bluuebunny/crossref_metadata_2025 huggingface dataset:
ASD mutation of Katnal2 impairs ependymal ciliary motion and causes hydrocephalus
Authors: Qiu Shuai , Cao Huaqiang , Xue Yao , Zhao Wenlong , Xie Shuangyi , Wu Nan , Song Meilin , Pan Yi-Hsuan , Baas Peter W. , Ma Ji , Yuan Xiao-Bing
Published: July 2023

Katanin catalytic subunit A1 like 2 (KATNAL2) is a high-risk gene associated with autism spectrum disorders (ASD), however its impact on brain development and disease remains unclear. The present study revealed an unexpected role of KATNAL2 in regulating ependymal ciliary motion and cerebrospinal fluid flow during brain development, an important contributing factor for ASD. We discovered a distinct expression pattern ofKATNAL2in multiciliated ependymal cells of both human and mouse brains. Notably, an ASD-associated mutation ofKatnal2disrupted its molecular function and resulted in ASD-related behavioral deficits in mice. Additionally, this mutation affected the polarized organization and beating of ependymal cilia, leading to delayed cerebrospinal fluid flow and sustained ventricular enlargement from the early postnatal stage. Conditional ablation ofKatnal2specifically in the ependymal cells of neonatal mice is sufficient to cause ventricular dilation, whereas no such effect was observed in adult mice. Our findings highlight the importance of ependymal motile cilia and hydrocephalus in ASD, offering insights into its pathogenesis and potential intervention.
Enamel proteins reveal biological sex and genetic variability within southern AfricanParanthropus
Authors: Madupe Palesa P. , Koenig Claire , Patramanis Ioannis , Rüther Patrick L. , Hlazo Nomawethu , Mackie Meaghan , Tawane Mirriam , Krueger Johanna , Taurozzi Alberto J. , Troché Gaudry , Kibii Job , Pickering Robyn , Dickinson Marc , Sahle Yonatan , Kgotleng Dipuo , Musiba Charles , Manthi Fredrick , Bell Liam , DuPlessis Michelle , Gilbert Catherine , Zipfel Bernhard , Kuderna Lukas F. K. , Lizano Esther , Welker Frido , Kyriakidou Pelagia , Cox Jürgen , Mollereau Catherine , Tokarski Caroline , Blackburn Jonathan , Ramos-Madrigal Jazmín , Marques-Bonet Tomas , Penkman Kirsty , Zanolli Clément , Schroeder Lauren , Racimo Fernando , Olsen Jesper V. , Ackermann Rebecca R. , Cappellini Enrico
Published: July 2023

The evolutionary relationships among extinct African hominin taxa are highly debated and largely unresolved, due in part to a lack of molecular data. Even within taxa, it is not always clear, based on morphology alone, whether ranges of variation are due to sexual dimorphism versus potentially undescribed taxonomic diversity. ForParanthropus robustus, a Pleistocene hominin found only in South Africa, both phylogenetic relationships to other taxa1,2and the nature of intraspecific variation3–6are still disputed. Here we report the mass spectrometric (MS) sequencing of enamel proteomes from four ca. 2 million year (Ma) old dental specimens attributed morphologically toP. robustus,from the site of Swartkrans. The identification of AMELY-specific peptides and semi-quantitative MS data analysis enabled us to determine the biological sex of all the specimens. Our combined molecular and morphometric data also provide compelling evidence of a significant degree of variation within southern AfricanParanthropus, as previously suggested based on morphology alone6. Finally, the molecular data also confirm the taxonomic placement ofParanthropuswithin the hominin clade. This study demonstrates the feasibility of recovering informative Early Pleistocene hominin enamel proteins from Africa. Crucially, it also shows how the analysis of these proteins can contribute to understanding whether hominin morphological variation is due to sexual dimorphism or to taxonomic differences. We anticipate that this approach can be widely applied to geologically-comparable sites within South Africa, and possibly more broadly across the continent.
Mechanism of branching morphogenesis inspired by diatom silica formation
Authors: Babenko Iaroslav , Kröger Nils , Friedrich Benjamin M.
Published: July 2023

The silica-based cell walls of diatoms are prime examples of genetically controlled, species-specific mineral architectures. The physical principles underlying morphogenesis of their hierarchically structured silica patterns are not understood, yet such insight could indicate novel routes towards synthesizing functional inorganic materials. Recent advances in imaging nascent diatom silica allow rationalizing possible mechanisms of their pattern formation. Here, we combine theory and experiments on the model diatomThalassiosira pseudonanato put forward a minimal model of branched rib patterns – a fundamental feature of the silica cell wall. We quantitatively recapitulate the time-course of rib pattern morphogenesis by accounting for silica biochemistry with autocatalytic formation of diffusible silica precursors followed by conversion into solid silica. We propose that silica deposition releases an inhibitor that slows down up-stream precursor conversion, thereby implementing a self-replicating reaction-diffusion system featuring a non-classical Turing mechanism. The proposed mechanism highlights the role of geometrical cues for guided self-organization, rationalizing the instructive role for the single initial pattern seed known as primary silicification site. The mechanism of branching morphogenesis that we characterize here is possibly generic and may apply also in other biological systems.

