bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalizable links between symptoms of borderline personality disorder and functional connectivity
Authors: Shafiei Golia , Keller Arielle S. , Bertolero Maxwell , Shanmugan Sheila , Bassett Dani S. , Chen Andrew A. , Covitz Sydney , Houghton Audrey , Luo Audrey , Mehta Kahini , Salo Taylor , Shinohara Russell T. , Fair Damien , Hallquist Michael N. , Satterthwaite Theodore D.
Published: August 2023

Background

Symptoms of borderline personality disorder (BPD) often manifest in adolescence, yet the underlying relationship between these debilitating symptoms and the development of functional brain networks is not well understood. Here we aimed to investigate how multivariate patterns of functional connectivity are associated with symptoms of BPD in a large sample of young adults and adolescents.

Methods

We used high-quality functional Magnetic Resonance Imaging (fMRI) data from young adults from the Human Connectome Project: Young Adults (HCP-YA;N= 870, ages 22-37 years, 457 female) and youth from the Human Connectome Project: Development (HCP-D;N= 223, age range 16-21 years, 121 female). A previously validated BPD proxy score was derived from the NEO Five Factor Inventory (NEO-FFI). A ridge regression model with 10-fold cross-validation and nested hyperparameter tuning was trained and tested in HCP-YA to predict BPD scores in unseen data from regional functional connectivity, while controlling for in-scanner motion, age, and sex. The trained model was further tested on data from HCP-D without further tuning. Finally, we tested how the connectivity patterns associated with BPD aligned with agerelated changes in connectivity.

Results

Multivariate functional connectivity patterns significantly predicted out-of-sample BPD proxy scores in unseen data in both young adults (HCP-YA;pperm= 0.001) and older adolescents (HCP-D;pperm= 0.001). Predictive capacity of regions was heterogeneous; the most predictive regions were found in functional systems relevant for emotion regulation and executive function, including the ventral attention network. Finally, regional functional connectivity patterns that predicted BPD proxy scores aligned with those associated with development in youth.

Conclusion

Individual differences in functional connectivity in developmentally-sensitive regions are associated with the symptoms of BPD.
Ectopically Expressed Rhodopsin is Not Sensitive to X-rays
Authors: Cannon Kelli , Bartley Aundrea , Dobrunz Lynn , Bolding Mark
Published: August 2023

Visual perception of X-radiation is a well-documented, but poorly understood phenomenon. Early literature implicates scotopic rod cells and rod opsin in X-ray detection, however, evidence suggests that X-rays excite the retina via a different mechanism than visible light. While rhodopsin’s role in X-ray perception is unclear, the possibility that it could function as an X-ray receptor has led to speculation that it could act as a transgenically expressed X-ray receptor. If so, it could be used to transduce transcranial X-ray signals and control the activity of genetically targeted populations of neurons in a less invasive version of optogenetics, X-genetics. Here we investigate whether human rhodopsin (hRho) is capable of transducing X-ray signals when expressed outside of the retinal environment. We use a live-cell cAMP GloSensor luminescence assay to measure cAMP decreases in hRho-expressing HEK293 cells in response to visible light and X-ray stimulation. We show that cAMP GloSensor luminescence decreases are not observed in hRho-expressing HEK293 cells in response to X-ray stimulation, despite the presence of robust responses to visible light. Additionally, irradiation had no significant effect on cAMP GloSensor responses to subsequent visible light stimulation. These results indicate that ectopically expressed rhodopsin does not function as an X-ray receptor, and suggest that it is not capable of transducing transcranial X-ray signals into neural activity for X-ray mediated, genetically targeted neuromodulation.
Environmental DNA (eDNA) metabarcoding differentiates between micro-habitats within the rocky intertidal
Authors: Shea Meghan M. , Boehm Alexandria B.
Published: August 2023

While the utility of environmental DNA (eDNA) metabarcoding surveys for biodiversity monitoring continues to be demonstrated, the spatial and temporal variability of eDNA, and thus the limits of the differentiability of an eDNA signal, remains under-characterized. In this study, we collected eDNA samples from distinct micro-habitats (∼40 m apart) in a rocky intertidal ecosystem over their exposure period in a tidal cycle. During this period, the micro-habitats transitioned from being interconnected, to physically isolated, to interconnected again. Using a well-established eukaryotic (cytochrome oxidase subunit I) metabarcoding assay, we detected 415 species across 28 phyla. Across a variety of univariate and multivariate analyses, using just taxonomically-assigned data as well as all detected amplicon sequence variants (ASVs), we identified unique eDNA signals from the different micro-habitats sampled. This differentiability paralleled ecological expectations and increased as the sites became more physically disconnected. Our results demonstrate that eDNA biomonitoring can differentiate micro-habitats in the rocky intertidal only 40 m apart, that these differences are ecologically meaningful, and that physical connectivity informs the degree of differentiation possible. These findings showcase the potential power of eDNA biomonitoring to increase the spatial and temporal resolution of marine biodiversity data, aiding research, conservation, and management efforts.
Restoration of locomotor function following stimulation of the A13 region in Parkinson’s mouse models
Authors: Kim Linda H. , Lognon Adam P. , Sharma Sandeep , Tran Michelle A. , Badenhorst Cecilia , Chomiak Taylor , Tam Stephanie , McPherson Claire , Stang Todd E. , Eaton Shane E. A. , Kiss Zelma H. T. , Whelan Patrick J.
Published: August 2023

