bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal Variability of Brain-Behavior Relationships in Fine-Scale Dynamics of Edge Time Series
Authors: Cutts Sarah A. , Chumin Evgeny J. , Betzel Richard F. , Sporns Olaf
Published: September 2023

Most work on functional connectivity (FC) in neuroimaging data prefers longer scan sessions or greater subject count to improve reliability of brain-behavior relationships or predictive models. Here, we investigate whether systematically isolating moments in time can improve brain-behavior relationships and outperform full scan data. We perform optimizations using a temporal filtering strategy to identify time points that improve brain-behavior relationships across 58 different behaviors. We analyzed functional brain networks from resting state fMRI data of 352 healthy subjects from the Human Connectome Project. Templates were created to select time points with similar patterns of brain activity. Optimizations were performed to produce templates for each behavior that maximize brain-behavior relationships from reconstructed functional networks. With 10% of scan data, optimized templates of select behavioral measures achieved greater strength of brain-behavior correlations and greater transfer between groups of subjects than full FC across multiple cross validation splits of the dataset. Therefore, selectively filtering time points may allow for development of more targeted FC analyses and increased understanding of how specific moments in time contribute to behavioral prediction.

Significance Statement

Individuals exhibit significant variations in brain functional connectivity, and these individual differences relate to variations in behavioral and cognitive measures. Here we show that the strength and similarity of brain-behavior associations across groups vary over time and that these relations can be improved by selecting time points that maximize brain-behavior correlations. By employing an optimization strategy for 58 distinct behavioral variables we find that different behaviors load onto different moments in time. Our work suggests new strategies for revealing brain signatures of behavior.
Deep Learning for Protein–peptide binding Prediction: Incorporating Sequence, Structural and Language Model Features
Authors: Chandra Abel , Sharma Alok , Dehzangi Iman , Tsunoda Tatsuhiko , Sattar Abdul
Published: September 2023

Protein-peptide interactions play a crucial role in various cellular processes and are implicated in abnormal cellular behaviors leading to diseases such as cancer. Therefore, understanding these interactions is vital for both functional genomics and drug discovery efforts. Despite a significant increase in the availability of protein-peptide complexes, experimental methods for studying these interactions remain laborious, time-consuming, and expensive. Computational methods offer a complementary approach but often fall short in terms of prediction accuracy. To address these challenges, we introduce PepCNN, a deep learning-based prediction model that incorporates structural and sequence-based information from primary protein sequences. By utilizing a combination of half-sphere exposure, position specific scoring matrices, and pre-trained transformer language model, PepCNN outperforms state-of-the-art methods in terms of specificity, precision, and AUC. The PepCNN software and datasets are publicly available athttps://github.com/abelavit/PepCNN.git.
A Quantitative Study of Inappropriate Image Duplication in the JournalToxicology Reports
Authors: David Sholto
Published: September 2023

Inappropriate image duplication is a type of scientific error that can be detected by examining published literature. Few estimates of the frequency of this problem have been published. This study aimed to quantify the rate of image duplication in the journalToxicology Reports. In total 1540 unique articles (identified by DOI) were checked for the presence of research related images (microscopy, photography, western blot scans, etc). Each research paper containing at least one such image was scrutinized for the presence of inappropriate duplications, first by manual review only, and subsequently with the assistance of an AI tool (ImageTwin.ai). Overall,Toxicology Reportspublished 715 papers containing relevant images, and 115 of these papers contained inappropriate duplications (16%). Screening papers with the use of ImageTwin.ai increased the number of inappropriate duplications detected, with 41 of the 115 being missed during the manual screen and subsequently detected with the aid of the software. In summary, the rate of inappropriate image duplication in this journal has been quantified at 16%, most of these errors could have been detected at peer review by careful reading of the paper and related literature. The use of ImageTwin.ai was able to increase the number of detected problematic duplications.
Accurate single-molecule spot detection for image-based spatial transcriptomics with weakly supervised deep learning
Authors: Laubscher Emily , Wang Xuefei (Julie) , Razin Nitzan , Dougherty Tom , Xu Rosalind J. , Ombelets Lincoln , Pao Edward , Graf William , Moffitt Jeffrey R. , Yue Yisong , Van Valen David
Published: September 2023

Image-based spatial transcriptomics methods enable transcriptome-scale gene expression measurements with spatial information but require complex, manually-tuned analysis pipelines. We present Polaris, an analysis pipeline for image-based spatial transcriptomics that combines deep learning models for cell segmentation and spot detection with a probabilistic gene decoder to quantify single-cell gene expression accurately. Polaris offers a unifying, turnkey solution for analyzing spatial transcriptomics data from MERFSIH, seqFISH, or ISS experiments. Polaris is available through the DeepCell software library (https://github.com/vanvalenlab/deepcell-spots) andhttps://www.deepcell.org.
Egocentric vector coding of geometric vertex in the retrosplenial cortex
Authors: Park Kyerl , Yeo Yoonsoo , Shin Kisung , Kwag Jeehyun
Published: September 2023