Significance statement

The formation of minerals by living organisms is a widespread biological phenomenon occurring throughout the evolutionary tree-of-life. The silica-based cell walls of diatom microalgae are impressive examples featuring intricate architectures and outstanding materials properties that still defy their reconstitutionin vitro. Here, we developed a minimal mathematical model that explains the formation of branched patterns of silica ribs, providing unprecedented understanding of basic physico-chemical processes capable of guiding silica morphogenesis in diatoms. The generic mechanism of branching morphogenesis identified here could provide recipes for bottom-up synthesis of mineral-nanowire networks for technological applications. Moreover, similar mechanisms may apply in the biological morphogenesis of other branched structures, like corals, bacterial colonies, tracheal networks, fungal plexuses, or the vascular system.
Solute Transport in Engineered Living Materials using Bone Inspired Microscale Channel Networks
Authors: van Wijngaarden Ellen W. , Bratcher Samantha , Lewis Karl J. , Hernandez Christopher J.
Published: July 2023

Engineered living materials (ELMs) are an emerging class of materials that is synthesized and/or populated by living cells. Maintaining living cells within an ELM over prolonged periods remains a major technical challenge that limits the service life of a material. Biological materials regularly maintain robust populations of living cells. Bone maintains living cells for decades by delivering nutrients through a network of nanoscale channels punctuated by microscale pores. Nutrient transfer in bone is enabled by mechanical loading experienced during regular use. Here we identify the characteristics of channel-pore network geometries and external mechanical loading that can be used in engineered living materials to deliver nutrients to resident cell populations. Transport occurs when deformation in the microscale pore network exceeds the volume of the connecting channels. Computational models show that transport is enhanced at greater load magnitudes and lower loading frequencies and are consistent with experimental validation using microfluidic systems. Our findings provide quantitative design principles for channel-pore networks capable of delivering nutrients to materials designed to house living cells.
Effect of Aging on the Human Myometrium at Single-Cell Resolution
Authors: Punzón-Jiménez P , Machado-Lopez A , Pérez-Moraga R , Llera-Oyola J , Grases D , Galvez-Viedma M , AlSibai M , Satorres E , Badenes R , Ferrer C , Porta-Pardo E , Roson B , Simón C , Mas A
Published: July 2023

The myometrial dysfunction associated with aging can prompt complications during pregnancy and labor, causing a 7.8-fold increase in maternal mortality in women over 40. Using single-cell/single-nucleus RNA sequencing and spatial transcriptomics, we constructed a cellular atlas of the aging myometrium from 186,120 cells across twenty peri- and post-menopausal women. We identified 23 myometrial cell subpopulations, including novel contractile capillary, venous capillary, immune-modulated fibroblasts, and nervous system regulatory fibroblasts. Myometrial aging leads to fewer contractile capillary cells, a reduced level of ion channel expression in smooth muscle cells, and impaired gene expression in endothelial, smooth muscle, fibroblast, perivascular, and immune cells. We observed altered myometrial cell-to-cell communication as an aging hallmark associated with the loss of 25/229 signaling pathways, including those related to angiogenesis, tissue repair, contractility, immunity, and nervous system regulation. These insights may contribute to a better understanding of the complications faced by older women during pregnancy and labor.
Unraveling the Interplay of Different Traits and Parameters Related to Nitrogen Use Efficiency in Wheat: Insights for Grain Yield Influence
Authors: Gayatri  , Mandal Puja , Venkatesh Karnam , Mandal Pranab Kumar
Published: July 2023

Enhancing Nitrogen Use Efficiency (NUE) in wheat to optimize grain yield is a significant challenge. To address this challenge, a comprehensive study was conducted to investigate various morphological, biochemical, molecular parameters, and agronomic traits related to NUE. By examining various traits under both optimum-N (ON) and stressed-N (SN) conditions, the study explores the interrelationships among these traits, providing novel insights not previously reported. A set of 278 diverse wheat genotypes were assessed, encompassing eight NUE-related traits: Grain Yield, Biomass, Grain nitrogen, N at head, N at harvest, N-uptake, Nitrogen Uptake Efficiency, Nitrogen Utilization Efficiency, and NUE under both ON and SN conditions in the field. The findings demonstrated a significant positive correlation between grain yield and all NUE-related traits, highlighting their significance in comprehending the biological NUE of wheat plants. Notably, the study identified N-uptake and N-uptake related traits as key factors influencing the impact of soil nitrogen status on yield and associated parameters. These traits hold particular importance for selecting wheat genotypes with optimal yield and NUE in wheat cultivation. To complement the field data, representative genotypes were further subjected to a hydroponics experiment under absolute nitrogen control. This experiment provided insights into the effects of nitrogen stress on morphological parameters and the performance of eight essential nitrogen and carbon metabolizing enzymes. Correlation analysis highlighted the substantial influence of four key N-metabolizing enzymes, namely Nitrate Reductase, Glutamine Synthetase, Glutamate Oxo-Glutarate Amino Transferase, and Glutamate Dehydrogenase, on grain yield. Additionally, this study underscored the direct and indirect associations between seedling parameters and field traits, emphasizing the significance of shoot and root length parameters in nitrogen acquisition under nitrogen stress. In conclusion, these findings offer valuable insights into the intricate network of traits and parameters that influence wheat grain yield under varying nitrogen regimes. This knowledge can aid in the selection of wheat genotypes with enhanced NUE and grain yield, particularly in scenarios of reduced nitrogen application.