Parkinson’s disease (PD) is characterized by extensive motor and non-motor dysfunction, including gait disturbance, which is difficult to treat effectively. This study explores the therapeutic potential of targeting the A13 region, a heterogeneous region of the medial zona incerta (mZI) containing dopaminergic, GABAergic, and glutamatergic neurons that has shown relative preservation in PD models. The A13 is identified to project to the mesencephalic locomotor region (MLR), with a subpopulation of cells displaying activity correlating to movement speed, suggesting its role in locomotion. We show that photoactivation of this A13 region can alleviate bradykinesia and akinetic features, while increasing turning in a mouse model of PD. These effects combine disease-specific rescue of function with a possible gain of function. We identified areas of preservation and plasticity within the mZI connectome using whole-brain imaging. Our findings suggest a global remodeling of afferent and efferent projections of the A13 region, highlighting the zona incerta’s role as a crucial hub for the rapid selection of motor function. The study unveils the significant pro-locomotor effects of the A13 region and suggests its promising potential as a therapeutic target for PD-related gait dysfunction.

SIGNIFICANCE STATEMENT

This work examines the function of the A13 region in locomotion, an area with direct connectivity to locomotor regions in the brainstem. A13 stimulation can restore locomotor function and improve bradykinesia in a PD mouse model.
VACmap: An Accurate Long-Read Aligner for Unraveling Complex Genomic Rearrangements
Authors: Ding Hongyu , Sedlazeck Fritz J , Proukakis Christos , Morley Caoimhe , Toffoli Marco , Schapira Anthony Henry Vernon , Liao Zhirui , Pu Lianrong , Zhu Shanfeng
Published: August 2023

Inversions, duplications, and other critical medically challenging variations are often ignored by routine genetic analyses. This is due to the complexity of these alleles but also because of the inability to accurately align them with state-of-the-art methods. We introduce VACmap, a novel non-linear long-read mapping method designed to improve detection of these difficult genomic regions, including critical genes like LPA and GBA1, which are significant risk factors for cardiovascular disease and Parkinson disease, respectively.
Model-based inference of RNA velocity modules improves cell fate prediction
Authors: Aivazidis Alexander , Memi Fani , Kleshchevnikov Vitalii , Clarke Brian , Stegle Oliver , Bayraktar Omer Ali
Published: August 2023

RNA velocity is a powerful paradigm that exploits the temporal information contained in spliced and unspliced RNA counts to infer transcriptional dynamics. Existing velocity models either rely on coarse biophysical simplifications or require extensive numerical approximations to solve the underlying differential equations. This results in loss of accuracy in challenging settings, such as complex or weak transcription rate changes across cellular trajectories. Here, we present cell2fate, a formulation of RNA velocity based on alinearizationof the velocity ODE, which allows solving a biophysically accurate model in a fully Bayesian fashion. As a result, cell2fate decomposes the RNA velocity solutions intomodules, which provides a new biophysical connection between RNA velocity and statistical dimensionality reduction. We comprehensively benchmark cell2fate in real-world settings, demonstrating enhanced interpretability and increased power to reconstruct complex dynamics and weak dynamical signals in rare and mature cell types. Finally, we apply cell2fate to a newly generated dataset from the developing human brain, where we spatially map RNA velocity modules onto the tissue architecture, thereby connecting the spatial organisation of tissues with temporal dynamics of transcription.
Bulky glycocalyx drives cancer invasiveness by modulating substrate-specific adhesion
Authors: Barai Amlan , Piplani Niyati , Gomathi V , Ghogale Mayank M , Kumar Sushil , Kulkarni Madhura , Sen Shamik
Published: August 2023

Majority of the eukaryotic cell surface is decorated with a layer of membrane attached polysaccharides and glycoproteins collectively referred to as the glycocalyx. While formation of a bulky glycocalyx has been associated with cancer progression, the mechanisms by which the glycocalyx regulates cancer invasiveness is incompletely understood. We address this question by first documenting sub-type specific expression of the major glycocalyx glycoprotein Mucin-1 (MUC1) in breast cancer patient samples and breast cancer cell lines. Strikingly, glycocalyx disruption led to inhibition of 2D motility, loss of 3D invasion and reduction of clonal scattering of breast cancer cells at the population level. Tracking of 2D cell motility and 3D invasiveness of MUC1-based sorted sub-populations revealed fastest motility and invasiveness in intermediate MUC1-expressing cells, with glycocalyx disruption abolishing these effects. While differential sensitivity in 2D motility is attributed to a non-monotonic dependence of focal adhesion size on MUC1 levels, higher MUC1 levels enhance 3D invasiveness via increased traction generation. In contrast to inducing cell rounding on collagen-coated substrates, high MUC1 level promotes cell adhesion and confers resistance to shear flow on substrates coated with the endothelial surface protein E-selectin. Collectively, our findings illustrate how MUC1 drives cancer invasiveness by differentially regulating cell-substrate adhesion in a substrate-dependent manner.
Cross-pollination is more important than gibberellin application in the germination of the everlasting flowers ofJaneirona carrasqueira(morphotype ofComanthera bisulcata)
Authors: de Azevedo Maria Luiza , Oliveira Maria Neudes Sousa de , Rech André Rodrigo , Barbosa Jose Carlos , Gorgens Eric Bastos , Machado Evandro Luiz Mendonça , Pereira Israel Marinho
Published: August 2023