Neural representation of the environmental features in a self-centered, egocentric manner is important in constructing an egocentric cognitive map that is critical for goal-directed navigation and episodic memory formation1. To create a geometrically detailed egocentric cognitive map, neural representations of edges and vertices of environmental features are needed. While egocentric neural representations of edges, like egocentric boundary vector cells2–6and border cells exist7, those of vertices are unknown. Here we report that single neurons in the granular retrosplenial cortex (RSC) generate spatial receptive fields exclusively near the vertices of environmental geometries during free exploration, which we termed vertex cells. Each spatial receptive field of vertex cells occurred at a specific orientation and distance relative to the animal, tuned by head direction, indicating an egocentric vector coding of the vertex. The removal of physical boundaries that define the environmental geometry abolished egocentric vector coding vertex cells. Moreover, goal-directed navigation selectively strengthened the egocentric vertex vector coding at the vertex near the goal location. Overall, our results suggest that egocentric vector coding of vertex by granular RSC neurons help to construct a geometrically detailed egocentric cognitive map that guides goal-directed navigation.
Pathogen infection alters the gene expression landscape of transposable elements inDrosophila melanogaster: A meta-analysis
Authors: Mostoufi Sabrina L. , Singh Nadia D.
Published: September 2023

Transposable elements (TEs) are remnants of ancient viral infections and make up substantial proportions of eukaryotic genomes. Current research has begun to highlight the role TEs can play in the immune system response to infections. However, most of our knowledge about TE expression during infection is limited by the specific host and pathogen factors from each study, making it difficult to compare studies and develop broader patterns regarding the role of TEs during infection. Here, we use the tools and resources available in the model,Drosophila melanogaster, to analyze multiple RNAseq datasets of flies subject to bacterial, fungal, and viral infections. We analyzed differences in pathogen species, host genotype, host tissue, and sex to understand how these factors impact TE expression during infection. Our results highlight both shared and unique TE expression patterns between pathogens and suggest a larger effect of pathogen factors over host factors for influencing TE expression.

AUTHOR SUMMARY

Transposable elements (TEs) are short, repetitive genetic elements that make up substantial proportions of the genomes of all eukaryotic species. These TEs can become expressed during infections, either as a by-product of the infection itself or as a part of the defense mechanism of the immune system. Many studies have investigated TE activity during infection, often focusing on a single pathogen species, one specific host species and genotype, or even a small number of specific TEs. Though these studies provide important detail on these particular cases, less is known about broader patterns of TE activity during infections. Is TE expression the same across different types of infections, and how does the host affect these expression patterns? Here, we analyzed multiple gene expression datasets from infected flies to uncover these broader patterns in TE expression. We found that the type of infection, whether bacterial, fungal, or viral, has a large effect on TE expression. We also found that host factors, like sex, tissue, or genotype, have a much smaller effect on TE expression during infection compared to infection type. Our results offer a broader perspective on how TEs are activated during infections in flies.
Dietary14C reservoir effects and the chronology of prehistoric burials at Sakhtysh, central European Russia
Authors: Meadows John , Khramtsova Anastasia , Kostyleva Elena , Vasilyev Sergey , Veselovskaya Elizaveta , Dobrovolskaya Maria , Silva Nicolas da , Krause-Kyora Ben , Piezonka Henny
Published: September 2023

We present the first robust radiocarbon (14C) chronology for prehistoric burial activity at Sakhtysh, in European Russia, where nearly 180 inhumations attributed to Lyalovo and Volosovo pottery‐using hunter‐gatherer‐fishers represent the largest known mortuary populations of these groups. Past attempts at14C dating were restricted by poor preservation and limited understanding of diet and dietary14C reservoir effects (DREs). We obtained 32 new AMS (Accelerator Mass Spectrometry)14C dates on human petrous bones. Dietary stable isotopes (δ13C, δ15N) for all AMS‐dated human samples allow us to propose a novel DRE correction model, using differences in14C, δ13C and δ15N from bones and teeth of the same individuals to predict DREs of up to c.90014C years. Our chronological model for 40 individuals dates Lyalovo burials to the early 5thmillennium cal BC, and Volosovo burials to the mid‐4thto early 3rdmillennium. It reveals a previously unrecognised shift in the Volosovo subsistence economy at c.3300 cal BC, coinciding with a reorientation of trade networks, and shows that the last burial at Sakhtysh was the only one in a crouched position, which coincided with the beginning of Fatyanovo practices, the regional expression of the Yamnaya/Corded Ware expansion.
Cell layer specific roles for hormones in root development: Gibberellins suppress infection thread progression, promote nodule and lateral root development in the endodermis and interact with auxin and cytokinin
Authors: Velandia Karen , Correa-Lozano Alejandro , McGuiness Peter M. , Reid James B. , Foo Eloise
Published: September 2023

Gibberellins have a profound influence on the formation of lateral root organs. However, the precise role this hormone plays in the cell-specific events during lateral root formation, rhizobial infection and nodule organogenesis, including interactions with auxin and cytokinin, is not clear.