Key Points

A comprehensive study in field and hydroponics conditions revealed differential responses of various morphological, biochemical, molecular parameters, and agronomic traits to different nitrogen levels.

N-uptake related traits in field condition and chlorophyll content and morphological parameters in hydroponics condition were found as essential factors contributing to variations under both optimum and stressed N conditions.

Among the parameters observed in the seedling stage, SL and RL, along with the enzymes NR, GS, GOGAT, and GDH, demonstrated their influence on GY.
Incorporating slow NMDA-type receptors with nonlinear voltage-dependent magnesium block in a next generation neural mass model: derivation and dynamics
Authors: Sheheitli Hiba , Jirsa Viktor
Published: July 2023

We derive a next generation neural mass model of a population of quadratic-integrate-and-fire neurons, with slow adaptation, and conductance-based AMPAR, GABAR and nonlinear NMDAR synapses. We show that the Lorentzian ansatz assumption can be satisfied by introducing a piece-wise polynomial approximation of the nonlinear voltage-dependent magnesium block of NMDAR current. We study the dynamics of the resulting system for two example cases of excitatory cortical neurons and inhibitory striatal neurons. Bifurcation diagrams are presented comparing the different dynamical regimes as compared to the case of linear NMDAR currents, along with sample comparison simulation time series demonstrating different possible oscillatory solutions. The omission of the nonlinearity of NMDAR currents results in a shift in the range (and possible disappearance) of the constant high firing rate regime, along with a modulation in the amplitude and frequency power spectrum of oscillations. Moreover, nonlinear NMDAR action is seen to be state-dependent and can have opposite effects depending on the type of neurons involved and the level of input firing rate received. The presented model can serve as a computationally efficient building block in whole brain network models for investigating the differential modulation of different types of synapses under neuromodulatory influence or receptor specific malfunction.

Statements and Declarations

The authors have no competing interests to declare.

Funding

We acknowledge support by H2020 Research and Innovation Action grants Human Brain Project SGA3 number 945539.
Efficient inference of large pangenomes with PanTA
Authors: Le Duc Quang , Nguyen Tien Anh , Nguyen Son Hoang , Nguyen Tam Thi , Nguyen Canh Hao , Phung Huong Thanh , Ho Tho Huu , Vo Nam S. , Nguyen Trang , Nguyen Hoang Anh , Cao Minh Duc
Published: July 2023

Pangenome analysis is an indispensable step in bacterial genomics to address the high variability of bacteria genomes. However, speed and scalability remain a challenge for pangenome inference software tools to cope with the fast-growing genomic collections. We present PanTA, a software package for constructing the pangenomes of large bacterial collections. We show that PanTA exhibits an unprecedented multiple times more efficient than the current state-of-the-arts while maintaining a similar pangenome accuracy. In addition, PanTA introduces a novel mechanism to construct the pangenome progressively where new samples are added into an existing pangenome without rebuilding the accumulated collection from scratch. In the progressive mode, PanTA is demonstrated to consume orders of magnitude less computational resource than existing solutions in managing the pangenomes of growing microbial datasets. We further show that PanTA can build the pangenome of the entire collection of >28000Escherichia coligenomes from the RefSeq database on a laptop computer in 32 hours, highlighting the scalability and practicality of PanTA.The software is open source and is publicly available athttps://github.com/amromics/pantaunder an MIT license.
Global gradients in species richness of marine plankton functional groups
Authors: Benedetti Fabio , Gruber Nicolas , Vogt Meike
Published: July 2023

The patterns of species diversity of plankton functional groups (PFGs) remain poorly understood although they matter for marine ecosystem functioning. Here, we use an ensemble of empirical species distribution models for 845 plankton species to estimate the mean annual global species richness of three phytoplankton and eleven zooplankton functional groups as a function of objectively selected environmental predictors. The species richness of all PFGs decreases from the low to the high latitudes, but the steepness and the shape of this decrease varies significantly across PFGs. Pteropods, small copepods (Oithonids and Poecilostomatoids) and Salps show the steepest latitudinal gradients, whereas Amphipods and the three phytoplankton groups show the weakest ones. While the position of such peaks and troughs in richness is modulated by the presence of upwelling systems, boundary currents and oxygen minimum zones, the gradients of temperature, irradiance, and nutrient concentration are the first-order control on the main latitudinal richness patterns. The species richness of all PFGs increases with net primary production but decreases with particles size and the efficiency of the biological carbon pump. Our study puts forward emergent Biodiversity-Ecosystem Functioning relationships and hypotheses about their underlying drivers for future field-based and modelling research.
Detecting ataxia using an automated analysis of motor coordination and balance of mice on the balance beam
Authors: Wahl Lucas , Kaiser Fabian M.P. , Bentvelzen Mieke , White Joshua , Schonewille Martijn , Badura Aleksandra
Published: July 2023

Background

The balance beam assay is a well-known paradigm to assess motor coordination in mouse models of neurodegenerative diseases. Classically, these experiments have been quantified using manual annotation, which is time-consuming and prone to inter-experimenter variability.

