bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of human dynamic object recognition revealed by sequential deep neural networks
Authors: Sörensen Lynn K. A. , Bohté Sander M. , de Jong Dorina , Slagter Heleen A. , Scholte H. Steven
Published: April 2022

Humans can rapidly recognize objects in a dynamically changing world. This ability is showcased by the fact that observers succeed at recognizing objects in rapidly changing image sequences, at up to 13 ms/image. To date, the mechanisms that govern dynamic object recognition remain poorly understood. Here, we developed deep learning models for dynamic recognition and compared different computational mechanisms, contrasting feedforward and recurrent, single-image and sequential processing as well as different forms of adaptation. We found that only models that integrate images sequentially via lateral recurrence mirrored human performance (N=36) and were predictive of trial-by-trial responses across image durations (13-80 ms/image) while also displaying a temporal correspondence. Augmenting this model with adaptation markedly improved dynamic recognition and accelerated its representational dynamics, thereby predicting human trial-by-trial responses using fewer processing resources. These findings provide new insights into the mechanisms rendering object recognition so fast and effective in a dynamic visual world.
Multimodal deep neural decoding of visual object representation in humans
Authors: Watanabe Noriya , Miyoshi Kosuke , Jimura Koji , Shimane Daisuke , Keerativittayayut Ruedeerat , Nakahara Kiyoshi , Takeda Masaki
Published: April 2022

Perception and categorization of objects in a visual scene are essential to grasp the surrounding situation. However, it is unclear how neural activities in spatially distributed brain regions, especially in terms of temporal dynamics, represent visual objects. To address this issue, we explored the spatial and temporal organization of visual object representations using concurrent functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), combined with neural decoding using deep neural networks (DNNs). Visualization of the fMRI DNN revealed that visual categorization (faces or non-face objects) occurred in brain-wide cortical regions, including the ventral temporal cortex. Interestingly, the EEG DNN valued the earlier phase of neural responses for categorization and the later phase of neural responses for sub-categorization. Combination of the two DNNs improved the classification performance for both categorization and sub-categorization. These deep learning-based results demonstrate a categorization principle in which visual objects are represented in a spatially organized and coarse-to-fine manner.
Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses
Authors: Macnair Will , Calini Daniela , Agirre Eneritz , Bryois Julien , Jäkel Sarah , Kukanja Petra , Stokar Nadine , Ott Virginie , Foo Lynette C. , Collin Ludovic , Schippling Sven , Urich Eduard , Nutma Erik , Marzin Manuel , Amor Sandra , Magliozzi Roberta , Heidari Elyas , Robinson Mark , ffrench-Constant Charles , Castelo-Branco Gonçalo , Williams Anna , Malhotra Dheeraj
Published: April 2022

The lack of understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. Here, to address this gap, we analysed 632,000 single nuclei RNAseq profiles of 156 brain tissue samples, comprising white matter (WM) lesions, normal appearing WM, grey matter (GM) lesions and normal appearing GM from 54 MS patients and 26 controls. We observed the expected changes in overall neuronal and glial numbers previously described within the classical lesion subtypes. We found highly cell type-specific gene expression changes in MS tissue, with distinct differences between GM and WM areas, confirming different pathologies. However, surprisingly, we did not observe distinct gene expression signatures for the classical different WM lesion types, rather a continuum of change. This indicates that classical lesion characterization better reflects changes in cell abundance than changes in cell type gene expression, and indicates a global disease effect. Furthermore, the major biological determinants of variability in gene expression in MS WM samples relate to individual patient effects, rather than to lesion types or other metadata. We identify four subgroups of MS patients with distinct WM glial gene expression signatures and patterns of oligodendrocyte stress and/or maturation, suggestive of engagement of different pathological processes, with an additional more variable regenerative astrocyte signature. The discovery of these patterns, which were also found in an independent MS patient cohort, provides a framework to use molecular biomarkers to stratify patients for optimal therapeutic approaches for progressive MS, significantly advances our mechanistic understanding of progressive MS, and highlights the need for precision-medicine approaches to address heterogeneity among MS patients.
AURTHO: autoregulation as facilitator of cis-acting element discovery of orthologous transcription factors
Authors: Anderssen Sinaeda , Naômé Aymeric , Jadot Cédric , Brans Alain , Tocquin Pierre , Rigali Sébastien
Published: April 2022

Transcriptional regulation is key in bacteria for providing an adequate response in time and space to changing environmental conditions. However, despite decades of research, the binding sites and therefore the target genes and the function of most transcription factors (TFs) remain unknown. Filling this gap in knowledge through conventional methods represents a colossal task which we demonstrate here can be significantly facilitated by a widespread feature in transcriptional control: the autoregulation of TFs implying that the yet unknown transcription factor binding site (TFBS) is neighbouring the TF itself. In this work, we describe the “AURTHO” methodology (AUtoregulation of oRTHOlogous transcription factors), consisting of analyzing upstream regions of orthologous TFs in order to uncover their associated TFBSs. AURTHO enabled the de novo identification of novel TFBSs with an unprecedented improvement in terms of quantity and reliability. DNA-protein interaction studies on a selection of candidate cis-acting elements yielded an >90% success rate, demonstrating the efficacy of AURTHO at highlighting true TF-TFBS couples and confirming the identification in a near future of a plethora of TFBSs across all bacterial species.