We performed epidermal- and endodermal-specific complementation of the severely gibberellin-deficientnapea (Pisum sativum) mutant withAgrobacterium rhizogenes. Gibberellin mutants were used to examine the spatial expression pattern of cytokinin (TCSn) and auxin (DR5) responsive promoters and hormone levels.

We found that gibberellins produced in the endodermis promote lateral root and nodule organogenesis and can induce a mobile signal(s) that suppresses rhizobial infection. In contrast, epidermal-derived gibberellins suppress infection but have little influence on root or nodule development. Gibberellins suppress the cytokinin-responsiveTCSnpromoter in the cortex and are required for normal auxin activation during nodule primordia formation.

Our findings indicate that gibberellins regulate the checkpoints between infection thread penetration of the cortex and invasion of nodule primordial cells and promotes the subsequent progression of nodule development. It appears that gibberellins limit the progression and branching of infection threads in the cortex by restricting cytokinin response and activate auxin response to promote nodule primordia development.
EX VIVO GENE EDITING AND CELL THERAPY FOR HEREDITARY TYROSINEMIA TYPE 1
Authors: Ates Ilayda , Rathbone Tanner , Stuart Callie , Barzi Mercedes , He Gordon , Major Angela M. , Srinivasan Shanthi , Farris Alton Brad , Bissig Karl-Dimiter , Cottle Renee N.
Published: September 2023

Background & Aims

We previously demonstrated the successful use ofin vivoCRISPR gene editing to delete 4-hydroxyphenylpyruvate dioxygenase (HPD) to rescue mice deficient in fumarylacetoacetate hydrolase (FAH), a disorder known as hereditary tyrosinemia type 1 (HT1). The goal of this study was to develop anex vivogene editing protocol and apply it as a cell therapy for HT1.

Methods

We isolated hepatocytes from wild-type (C57BL/6) andFah-/-mice and then used an optimized electroporation protocol to deliverHpd-targeting CRISPR-Cas9 ribonucleoproteins (RNP) into hepatocytes. Next, hepatocytes were transiently incubated in cytokine recovery media that we formulated to block apoptosis, followed by splenic injection into recipientFah-/-mice.

Results

We observed robust engraftment and expansion of transplanted gene-edited hepatocytes from wild-type donors in the liver of recipient mice when transient incubation with our cytokine recovery media was used after electroporation and negligible engraftment without the media (mean 46.8% and 0.83%, respectively, p = 0.0025). Thus, the cytokine recovery media was a critical component of our electroporation protocol. When hepatocytes fromFah-/-mice were used as donors for transplantation, we observed 35% and 28% engraftment forHpd-Cas9 RNPs and Cas9 mRNA, respectively. Tyrosine, phenylalanine, and biochemical markers of liver injury normalized in bothHpd-targeting Cas9 RNP and mRNA groups independent of drug induced-inhibition of Hpd through nitisinone, indicating correction of disease indicators inFah-/-mice.

Conclusions

The successful liver cell therapy for HT1 validates our protocol and, despite the known growth advantage of HT1, showcaseex vivogene editing using electroporation in combination with liver cell therapy to cure a disease model. These advancements showcase the impacts of electroporation combined with transplantation as a cell therapy.
Structural Basis ofStreptomycesAntibiotic Regulatory Proteins Activating Transcription
Authors: Wang Yiqun , Yang Xu , Yu Feng , Deng Zixin , Lin Shuangjun , Zheng Jianting
Published: September 2023

Streptomycetes are renowned antibiotic producers, withStreptomycesantibiotic regulatory proteins (SARPs) acting as activators for antibiotic biosynthesis. However, the precise mechanism underlying SARPs’ transcriptional activation remains elusive. Here, we used cryo-electron microscopy (cryo-EM) to unravel the interplay between SARP, DNA, and RNA polymerase (RNAP) during transcriptional activation. The SARP domain ofStreptomyces coelicolorAfsR (SAS) forms a side-by-side dimer contacting theafs boxcentered at −29.5 relative to the transcription start site. The upstream protomer binds to the direct repeat encompassing the −35 element while the σHrdBregion 4 (R4) is positioned on top of both protomers, causing the removal of R4 from the major groove of the −35 element. Both SAS protomers establish interactions with C-terminal domain of one RNAP α subunits, while specific regions of the RNAP β flap tip helix and β’ zinc-binding domain also engage with SAS. Key interfacial residues accounting for transcriptional activation were confirmed by mutational studies andin vitrotranscriptional assays. Overall, our results present a detailed molecular view of how SARPs serve to activate transcription.
Mitotic chromatin marking governs asymmetric segregation of DNA damage
Authors: Ferrand Juliette , Dabin Juliette , Chevallier Odile , Kane-Charvin Matteo , Kupai Ariana , Hrit Joel , Rothbart Scott B. , Polo Sophie E.
Published: September 2023