Methods

We present an open-source analysis pipeline that allows for the automated quantification of motor function. Using an established ataxia model, we validated the pipeline by comparing its output to three independent observers.

Results

Pcp2-Ppp3r1mutant animals showed a significant increase in the number of missteps and increased time to traverse the beam.

Conclusion

We show that our pipeline can reliably report crossing time, missteps, stops, and falls, thereby offering a high-throughput option with increased inter-experimenter reliability for the analysis of balance beam data.

Significance statement

The analysis of mouse behaviour and motor coordination experiments often lacks automation and standardisation and is thus time-consuming and prone to inter-experimenter variability and poor reproducibility. The balance beam assay is a well-established motor coordination paradigm and currently lacks such an automated, standardised analysis platform. We have developed an open-source pipeline that allows for the automated analysis of crossing time, missteps, stops, and falls. Together with a standardised, easy to assemble balance beam setup, our pipeline offers a cost-effective, and high-throughput option to generate and analyse balance beam data with increased inter-experimenter and intra-experimenter reliability.
Neural envelope tracking predicts speech intelligibility and hearing aid benefit in children with hearing loss
Authors: Van Hirtum Tilde , Somers Ben , Dieudonné Benjamin , Verschueren Eline , Wouters Jan , Francart Tom
Published: July 2023

Early assessment of hearing aid benefit is crucial, as the extent to which hearing aids provide audible speech information predicts speech and language outcomes. A growing body of research has proposed neural envelope tracking as an objective measure of speech, particularly for individuals unable to provide reliable behavioral feedback. However, its potential for evaluating speech intelligibility and hearing aid benefit in hearing-impaired children remains unexplored. This study examined neural envelope tracking in hearing-impaired children through two separate experiments. EEG data was recorded while children listened to age-appropriate stories (experiment 1) or an animated movie (experiment 2) under aided and unaided conditions (using personal hearing aids) at multiple stimulus intensities. Results in the delta band demonstrated that neural tracking increased with increasing stimulus intensity, but only in the unaided condition. In the aided condition, neural tracking remained stable across a wide range of intensities, as long as speech intelligibility was maintained. This suggests that acoustic degradation of the speech signal does not necessarily impact neural tracking. Additionally, the use of personal hearing aids significantly enhanced neural envelope tracking, particularly in challenging speech conditions (which would be inaudible when unaided). Furthermore, neural envelope tracking strongly correlated with behaviorally measured speech intelligibility. Altogether, these findings indicate that neural envelope tracking could be a valuable tool for predicting speech intelligibility benefits derived from personal hearing aids in hearing-impaired children. Incorporating narrated stories or engaging movies expands the accessibility of these methods even in clinical settings, offering new avenues for using objective speech measures to guide pediatric audiology decision-making.
Combining high-density electromyography and ultrafast ultrasound to assess individual motor unit propertiesin vivo
Authors: Carbonaro M. , Rohlén R. , Seoni S. , Meiburger K. M. , Vieira T. , Grönlund C. , Botter A.
Published: July 2023

This study aims to compare two methods for the identification of anatomical and mechanical motor unit (MU) properties through the integration of high-density surface electromyography (HDsEMG) and ultrafast ultrasound (UUS). The two approaches rely on a combined analysis of the firing pattern of active MUs, identified from HDsEMG, and tissue velocity sequences of the muscle cross-section, obtained from UUS. The first method is the spike-triggered averaging (STA) of the tissue velocity sequence based on the occurrences of MU firings. The second is a method based on spatio-temporal independent component analysis (STICA) enhanced with the information of single MU firings. We compared the capability of these two approaches to identify the regions where single MU fibers are located within the muscle cross-section (MU displacement area)in vivo. HDsEMG signals and UUS images were detected simultaneously from biceps brachii in ten participants (6 males and 4 females) during low-level isometric elbow flexions. Experimental signals were processed by implementing both STA and STICA approaches. The medio-lateral distance between the estimated MU displacement areas and the centroid of the MU action potential distributions was used to compare the two methods. We found that STICA and STA are able to detect MU displacement areas. However, STICA provides more precise estimations to the detriment of higher computational complexity.
Dynein and dynactin move long-range but are delivered separately to the axon tip
Authors: Fellows Alexander D , Bruntraeger Michaela , Burgold Thomas , Bassett Andrew R , Carter Andrew P
Published: July 2023