Key points

Transcription factor (TF) autoregulation implies that their binding site (TFBS) is in their close vicinity

We developed and assessed the AURTHO methodology (AUtoregulation of oRTHOlogous TFs) for TFBS discovery

Our results shows that AURTHO greatly facilitates the identification of highly reliable novel TFBSs
Thresholding Gini Variable Importance with a single trained Random Forest: An Empirical Bayes Approach
Authors: Dunne Robert , Reguant Roc , Ramarao-Milne Priya , Szul Piotr , Sng Letitia , Lundberg Mischa , Twine Natalie A. , Bauer Denis C.
Published: April 2022

Background

Random Forests (RF) are a widely used modelling tool, enabling feature-selection via a variable importance measure. For this, a threshold is required that separates label-associated features from false positives. In the absence of a good understanding of the characteristics of the variable importance measures, current approaches attempt to select features by training multiple RFs to generate statistical power via a permutation null, employ recursive feature elimination or a combination of both. However, for high-dimensional datasets, such as genome data with millions of variables, this is computationally infeasible.

Method

We present RFlocalfdr, a statistical approach for thresholding that identifies which features are significantly associated with the prediction label and reduces false positives. It builds on the empirical Bayes argument of Efron (2005) and models the variable importance as mixture of two distributions – null and non-null “genes.”

Result

We demonstrate on synthetic data that RFlocalfdr has an equivalent accuracy to computationally more intensive approaches, while being up to 100 times faster. RFlocalfdr is the only tested method able to successfully threshold a dataset with 6 Million features and 10,000 samples. RFlocalfdr performs analysis in real-time and is compatible with any RF implementation that returns variable importance and counts, such as ranger or VariantSpark.

Conclusion

RFlocalfdr allows for robust feature selection by placing a confidence value on the predicted importance score. It does so without repeated fitting of the RF or the use of additional shadow variables and is thus usable for data sets with very large numbers of variables.
ERPs responses to dominance features from human faces
Authors: Miao Chengguo , Li Xiaojun , Derrington Edmund , Li Yansong , Dreher Jean-Claude
Published: April 2022

Social dominance is an important feature of social life. Dominance has been proposed to be one of two trait dimensions underpinning social judgments of human faces. Yet, the neural bases of the ability to identify different dominance levels in others based on facial features remains poorly understood. Here, we used event-related potentials (ERPs) to determine the temporal dynamics of facial dominance evaluation based on facial features signaling physical strength/weakness in humans. Twenty-seven participants performed a dominance perception task where they passively viewed faces with different dominance levels. Dominance levels did not modulate an early component of face processing, known as the N170 component, but did modulate the Late Positive Potential (LPP) component. These findings indicate that participants inferred dominance levels at a late stage of face evaluation. Furthermore, the highest level of dominant faces and the lowest level of submissive faces both elicited higher LPP amplitudes than faces with a neutral dominance level. Taken together, the present study provides new insights regarding the dynamics of the neurocognitive processes underlying facial dominance evaluation.
Hazel dormouse in managed woodland select for young, dense, and species-rich tree stands
Authors: Mortensen Rasmus Mohr , Fuller Michelle Fyrstelin , Dalby Lars , Berg Thomas Bjørneboe , Sunde Peter
Published: April 2022

In fragmented forest landscapes, population persistence of arboreal species with limited dispersal ability may strongly depend on the quality of the remaining forest habitat. Using the hazel dormouse (Muscardinus avellanarius) as a model species, we studied habitat selection at two spatial scales (home range and within home range) in intensely managed woodlands at its northern distributional range in Denmark. We modelled selection at home range level as the conditional probability of occupancy of 588 nest boxes and nest tubes in 15 managed forests relative to habitat variables measured within 25 m radius. Habitat selection within home ranges was modelled by comparing habitat variables within 3 m radius of triangulated locations by 19 radio-tracked individuals (12 M, 7 F) when active at night with regularly distributed available locations within their home ranges.

At both spatial scales, hazel dormice strongly selected sites with high abundance-weighted species richness and high vegetation density of woody plants. On home range level, they furthermore selected for young tree vegetation, while they within home ranges selected for intermediate aged tree stands (maximum trunk circumference: 1.50 m). The predicted probability of presence in nest boxes or nest tubes varied from less than 1% to more than 99% as a combined function of three habitat variables. From May to October, selection for abundance-weighted species richness of woody plants of radio-tagged individuals decreased with date and body weight, suggesting that a diverse food base is particularly important early in their season of activity and for lean and small (growing) individuals. Selection for dense vegetation increased with body mass and mean available vegetation density within home ranges, indicating behavioural variability related to changes in energy expenditure and need for safety among individuals.