The faithful segregation of intact genetic material and the perpetuation of chromatin states through mitotic cell divisions are pivotal for maintaining cell function and identity across cell generations. However, most exogenous mutagens generate long-lasting DNA lesions that are segregated during mitosis. How this segregation is controlled is unknown. Here, we uncover a mitotic chromatin-marking pathway that governs the segregation of UV-induced damage in human cells. Our mechanistic analyses reveal two layers of control: histone ADP-ribosylation, and the incorporation of newly synthesized histones at UV damage sites, that both prevent local mitotic phosphorylations on histone H3 serine residues. Functionally, this chromatin-marking pathway drives the asymmetric segregation of UV damage in the cell progeny with consequences on daughter cell fate. We propose that this mechanism may help preserve the integrity of stem cell compartments during asymmetric cell divisions.
Male-biased stone tool use by wild white-faced capuchins (Cebus capucinus imitator)
Authors: Goldsborough Zoë , Crofoot Margaret C. , Barrett Brendan J.
Published: September 2023

Tool-using primates often show sex differences in both the frequency and efficiency of tool use. In species with sex-biased dispersal, such within-group variation likely shapes patterns of cultural transmission of tool-use traditions between groups. On the Panamanian islands of Jicarón and Coiba, a population of white-faced capuchins (Cebus capucinus imitator)—some of which engage in habitual stone tool use—provide an opportunity to test hypotheses about why such sex-biases arise. On Jicarón, we have only observed males engaging in stone tool use, whereas on Coiba, both sexes are known to use tools. Using 5 years of camera trap data, we show that this variation reflects a true sex difference in tool use rather than a sampling artefact, and then test hypotheses about the factors driving this pattern. Differences in physical ability or risk-aversion, and competition over access to anvils do not account for the sex-differences in tool-use we observe. Our data show that females are physically capable of stone tool use: females on Coiba and juveniles on Jicarón as small and smaller than adult females regularly engage in tool use. Females also have ample opportunity to use tools: the sexes are equally terrestrial, and competition over anvils is low. Finally, females rarely scrounge on left-over food items either during or after tool-using events, suggesting they are not being provisioned by males. Although it remains unclear why white-faced capuchin females on Jicarón do not use stone-tools, our results illustrate that such sex biases in socially learned behaviors can arise even in the absence of obvious physical, environmental and social constraints. This suggests that a much more nuanced understanding of the differences in social structure, diet and dispersal patterns are needed to explain why sex-biases in tool use arise in some populations but not in others.
Transcranial Focused Ultrasound to V5 Enhances Human Visual Motion Brain-Computer Interface by Modulating Feature-Based Attention
Authors: Kosnoff Joshua , Yu Kai , Liu Chang , He Bin
Published: September 2023

Paralysis affects roughly 1 in 50 Americans. While there is no cure for the condition, brain-computer interfaces (BCI) can allow users to control a device with their mind, bypassing the paralyzed region. Non-invasive BCIs still have high error rates, which is hypothesized to be reduced with concurrent targeted neuromodulation. This study examines whether transcranial focused ultrasound (tFUS) modulation can improve BCI outcomes, and what the underlying mechanism of action might be through high-density electroencephalography (EEG)-based source imaging (ESI) analyses. V5-targeted tFUS significantly reduced the error for the BCI speller task. ESI analyses showed significantly increased theta activity in the tFUS condition at both V5 and downstream the dorsal visual processing pathway. Correlation analysis indicates that the dorsal processing pathway connection was preserved during tFUS stimulation, whereas extraneous connections were severed. These results suggest that V5-targeted tFUS’ mechanism of action is to raise the brain’s feature-based attention to visual motion.
Spontaneous dynamics of hippocampal place fields in a model of combinatorial competition among stable inputs
Authors: Savelli Francesco
Published: September 2023

We present computer simulations illustrating how the plastic integration of spatially stable inputs could contribute to the dynamic character of hippocampal spatial representations. In novel environments of slightly larger size than typical apparatus, the emergence of well-defined place fields in real place cells seems to rely on inputs from normally functioning grid cells. Theoretically, the grid-to-place transformation is possible if a place cell is able to respond selectively to a combination of suitably aligned grids. We previously identified the functional characteristics that allow a synaptic plasticity rule to accomplish this selection by synaptic competition during rat foraging behavior. Here, we show that the synaptic competition can outlast the formation of place fields, contributing to their spatial reorganization over time, when the model is run in larger environments and the topographical/modular organization of grid inputs is taken into account. Co-simulated cells that differ only by their randomly assigned grid inputs display different degrees and kinds of spatial reorganization—ranging from place-field remapping to more subtle in-field changes or lapses in firing. The model predicts a greater number of place fields and propensity for remapping in place cells recorded from more septal regions of the hippocampus and/or in larger environments, motivating future experimental standardization across studies and animal models. In sum, spontaneous remapping could arise from rapid synaptic learning involving inputs that are functionally homogeneous, spatially stable, and minimally stochastic.