Axonal transport is essential for neuronal survival. This is driven by microtubule motors including dynein, which transports cargo from the axon tip back to the cell body. This function requires its cofactor dynactin and regulators LIS1 and NDEL1. Due to difficulties imaging dynein at a single-molecule level, it is unclear how this motor and its regulators coordinate transport along the length of the axon. Here we use neuron-inducible human stem-celllines (NGN2-OPTi-OX) to endogenously tag dynein components and visualise them at a near-single molecule regime. In the retrograde direction, we find that dynein and dynactin can move the entire length of the axon (>500μm) in one go. Furthermore, LIS1 and NDEL1 also undergo longdistance movement, despite being mainly implicated with initiation of dynein transport. Intriguingly, in the anterograde direction, dynein/LIS1 move faster than dynactin/NDEL1 consistent with transport on different cargos. Therefore, neurons ensure efficient transport by holding dynein/dynactin on cargos over long distances, but keeping them separate until required.
Maintenance of colour memoranda in activity-quiescent working memory states: Evidence from impulse perturbation
Authors: Kandemir Güven , Wilhelm Sophia A. , Axmacher Nikolai , Akyürek Elkan G.
Published: July 2023

The neural mechanisms underlying working memory maintenance pose a challenge for investigation, as sustained neural activity may not always be observable. To address this, the method of impulse perturbation has been employed to examine memorized information during activity-quiescent periods. However, this approach has mainly focused on spatially localized or referenced stimuli, leaving it unclear whether non-spatial memoranda share similar neural maintenance mechanisms. This study aimed to fill this gap by applying the impulse perturbation method to working memory for colours, which are inherently non-spatial stimuli. EEG data from 30 participants performing a delayed match-to-sample task were analysed, with one of the presented items being retro-cued as task-relevant. Our findings indicate that both cued and uncued colours could be decoded from impulse-evoked activity, in contrast to previous reports on working memory for orientation gratings. Additionally, we explored colour decoding from ongoing oscillations in the alpha band and discovered that cued items could be decoded, potentially influenced by attention, whereas uncued items could not. These results suggest subtle differences between the representation of colours and stimuli with spatial properties. However, they also demonstrate that both types of information can be accessed through visual impulse perturbation, regardless of their specific neural states.
A unified framework to identify demographic buffering in natural populations
Authors: Santos Gabriel Silva , Gascoigne Samuel J L , Dias André Tavares Corrêa , Kajin Maja , Salguero-Gómez Roberto
Published: July 2023

The Demographic Buffering Hypothesis (DBH) predicts that natural selection reduces the temporal fluctuations in demographic processes (such as survival, development, and reproduction), due to their negative impacts on population dynamics. However, a comprehensive approach that allows for the examination of demographic buffering patterns across multiple species is still lacking. Here, we propose a three-step framework aimed at identifying and quantifying demographic buffering. Firstly, we categorize species along a continuum of variance based on their stochastic elasticities. Secondly, we examine the linear selection gradients, followed by the examination of nonlinear selection gradients as the third step. With these three steps, our framework overcomes existing limitations of conventional approaches to identify and quantify demographic buffering, allows for multi-species comparisons, and offers an insight into the evolutionary forces that shape demographic buffering. We apply this framework to mammal species and discuss both the advantages and potential of our framework.
Modeling of the Network Mediated by IL-36 Involved in Psoriasis
Authors: Pandey Sneha , Tiwari Syona , Basu Sulagna , Mishra Rajiv Kumar , Pandey Rakesh
Published: July 2023

Pathogenesis of inflammatory, chronic and common skin disease Psoriasis involves immune cells, skin cells (keratinocytes) and cytokines secreted by them. Hyperproliferation and abnormal differentiation of keratinocytes are believed to be a hallmark of it. Roles of several cytokines such as TNFα, IL-15, IL-17 and IL-23 in Psoriasis have been explored through mathematical/computational models as well as experimentally. However, the role of pro-inflammatory cytokine IL-36 is still elusive, especially in the case of General Pustular Psoriasis, a prevalent type of Psoriasis. To explore the role of that here, we construct a network embodying indirect cell-cell interactions of a few immune and skin cells mediated by IL-36 based on the existing knowledge. Further, we develop a mathematical model for the network and study the steady-state behaviour of that. Our results demonstrate that an increase in the level of IL-36 could lead to the hyper-proliferation of keratinocytes and, thus, Psoriasis. In addition, the analysis suggests that the plaque formation and progression of Psoriasis could occur via a gradual or switch-like increase in the population of keratinocytes. The switch-like increase would be due to the bistable behaviour of the network and could be used as a novel treatment strategy, as proposed and demonstrated earlier.
Exploring the Dose-Dependency of After-Effects: A Computational Model for Theta-Burst Transcranial Magnetic Stimulation
Authors: Ma Ke , Chung Sung Wook , Goetz Stephan M.
Published: July 2023