The study demonstrates that the hazel dormouse has specific habitat requirements related to food and safety that can be accommodated with relatively simple means in managed forests.

Graphical abstract
PhenoComb: A discovery tool to assess complex phenotypes in high-dimension, single-cell datasets
Authors: Burke Paulo E. P. , Strange Ann , Monk Emily , Thompson Brian , Amato Carol M. , Woods David M.
Published: April 2022

Motivation

High-dimension cytometry assays can simultaneously measure dozens of markers, enabling the investigation of complex phenotypes. However, as manual gating relies on previous biological knowledge, few marker combinations are often assessed. This results in complex phenotypes with potential for biological relevance being overlooked. Here we present PhenoComb, an R package that allows agnostic exploration of phenotypes by assessing all combinations of markers.

Design

PhenoComb uses signal intensity thresholds to assign markers to discrete states (e.g. negative, low, high) and then counts the number of cells per sample from all possible marker combinations in a memory-safe manner. Time and disk space are the only constraints on the number of markers evaluated. PhenoComb also provides several approaches to perform statistical comparisons, evaluate the relevance of phenotypes, and assess the independence of identified phenotypes. PhenoComb allows users to guide analysis by adjusting several function arguments such as identifying parent populations of interest, filtering of low-frequency populations, and defining a maximum complexity of phenotypes to evaluate. We have designed PhenoComb to be compatible with local computer or server-based use.

Results

In testing of PhenoComb’s performance on synthetic datasets, computation on 16 markers was completed in the scale of minutes and up to 26 markers in hours. We applied PhenoComb to two publicly available datasets: an HIV flow cytometry dataset (12 markers and 421 samples) and the COVIDome CyTOF dataset (40 markers and 99 samples). In the HIV dataset, PhenoComb identified immune phenotypes associated with HIV seroconversion, including those highlighted in the original publication. In the COVID dataset, we identified several immune phenotypes with altered frequencies in infected individuals relative to healthy individuals. Collectively, PhenoComb represents a powerful discovery tool for agnostically assessing high-dimension, single-cell data.

Availability

The PhenoComb R package can be downloaded from https://github.com/SciOmicsLab/PhenoComb
A Novel Caenorhabditis elegans Gene Network Uncovers Mechanisms of Mitochondrial Maintenance
Authors: Moreno Armando , Taffet Allison , Tjahjono Elissa , Kirienko Natalia V.
Published: April 2022

Mitochondria play key roles in cellular health and metabolism and are a critical determinant of the activation of multiple cell death processes. Although several pathways for regulating and re-establishing mitochondrial homeostasis have been identified within the past twenty years, large gaps remain in our understanding of how cells keep mitochondria healthy.

To address this limitation, have developed a network of genes that underlie mitochondrial health. We began by compiling a list of frequently mutated genes using publicly available data from multiple human cancer cell lines. RNAi was used to disrupt orthologous genes in the model organism Caenorhabditis elegans in a series of assays to evaluate these genes’ ability to support mitochondrial health, as evidenced by precocious activation of mitochondrial autophagy and sensitivity to acute mitochondrial damage. Iterative screening of ~1000 genes yielded a network of 139 genes showing significant connectivity.

Functional validation of a panel of genes from the network indicated that disruption of each gene triggered at least one phenotype consistent with mitochondrial dysfunction, including increased fragmentation of the mitochondrial network, abnormal steady-state levels of ATP, NADH, or ROS, and altered oxygen consumption. Importantly, RNAi-mediated knockdown of these genes often exacerbated α-synuclein aggregation in a C. elegans model of Parkinson’s disease, indicating significant changes to cellular health. Additionally, human orthologs of the final mitochondrial health gene network showed enrichment for roles in a number of human disorders identified in the OMIM database. This gene network provides a foundation for identifying new mechanisms that support mitochondrial and cellular homeostasis.
Genotype error biases trio-based estimates of haplotype phase accuracy
Authors: Browning Brian L. , Browning Sharon. R.
Published: April 2022