Significance Statement

In both AI and theoretical neuroscience, learning systems often rely on the asymptotic convergence of slow-acting learning rules applied to input spaces that are presumed to be sampled repeatedly, for example over developmental timescales. Place cells of the hippocampus testify to a neural system capable of rapidly encoding cognitive variables—such as the animal’s position in space—from limited experience. These internal representations undergo “spontaneous” changes over time, spurring much interest in their cognitive significance and underlying mechanisms. We investigate a model suggesting that some of these changes could be a tradeoff of rapid learning.
3D human retinal organoid model for the study of early diabetic retinopathy
Authors: de Lemos Luisa , Antas Pedro , Ferreira Inês S. , Santos Inês Paz , Gomes Catarina M. , Brito Catarina , Seabra Miguel C. , Tenreiro Sandra
Published: September 2023

Diabetic retinopathy (DR) is a significant complication of diabetes and a primary cause of visual impairment among working-age individuals. DR is a degenerative condition in which hyperglycaemia results in morphological and functional changes in certain retinal cells. Existing treatments mainly address the advanced stages of the disease, which involve vascular defects such as macular edema or neovascularization. However, it is now known that retinal neurodegeneration and inflammation precede these vascular changes. Therefore, there is a pressing need to identify new therapeutic approaches that target the early stages of DR and prevent its progression.

In the last decade, the development of reliablein vitromodels resembling the complexity of the retinal tissue has significantly improved. Namely, three-dimensional (3D) retinal organoids derived from human induced-pluripotent stem cells (hiPSCs) recapitulate the cellular organization and complexity of the human retina.

Here, we used hiPSCs-derived retinal organoids to generate a model of early DR. In this model, we observe well-established molecular and cellular features of early DR:i) loss of retinal ganglion and amacrine cells;ii) glial reactivity and inflammation, with increased expression of the vascular endothelial-derived growth factor (VEGF)and interleukin-1β (IL-1β),and monocyte chemoattractant protein-1 (MCP-1) secretion;iii) increased levels of reactive oxygen species accompanied by activation of key enzymes involved in antioxidative stress response. The data provided highlight the utility of retinal organoid technology in modelling early-stage DR. This offers new avenues for the development of targeted therapeutic interventions on neurodegeneration and inflammation in the initial phase of DR, potentially slowing the disease’s progression.
Psychometric properties of the Perceived Stress Scale-4 (PSS-4) in Colombians with university education
Authors: Sanabria-Mazo Juan P. , Gómez-Acosta Andrés , Annicchiarico-Lobo Julio , Luciano Juan V. , Sanz Antoni
Published: September 2023

The Perceived Stress Scale-4 (PSS-4) is an ultra-brief self-report measure to assess perceived psychological stress. This study evaluated the psychometric properties of the PSS-4 in Colombia. A total of 1911 adult participants with university education completed the PSS-4. Characteristics of the items and the subscales were explored. Dimensionality was assessed using confirmatory factor analysis (CFA), incorporating an examination of invariance (configural, metric, scalar, and strict) across socio-demographic characteristics. Construct validity (convergent and discriminant), reliability indices, know-groups, and predictive validity were also computed. The CFA showed adequate fit indices for the two-factor model (hopelessness and coping), being invariant across gender, income level, age, and work status. Internal consistency was adequate for the PSS-4 (α= .73,ω= .72,λ2= .74). Significant positive correlations of the PSS-4 were identified with depression (r= .59) and anxiety (r= .55), as well as significant negative with post-traumatic growth (r= –.37) and resilience (r= –.47). The PSS-4 showed adequate capacity to predict potential depressive and anxiety symptoms, as well as protective factors such as resilience and posttraumatic growth. Higher scores on the PSS-4 were observed among young people, as well as among people with lower incomes and those unemployed. These findings suggest that the PSS-4 can be a reliable and valid tool for assessing psychological stress in Colombians with university education.
Targeted and optimized multi-channel transcranial direct current stimulation for focal epilepsy: An N-of-1 trial
Authors: Antonakakis Marios , Kaiser Fabian , Rampp Stefan , Kovac Stjepana , Wiendl Heinz , Stummer Walter , Gross Joachim , Kellinghaus Christoph , Khaleghi-Ghadiri Maryam , Möddel Gabriel , Wolters Carsten H.
Published: September 2023

Transcranial direct current stimulation (tDCS) has been used to noninvasively reduce epileptic activity in focal epilepsy. In this proof-of-principle N-of-1 trial in a patient with drug-resistant focal epilepsy, we propose distributed constrained maximum intensity (D-CMI) for individually targeted and optimized multi-channel (mc-) tDCS to reduce epileptic activity. Combined electro- and magnetoencephalography (EMEG) source analysis in a realistic calibrated head model defines location and orientation of the target epileptogenic source. Converging evidence for this determination is achieved by retrospective identification of a cortical malformation in magnetic resonance imaging and by successful EMEG-guided invasive EEG. We applied D-CMI in a double-blind, sham-controlled stimulation experiment. In two stimulation weeks, either D-CMI or sham stimulation with 4 mA injection current were applied twice every week-day for 20 min each, with a 20 min pause in between. EEG was recorded 1 h before and after stimulation. For D-CMI, we find a highly significant reduction in IED frequency (p < 0.0001) marked by three experts of on average 37% to 81% over the five days of stimulation (mean ± SD: 58% ± 19%), while this is not the case for sham. The proposed procedure was well-tolerated and parameterizes a group clinical trial (Study registration number: DRKS00029384).
Segment-specific axon guidance by Wnt/Fz signaling diversifies motor commands inDrosophilalarvae
Authors: Takagi Suguru , Takano Shiina , Hashimoto Yusaku , Morise Shu , Zeng Xiangsunze , Nose Akinao
Published: September 2023

