bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of Robson classification for caesarean section using health insurance claims: the experience of Indonesia
Authors: Khoe Levina Chandra , Sari Euis Ratna , Amelia Dwirani , Islamy Tauhid , Megraini Amila , Nadjib Mardiati , Wiweko Budi , Widyahening Indah Suci
Published: April 2024

Robson classification has been recommended by the World Health Organization (WHO) as a monitoring tool for caesarean section (CS), however, it has not been implemented in Indonesia. In this study, we hypothesize that the National Health Insurance (NHI) claims data can be used to classify pregnant women into several obstetric groups. This study aims to examine the use of NHI claims database for analyzing CS according to the WHO manual for Robson classification. This study is a cross-sectional analysis using delivery claims from NHI sample set data from 2017 to 2018. We categorized the International Classification of Diseases (ICD) 10 codes in the claims data according to the Robson classification system using the following variables: multiple pregnancy, fetal presentation, previous obstetric record, previous CS record, gestational age, and onset of labor. Data was analyzed using IBM SPSS Statistics. A total of 31,375 deliveries were included in the analysis. Overall, mean age of mothers was 29.2±5.9 years. The CS rate in this population was 37.0% in 2017 and 38.7% in 2018. Highest CS rate was found in nulliparous (group 2: 26.6%) and multiparous women (group 4: 24.8%) if labour induced or had prelabour CS, followed by multiparous women with previous uterine scar (group 5: 22.5%). We found an alarmingly high rate of CS among Indonesian women. Implementation of Robson classification in the National Health Insurance claims data is feasible and should be considered by the policy makers as an audit tool to identify the groups that contributes the most to the CS rate.
Detecting directed motion and confinement in single-particle trajectories using hidden variables
Authors: Simon François , Ramadier Guillaume , Fonquernie Inès , Zsok Janka , Patskovsky Sergiy , Meunier Michel , Boudoux Caroline , Dultz Elisa , Weiss Lucien E.
Published: April 2024

Single-particle tracking is a powerful tool for understanding protein dynamics and characterizing microenvironments. As the motion of unconstrained nanoscale particles is governed by Brownian diffusion, deviations from this behavior are biophysically insightful. However, the stochastic nature of particle movement and the presence of localization error pose a challenge for the robust classification of non-Brownian motion. Here, we presentaTrack, a versatile tool for classifying track behaviors and extracting key parameters for particles undergoing Brownian, confined, or directed motion. Our tool quickly and accurately estimates motion parameters from individual tracks and determines their likely motion state. Further, our tool can analyze populations of tracks and determine the most likely number of motion states. We determine the working range of our approach on simulated tracks and demonstrate its application for characterizing particle motion in cells and for biosensing applications. Our tool is implemented as a stand-alone software package, making it simple to analyze tracking data.
Mice tails function in response to external and self-generated balance perturbation on the roll plane
Authors: Lacava Salvatore Andrea , Isilak Necmettin , Uusisaari Marylka Yoe
Published: April 2024

The functionality of mouse tails has been unexplored in the scientific literature, to the extent that they might seem to be considered as a passive appendage. Previous research on mouse locomotion has largely omitted tail dynamics, but hints at its potential use in balancing can be seen in the natural habitats and behaviors of these rodents. Here, leveraging high-speed videography, a novel naturalistic locomotory task and a simple biomechanical model analysis, we investigated the behavioral utility of the mouse tail.

We observed that mice engage their tails on narrow ridge environments that mimic tree branches with narrow footholds prone to roll-plane perturbations, using different control strategies under two defined conditions: during external perturbations of the ridge where they primarily work to maintain posture and avoid falling, and during non-perturbated locomotion on the ridge, where the challenge is to dynamically control the center of mass while progressing forward.

These results not only advance the existing understanding of mouse tail functionality but also open avenues for more nuanced explorations in neurobiology and biomechanics. Furthermore, we call for inclusions of tail dynamics for a holistic understanding of mammalian locomotor strategies.

Author summary

We describe and quantify the rapid mouse tail movements in response to external balance perturbations, possibly constituting a novel balance-compensatory motor program. Furthermore, we bring to light the consistent, context-dependent movements of the tail during increasingly precarious locomotion. The observations highlight the tail as an integral component of the mouse locomotory system, contributing to balancing and putatively movement efficacy, and call for inclusion of the tail in future works examining motor (dys)function.
Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells
Authors: Lee Derek C. , Ta Linh , Mukherjee Purna , Duraj Tomas , Domin Marek , Greenwood Bennett , Karmacharya Srada , Narain Niven R. , Kiebish Michael , Chinopoulos Christos , Seyfried Thomas N.
Published: April 2024

Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: 1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; 2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; 3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.