The “sempre-vivas” are plants known as “everlasting flowers” because they have inflorescences that retain the appearance of living structures even after being harvested and dried. Given their ornamental potential, some species are widely exploited commercially, and their production occurs almost exclusively through extractivism. However, data on their pollination, reproduction, and germination are limited. Extractivism is an activity of great importance for the residents of the Espinhaço Meridional municipalities, and research is essential for establishing plans and proposals for the management of these native species. Given this scenario, we studied the pollinators and the importance of cross- and autogamy for reproductive success ofJaneirona carrasqueira(morphotype ofComanthera bisulcata(Körn) L.R. Parra & Giul), commercially collected in Diamantina, Minas Gerais. We also evaluated germination and the influence of the exogenous application of gibberellin (GA3) on seeds. Pollinators were observed during the flowering period in beds cultivated with this species in the native Campo Rupestre area of Diamantina, Minas Gerais. The inflorescences of the species were collected from two different environments: one isolated from pollinating insects (inside the greenhouse), and the other open in the presence of pollinators. The seeds were removed from the flower heads and subjected to exogenous application of gibberellin (0–control and 500 ppm). The flowers showed a generalist pollination strategy, including visitors who collected pollen and nectar as well as those who exclusively collected nectar. For germination, the most influential factor was cross-pollination and not gibberellin application. We conclude that the pollination system represents a determining mechanism and is a very important factor to be considered in management plans aimed at species conservation.

Highlights

–Comanthera bisulcataemploys a generalist pollination strategy.

– The pollination system is a crucial mechanism for germination.

– Cross-pollination is more important than gibberellin application

– Reproduction is a crucial aspect to be taken into account in the management plans of the species.
Evaluation of the Ability of AlphaFold to Predict the Three-Dimensional Structures of Antibodies and Epitopes
Authors: Polonsky Ksenia , Pupko Tal , Freund Natalia T
Published: August 2023

Being able to accurately predict the three-dimensional structure of an antibody can facilitate fast and precise antibody characterization and epitope prediction, with important diagnostic and clinical implications. In the current study, we evaluate the ability of AlphaFold to predict the structures of 222 recently published, non-redundant, high resolution Fab heavy and light chain structures of antibodies from different species (human,Macaca mulatta, mouse, rabbit, rat) directed against different antigens. Our analysis reveals that while the overall prediction quality of antibody chains is in line with the results available in CASP14, other antibody regions like the complementarity-determining regions (CDRs) of the heavy chain, which are prone to higher genetic variation, generate a less accurate prediction. Moreover, we discovered that AlphaFold often mis-predicts the bending angles between the variable and constant domains within a Fab. To evaluate the ability of AlphaFold to model antibody:antigen interactions based only on sequence, we used AlphaFold-multimer in combination with ZDOCK docking to predict the structures of 26 known antibody:antigen complexes. ZDOCK succeeded in predicting 11, and AlphaFold only two, out of 26 models with medium or high accuracy, with significant deviations in the docking contacts predicted in the rest of the molecules. In summary, our study provides important information about the abilities and limitations of using AlphaFold to predict antibody:antigen interactions and suggests areas for possible improvement.

Key Points

AlphaFold was used to predict 222 new 3D hi-res atomic structures of Ab chains.

Low accuracy was observed in the prediction of HC-CDR3 and the elbow angles.

Predicting Ab-Ag complexes and epitope mapping using AlphaFold-Multimer was limited.
Distance v.s. Resolution: Neuromapping of Effective Resolution onto Physical Distance
Authors: Arslan Suayb S. , Fux Michal , Sinha Pawan
Published: August 2023

The main focus of this work is on determining the effective resolution of a face image on the retina when the face is at a particular distance from the eye. Despite its straightforward articulation, arriving at a satisfactory solution might be unexpectedly challenging. The relationship between viewing distance and effective resolution cannot be easily obtained through Snellen acuity, contrast sensitivity, photoreceptor packing density or ganglion cell convergence rate in the retina. We used theoretical modelling to establish preliminary guidelines and then tested them empirically. We showed participants a 2×2 array of images in different resolutions at various viewing distances. At each distance, participants were expected to perform an “odd one out” task, identifying the image that was blurrier than the other three. As the study progressed, viewing distance was gradually reduced. The data collected enabled us to determine the upper and lower limits of the available effective resolution for human vision under normal conditions, as a function of viewing distance. Notably, human performance in blur detection is superior to what a theoretical model based on projected image size, cone density, and foveal extent predicts, especially at close ranges. Therefore, we propose that future theoretical models must account for non-uniform in–fovea density and the less pronounced decline in acuity outside the fovea to establish a reliable relationship between viewing distance and perceived image characteristics. The  mapping allows for a direct comparison of human face recognition performance across different levels of blur and viewing distance. It also enables us to systematically compare human performance to that of machine vision systems using resolution as a common factor.
scMD: cell type deconvolution using single-cell DNA methylation references
Authors: Cai Manqi , Zhou Jingtian , McKennan Chris , Wang Jiebiao
Published: August 2023