Functional diversification of homologous neuronal microcircuits is a widespread feature observed across brain regions as well as across species, while its molecular and developmental mechanisms remain largely unknown. We address this question inDrosophilalarvae by focusing on segmentally homologous Wave command-like neurons, which diversify their wiring and function in a segment-specific manner. Anterior Wave (a-Wave) neurons extend axons anteriorly and connect to circuits inducing backward locomotion, whereas posterior Wave (p-Wave) neurons extend axons posteriorly and trigger forward locomotion. Here, we show that Frizzled receptors DFz2 and DFz4, together with the DWnt4 ligand, regulate the segment-specific Wave axon projection.DFz2knock-down (KD) not only reroutes Wave axons to posterior neuromeres but also biases its motor command to induce forward instead of backward locomotion as tactile response. Thus, segment-specific axon guidance diversifies the function of homologous command neurons in behavioral regulation. Since control of anterior-posterior (A-P) axon guidance by Wnt/Fz-signaling is evolutionarily conserved, our results reveal a potentially universal molecular principle for formation and diversification of the command system in the nerve cord. Furthermore, this work indicates that sensorimotor transduction can be rerouted by manipulating a single gene in a single class of neurons, potentially facilitating the evolutionary flexibility in action selection.

Impact statement

Rewiring the command neurons in the tactile circuit suffices to change the behavioral strategy of a whole animal, implying a “plug-and-play” flexibility in sensorimotor circuits.
Rethinking sinking: Imaging flow fields of natural marine aggregates to infer porosity-dependent changes in sinking velocity and carbon flux
Authors: Flintrop Clara M. , Ahmerkamp Soeren , Moradi Nasrollah , Klawonn Isabell , März Jöran , Hörstmann Cora , Kiko Rainer , Khalili Arzhang , Grossart Hans-Peter , Álvarez-Salgado Xosé A. , Arístegui Javier , Iversen Morten H.
Published: September 2023

The marine biological carbon pump is mainly driven by the interplay between aggregate sinking velocity and remineralization. Sinking velocity of natural marine aggregates is not routinely measured but often calculated using Stokes’ law, which does not consider size-dependent changes in porosity. We analyzed the flow fields around 81in situ-formed aggregates using Particle Image Velocimetry (PIV) to determine the factors controlling aggregate settling. Using an independently derived scaling of porosity with size, we predicted the sinking velocity of laboratory-formed andin situ-formed aggregates with known densities. Small aggregates (<500 µm) have relatively lower porosities than large aggregates, and their increased compactness and density leads to higher size-specific settling velocities, and generally higher carbon-to-volume ratios. Applying our scaling approach to a global data set of vertical aggregate abundance and size distribution, we found that small aggregates contribute 40-70% to total carbon fluxesin situ.

Teaser

Improved sinking velocity prediction for marine aggregates highlights the contribution of small aggregates to carbon sequestration.
Naturally occurring viruses ofDrosophilareduce offspring number and lifespan
Authors: Wallace Megan A. , Obbard Darren J.
Published: September 2023

Drosophilaremains a pre-eminent insect model system for host-virus interaction, but the host range and fitness consequences of the drosophilid virome are poorly understood. Metagenomic studies have reported over 160 viruses associated withDrosophilidae, but few isolates are available to characterise theDrosophilaimmune response, and most characterisation has relied on injection and systemic infection. Here we use a more natural infection route to characterise the fitness effects of infection and to study a wider range of viruses. We exposed laboratoryD. melanogasterto 23 naturally occurring viruses from wild-collected drosophilids. We recorded transmission rates along with two components of female fitness: survival and the lifetime number of adult offspring produced. Nine different viruses transmitted during contact with laboratoryD. melanogaster, although for the majority, rates of transmission were less than 20%. Five virus infections led to a significant decrease in lifespan (D. melanogaster nora virus, D. immigrans nora virus, Muthill virus, galbut virus and Prestney Burn virus), and three led to a reduction in the total number of offspring. Our findings demonstrate the utility of theDrosophilamodel for community-level studies of host-virus interactions, and suggest that viral infection could be a substantial fitness burden on wild flies.
Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular cells
Authors: Chen Yihong , Gialeli Chrysostomi , Shen Junyan , Dunér Pontus , Walse Björn , Duelli Annette , Caing-Carlsson Rhawnie , Blom Anna M. , Zibert John , Hultgårdh Nilsson Anna , Alenfall Jan , Liang Chun , Nilsson Jan
Published: September 2023

Background

The osteopontin-derived peptide FOL-005 has been shown to stimulate hair growth. Using ligand-receptor glycocapture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005. Considering that induction of perifollicular angiogenesis by VEGF is a critical step in activation of the anagen growth phase of hair follicles, we investigated the effect of the more stable FOL-005 analogue FOL-026 on vascular cells.