Transcranial magnetic stimulation (TMS) is a non-invasive neurostimulation and neuromodulation technique that is widely applied in brain research and clinical applications. However, the optimal parameters of neuromodulating TMS protocols describing the specific rhythms, such as number of pulses, frequency, and stimulation strength, are widely unknown. Improving previous rather limited and ad-hoc models, we aimed to investigate the dose-dependency of theta-burst stimulation (TBS) protocols with a more elaborate but still parsimonious quantitative model representing the non-linearities of the mechanisms of synaptic plasticity and metaplasticity during repetitive magnetic stimulation. Our model, which considers the interaction between facilitatory and inhibitory processes, successfully reproduced results from TBS experiments and provide testable predictions for prolonged TBS protocols. Moreover, we suggested that the activation of kinases and phosphatases could be potential candidates for later TMS modelling research. Although this model still simplifies the complex dynamics of cellular and molecular processes, it offers a starting basis for future studies to incorporate more intricate mechanisms. By further refining our understanding of the underlying mechanisms and improving the accuracy of prediction models, we can advance the efficacy and clinical application of TBS protocols in various neurological and psychiatric conditions.
Microbiome Prevents Sudden Death Through Occult Cardiac Sub-micrometastasis in Mice
Authors: Aalam Syed Mohammed Musheer , Tang Xiaojia , Hari PS , Salem Salem M. , Al Jarrad Ahmad , Noseworthy Peter A. , Behfar Atta , Sadanandam Anguraj , Kalari Krishna , Kashyap Purna C. , Kannan Nagarajan
Published: July 2023

Sudden cardiac deaths (SCDs) pose a formidable clinical challenge, and their underlying risk mechanisms are poorly understood. Using a gnotobiotic, germ-free mouse model, we fortuitously discovered SCD incidences resulting from occult cardiac metastases. Female germ-free C57BL/6 mice (n=22) were raised in isolation and injected with mammary Py230 cells. Significantly higher SCD probabilities (36.3%) were observed in germ-free mice compared to gut-colonized groups (0%). Extensive examinations revealed no physical anomalies but demonstrated occult cardiac sub-micrometastasis in three out of four sudden death cases. Further analysis supported the role of occult cardiac sub-micrometastasis as the leading cause of SCDs. The remaining germ-free mice exhibited minimal primary tumors but high levels of cardiac metastases and morbidity. The gnotobiotic SCD model represents a crucial milestone in our understanding of the complex interplay between the gut microbiota and the development of occult oncological processes that ultimately culminate in SCDs and warrants further investigation into their mechanisms.
When the tap runs dry: The physiological effects of acute experimental dehydration inPeromyscus eremicus
Authors: Blumstein Danielle M. , MacManes Matthew D.
Published: July 2023

Desert organisms have evolved physiological, biochemical, and genomic mechanisms to survive the extreme aridity of desert environments. Studying desert-adapted species provides a unique opportunity to investigate the survival strategies employed by organisms in some of the harshest habitats on Earth. Two of the primary challenges faced in desert environments are maintaining water balance and thermoregulation. We collected data in a simulated desert environment and a captive colony of cactus mice (Peromyscus eremicus) and used lab-based experiments with real time physiological measurements to characterize the response to water-deprivation. Mice without access to water had significantly lower energy expenditures and in turn, reduced water loss compared to mice with access to water after the first 24 hours of the experiment. Additionally, we observed significant weight loss likely related to dehydration-associated anorexia a response to limit fluid loss by reducing waste and the solute load as well as allowing water reabsorption from the kidneys and gastrointestinal tract. Finally, we observed body temperature correlated with sex, with males without access to water maintaining body temperature when compared to hydrated males while body temperature decreased for females without access to water compared to hydrated, suggesting daily torpor in females.
Purkinje cell dysfunction causes disrupted sleep in ataxic mice
Authors: Salazar Leon Luis E. , Brown Amanda M. , Kaku Heet , Sillitoe Roy V.
Published: July 2023

Purkinje cell dysfunction causes movement disorders such as ataxia, however, recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxia mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity is unaltered in the mutant mice, although their sleep parameters and ECoG patterns are modified. TheL7Cre;Vgatfx/fxmutant mice have decreased wakefulness and rapid eye movement (REM) sleep, while non-rapid eye movement (NREM) sleep is increased. The mutant mice have an extended latency to REM sleep, which is also observed in human ataxia patients. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders.