The proliferation of single-cell RNA sequencing data has led to the widespread use of cellular deconvolution, aiding the extraction of cell type-specific information from extensive bulk data. However, those advances have been mostly limited to transcriptomic data. With recent development in single-cell DNA methylation (scDNAm), new avenues have been opened for deconvolving bulk DNAm data, particularly for solid tissues like the brain that lack cell-type references. Due to technical limitations, current scDNAm sequences represent a small proportion of the whole genome for each single cell, and those detected regions differ across cells. This makes scDNAm data ultrahigh dimensional and ultra-sparse. To deal with these challenges, we introduce scMD (single cell Methylation Deconvolution), a cellular deconvolution framework to reliably estimate cell type fractions from tissue-level DNAm data. To analyze large-scale complex scDNAm data, scMD employs a statistical approach to aggregate scDNAm data at the cell cluster level, identify cell-type marker DNAm sites, and create a precise cell-type signature matrix that surpasses state-of-the-art sorted-cell or RNA-derived references. Through thorough benchmarking in several datasets, we demonstrate scMD’s superior performance in estimating cellular fractions from bulk DNAm data. With scMD-estimated cellular fractions, we identify cell type fractions and cell type-specific differentially methylated cytosines associated with Alzheimer’s disease.
Quantification of sporozoite expelling byAnophelesmosquitoes infected with laboratory and naturally circulatingP. falciparumgametocytes
Authors: Andolina Chiara , Graumans Wouter , Guelbeogo Moussa , van Gemert Geert Jan , Ramjith Jordache , Harouna Soré , Soumanaba Zongo , Stoter Rianne , Vegte-Bolmer Marga , Pangos Martina , Sinnis Photini , Collins Katharine , Staedke Sarah G , Tiono Alfred B , Drakeley Chris , Lanke Kjerstin , Bousema Teun
Published: August 2023

It is currently unknown whether allPlasmodium falciparuminfected mosquitoes are equally infectious. We assessed sporogonic development using cultured gametocytes in the Netherlands and naturally circulating strains in Burkina Faso. We quantified the number of sporozoites expelled into artificial skin in relation to intact oocysts, ruptured oocysts, and residual salivary gland sporozoites. Sporozoites were quantified by highly sensitive qPCR; intact and ruptured oocysts by fluorescence microscopy following antibody staining of circumsporozoite protein. In laboratory conditions, higher total sporozoite burden in mosquitoes was associated with a shorter duration of sporogony (p<0.001). Overall, 53% (116/216) ofP. falciparuminfectedAn. stephensimosquitoes expelled sporozoites into artificial skin. The medians of expelled and residual salivary gland sporozoites were 136 (IQR: 34-501) and 23,947 (IQR: 9127-78,380), respectively. There was a strong positive correlation between ruptured oocyst number and salivary gland sporozoite load (ρ=0.8; p<0.0001) and a weaker positive correlation between salivary gland sporozoite load and the number of sporozoites expelled (ρ=0.35; p=0.0002). In Burkina Faso,An. coluzziimosquitoes were infected by natural gametocyte carriers. Among mosquitoes that were salivary gland sporozoite positive, 89% (33/37) expelled sporozoites with a median of 1035 expelled sporozoites (IQR: 171-2969) and harbored a median of 45,100 residual salivary gland sporozoites (IQR: 20,310-164,900). Again, we observed a strong correlation between ruptured oocyst number and salivary gland sporozoite load (ρ=0.9; p<0.0001) and a positive correlation between salivary gland sporozoite load and the number of sporozoites expelled (ρ=0.7; p<0.0001). Mosquito salivary glands in Burkina Faso harbored 1-3 distinct parasite clones; several mosquitoes expelled multiple parasite clones during probing.

Whilst sporozoite expelling was regularly observed from mosquitoes with low infection burdens, our findings indicate that mosquito infection burden is associated with the number of expelled sporozoites. Future work is required to determine the direct implications of these findings for transmission potential.
An adaptable, reusable, and light implant for chronic Neuropixels probes
Authors: Bimbard C. , Takács F. , Catarino J. A. , Fabre J. M. J. , Gupta S. , Lenzi S. C. , Melin M. D. , O’Neill N. , Orsolic I. , Robacha M. , Street J. S. , Teixeira J. , Townsend S. , van Beest E. H. , Zhang A. M. , Churchland A. K. , Duan C. A. , Harris K. D. , Kullmann D. M. , Lignani G. , Mainen Z. F. , Margrie T. W. , Rochefort N.L. , Wikenheiser A. M. , Carandini M. , Coen P.
Published: August 2023