Haplotypes can be estimated from unphased genotype data using statistical methods. When parent-offspring data are available for inferring true phase from Mendelian inheritance rules, the accuracy of statistical phasing is usually measured by the switch error rate, which is the proportion of pairs of consecutive heterozygotes that are incorrectly phased. We present a method for estimating the genotype error rate from parent-offspring trios and a method for estimating the bias in the observed switch error rate that is caused by genotype error. We apply these methods to 485,301 genotyped UK Biobank samples that include 899 White British trios and to 38,387 sequenced TOPMed samples that include 217 African Caribbean trios and 669 European American trios. We show that genotype error inflates the observed switch error rate and that the relative bias increases with sample size. For the UK Biobank White British trios, we estimate that the observed switch error rate in the trio offspring is 2.4 times larger than the true switch error rate (1.41 × 10−3 vs 5.79 × 10−4) and that the average distance between phase errors is 64 megabases.
Drug combination prioritization for cancer treatment using single-cell RNA-seq based transfer learning
Authors: Osorio Daniel , McGrail Daniel J. , Sahni Nidhi , Yi S. Stephen
Published: April 2022

Precision oncology seeks to match patients to the optimal pharmacological regimen; yet, due to tumor heterogeneity, this is challenging. Numerous studies have been conducted to produce clinically relevant pharmacological response forecasts by integrating modern machine learning algorithms and several data types. Insufficient patient numbers and lack of knowledge of the molecular targets for each drug under study limit their use. As a proof of concept, we use single-cell RNA-seq based transfer learning to contextualize patients’ tumor cells in terms of their more similar cell lines with known susceptibility to drug combinations. Our objective is to maximize the translational potential of in-vitro assays for identifying synergistic drug combinations and prioritizing them for clinical use. Consistent findings in a cohort of breast cancer patients corroborated our understanding of the disease’s molecular subtypes. To aid in creating personalized treatments and data-driven clinical trials, we identified the most prevalent cell lines and prioritized synergistic combinations based on tumor compositions at various resolution levels.
Mouse brain-wide transgene expression by systemic injection of genetically engineered exosomes: CAP-Exosomes
Authors: Sarkar Saumyendra N , Corbin Debora , Simpkins James W
Published: April 2022

The bottleneck in drug discovery for central nervous system diseases is the absence of effective systemic drug delivery technology for delivering therapeutic drugs into the brain. Although some Adeno Associated Virus (AAV) serotype can cross blood brain barrier and deliver virus genome packaged therapeutic DNA (gene) or RNA molecules to brain cells along with other organs, several hurdles have emerged in the AAV9 vector gene transfer technology in both preclinical studies and clinical trials. In order to overcome some of the hurdles, we have developed a workflow to generate a novel brain targeted drug delivery system (DDS) that involves generation of genetically engineering exosomes by first selecting various functional AAV capsid specific peptides (collectively called CAP) known to be involved in brain targeted high expression gene delivery, and then expressing the CAP in frame with lysosome-associated membrane glycoprotein (Lamp2b) followed by expressing CAP-Lamp2b fusion protein on the surface of mesenchymal stem cell derived exosomes, generating CAP-exosomes. Intravenous injection of green fluorescent protein (GFP) gene loaded CAP-exosomes in mice transfer GFP gene throughout the CNS as measured by monitoring brain sections for GFP expression with confocal microscopy. GFP gene transfer efficiency is at least 20-fold greater than that of control Lamp2b-exosomes. GFP gene transduction to mouse liver was low. CAP-exosome has advantage over AAV-vector including, 1) no restriction in gene size to be delivered, 2) expected reduced production of neutralizing antibody, and 3) can be used separately for drug repurposing and/or in combination with therapeutic genes.

Graphical Abstract
Analysis of flavonol regulator evolution in the Brassicaceae reveals MYB12, MYB111 and MYB21 duplications associated with MYB11 and MYB24 gene loss
Authors: Schilbert Hanna M. , Glover Beverley J.
Published: April 2022

Background

Flavonols are the largest subgroup of flavonoids, possessing multiple functions in plants including protection against ultraviolet radiation, antimicrobial activities, and flower pigmentation together with anthocyanins. They are of agronomical and economical importance because the major off-taste component in rapeseed protein isolates is a flavonol derivative, which limits rapeseed protein use for human consumption. Flavonol production in Arabidopsis thaliana is mainly regulated by the subgroup 7 (SG7) R2R3-MYB transcription factors MYB11, MYB12, and MYB111. Recently, the SG19 MYBs MYB21, MYB24, and MYB57 were shown to regulate flavonol accumulation in pollen and stamens. The members of each subgroup are closely related, showing gene redundancy and tissue-specific expression in A. thaliana. However, the evolution of these flavonol regulators inside the Brassicaceae, especially inside the Brassiceae, which include the rapeseed crop species, is not fully understood.

Results

We studied the SG7 and SG19 MYBs in 44 species, including 31 species of the Brassicaceae, by phylogenetic analyses followed by synteny and gene expression analyses. Thereby we identified a deep MYB12 and MYB111 duplication inside the Brassicaceae, which likely occurred before the divergence of Brassiceae and Thelypodieae. These duplications of SG7 members were followed by the loss of MYB11 after the divergence of Eruca vesicaria from the remaining Brassiceae species. Similarly, MYB21 experienced duplication before the emergence of the Brassiceae family, where the gene loss of MYB24 is also proposed to have happened. Due to the overlapping spatio-temporal expression patterns of the SG7 and SG19 MYB members in B. napus, the loss of MYB11 and MYB24 is likely to be compensated by the remaining homologs.

