. Avifaunal diversity and abundance were compared using multivariate analysis to determine bird responses to different land use characteristics. The primary forest held a distinctive bird community, while the bird communities of farmlands and plantation forest were more similar to each other. Land use had a significant effect on overall avian diversity and abundance. The current forest avifauna was divided into forest specialists (16 species), forest generalists (26 species) and forest visitors (30 species). Seven species of forest specialist and generalists recorded prior to 1980 may no longer occur in the forest. Of 38 specialists and generalists recorded in our point counts, 19 were also recorded on farmland and 28 in plantations. One forest specialist, the Green Barbet, was most encountered outside the forest. Future research should focus on habitat use by these bird species, and the extent of movement by forest birds between the remaining patches of coastal forest. Patterns of habitat use by birds in the area suggest that vegetation heterogeneity and habitat complexity are especially significant in sustaining diverse and abundant bird populations. The management of plantations and farmland will be critical for the conservation of forest generalists and forest visitors.
Chromatin profiling reveals genome stability heterogeneity in clinical isolates of the human pathogenAspergillus fumigatus
Authors: Colabardini Ana Cristina , Wang Fang , Miao Zhengqiang , Pardeshi Lakhansing , Valero Clara , de Castro Patrícia Alves , Akiyama Daniel Yuri , Tan Kaeling , Nora Luisa Czamanski , Silva-Rocha Rafael , Marcet-Houben Marina , Gabaldón Toni , Fill Taicia , Wong Koon Ho , Goldman Gustavo H.
Published: April 2021

Invasive Pulmonary aspergillosis is a life-threatening infection in immunosuppressed patients caused by the filamentous fungusAspergillus fumigatus. Chromatin structure regulation is important for genome stability maintenance and has the potential to lead to genome rearrangements driving differences in virulence and pathogenesis of differentA. fumigatusisolates. Here, we compared the chromatin activities of the most investigated clinical isolates Af293 and CEA17 and uncovered striking differences in the number, locations and expression of transposable elements. We found evidence for higher genome instability in Af293 as compared to CEA17 and identified a spontaneous Af293 variant that exhibits gross chromosomal alterations including the loss of a 320 kb long segment in chromosome VIII and the amplification of a biosynthetic gene cluster. As a consequence of these re-arrangements, the variant shows increased secondary metabolites production, growth and virulence. Our work emphasizes genome stability heterogeneity as an evolutionary driver ofA. fumigatusfitness and virulence.
MRI-derived brain age as a biomarker of ageing in rats: validation using a healthy lifestyle intervention
Authors: Brusini Irene , MacNicol Eilidh , Kim Eugene , Smedby Örjan , Wang Chunliang , Westman Eric , Veronese Mattia , Turkheimer Federico , Cash Diana
Published: April 2021

MRI data can be used as input to machine learning models to accurately predict brain age in healthy human subjects. A large difference between predicted and chronological brain age (the so-called BrainAGE score) has been associated with disease and neurodegeneration, indicating the potential utility of neuroimaging-based ageing biomarkers. So far, most brain age prediction studies have been carried out on humans. However, it is important for such a biomarker to be validated on laboratory animals too, in order to better account for specific environmental or genetic factors within a more controlled laboratory framework.

In this work, we developed a new algorithm for rat brain age prediction based on the combination of Gaussian process regression and a logistic regression classifier. The algorithm was trained on a cohort of 31 normal rats. High prediction accuracy was achieved using leave-one-out cross-validation (mean absolute error = 4.87 weeks, correlation between predicted and chronological ager= 0.92), supporting the validity and potential of the method.

Furthermore, the trained model was tested on two independent groups of 24 rats each: a new normal control group and a “healthy lifestyle” group that underwent long-term environmental enrichment and dietary restriction (EEDR) between 3 and 17 months of age. After fitting a linear mixed-effects model, the BrainAGE values were found to increase more slowly with chronological age in the EEDR group than in the controls (slope = 0.52 vs. 0.61;p= 0.015 for the interaction term). When survival analysis was performed with a Cox regression model, the BrainAGE score at 5 months of age had a significant prediction power (p= 0.03).