Electrophysiology has proven invaluable to record neural activity, and the development of Neuropixels probes dramatically increased the number of recorded neurons. These probes are often implanted acutely, but acute recordings cannot be performed in freely moving animals and the recorded neurons cannot be tracked across days. To study key behaviors such as navigation, learning, and memory formation, the probes must be implanted chronically. An ideal chronic implant should (1) allow stable recordings of neurons for weeks; (2) allow reuse of the probes after explantation; (3) be light enough for use in mice. Here, we present the “Apollo Implant”, an open-source and editable device that meets these criteria and accommodates up to two Neuropixels 1.0 or 2.0 probes. The implant comprises a “payload” module which is attached to the probe and is recoverable, and a “docking” module which is cemented to the skull. The design is adjustable, making it easy to change the distance between probes, the angle of insertion, and the depth of insertion. We tested the implant across eight labs in head-fixed mice, freely moving mice, and freely moving rats. The number of neurons recorded across days was stable, even after repeated implantations of the same probe. The Apollo implant provides an inexpensive, lightweight, and flexible solution for reusable chronic Neuropixels recordings.
Ribosomal DNA copy number is associated with body mass in humans and other mammals
Authors: Law Pui Pik , Rodriguez-Algarra Francisco , Asenius Fredrika , Gregori Maria , Seaborne Robert AE , Yildizoglu Selin , Miller James RC , Mesnage Robin , Antoniou Michael N , Li Weilong , Tan Qihua , Hillman Sara L , Rakyan Vardhman K , Williams David J , Holland Michelle L
Published: August 2023

Body mass results from a complex interplay between genetics and environment. The contribution of genetic variation to body mass has been extensively studied, but due to the technical limitations of platforms used for population scale studies, repetitive parts of the genome have not previously been considered. Here we applied genome-wide approaches to identify an association between adult body mass and the copy number (CN) of 45S-ribosomal DNA (rDNA). rDNA codes for the rRNA components of the ribosome and exists in hundreds of copies/cell in mammals. Inter-individual variation in rDNA CN has not previously been documented but has not been associated with a mammalian phenotype. Here, we show that germ-line inherited rDNA CN is associated with post-pubertal growth rate in rats and BMI in adult humans. rDNA CN variation is not associated with rRNA transcription rates in adult tissues, suggesting the mechanistic link occurs earlier in development. This is supported by our observation that it is growth rate and body mass, rather than obesity that are associated with copy number and that these phenotypes emerge prior to adulthood. We present hypotheses for future investigation into the mechanistic basis of this association.
The black-legged tickIxodes scapularisdetects CO2without the Haller’s organ
Authors: Städele Carola
Published: August 2023

Both male and female ticks have a strong innate drive to find and blood-feed on hosts. Carbon dioxide (CO2) is considered a critical behavioral activator and attractant for ticks and an essential sensory cue to find hosts. Yet, how CO2activates and promotes host-seeking in ticks is poorly understood. We studied CO2responses in the black-legged tickIxodes scapularis, the primary vector for Lyme disease in North America. Adult males and females were exposed to 1, 2, 4, or 8% CO2, and changes in walking behavior and foreleg movement were analyzed. We find that CO2is a potent stimulant for adultIxodes scapularis, even at lower concentrations (1%). Behavioral reactions depend on the animal’s state: Walking ticks increase their walking speed, while stationary ticks start to wave their forelegs and begin to quest – both behaviors resembling aspects of host-seeking. Furthermore,Ixodes scapularishas no clear concentration preference and is not tuned more robust to breath-like CO2concentrations (∼4%) than to the other concentrations tested. As soon as the CO2level is above a certain threshold,Ixodes scapularisreact, indicating that CO2acts as a behavioral activator and can be used as a long-distance cue to detect approaching hosts. Moreover, we provide convincing evidence that the foreleg Haller’s organ is not necessary for CO2detection. Even with disabled or amputated Haller’s organ,Ixodes scapularisrespond robustly to CO2, signifying that there must be CO2-sensitive structures important for tick host-seeking that have not yet been identified.
Impact of odorants on perception of sweetness by honey bees
Authors: Pel Allyson V. , Van Nest Byron N. , Hathaway Stephanie R. , Fahrbach Susan E.
Published: August 2023

Organic volatiles produced by fruits can result in overestimation of sweetness by humans, but it is unknown if a comparable phenomenon occurs in other species. Honey bees collect nectar of varying sweetness at different flowering plants. Bees discriminate sugar concentration and generally prefer higher concentrations; they encounter floral volatiles as they collect nectar, suggesting that they, like humans, could be susceptible to sweetness enhancement by odorant. In this study, limonene, linalool, geraniol, and 6-methyl-5-hepten-2-ol were tested for their ability to alter behaviors related to perception of sweetness by honey bees. Honey bees were tested in the laboratory using proboscis extension response-based assays and in the field using feeder-based assays. In the laboratory assays, 6-methyl-5-hepten-2-ol and geraniol, but neither linalool nor limonene, significantly increased responses to low concentrations of sucrose compared with no odorant conditions in 15-day and 25-day-old adult worker honey bees, but not in 35-day-old bees. Limonene reduced responding in 15-day-old bees, but not in the older bees. There was no odorant- based difference in performance in field assays comparing geraniol and limonene with a no odorant control. The interaction of the tested plant volatiles with sucrose concentration revealed in laboratory testing is therefore unlikely to be a major determinant of nectar choice by honey bees foraging under natural conditions. Because geraniol is a component of honey bee Nasonov gland pheromone as well as a floral volatile, its impact on responses in the laboratory may reflect conveyance of different information than the other odorants tested.
Decrease in reaction time for volleyball athletes during saccadic eye movement task: An associative analysis with evoked potentials
Authors: Costa Élida , Gongora Mariana , Bittencourt Juliana , Marinho Victor , Cagy Mauricio , Teixeira Silmar , Nicoliche Eduardo , Fernandes Isabelle , Wienecke Jacob , Ribeiro Pedro , Gupta Daya S. , Velasques Bruna , Budde Henning
Published: August 2023

Aim

The current study investigated the differences to event-related potential and reaction time under two groups (athletesvs. non-athletes).