Conclusions

We identified a duplication of MYB12, MYB111, and MYB21 inside the Brassicaceae which is associated with MYB11 and MYB24 gene loss inside the tribe Brassiceae. We propose that gene redundancy and meso-polyploidization events have shaped the evolution of the flavonol regulators in the Brassicaceae, especially in the Brassiceae.
The effects of environmental heterogeneity within a city on the evolution of clines
Authors: Santangelo James S. , Roux Cindy , Johnson Marc T. J.
Published: April 2022

There is increasing evidence that environmental change associated with urbanization can drive rapid adaptation. However, most studies of urban adaptation have focused on coarse urban vs. rural comparisons or sampled along a single urban-rural environmental gradient, thereby ignoring the role that within-city environmental heterogeneity might play in adaptation to urban environments.

In this study, we examined fine-scale variation in the presence of HCN—a potent anti-herbivore defense—and its two underlying genes (Ac and Li) between park green spaces and surrounding suburban habitats for five city parks in the Greater Toronto Area.

We show that fine-scale urbanization has driven the formation of micro-clines in HCN on a scale of < 2 km, though the presence and strength of micro-clines varied across parks. Interestingly, these micro-clines were driven by lower HCN frequencies inside park green spaces, and are therefore in the opposite direction to that predicted based on previously described patterns of HCN frequency change along urban-rural gradients.

Synthesis: These results suggest larger scale, adaptive urban-rural clines occur across a complex matrix of environmental heterogeneity within cities that drives fine-scale adaptive microclines of varying strengths and directions.
Experimental identification of individual insect visual tracking delays in free flight and their effects on visual swarm patterns
Authors: Islam Md. Saiful , Faruque Imraan A.
Published: April 2022

Insects are model systems for swarming robotic agents, yet engineered descriptions do not fully explain the mechanisms by which they provide onboard sensing and feedback to support such motions; in particular, the exact value and population distribution of visuomotor processing delays are not yet quantified, nor the effect of such delays on a visually-interconnected swarm. This study measures untethered insects performing a solo in-flight visual tracking task and applies system identification techniques to build an experimentally-consistent model of the visual tracking behaviors, and then integrates the measured experimental delay and its variation into a visually interconnected swarm model to develop theoretical and simulated solutions and stability limits. The experimental techniques include the development of a moving visual stimulus and real-time multi camera based tracking system called VISIONS1 providing the capability to recognize and simultaneously track both a visual stimulus (input) and an insect at a frame rate of 60-120 Hz. A frequency domain analysis of honeybee tracking trajectories is conducted via fast Fourier and Chirp Z transforms, identifying a coherent linear region and its model structure. The model output is compared in time and frequency domain simulations. The experimentally measured delays are then related to probability density functions, and both the measured delays and their distribution are incorporated as inter-agent interaction delays in a second order swarming dynamics model. Linear stability and bifurcation analysis on the long range asymptotic behavior is used to identify delay distributions leading to a family of solutions with stable and unstable swarm center of mass (barycenter) locations. Numerical simulations are used to verify these results with both continuous and modeled distributions.

The results of this experiment quantify a model structure and temporal lag (transport delay) in the closed loop dynamics, and show that this delay varies across 50 individuals from 5-110ms, with an average delay of 22ms and a standard deviation of 40ms. When analyzed within the swarm model, the measured delays support a diversity of solutions and indicate an unstable barycenter.
Beyond control: experimental control protocol slightly affects prepubescent mice behavior in a sex-specific manner
Authors: Moraes Muiara A , Árabe Laila Blanc , Resende Bruna Lopes , Codo Beatriz Campos , Reis Ana Luíza A. L. , Souza Bruno Rezende
Published: April 2022

Study design and experimental tools are crucial for good quality science, and an important part of it is the choice of control groups to best test the hypothesis. Two of the most common control groups in research are needle prickling without substance injection (Sham) and/or vehicle injection (Saline). Very few studies investigated the behavioral effects of a single intraperitoneal (i.p) Sham and/or single i.p. Saline administration in mice, mostly using adult males. In this study, we investigated if a single i.p. Sham and/or i.p. Saline administration affects female and male prepubertal (4-weeks-old) mice behavior. After Sham or Saline injection, we examined exploratory/motor behavior (open field test – OFT), anxiety-like behavior (elevated plus-maze – EPM), and behavioral despair/depressive-like behavior (forced swimming test – FST). We observed that both Sham prepubertal females and males showed minor behavioral alterations in OFT and EPM, and Saline males showed behavioral alterations in OFT and FST. On the other hand, prepubertal Saline females showed an increase in exploratory behavior, risk assessment/anxiety-like behavior, and behavioral despair/depressive-like behavior. Thus, we observed that the experimental procedures used as control have mild (but not insignificant) consequences on prepubescent mice behavior. However, the consequences of control protocols in prepubescent females are stronger than in males. To the best of our knowledge, this is the first study investigating the consequences of Sham and Saline protocols in prepubertal mice. This study highlights how important is to include Naïve animals (Negative control) together with Sham and/or Vehicle for a better and more honest interpretation of the data.
Hippocampal hypothyroidism in mice promotes glial cell activation and spatial memory deficits
Authors: Chamas Lamis , Seugnet Isabelle , Poirier Roseline , Clerget-Froidevaux Marie-Stéphanie , Enderlin Valérie
Published: April 2022

Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism, neuroinflammation and spatial memory, from a protective prospective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulating TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of local TH levels over circulating levels and the major role of hippocampal glia reactivity in the establishment of memory deficits.
Abstinence-dependent effects of long-access cocaine self-administration on nucleus accumbens astrocytes are observed in male, but not female rats
Authors: Kim Ronald , Testen Anze , Harder Eden V. , Brown Natalie E. , Witt Emily A. , Bellinger Tania J. , Franklin Janay P. , Reissner Kathryn J.
Published: April 2022

Accumulating evidence indicates significant consequences for astrocytes associated with drug abuse. For example, reductions in structural features and synaptic colocalization of male rat nucleus accumbens (NAc) astrocytes are observed following short-access (ShA, 2 hours/day) self-administration and extinction from cocaine, methamphetamine, and heroin. However, it is unknown whether these observations extend to other rodent models of drug abuse, how enduring these effects may be, and whether similar effects are observed in female rats. Here we assess the effects of long-access (LgA, 6 hours/day) cocaine self-administration and abstinence on NAc astrocytes separately in male and female rats, a commonly used behavioral approach to investigate the incubation of cocaine craving. NAc astrocytes from male rats exhibit extensive (∼40%) reductions in surface area, volume, and postsynaptic colocalization 45 days, but not 24 hours after the last self-administration session. In contrast, no effect of self-administration was observed in astrocytes from female rats. Moreover, no effect of LgA self-administration and abstinence was observed on NAc GLT-1 expression in female rats, an effect that has been well described in males. The results indicate striking and sexually dimorphic effects of abstinence subsequent to LgA self-administration on astrocytes. Taken together, these results indicate a pivotal role of prolonged abstinence in the effects of cocaine self-administration on NAc astrocytes, and extend a growing body of evidence regarding sex differences in the cellular consequences of drug self-administration in the brain.
Functional recovery from tactile stimulation after perinatal cortical injury is mediated by FGF-2
Authors: Gibb Robbin , Kolb Bryan
Published: April 2022

The consequences of perinatal brain injury can be devastating but currently there are few effective treatments. We sought to determine if tactile stimulation (TS) or exogenous application of fibroblast growth factor-2 (FGF-2) following injury could reverse the behavioral loss. Infant rats received frontal cortex removals on postnatal day 4 (P4) or a sham surgery. The TS animals received thrice-daily 15-minute bouts of stimulation (Experiment 1) on the day following surgery until weaning. In Experiment 2, treated animals received subcutaneous injections of FGF-2 once daily for one week, postsurgery. Behavioral testing began on postnatal day 60. Brains were later processed for Golgi analysis. We show in Experiment 1, that tactilely stimulating infant rats with perinatal cortical injury stimulates functional recovery and reverses injury-related changes in neuronal morphology in the cerebral cortex. The TS induction of recovery is associated with changes in expression of FGF-2 in both the skin and brain. Direct administration of FGF-2 (Experiment 2) is also effective in facilitating recovery, although not as completely as TS. These results suggest that early behavioral intervention after perinatal cortical injury can stimulate plastic neuronal changes that can underlie functional recovery and that these changes are mediated, in part, through an upregulation of FGF-2.
Proteome-wide identification of amino acid substitutions deleterious for protein function
Authors: Rodriguez-Mias Ricard A. , Hess Kyle N. , Ruiz Bianca Y. , Smith Ian R. , Barente Anthony S. , Zimmerman Stephanie M. , Lu Yang Y. , Noble William S. , Fields Stanley , Villén Judit
Published: April 2022

DNA sequencing has led to the discovery of millions of mutations that change the encoded protein sequences, but the impact of nearly all of these mutations on protein function is unknown. We addressed this scarcity of functional data by developing Miro, a proteomic technology that uses mistranslation to introduce amino acid substitutions and biochemical assays to quantify functional differences of thousands of protein variants by mass spectrometry. We apply this technology to the proteome of yeast to reveal amino acid substitutions that impact protein structure, ligand binding, protein-protein interactions, protein post-translational modifications, and protein thermal stability. Adapting Miro to human cells will provide a means to efficiently accelerate our mechanistic interpretation of genomic mutations to predict disease risk.
Plastic loss of motile cilia in the gills ofPolypterusin response to high CO2or terrestrial environments
Authors: Kimura Yuki , Nakamuta Nobuaki , Nikaido Masato
Published: April 2022