Summary Statement

Utilizing a precise genetic mouse model of ataxia, we provide insights into the cerebellum’s role in sleep regulation, highlighting its potential as a therapeutic target for motor disorders-related sleep disruptions.
Human behavior and comfort during load carrying to autonomous mobile robot
Authors: Tamura Hideki , Konno Taiki , Nakauchi Shigeki , Minami Tetsuto
Published: July 2023

Interactions between humans and autonomous mobile robots (AMRs) are expected to grow in smart cities to improve logistics operations, such as depositing packages on AMRs for pickup on the street. However, the way that humans walk and pass objects to an AMR when approaching each other remains largely unknown. We conducted two psychophysical experiments to clarify the behavior and comfort of humans when carrying a package and placing it on an AMR for load carrying. Participants were asked to approach a programmed AMR and pass the package in two experiments: 1) changing the stop distance and AMR speed and 2) changing the stop distance and package weight. Motion trackers quantified the participants’ walking speed and frequency of hesitation to walk. In addition, the subjective heaviness and comfort were recorded through a questionnaire during each trial. The results indicated that the participants’ speed decreased and hesitation probability increased when the stop distance of the AMR decreased. Nevertheless, the participants felt more comfortable with the close approach, whereas the package weight did not affect their behavior. By contrast, they felt uncomfortable when AMR remained still. These findings suggest that humans regard the AMR approach as load-carrying assistance and not as invading their personal space. To achieve a comfortable interaction in load carrying from humans to AMRs, we suggest that the AMR can closely approach a person without eliciting personal space invasion.
SrcapHaploinsufficiency Induced Autistic-Like Behaviors in Mice through Disruption ofSatb2Expression
Authors: Ding Chaodong , Shi Yuhan , Shan Shifang , Yuan Yiting , Zhang Yuefang , Qiu Zilong
Published: July 2023

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with significant genetic predispositions. Among these, loss-of-function mutations of the chromatin remodeling geneSRCAPhave been identified in individuals with ASD, but their pathogenic mechanisms have yet to be fully elucidated. In this study, we established a germline mutant mouse model harboring a heterozygous frameshift mutation in theSrcapgene (Srcap+/-). TheSrcap+/-mice exhibited notable impairments in social novelty, repetitive and stereotyped behaviors, anxiety, and learning and memory deficits. We observed a decreased number of parvalbumin (PV)-expressing neurons in their retrosplenial cortex (RSC) and dentate gyrus (DG). Furthermore, abnormalities in dendritic structure, synaptic density, and synaptic transmission were noted in the DG ofSrcap+/-mice. RNA sequencing revealed that the expression of 27 genes, implicated in ASD, was dysregulated in theSrcaphaploinsufficiency mice. Among these genes, we found thatSrcaphaploinsufficiency resulted in decreasedSatb2expression due to diminished H2A.z-binding within the promoter region ofSatb2. Remarkably, intervention through retro-orbital injection of AAV vectors expressingSatb2in newbornSrcap+/-mice reversed autistic-like behaviors and developmental defects in the RSC and DG regions. Similarly, in adolescentSrcap+/-mice, stereotactic injection of AAV expressingSatb2into the RSC ameliorated deficits in social novelty. Collectively, these findings highlight the crucial role of theSrcapin neurodevelopment by regulatingSatb2expression, particularly impacting the development of RSC and DG regions.
A scalable, data analytics workflow for image-based morphological profiles
Authors: Forsgren Edvin , Cloarec Olivier , Jonsson Pär , Trygg Johan
Published: July 2023

Cell Painting is an established community-based, microscopy-assay platform that provides high-throughput, high-content data for biological readouts. In November 2022, the JUMP-Cell Painting Consortium released the largest annotated, publicly available dataset, comprising more than 2 billion cell images. This dataset is designed for predicting the activity and toxicity of 100k drug compounds, with the aim to make cell images as computable as genomes and transcriptomes.

In this paper, we have developed a data analytics workflow that is both scalable and computationally efficient, while providing significant, biologically relevant insights for biologists estimating and comparing the effects of different drug treatments.

The two main objectives proposed include: 1) a simple, yet sophisticated, scalable data analytics metric that utilizes negative controls for comparing morphological cell profiles. We call this metric the equivalence score (Eq. score). 2) A workflow to identify and amplify subtle morphological image profile changes caused by drug treatments, compared to the negative controls. In summary, we provide a data analytics workflow to assist biologists in interpreting high-dimensional image features, not necessarily limited to morphological ones. This enhances the efficiency of drug candidate screening, thereby streamlining the drug development process. By increasing our understanding of using complex image-based data, we can decrease the cost and time to develop new, life-saving treatments.

Author summary

Microscopy-assays are often used to study cell responses to treatments in the search for new drugs. In this paper, we present a method that simplifies the understanding of the data generated from such assays. The data in this study consists of 750 morphological features, which describe the traits and characteristics of the cells, extracted from the images. By using untreated cells as a biological baseline, we’re able to detect subtle changes that occur in the treated cells. These changes are then transformed into an equivalence score (Eq. score), a metric that lets us compare the similarities among different treatments relative to our baseline of untreated cells. Our Eq. score approach transforms complex, high-dimensional data about cell morphology into something more interpretable and understandable. It reduces the “noise” in the features and highlights important changes, the “signal”. Our method can be integrated into existing workflows, aiding researchers in understanding and interpreting complex morphological data derived from cell images more easily. Understanding cell morphology is crucial to deepening our knowledge of biological systems. Ultimately, this could contribute to the faster and more cost-effective development of new, life-saving treatments.
Cryptic mitochondrial ageing coincides with mid-late life and is pathophysiologically informative in single cells across tissues and species
Authors: Green Alistair P. , Klimm Florian , Marshall Aidan S. , Leetmaa Rein , Aryaman Juvid , Gómez-Durán Aurora , Chinnery Patrick F. , Jones Nick S.
Published: July 2023

Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA (mtDNA) mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mtDNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mtDNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mtDNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory, hits high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and ER stress. We identify mechanistic links to ER stress experimentally and further give evidence that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.
Genotypic and Phenotypic Diversity ofKluyveromyces marxianusIsolates Obtained from the Elaboration Process of Two Traditional Mexican Alcoholic Beverages Derived from Agave: Pulque and Henequen (Agave fourcroydes) Mezcal
Authors: Lappe-Oliveras Patricia , Avitia Morena , Sánchez-Robledo Sara Darinka , Castillo-Plata Ana Karina , Pedraza Lorena , Baquerizo Guillermo , Borgne Sylvie Le
Published: July 2023

SevenKluyveromyces marxianusisolates from the elaboration process of pulque and henequen mezcal were characterized. The isolates were identified based on the sequences of the D1/D2 domain of the 26S rRNA gene and the internal transcribed spacer (ITS-5.8S) region. Genetic differences were found between pulque and henequen mezcal isolates and within henequen mezcal isolates, as shown by different branching patterns in the ITS-5.8S phylogenetic tree and (GTG)5 microsatellite profiles, suggesting that sub-strate and process selective conditions may originate differentK. marxianuspopulations. All the isolates fermented and assimilated inulin and lactose and some henequen isolates could also assimilate xylose and cellobiose. Henequen isolates were more thermotolerant than pulque isolates which in contrast presented more tolerance to the cell wall-disturbing agent calcofluor white (CFW) suggesting that they had a different cell wall structure. Additionally, depending on their origin, the isolates presented different maximum specific growth rates (µmax) patterns at different temperatures. Concerning tolerance to stress factors relevant for lignocellulosic hydrolysates fermentation, tolerance limits were lower at 42 than 30°C except for glucose and furfural. Pulque isolates were less tolerant to ethanol, NaCl, and Cd. Finally, all the isolates could produce ethanol by simultaneous saccharification and fermentation (SSF) of a corncob hydrolysate under laboratory conditions at 42°C.
Structure of a membrane-bound menaquinol:organohalide oxidoreductase
Authors: Cimmino Lorenzo , Duarte Américo G. , Ni Dongchun , Ekundayo Babatunde E. , Pereira Inês A.C. , Stahlberg Henning , Holliger Christof , Maillard Julien
Published: July 2023

Organohalide-respiring bacteria are key organisms for the bioremediation of soils and aquifers contaminated with halogenated organic compounds. The major players in this process are respiratory reductive dehalogenases, corrinoid enzymes that use organohalides as substrates and contribute to energy conservation. Here, we present the first structure of a functional menaquinol:organohalide oxidoreductase (MOOR) obtained by cryo-EM. The membrane-bound protein was isolated fromDesulfitobacterium hafniensestrain TCE1 as a PceA2B2complex catalysing the dechlorination of tetrachloroethene (PCE). Two catalytic PceA subunits are anchored to the membrane by two small integral membrane PceB subunits. The structure reveals two menaquinone molecules bound at the interface of the two different subunits, which are the starting point of a chain of redox cofactors for electron transfer to the active site. This structure elucidates how energy is conserved during organohalide respiration in menaquinone-dependent organohalide-respiring bacteria.
Single-cell profiling of bronchoalveolar cells reveals a Th17 signature in neutrophilic severe equine asthma
Authors: Sage Sophie E. , Leeb Tosso , Jagannathan Vidhya , Gerber Vinzenz
Published: July 2023

Severe equine asthma (SEA) shares clinical and pathological features with human neutrophilic asthma, serving as a rare natural model for this condition. To uncover the elusive immune mechanisms driving SEA, we performed single-cell mRNA sequencing (scRNA-seq) on cryopreserved bronchoalveolar cells from 11 Warmblood horses, five controls and six with SEA. We identified six major cell types, showing significant heterogeneity and novel subtypes. Notably, we observed monocyte-lymphocyte complexes and detected a robust Th17 signature in SEA, withCXCL13upregulation in intermediate monocytes. Asthmatic horses exhibited expansion of the B cell population, Th17 polarization of the T cell populations, and dysregulation of genes associated with T cell function. Neutrophils demonstrated enhanced migratory capacity and heightened aptitude for neutrophil extracellular trap formation. These findings provide compelling evidence for a predominant Th17 immune response in neutrophilic SEA, driven by dysregulation of monocyte and T cell genes. The dysregulated genes identified through scRNA-seq have potential as biomarkers and therapeutic targets for SEA and provide insights into human neutrophilic asthma.

One Sentence Summary

Single-cell mRNA sequencing identifies a predominant Th17-mediated immune response in severe equine asthma