Material and Methods

The P300 was analyzed for Fz, Cz and Pz electrodes in thirty-one healthy volunteers divided into two groups (volleyball athletes and non-athletes). In addition, the participants performed a saccadic eye movement task to measure reaction time.

Results

The EEG analysis showed that the athletes in comparison to the no-athletes has differences of the P300 in the frontal area (p=0.021). In relation to reaction time, the results show lower reaction time for athletes (p=0.001).

Conclusions

The volleyball athletes may present a greater allocation of attention during the execution of the inhibition task, since they have a lower reaction time for responses when compared to non-athletes.
Embryonic life histories in annual killifish: adapted to what?
Authors: Van Dooren Tom JM
Published: August 2023

Adaptation requires an evolving strategy and an environment. Given an environment, we predict or estimate which strategies are adapted. Given a strategy, we want to know in which environments it might be adapted. Example calculations aiming to determine such environments, named evolutionarily singular environments ESE, are presented using lab data on embryonic life histories ofAustrolebiasannual killifish. Annual killifish embryos can arrest development and survive desiccation of temporary ponds in the soil. They might implement diversified bet-hedging, generally seen as an adaptation to uncertain environments. Using parameter estimates and parsimonious assumptions, a population dynamical model is constructed with explicit developmental stages. Using invasion fitness gradients of rates of development and hatching probabilities, it is investigated whether these could be adapted to pond filling regimes with gradual filling and drying and deterministic within-year variation only. The life history as a whole is not adapted to the regular within-year annual cycles investigated, with one or two periods where reproduction can occur. Faster development rates were always favoured, just as in constant environments. Only for hatching probabilities, pond filling regimes were found which made their invasion fitness sensitivities zero. However, the observed trait values did not have long-term evolutionary stability in these ESE. Therefore, neither the developmental rates nor the hatching strategy seem adapted to within-year patterns of environmental change.
Quantifying the Influence of the Actin Cytoskeleton on Ion Transport in Dendritic Spines by Homogenization of the Poisson-Nernst-Planck Equations
Authors: Eberhardt Florian
Published: August 2023

Dendritic spines are filled with a very dense actin cytoskeleton. However, due to their small size, the impact of this mesh on biophysical parameters has not been studied so far, and it remains unclear to what extent it might affect ion flow in dendritic spines. Only recently has the three-dimensional internal structure of dendritic spines been quantified in great detail in electron microscopic tomography data. Based on these results, we estimate the effect of the spine actin cytoskeleton on diffusion and permittivity. We apply a method called homogenization to estimate effective diffusion tensors and permittivity tensors in Poisson-Nernst-Planck (PNP) equations. We find that the volume taken up by the intracellular structure alone cannot explain the changes in these biophysical parameters. The characteristic architecture of the intracellular space in dendritic spines will reduce the diffusion of ions by 33% to 46% and the permittivity by 30% to 42%, compared to values found for the cytosol free of intracellular structures.

These results can be used to improve computational studies using PNP equations and help to better interpret experimental results of electrical and chemical compartmentalization.
In-depth immunometabolic profiling by measuring cellular protein translation inhibition via bioorthogonal noncanonical amino acid tagging (CENCAT)
Authors: Vrieling Frank , van der Zande Hendrik J.P. , Naus Britta , Smeehuijzen Lisa , Ignacio Bob J. , Bonger Kimberly M. , Van den Bossche Jan , Kersten Sander , Stienstra Rinke
Published: August 2023

Motivation

Extracellular Flux (XF) analysis has been a key technique in immunometabolism research, measuring cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to determine immune cell metabolic profiles. However, XF analysis has several limitations, including the need for purified adherent cells, relatively high cell numbers, and specialized equipment. Recently, a novel flow cytometry-based technique called SCENITH (Single Cell Energetic metabolism by profiling Translation inhibition) was introduced, which measures the inhibition of cellular protein synthesis as a proxy for metabolic activity in single cells. A limitation of this technique is its reliance on fluorescent staining of intracellular puromycin, a toxic antibiotic. To address this, we propose an alternative approach using biorthogonal noncanonical amino acid tagging (BONCAT) to measure protein synthesis.

The field of immunometabolism has revealed that cellular energy metabolism significantly contributes to immune cell function. Disturbances in immune cell metabolism have been associated with various diseases, including obesity, atherosclerosis, and cancer. To further advance immunometabolic research, developing novel methods to study the metabolism of immune cells in complex samples is essential. Here, we introduce CENCAT (Cellular Energetics through Non-Canonical Amino acid Tagging). This technique utilizes click-labeling of alkyne-bearing non-canonical amino acids (ncAAs) to measure protein synthesis inhibition as a proxy of metabolic activity. CENCAT successfully reproduced known metabolic signatures of immune cell activation. Specifically, LPS/IFNγ-induced classical activation increased glycolytic capacity, and IL-4-induced alternative activation enhanced mitochondrial dependence in human primary macrophages. The assay’s applicability was further explored in more complex samples, including peripheral blood mononuclear cells (PBMCs) from healthy volunteers, which revealed diverse metabolic rewiring in immune cell subsets upon stimulation with different activators. Finally, CENCAT was used to analyze the cellular metabolism of murine tissue-resident immune cells from various organs. Principal component analysis (PCA) revealed tissue-specific clustering based on metabolic profiles, likely driven by microenvironmental priming of tissue-resident immune cells. In conclusion, CENCAT offers valuable insights into immune cell metabolic responses and presents a powerful platform for studying immune cell metabolism in complex samples and tissue-resident immune populations in both human and murine studies.
Social attention across development in common ravens and carrion crows
Authors: Miller Rachael , Boeckle Markus , Ridgway Sophie , Richardson James , Uhl Florian , Bugnyar Thomas , Schwab Christine
Published: August 2023