Our results demonstrate that BrainAGE, as computed by the proposed approach, is significantly modulated by EEDR intervention, hence it is a sensitive marker of biological ageing. These findings also support the potential of lifestyle-related prevention approaches to slow down the brain ageing process. Moreover, the results of the survival analysis further demonstrate that BrainAGE is indeed a predictor of ageing outcome.
Cellular and molecular mechanisms involved in LTP induced by mild theta-burst stimulation in hippocampal slices from young male rats: from weaning to adulthood
Authors: Rodrigues NC , Silva-Cruz A , Caulino-Rocha A , Bento-Oliveira A , Ribeiro JA , Cunha-Reis D
Published: April 2021

Long-term potentiation (LTP) is a highly studied cellular process yet determining the transduction and GABAergic pathways that are the essential vs. modulatory for LTP elicited by theta-burst stimulation (TBS) in the hippocampal CA1 area is still elusive, due to the use of different TBS intensities, patterns, or different rodent/cellular models. We now characterized the developmental maturation and the transduction and GABAergic pathways required for mild TBS-induced LTP in hippocampal CA1 area in male rats. LTP induced by TBS (5×4) (5 bursts of 4 pulses delivered at 100Hz) lasted for up to 3h and was increasingly larger from weaning to adulthood. Stronger TBS patterns - TBS (15×4) or three TBS (15×4) separated by 6 min induced nearly maximal LTP not being the best choice to study the value of LTP-enhancing drugs. LTP induced by TBS (5×4) in young adults was fully dependent on NMDA receptor and CaMKII activity but independent of PKA or PKC activity. Furthermore, it was partially dependent on GABABreceptor activation and was potentiated by GABAAreceptor blockade and less by GAT-1 transporter blockade. AMPA GluA1 phosphorylation on Ser831(CaMKII target) but not GluA1 Ser845(PKA target) was essential for LTP expression. The phosphorylation of the Kv4.2 channel was observed at Ser438(CaMKII target) but not at Thr602or Thr607(ERK/MAPK pathway target). This suggests that cellular kinases like PKA, PKC or kinases of the ERK/MAPK family although important modulators of TBS (5×4)-induced LTP may not be essential for its expression in the CA1 area of the hippocampus.

Graphical abstract

LTP induced by theta-burst stimulation (TBS) in young adult male rat hippocampal CA1 area is increasingly more robust with the number of bursts and number of spaced TBS trains. LTP induced by TBS shows developmental maturation increasing potentiation from weaning to adulthood. Expression of LTP induced bymild TBS (5×4)in young adults requires NMDA receptor and CaMKII activity and AMPA Ser831 phosphorylation, but not PKA or PKC activity, and is likely curtailed by Kv4.2 Ser438 phosphorylation.
Pooling in a predictive model of V1 explains functional and structural diversity across species
Authors: Franciosini Angelo , Boutin Victor , Chavane Frédéric , Perrinet Laurent U
Published: April 2021

Neurons in the primary visual cortex are selective to orientation with various degrees of selectivity to the spatial phase, from high selectivity in simple cells to low selectivity in complex cells. Various computational models have suggested a possible link between the presence of phase invariant cells and the existence of cortical orientation maps in higher mammals’ V1. These models, however, do not explain the emergence of complex cells in animals that do not show orientation maps. In this study, we build a model of V1 based on a convolutional network called Sparse Deep Predictive Coding (SDPC) and show that a single computational mechanism, pooling, allows the SDPC model to account for the emergence of complex cells as well as cortical orientation maps in V1, as observed in distinct species of mammals. By using different pooling functions, our model developed complex cells in networks that exhibit orientation maps (e.g., like in carnivores and primates) or not (e.g., rodents and lagomorphs). The SDPC can therefore be viewed as a unifying framework that explains the diversity of structural and functional phenomena observed in V1. In particular, we show that orientation maps emerge naturally as the most cost-efficient structure to generate complex cells under the predictive coding principle.