The evolutionary transition of vertebrates from water to land during the Devonian period was accompanied by major changes in animal respiratory systems in terms of physiology and morphology. Indeed, the fossil record of the early tetrapods has revealed the existence of internal gills, which are vestigial fish-like traits used underwater. However, the fossil record provides only limited data on the process of the evolutionary transition of gills from fish to early tetrapods. This study investigated the gills ofPolypterus senegalus, a basal ray-finned/amphibious fish which shows many ancestral features of stem Osteichthyes. Based on scanning electron microscopy observations and transcriptome analysis, the existence of motile cilia in the gills was revealed which may create a flow on the gill surface leading to efficient ventilation or remove particles from the surface. Interestingly, these cilia were observed to disappear after rearing in terrestrial or high CO2environments, which mimics the environmental changes in the Devonian period. The cilia re-appeared after being returned to the original aquatic environment. The ability of plastic changes of gills inPolypterusrevealed in this study may allow them to survive in fluctuating environments, such as shallow swamps. The ancestor of Osteichthyes is expected to have possessed such plasticity in the gills, which may be one of the driving forces behind the transition of vertebrates from water to land.
Evaluation of in silico predictors on short nucleotide variants in HBA1, HBA2 and HBB associated with haemoglobinopathies
Authors: Tamana Stella , Xenophontos Maria , Minaidou Anna , Stephanou Coralea , Harteveld Cornells L. , Bento Celeste , Traeger-Synodinos Joanne , Fylaktou Irene , Yasin Norafiza Mohd , Hamid Faidatul Syazlin Abdul , Esa Ezalia , Halim-Fikri Hashim , Zilfalil Bin Alwi , Kakouri Andrea C. ,   ClinGen Hemoglobinopathy VCEP, Kleanthous Marina , Kountouris Petros
Published: April 2022

Introduction

Haemoglobinopathies are the commonest monogenic diseases worldwide and are caused by variants in the globin gene clusters. With over 2400 variants detected to date, their interpretation using the ACMG/AMP guidelines is challenging, with computational evidence able to provide valuable input about their functional annotation. While many in silico predictors have already been developed, their performance varies for different genes and diseases.

Materials and Methods

We evaluate 31 in silico predictors using a dataset of 1627 variants in HBA1, HBA2, and HBB. Through varying the decision threshold for each tool, we analyse their performance (a) as binary classifiers of pathogenicity, and (b) using different nonoverlapping pathogenic and benign thresholds for their optimal use in the ACMG/AMP framework.

Results

CADD, Eigen-PC, and REVEL are the overall top performers, with the former reaching moderate strength level for pathogenic prediction. Eigen-PC and REVEL achieve the highest accuracies for missense variants, while CADD is also a reliable predictor of nonmissense variants. Moreover, SpliceAl is the top performing splicing predictor, reaching strong level of evidence, while GERP++ and phyloP are the most accurate conservation tools.

Discussion

This study provides evidence about the optimal use of computational evidence in globin gene clusters under the ACMG/AMP framework.
A six-months, long acting, one-shot injectable formulation of Ivermectin as a complementary malaria vector control tool to target zoophagic Anopheles : laboratory and model-based proofs of concept
Authors: Pooda Sié Hermann , Moiroux Nicolas , Porciani Angélique , Courgeault Anne-Laure , Roberge Christophe , Gaudriault Georges , Sidibé Issa , Belem Adrien Marie Gaston , Rayaissé Jean-Baptiste , Dabiré Roch K. , Mouline Karine
Published: April 2022

Context

In the current context of residual plasmodium transmission where zoophagic proclivities of Anopheles intervene, we propose to treat peridomestic animals using the endectocide Ivermectin as a complementary approach to bednets. As Ivermectin remanence with classic veterinary compounds is insufficient to induce a significant decrease in vectors’ populations, we developed a long-lasting injectable formulation of ivermectin from the BEPO® technology designed to release insecticidal concentrations of the molecule for 6 months. The work reported here is a proof of concept that using this new technology could help decrease field Anopheles populations.

Methods

Eight calves were injected with Ivermectin therapeutic doses of 1.2 mg/kg body weight using 2 long lasting formulations (A and B). Efficacy of the product at killing wild derivedAn. coluzziihas been evaluated by direct-skin feeding assays from 1 to 210 days after injection (DAI). Efficacy on survival was estimated with Cox proportional hazards mixed models and Kaplan meier estimates. To predict efficacy in field-based scenarii, we used a transmission model fed with an entomological model considering different levels for the Anopheles’ zoophagic preference, calves vs humans ratios, and bed net use variables.