Underlying social learning and other important aspects of successful adaptation to social life is social awareness, where individuals are required to pay attention and respond flexibly to others in their environment. We tested the influence of social context (alone, affiliate, non-affiliate, heterospecific) on behavioural interactions (manipulation, caching, head & body out of sight i.e. barrier use) with food and objects during development at fledging (1-2 months), juvenile (3-8 months) and sub-adult (14-18 months old) in 10 carrion crows (Corvus corone; C. cornix) and nine common ravens (C. corax). These species are closely related, generalist corvids and subjects were all hand-reared and housed in highly comparable conditions. Both species will routinely cache, i.e. hide food and other items for later recovery, and engage in cache-pilfering (stealing) strategies. They will interact and ‘play’ with objects, potentially as part of developing social bonding and/or physical skills. We found that corvid behaviour was influenced by social context, with birds showing higher frequency of ‘head & body out of sight’ behaviour while others were observing than when alone, suggesting they have an awareness of other’s presence and respond by using barriers when interacting with items. There were no differences based on observer identity, supporting an interpretation of item interaction and play potentially driving development of physical skills in this setting. There were developmental effects, including increased manipulation and use of barriers as juveniles as well as increased caching with age. Ravens generally cached more than crows. Objects were manipulated more frequently than food, while barriers were used more with food, indicating that food was more likely to be actively hidden while objects may promote open play. We discuss our findings in relation to other social and developmental influences on behaviour and the wider ramifications for identifying the drivers of play in animals.
Constitutive activity of ionotropic glutamate receptors via hydrophobic substitutions in the ligand-binding domain
Authors: Seljeset Sandra , Sintsova Oksana , Wang Yuhong , Harb Hassan Y. , Lynagh Timothy
Published: August 2023

Neurotransmitter ligands electrically excite neurons by activating ionotropic glutamate receptor (iGluR) ion channels. Knowledge of the iGluR amino acid residues that dominate ligand-induced activation would enable the prediction of function from sequence. We therefore explored the molecular determinants of activity in rat NMDA-type iGluRs (NMDA receptors), complex heteromeric iGluRs comprising two glycine-binding GluN1 and two glutamate-binding GluN2 subunits, using amino acid sequence analysis, mutagenesis, and electrophysiology. We find that a broadly conserved aspartate residue controls both ligand potency and channel activity, to the extent that certain substitutions at this position bypass the need for ligand-binding in GluN1 subunits, generating NMDA receptors activated solely by glutamate. Furthermore, we identify a homomeric iGluR from the placozoanTrichoplax adhaerensthat has utilized native mutations of this crucial residue to evolve into a leak channel that is inhibited by neurotransmitter binding, pointing to a dominant role of this residue throughout the iGluR superfamily.
NaV1.6 inhibition drives the efficacy of voltage-gated sodium channel inhibitors to prevent electrically induced seizures in both wild type andScn8aN1768D/+gain-of-function mice
Authors: Johnson JP , Focken Thilo , Tari Parisa Karimi , Dube Celine , Goodchild Samuel J , Andrez Jean-Christophe , Bankar Girish , Burford Kristen , Chang Elaine , Chowdhury Sultan , Christabel Jessica , Dean Richard , de Boer Gina , Dehnhardt Christoph , Gong Wei , Grimwood Michael , Hussainkhel Angela , Jia Qi , Khakh Kuldip , Lee Stephanie , Li Jenny , Lin Sophia , Lindgren Andrea , Lofstrand Verner , Mezeyova Janette , Nelkenbrecher Karen , Shuart Noah Gregory , Sojo Luis , Sun Shaoyi , Waldbrook Matthew , Wesolowski Steven , Wilson Michael , Xie Zhiwei , Zenova Alla , Zhang Wei , Scott Fiona , Cutts Alison J , Sherrington Robin P , Winquist Raymond , Cohen Charles J , Empfield James R
Published: August 2023

Inhibitors of voltage-gated sodium channels (NaVs) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are nonselective. We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. Mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) responded with a tonic-clonic seizure to a mild 6 Hz stimulus that was innocuous to wild-type mice. Pharmacologic inhibition of NaV1.6 inScn8aN1768D/+mice prevented seizures. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaVisoforms. Our data suggest NaV1.6 inhibition is a driver of efficacy for NaVinhibitor anti-seizure medicines. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and better tolerated treatments for idiopathic epilepsies.