Significance

Cortical orientation maps are among the most fascinating structures observed in higher mammals brains: In such maps, similar orientations in the input image activate neighboring cells in the cortical surface. However, the computational advantage brought by these structures remains unclear, as some species (rodents and lagomorphs) completely lack orientation maps. In this study, we introduce a computational model that links the presence of orientation maps to a class of nonlinear neurons called complex cells. In particular, we propose that the presence or absence orientation maps correspond to different strategies employed by different species to generate invariance to complex stimuli.
AIE nanoparticles camouflaged with tumor cell-derived exosomes for NIR-II imaging-guided photothermal therapy
Authors: Li Yirun , Fan Xiaoxiao , Li Yuanyuan , Chen Runze , Ni Huwei , Zhang Yiyin , Xia Qiming , Feng Zhe , Tang Ben Zhong , Qian Jun , Lin Hui
Published: April 2021

Nanoparticles (NPs) assisted photothermal therapy (PTT) is a promising cancer treatment modality and has attracted the attention of the scientific mainstream. However, developing NPs that exhibit efficient optical properties and specific tumor targeting capability simultaneously is difficult. Herein, we develop hybrid nanovesicles consisting of tumor cell-derived exosomes (EXO) and organic aggregation-induced emission (AIE) nanoparticles (TT3-oCB NP@EXOs) with enhanced second near-infrared (NIR-II, 900-1700 nm) fluorescence property and PTT functionality. Compared with TT3-oCB NPs, TT3-oCB NP@EXOs exhibit excellent biocompatibility, specific targeting abilityin vitro, homing to homologous tumorsin vivo, and prolonged circulation time. Furthermore, TT3-oCB NP@EXOs were utilized as biomimetic NPs for NIR-II fluorescence imaging-guided PTT of tumors, due to their high and stable photothermal conversion capacity under 808 nm irradiation. Therefore, the tumor cell-derived EXO/AIE NP hybrid nanovesicles may provide an alternative artificial targeting strategy for improving tumor diagnosis and PTT.
The power of universal contextualised protein embeddings in cross-species protein function prediction
Authors: van den Bent Irene , Makrodimitris Stavros , Reinders Marcel
Published: April 2021

Computationally annotating proteins with a molecular function is a difficult problem that is made even harder due to the limited amount of available labelled protein training data. A recently published supervised molecular function predicting model partly circumvents this limitation by making its predictions based on the universal (i.e. task-agnostic) contextualised protein embeddings from the deep pre-trained unsupervised protein language model SeqVec. SeqVec embeddings incorporate contextual information of amino acids, thereby modelling the underlying principles of protein sequences insensitive to the context of species.

We applied the existing SeqVec-based molecular function prediction model in a transfer learning task by training the model on annotated protein sequences of one training species and making predictions on the proteins of several test species with varying evolutionary distance. We show that this approach successfully generalises knowledge about protein function from one eukaryotic species to various other species, proving itself an effective method for molecular function prediction in inadequately annotated species from understudied taxonomic kingdoms. Furthermore, we submitted the performance of our SeqVec-based prediction models to detailed characterisation, first to advance the understanding of protein language models and second to determine areas of improvement.

Author summary

Proteins are diverse molecules that regulate all processes in biology. The field of synthetic biology aims to understand these protein functions to solve problems in medicine, manufacturing, and agriculture. Unfortunately, for many proteins only their amino acid sequence is known whereas their function remains unknown. Only a few species have been well-studied such as mouse, human and yeast. Hence, we need to increase knowledge on protein functions. Doing so is, however, complicated as determining protein functions experimentally is time-consuming, expensive, and technically limited. Computationally predicting protein functions offers a faster and more scalable approach but is hampered as it requires much data to design accurate function prediction algorithms. Here, we show that it is possible to computationally generalize knowledge on protein function from one well-studied training species to another test species. Additionally, we show that the quality of these protein function predictions depends on how structurally similar the proteins are between the species. Advantageously, the predictors require only the annotations of proteins from the training species and mere amino acid sequences of test species which may particularly benefit the function prediction of species from understudied taxonomic kingdoms such as the Plantae, Protozoa and Chromista.
Accurate assignment of disease liability to genetic variants using only population data
Authors: Collaco Joseph M. , Raraigh Karen S. , Betz Joshua , Aksit Melis Atalar , Blau Nenad , Brown Jordan , Dietz Harry C. , MacCarrick Gretchen , Nogee Lawrence M. , Sheridan Molly B. , Vernon Hilary J. , Beaty Terri H. , Louis Thomas A. , Cutting Garry R.
Published: April 2021

Purpose

The growing size of public variant repositories prompted us to test the accuracy of predicting pathogenicity of DNA variants using population data alone.