Methods

X-ray diffraction and microscale thermophoresis analysis were used to determine receptor binding of FOL-peptides. Cultured human arterial smooth muscle cells were used for studies of cell proliferation, migration, intracellular signaling, and apoptosis. A Matrigel plug assay was used to study angiogenesis in vivo. RNA seq. was used to analyze changes in gene expression patterns.

Results

FOL-026 was found to share binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of AKT and ERK1/2, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosisin vitro,as well as activation of angiogenesisin vivo.Down-regulation of NRP-1 by NRP-1-specific small interfering RNA blocked the stimulatory effects of FOL-026 on endothelial cells. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell proliferation, migration, inhibited apoptosis, and induced VEGF gene expression by an NRP-1-dependent mechanism.

Conclusions

These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and / or enhanced angiogenesis.

Clinical perspective

Insufficient vascular repair increases the risk of acute cardiovascular events, something that is of particular importance in diabetes.

A peptide derived from the extracellular matrix protein osteopontin (FOL-026) binds to the vascular endothelial growth factor (VEGF) co-receptor neuropilin-1 stimulating endothelial and vascular smooth muscle cell proliferation and migration as well as the formation of new vessels.

By mimicking the effects of VEGF FOL-026 may have therapeutical potential in conditions that require vascular repair and / or enhanced angiogenesis such as vascular complications to diabetes, peripheral artery disease and salvage of ischemic myocardium.
Inhibition of the serine protease HtrA1 by SerpinE2 suggests an extracellular proteolytic pathway in the control of neural crest migration
Authors: Pera Edgar M. , Moura Josefine Nilsson-De , Pomeshchik Yuriy , Roybon Laurent , Milas Ivana
Published: September 2023

We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibroblast growth factor (FGF) signaling in germ layer specification and head-to-tail development ofXenopusembryos. Here we present an extracellular proteolytic mechanism involving this serpin-protease system in the developing neural crest (NC). Knockdown of SerpinE2 by injected antisense morpholino oligonucleotides did not affect the specification of NC progenitors but instead inhibited the migration of NC cells, causing defects in dorsal fin, melanocyte and craniofacial cartilage formation. Similarly, overexpression of the HtrA1 protease impaired NC cell migration and the formation of NC-derived structures. The phenotype of SerpinE2 knockdown was overcome by concomitant downregulation of HtrA1, indicating that SerpinE2 stimulates NC migration by inhibiting endogenous HtrA1 activity. SerpinE2 binds to HtrA1, and the HtrA1 protease triggers degradation of the cell surface proteoglycan Syndecan-4 (Sdc4). Microinjection ofSdc4mRNA partially rescued NC migration defects induced both by HtrA1 upregulation and SerpinE2 downregulation. These epistatic experiments suggest a proteolytic pathway by a double inhibition mechanism:

SerpinE2 ┤HtrA1 protease ┤Syndecan-4 → NC cell migration
Probucol mitigates high-fat diet-induced cognitive and social impairments through disruption of redox-inflammation association
Authors: Wu Han-Ming , Huang Na-Jun , Yang Yang Vivian , Fan Li-Ping , Tang Tian-Yu , Liu Lin , Xu Yue , Liu Dong-Tai , Cai Ze-Xin , Ren Xin-Yi , Yao Zheng-Hao , Chen Jian-Zhen , Huang Xi , Zhang Cixiong , You Xiang , Wang Chen , He Ying , Ye Zhi-Yun , Hong Wei , Lin Sheng-Cai , Zhan Yi-Hong , Lin Shu-Yong
Published: September 2023

Obesity and its detrimental metabolic consequences are commonly recognized as risk factors for impairments in the central nervous system (CNS). However, the direct link between metabolic abnormalities and brain functions during high-fat feeding remains unclear. Here, we show that treatment with probucol, a cholesterol-lowering drug, counteracts the cognitive and social impairments induced by a high-fat diet in mice, while having no effect on mood disorders. Unexpectedly, the beneficial effects of probucol do not result from rectifying obesity or restoring glucose and lipid homeostasis, as evidenced by the lack of change in body weight, blood glucose and serum cholesterol levels. Interestingly, high-fat feeding led to association among the levels of redox factors, including oxidized low-density lipoprotein, glutathione and malondialdehyde, as well as a significant negative correlation between malondialdehyde levels and behavioral performance. Probucol treatment interrupts these linkages and differentially regulates the proteins for the generation of reactive oxygen species and reactive nitrogen species in the brain. These findings prompt a reconsideration of the mechanism of action of probucol, as well as the roles of altered metabolic profiles and free radicals in brain function.
Fast, safe and high-throughput Real-Time PCR protocol for molecular sex identification inSalmo salar, applicable to historic scale collections
Authors: Anne-Laure Besnard , Lisa Meslier , Thibaut Jousseaume , Marie Nevoux , Frédéric Marchand , Sophie Launey
Published: September 2023