Summary statement

Malignant gliomas, regardless of cell of origin or species, rely on fermentation mechanisms for ATP production due to OxPhos insufficiency. Glucose and glutamine together are necessary and sufficient for dysregulated tumor cell growth, whereas OxPhos is neither necessary nor sufficient.
A theory of brain-computer interface learning via low-dimensional control
Authors: Menéndez J. A. , Hennig J. A. , Golub M. D. , Oby E. R. , Sadtler P. T. , Batista A. P. , Chase S. M. , Yu B. M. , Latham P. E.
Published: April 2024

A remarkable demonstration of the flexibility of mammalian motor systems is primates’ ability to learn to control brain-computer interfaces (BCIs). This constitutes a completely novel motor behavior, yet primates are capable of learning to control BCIs under a wide range of conditions. BCIs with carefully calibrated decoders, for example, can be learned with only minutes to hours of practice. With a few weeks of practice, even BCIs with randomly constructed decoders can be learned. What are the biological substrates of this learning process? Here, we develop a theory based on a re-aiming strategy, whereby learning operates within a low-dimensional subspace of task-relevant inputs driving the local population of recorded neurons. Through comprehensive numerical and formal analysis, we demonstrate that this theory can provide a unifying explanation for disparate phenomena previously reported in three different BCI learning tasks, and we derive a novel experimental prediction that we verify with previously published data. By explicitly modeling the underlying neural circuitry, the theory reveals an interpretation of these phenomena in terms of biological constraints on neural activity.
Sensorimotor delays constrain robust locomotion in a 3D kinematic model of fly walking
Authors: Karashchuk Lili , Li Jing Shuang Lisa , Chou Grant M. , Walling-Bell Sarah , Brunton Steven L. , Tuthill John C. , Brunton Bingni W.
Published: April 2024

Walking animals must maintain stability in the presence of external perturbations, despite significant temporal delays in neural signaling and muscle actuation. Here, we develop a 3D kinematic model with a layered control architecture to investigate how sensorimotor delays constrain robustness of walking behavior in the fruit fly, Drosophila. Motivated by the anatomical architecture of insect locomotor control circuits, our model consists of three component layers: a neural network that generates realistic 3D joint kinematics for each leg, an optimal controller that executes the joint kinematics while accounting for delays, and an inter-leg coordinator. The model generates realistic simulated walking that resembles real fly walking kinematics and sustains walking even when subjected to unexpected perturbations, generalizing beyond its training data. However, we found that the model’s robustness to perturbations deteriorates when sensorimotor delay parameters exceed the physiological range. These results suggest that fly sensorimotor control circuits operate close to the temporal limit at which they can detect and respond to external perturbations. More broadly, we show how a modular, layered model architecture can be used to investigate physiological constraints on animal behavior.
Using muscle-tendon load limits to assess unphysiological musculoskeletal model deformation and Hill-type muscle parameter choice
Authors: Nölle Lennart V. , Wochner Isabell , Hammer Maria , Schmitt Syn
Published: April 2024

Musculoskeletal simulations are a useful tool for improving our understanding of the human body. However, the physiological validity of predicted kinematics and forces is highly dependent upon the correct calibration of muscle parameters and the structural integrity of a model’s internal skeletal structure. In this study, we show how ill-tuned muscle parameters and unphysiological deformations of a model’s skeletal structure can be detected by using muscle elements as sensors with which modelling and parameterization inconsistencies can be identified through muscle and tendon strain injury assessment.

To illustrate our approach, two modelling issues were recreated. First, a model repositioning simulation using the THUMS AM50 occupant model version 5.03 was performed to show how internal model deformations can occur during a change of model posture. Second, the muscle material parameters of the OpenSim gait2354 model were varied to illustrate how unphysiological muscle forces can arise if material parameters are inadequately calibrated. The simulations were assessed for muscle and tendon strain injuries using previously published injury criteria and a newly developed method to determine tendon strain injury threshold values.

Muscle strain injuries in the left and rightmusculus pronator tereswere detected during the model repositioning. This straining was caused by an unphysiologically large gap (12.92 mm) that had formed in the elbow joint. Similarly, muscle and tendon strain injuries were detected in the modified right-handmusculus gastrocnemius medialisof the gait2354 model where an unphysiological reduction of the tendon slack length introduced large pre-strain of the muscle-tendon-unit.

The results of this work show that the proposed method can quantify the internal distortion behaviour of musculoskeletal human body models and the validity of Hill-type muscle parameter choice via strain injury assessment. Furthermore, we highlight possible actions to avoid the presented issues and inconsistencies in literature data concerning the material characteristics of human tendons.
The advantage of periodic over constant signalling in microRNA-mediated repression
Authors: Ferro Elsi , Szischik Candela L. , Ventura Alejandra C. , Bosia Carla
Published: April 2024