Methods

Under thea prioriassumption that the ratio of the prevalence of variants in healthy and affected populations form two distinct distributions (pathogenic and benign), we used a Bayesian method to assign probability of a variant belonging to either distribution.

Results

The approach, termed BayPR, accurately parsed 300 of 313 expertly curatedcystic fibrosis transmembrane conductance regulator (CFTR)variants: 284 of 296 pathogenic/likely pathogenic (P/LP) variants in one distribution and 16 of 17 benign/likely benign (B/LB) variants in another. BayPR produced an area under the receiver operating curve (AUC) of 0.99 for 103 functionally-confirmed missenseCFTRvariants, equal to or exceeding ten commonly used algorithms (AUC range: 0.54 to 0.99). Application of BayPR to expertly curated variants in eight genes associated with seven Mendelian conditions assigned ≥80% disease-causing probability to 1,350 of 1,374 (98.3%) P/LP variants and ≤20% to 22 of 23 (95.7%) B/LB variants.

Conclusion

Agnostic to variant type or functional effect, BayPR provides probabilities of pathogenicity for DNA variants responsible for Mendelian disorders usingonlyvariant counts in affected and unaffected population samples.
Redundant neural circuits regulate olfactory masking
Authors: Yang Wenxing , Wu Taihong , Tu Shasha , Choi Myung-Kyu , Duan Fengyun , Zhang Yun
Published: April 2021

Olfactory masking is a complex olfactory response found in humans. However, the mechanisms whereby the presence of one odorant masks the sensory and behavioral responses elicited by another odorant are poorly understood. Here, we report thatCaenorhabditis elegansdisplays olfactory masking and that the presence of a repulsive odorant, 2-nonanone, that signals threat strongly masks the attraction of other odorants, such as isoamyl alcohol (IAA) or benzaldehyde that signals food. Using a forward genetic screen, we found that several genes,osm-5, osm-1, anddyf-7, known to regulate the structure and function of sensory neurons played a critical role in olfactory masking. Loss of these genes mildly reduces the response to 2-nonanone and disrupts the masking effect of 2-nonanone. Restoring the function of OSM-5 in either AWB or ASH, two sensory neurons known to mediate 2-nonanone-evoked avoidance, is sufficient to rescue olfactory masking. AWB is activated by the removal of 2-nonanone stimulation or the onset of IAA; however, the mixture of 2-nonanone and IAA stimulates AWB similarly as 2-nonanone alone, masking the cellular effect of IAA. The latency of the AWB response is critical for the masking effect. Thus, our results identify redundant neural circuits that regulate the robust masking effect of a repulsive odorant and uncover the neuronal and cellular basis for this complex olfactory task.

AUTHOR SUMMARY

In their natural environment, animals, including humans, encounter complex olfactory stimuli. However, regardless how complex the stimuli are, the behavioral output can only be one. Thus, how the brain processes multiple sensory cues to generate a coherent behavioral output is critical for the survival of the animal. In the present study, we combined molecular cellular genetics, optical physiology and behavioral analysis to study olfactory masking, a common olfactory phenomenon in which the presence of one odorant masks the stimulation of another odorant. Our results show that olfactory masking is regulated by redundant neuronal circuits, a mechanism that likely ensures the robust behavioral response to the sensory cue representing information critical for the survival.
A fossil fish assemblage from the middle Miocene of the Cocinetas Basin, northern Colombia
Authors: Ballen Gustavo A. , Jaramillo Carlos , Dagosta Fernando C. P. , De Pinna Mario C. C.
Published: April 2021