Conservation and management of wild species needs a detailed understanding of their population structure and dynamics. For instance, there are increasing evidence for sex-specific life history trajectories, even in species with limited morphological sexual dimorphism. In these species, identifying the sex of individuals in some or all life stages is a methodological challenge, which requires the development of new tools. Building on recent findings in molecular biology, we developed a new protocol for sex identification in Atlantic salmon (Salmo salar), aiming at the following criteria: accurate sex identification, fast diagnostic, applicable to large sample size, applicable to degraded DNA extracted from e.g. fish scales, and safe for the operator by limiting health and safety hazard. The protocol relies on multiplex Real-Time PCR using a set of specific primers. We tested its accuracy on a test set of 90 DNA samples from individuals of known morphological sex, and demonstrated its applicability on a large DNA sample from 384 individuals of unknown sex.
Fractionated irradiation of murine salivary glands resulted in focal acinar cell atrophy, immune cell infiltration, fibrosis, and hyposalivation
Authors: Juvkam Inga Solgård , Zlygosteva Olga , Malinen Eirik , Edin Nina Jeppesen , Galtung Hilde Kanli , Søland Tine Merete
Published: September 2023

Background

Radiotherapy of head and neck cancer may cause detrimental late side effects such as fibrosis and hyposalivation. Our aim was to investigate late radiation-induced cellular and molecular changes of the salivary glands after fractionated irradiation to the head and neck in a murine model.

Methods

12-week-old female C57BL/6J mice were irradiated with X-rays to a total dose of 66 Gy, given in 10 fractions over 5 days. The radiation field covered the oral cavity and major salivary glands. Salivary gland function was assessed by collecting saliva at baseline and at various time points after irradiation. The submandibular (SMG), sublingual (SLG), and parotid glands (PG) were dissected at day 105. Using different staining techniques, morphological, cellular, and molecular changes were investigated in the salivary glands.

Results

Saliva production was significantly reduced in irradiated compared to control mice at day 35, 80, and 105. We observed a significant decrease in total gland area and a significant increase in fibrotic area in irradiated compared to control SMG at day 105. Atrophy of acinar cells was observed in all irradiated SMG and SLG. Increased amount of chronic inflammatory cells, increased cell proliferation and altered expression of apoptotic markers were found in atrophic areas of irradiated glands.

Conclusion

Acinar and duct cells in irradiated salivary glands show increased cell proliferation and altered expression of apoptotic markers, proposing an attempt to overcome or withstand tissue damage caused by irradiation. This suggests a potential for regeneration of salivary glands after radiation therapy.
RGG-motif protein Scd6 affects oxidative stress response by regulating Cytosolic caTalase T1 (Ctt1)
Authors: Tiwari Sweta , Sj Sudharshan , Rajyaguru Purusharth I
Published: September 2023

In response to stress, cells undergo gene expression reprogramming to cope with external stimuli. As translation is energy consuming process, its regulation during stress is crucial for cellular adaptation. Cells utilize a conserved stress response mechanism called global downregulation of translation, leading to the storage of translationally repressed mRNAs in RNA granules or RNP condensates. During oxidative stress induced by H2O2, genes responsible for combating oxidative stress, such as catalases and glutathione peroxidase, are strongly induced. However, the post-transcriptional regulatory events affecting these genes during H2O2stress are not well-explored. RNA binding proteins such as RGG motif proteins play a critical role in mediating translation regulation and have diverse physiological functions. Scd6, an RGG motif-containing protein in yeast, acts as a translational repressor through its interaction with eIF4G. Although the role of Scd6 as a translational repressor and decapping activator is known, its specific mRNA targets are largely unknown.This study identifies the role of Scd6 in oxidative stress response by regulating cytoplasmic catalaseT1 (CTT1). Altering Scd6 levels influenced Ctt1 protein levels, thereby affecting oxidative stress response. Scd6 overexpression increased sensitivity, while deletion enhanced tolerance to H2O2treatment due to ROS accumulation in the yeast cell. In response to H2O2treatment, Scd6 forms dynamic puncta which contains RNA. Overall, this study proposes regulation of oxidative stress response via modulation ofCTT1mRNA by Scd6.
Motor cortex is required for flexible but not automatic motor sequences
Authors: Mizes Kevin G. C. , Lindsey Jack , Escola G. Sean , Ölveczky Bence P.
Published: September 2023

How motor cortex contributes to motor sequence execution is much debated, with studies supporting disparate views. Here we probe the degree to which motor cortex’s engagement depends on task demands, specifically whether its role differs for highly practiced, or ‘automatic’, sequences versus flexible sequences informed by external events. To test this, we trained rats to generate three-element motor sequences either by overtraining them on a single sequence or by having them follow instructive visual cues. Lesioning motor cortex revealed that it is necessary for flexible cue-driven motor sequences but dispensable for single automatic behaviors trained in isolation. However, when an automatic motor sequence was practiced alongside the flexible task, it became motor cortex-dependent, suggesting that subcortical consolidation of an automatic motor sequence is delayed or prevented when the same sequence is produced also in a flexible context. A simple neural network model recapitulated these results and explained the underlying circuit mechanisms. Our results critically delineate the role of motor cortex in motor sequence execution, describing the condition under which it is engaged and the functions it fulfills, thus reconciling seemingly conflicting views about motor cortex’s role in motor sequence generation.