Results

The release at mosquitocidal plasmatic concentrations of Ivermectin during 6 months is confirmed for both formulations (Hazard ratios > 1 for both formulations against their vehicle for 210 days). The Ivermectin concentration allowing to kill 90% of the mosquitoes before the extrinsic incubation period of the parasite is achieved (10 days) are 11 and 9 ng/ml for formulations A and B if the blood meal is taken before the infectious one, and 15 and 13 ng/ml if it was taken after. Modeling showed that Ivermectin treatment of calves using BEPO® technology would reduce infectious vector populations, from at least 35% for most anthropophagic Anopheles in villages where cattle to human ratio is the lowest, to more than 75% if vectors were zoophagic and calves numbers superior to humans’.

Conclusion

Our study gives the proof of concept that a long-lasting formulation of Ivermectin administered to calves could help decrease field malaria vectors’ populations, which may, ultimately, have an impact at the epidemiological level.
The molecular mechanism and physiological role of silent nociceptor activation
Authors: Nees Timo A. , Wang Na , Adamek Pavel , Verkest Clement , La Porta Carmen , Schaefer Irina , Virnich Julie , Balkaya Selin , Prato Vincenzo , Morelli Chiara , Zeitzschel Nadja , Begay Valerie , Lee Young Jae , Tappe-Theodor Anke , Lewin Gary R. , Heppenstall Paul A. , Taberner Francisco J. , Lechner Stefan G.
Published: April 2022

Silent nociceptors are sensory afferents that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli during inflammation. Using RNA-sequencing and quantitative RT-PCR we demonstrate that inflammation selectively upregulates the expression of the transmembrane protein TMEM100 in silent nociceptors and electrophysiology revealed that over-expression of TMEM100 is required and sufficient to un-silence silent nociceptors. Moreover, we show that mice lacking TMEM100 do not develop secondary allodynia – i.e. pain hypersensitivity that spreads beyond the site of inflammation – in a mouse model of knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce allodynia in remote skin regions without causing knee joint pain. Thus, our work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and reveals a physiological role for this hitherto enigmatic afferent subclass in triggering spatially remote secondary allodynia during inflammation.
Resetting H3K4me3, H3K27ac, H3K9me3 and H3K27me3 during the maternal-to-zygotic transition and blastocyst lineage specification in bovine embryos
Authors: Zhou Chuan , Halstead Michelle M. , Bonnet-Garnier Amèlie , Schultz Richard M. , Ross Pablo J.
Published: April 2022

It remains poorly understood how histone modifications regulate changes in gene expression during preimplantation development. Using a bovine model, we profiled changes in two activating (H3K4me3 and H3K27ac) and two repressive (H3K9me3 and H3K27me3) marks in oocytes, 2-, 4- and 8-cell embryos (that developed in the presence or absence of the transcription inhibitor a-amanitin), morula, blastocysts, inner cell mass cells and trophectoderm. In oocytes, we find that broad bivalent domains of H3K4me3 and H3K27me3 mark developmental genes, and that prior to genome activation, H3K9me3 and H3K27me3 co-occupy gene bodies. During genome activation, chromatin accessibility is established before canonical H3K4me3 and H3K27ac, and although embryonic transcription is required for this active remodeling, it is dispensable for maintenance of pre-established histone marks. Finally, blastocyst lineages are defined by differential Polycomb repression and transcription factor activity. Overall, these results further support the use of bovine as a more appropriate model system than the mouse to study genome activation and cell lineage specification during human preimplantation development.
Global disparity of research allocation and the Aichi biodiversity conservation targets
Authors: Mugerwa Badru , Niedballa Jürgen , Planillo Aimara , Sheil Douglas , Kramer-Schadt Stephanie , Wilting Andreas
Published: April 2022

Tracking progress towards global biodiversity conservation targets requires appropriate allocation of research and monitoring efforts. We conducted a global review of camera trap research on mammals as a proxy for biodiversity research and monitoring over the last two decades. We assessed how 3395 research locations from 2324 studies tracked priority regions for attaining the 2020 Aichi Biodiversity Targets. We used a geospatial distribution modelling approach to predict the spatial allocation of biodiversity research and to identify its key drivers. We show that conservation research in the past two decades has often failed to target areas important for conservation, and that 76.8% of the global research allocation can be attributed to country income, biome, mammal richness and accessibility. We predicted lowest probabilities of research allocation in low income countries. The Amazon and Congo Forest basins — two highly biodiverse ecosystems facing unprecedented human alteration — received inadequate research attention. Even in the most researched regions, an average of 51.4% of the research locations were outside the top 20% most important areas for the global biodiversity Aichi Targets. To support biodiversity conservation targets, policy and practice, more research and monitoring is required in regions with high importance for conservation.