Freshwater fossil fish faunas have been long used to infer past drainage connections, as they are bounded by physical freshwater barriers. Here we study a middle Miocene (15.0-–15.5 Ma) freshwater fish fossil fauna (Makaraipao) from the Castilletes Formation in northern Colombia, nowadays west of the Andes. We record the presence of lungfishes (Lepidosiren), pacus (MylossomaandPiaractus), armored catfishes (Callichthyidae), and red-tail catfishes (Phractocephalus). Extant members of all those groups (except the Callichthyidae, due to lack of taxonomic resolution) are found in Amazonian faunas east of the Andes and are absent from faunas west of the Andes, indicating that the riverine systems of the Guajira Peninsula were connected to Amazonia during the middle Miocene. The similarity of La Venta (west of the Andes) and Rio Acre (east of the Andes) fish faunas during the late Miocene further indicates that the northern Andean uplift was not a complete barrier at least until∼11 Myr ago. However, there is a continental-wide structuring of the Miocene fish faunas that is also found in the extant faunas, suggesting that other factors such as ecological conditions, in addition to the uplift of the Andes, have shaped the biogeographic evolution of South American fish faunas.
The salmon-peloton: hydraulic habitat shifts of adult Atlantic salmon (Salmo salar) due to behaviour thermoregulation
Authors: O’Sullivan Antóin M. , Linnansaari Tommi , Leavitt Jaime , Samways Kurt M. , Kurylyk Barret L. , Curry R. Allen
Published: April 2021

In recent decades there has been an increase in conservation and restoration projects targeting Atlantic salmon (Salmo salar– AS), as populations in eastern Canada decline. Missing however, is an understanding of thermo-hydraulic habitat use by adult AS during summer, and thus the actual benefits of altering in-river physical structures. Here, we illustrated how optical and thermal infrared (TIR) imagery acquired from a UAV can be used in concert within-situdepth and velocity data to map adult AS and develop models of thermo-hydraulic habitats in the Miramichi River, New Brunswick. We found during optimal thermal conditions (< 19 °C) proximity to boulders and Froude numbers, a non-dimensional hydraulic metric, were key parameters that characterized adult AS habitat. However, during behavioural thermoregulation events (>19 °C), proximity to the cool thermal plume and Froude number, a non-dimensional hydraulic parameter, were critical controls on habitat use. We also observed AS formed a distinct geometric formation during behavioural thermoregulation events, and term this formation a ‘thermal-peloton’. The primary function of the peloton is undoubtedly to reduce thermally induced stressed; however, we conceptualize the geometry of the peloton attenuates hydraulic-drag, and reduces energetic expenditure of individuals practicing behavioural thermoregulation. These data provide an unrivaled viewpoint of thermo-hydraulic habitat selection by adult AS, and a blue print for restoration work. The use of UAV-based sensors has the potential to instigate a paradigm shift for river sciences. The age of applying hyper-resolution, remote sensing for river science and aquatic ecology is immensely exciting.
Microbial genomic trait evolution is dominated by frequent and rare pulsed evolution
Authors: Gao Yingnan , Wu Martin
Published: April 2021

On the macroevolutionary timescale, does trait evolution proceed gradually or by rapid bursts (pulses) separated by prolonged periods of stasis or slow evolution? Although studies have shown pulsed evolution is prevalent in animals, our knowledge about the tempo and mode of evolution across the tree of life is very limited. This long-standing debate calls for a test in bacteria and archaea, the most ancient and diverse forms of life with unique population genetic properties (asexual reproduction, large population sizes, short generation times, high dispersal rates and extensive lateral gene transfers). Using a likelihood-based framework, we analyzed evolutionary patterns of four microbial genomic traits (genome size, genome GC%, 16S rRNA GC% and the nitrogen use in proteins) on a broad macroevolutionary timescale. Our model fitting of phylogenetic comparative data shows that pulsed evolution is not only present, but also prevalent and predominant in microbial genomic trait evolution. Interestingly, for the first time, we detected two distinct types of pulsed evolution (small frequent and large rare jumps) that are predicted by the punctuated equilibrium and quantum evolution theories. Our findings suggest that major bacterial lineages could have originated in quick bursts and pulsed evolution is a common theme across the tree of life despite the drastically different population genetic properties of bacteria, archaea and eukaryotes.