Graphical Abstract
Facilitating taxonomy and phylogenetics: An informative and cost-effective protocol integrating long amplicon PCRs and third generation sequencing
Authors: Gajski Domagoj , Wolff Jonas O. , Melcher Anja , Weber Sven , Prost Stefan , Krehenwinkel Henrik , Kennedy Susan R.
Published: August 2023

Phylogenetic inference has become a standard technique in integrative taxonomy and systematics, as well as in biogeography and ecology. DNA barcodes are often used for phylogenetic inference, despite being strongly limited due to their low number of informative sites. Also, because current DNA barcodes are based on a fraction of a single, fast-evolving gene, they are highly unsuitable for resolving deeper phylogenetic relationships due to saturation. In recent years, methods that analyse hundreds and thousands of loci at once have improved the resolution of the Tree of Life, but these methods require resources, experience and molecular laboratories that most taxonomists do not have. This paper introduces a PCR-based protocol that produces long amplicons of both slow- and fast-evolving unlinked mitochondrial and nuclear gene regions, which can be sequenced by the affordable and portable ONT MinION platform with low infrastructure or funding requirements. As a proof of concept, we inferred a phylogeny of a sample of 63 spider species from 20 families using our proposed protocol. The results were overall consistent with the results from approaches based on hundreds and thousands of loci, while requiring just a fraction of the cost and labour of such approaches, making our protocol accessible to taxonomists worldwide.

Highlights

DNA barcoding is an invaluable tool for fast and accurate taxonomic classification

Existing DNA barcodes are still insufficient for obtaining well-supported phylogenies

We present a protocol that produces long amplicons of unlinked loci for spiders

Amplicons are sequenced at very low cost per specimen with ONT MinION

Our recovered phylogeny is largely consistent with that of high-cost approaches.
A Multimodal Deep Learning Framework for Predicting PPI-Modulator Interactions
Authors: Sun Heqi , Wang Jianmin , Wu Hongyan , Lin Shenggeng , Chen Junwei , Wei Jinghua , Lv Shuai , Xiong Yi , Wei Dong-Qing
Published: August 2023

Protein-protein interactions (PPIs) are essential for various biological processes and diseases. However, most existing computational methods for identifying PPI modulators require either target structure or reference modulators, which restricts their applicability to novel PPI targets. To address this challenge, we propose MultiPPIMI, a sequence-based deep learning framework that predicts the interaction between any given PPI target and modulator. MultiPPIMI integrates multimodal representations of PPI targets and modulators, and uses a bilinear attention network to capture inter-molecular interactions. Experimental results on our curated benchmark dataset show that MultiPPIMI achieves an average AUROC of 0.837 in three cold-start scenarios, and an AUROC of 0.994 in the random-split scenario. Furthermore, the case study show that MultiPPIMI can assist molecular simulations in screening inhibitors of Keap1/Nrf2 PPI interactions. We believe that the proposed method provides a promising way to screen PPI-targeted modulators.
KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy
Authors: de Talhouët Capucine , Esteras Gallego Noemi , Soutar Marc , O’Callaghan Benjamin , Plun-Favreau Helene
Published: August 2023

It has recently been shown thatKAT8, a genome-wide association study (GWAS) candidate risk gene for Parkinson’s Disease, is involved in PINK1/Parkin-dependant mitophagy. TheKAT8gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal (NSL) epigenetic remodelling complex. In the current study, we show that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibits the initial steps of the PINK1-dependant mitophagy process. More specifically, our study shows that following mitochondrial depolarisation induced by mitochondrial toxins, MG149 treatment inhibits PINK1-dependant mitophagy initiation by impairing PINK1 activation, and subsequent phosphorylation of Parkin and ubiquitin. While this inhibitory effect of MG149 on PINK1-activation is potent, MG149 treatment in the absence of mitochondrial toxins is sufficient to depolarise the mitochondrial membrane, recruit PINK1 and promote partial downstream recruitment of the autophagy receptor p62, leading to an increase in mitochondrial delivery to the lysosomes. Altogether, our study provides additional support for KAT8 as a regulator of mitophagy and autophagy processes.
Is your data alignable? Principled and interpretable alignability testing and integration of single-cell data
Authors: Ma Rong , Sun Eric D. , Donoho David , Zou James
Published: August 2023

Single-cell data integration can provide a comprehensive molecular view of cells, and many algorithms have been developed to remove unwanted technical or biological variations and integrate heterogeneous single-cell datasets. Despite their wide usage, existing methods suffer from several fundamental limitations. In particular, we lack a rigorous statistical test for whether two high-dimensional single-cell datasets are alignable (and therefore should even be aligned). Moreover, popular methods can substantially distort the data during alignment, making the aligned data and downstream analysis difficult to interpret. To overcome these limitations, we present a spectral manifold alignment and inference (SMAI) framework, which enables principled and interpretable alignability testing and structure-preserving integration of single-cell data. SMAI provides a statistical test to robustly determine the alignability between datasets to avoid misleading inference, and is justified by high-dimensional statistical theory. On a diverse range of real and simulated benchmark datasets, it outperforms commonly used alignment methods. Moreover, we show that SMAI improves various downstream analyses such as identification of differentially expressed genes and imputation of single-cell spatial transcriptomics, providing further biological insights. SMAI’s interpretability also enables quantification and a deeper understanding of the sources of technical confounders in single-cell data.