Cells have been found out to exploit oscillatory rather than constant gene expression to encode biological information. Temporal features of oscillations such as pulse frequency and amplitude have been shown determinant for the outcome of signaling pathways. However, little effort has been devoted to unveiling the role of pulsatility in the context of post-transcriptional gene regulation, where microRNAs (miRNAs) - repressors of gene expression - act by binding to RNAs. Here we study the effects of periodic against constant miRNA synthesis. We model periodic pulses of miRNA synthesis in a minimal miRNA-target RNA network by ODEs, and we compare the RNA repression to that resulting from constant synthesis of the repressor. We find that a pulsatile synthesis can induce more effective target RNA repression in the same timespan, despite an identical amount of repressor. In particular, a stronger fold repression is induced if the miRNA is synthesized at optimal frequencies, thereby showing a frequency preference behaviour - also known as “band-pass filtering”. Moreover, we show that the preference for specific input frequencies is determined by relative miRNA and target kinetic rates, thereby highlighting a potential mechanism of selective target regulation. Such ability to differentially regulate distinct targets might represent a functional advantage in post-transcriptional repression, where multiple competing targets are regulated by the same miRNA. Thereby analyzing a model with two RNA target species, we show how competition influences the frequency-dependent RNA repression. Eventually, we find that periodic miRNA expression can lead to exclusive frequency-dependent repression on distinct RNA species, and we show how this depends on their relative kinetics of interaction with the repressor. Our findings might have implications for experimental studies aimed at understanding how periodic patterns drive biological responses through miRNA-mediated signalling, and provide suggestions for validation in a synthetic miRNA-target network.
A Bayesian Solution to Count the Number of Molecules within a Diffraction Limited Spot
Authors: Hillsley Alexander , Stein Johannes , Tillberg Paul W. , Stern David L. , Funke Jan
Published: April 2024

We address the problem of inferring the number of independently blinking fluorescent light emitters, when only their combined intensity contributions can be observed at each timepoint. This problem occurs regularly in light microscopy of objects that are smaller than the diffraction limit, where one wishes to count the number of fluorescently labelled subunits. Our proposed solution directly models the photo-physics of the system, as well as the blinking kinetics of the fluorescent emitters as a fully differentiable hidden Markov model. Given a trace of intensity over time, our model jointly estimates the parameters of the intensity distribution per emitter, their blinking rates, as well as a posterior distribution of the total number of fluorescent emitters. We show that our model is consistently more accurate and increases the range of countable subunits by a factor of two compared to current state-of-the-art methods, which count based on autocorrelation and blinking frequency. Furthermore, we demonstrate that our model can be used to investigate the effect of blinking kinetics on counting ability, and therefore can inform experimental conditions that will maximize counting accuracy.
Morphogenesis of bacterial colonies in polymeric environments
Authors: La Corte Sebastian Gonzalez , Stevens Corey A. , Cárcamo-Oyarce Gerardo , Ribbeck Katharina , Wingreen Ned S. , Datta Sujit S.
Published: April 2024

Many bacteria live in polymeric fluids, such as mucus, environmental polysaccharides, and extracellular polymers in biofilms. However, lab studies typically focus on cells in polymer-free fluids. Here, we show that interactions with polymers shape a fundamental feature of bacterial life—how they proliferate in space in multicellular colonies. Using experiments, we find that when polymer is sufficiently concentrated, cells generically and reversibly form large serpentine “cables” as they proliferate. By combining experiments with biophysical theory and simulations, we demonstrate that this distinctive form of colony morphogenesis arises from an interplay between polymer-induced entropic attraction between neighboring cells and their hindered ability to diffusely separate from each other in a viscous polymer solution. Our work thus reveals a pivotal role of polymers in sculpting proliferating bacterial colonies, with implications for how they interact with hosts and with the natural environment, and uncovers quantitative principles governing colony morphogenesis in such complex environments.
SpeciateIT and vSpeciateDB: Novel, fast and accurate per sequence 16S rRNA gene taxonomic classification of vaginal microbiota
Authors: Holm Johanna B. , Gajer Pawel , Ravel Jacques
Published: April 2024

Clustering of sequences into operational taxonomic units (OTUs) and denoising methods are a mainstream stopgap to taxonomically classifying large numbers of 16S rRNA gene sequences. We developed speciateIT, a novel taxonomic classification tool which rapidly and accurately classifies individual amplicon sequences (https://github.com/Ravel-Laboratory/speciateIT). Environment-specific reference databases generally yield optimal taxonomic assignment. To this end, we also present vSpeciateDB, a custom reference database for the taxonomic classification of 16S rRNA gene amplicon sequences from vaginal microbiota. We show that speciateIT requires minimal computational resources relative to other algorithms and, when combined with vSpeciateDB, affords accurate species level classification in an environment-specific manner.

Importance

Herein, two resources with new and practical importance are described. The novel classification algorithm, speciateIT, is based on 7thorder Markov chain models and allows for fast and accurate per-sequence taxonomic assignments (as little as 10 min for 107sequences). vSpeciateDB, a meticulously tailored reference database, stands as a vital and pragmatic contribution. Its significance lies in the superiority of this environment-specific database to provide more species-resolution over its universal counterparts.
Spatial Transcriptomics in Bone Mechanomics: Exploring the Mechanoregulation of Fracture Healing in the Era of Spatial Omics
Authors: Mathavan Neashan , Singh Amit , Correia Marques Francisco , Günther Denise , Kuhn Gisela , Wehrle Esther , Müller Ralph
Published: April 2024

In recent decades, the field of bone mechanobiology has sought experimental techniques to unravel the molecular mechanisms governing the phenomenon of mechanically-regulated fracture healing. Each cell within a fracture site resides within different local micro-environments characterized by different levels of mechanical strain - thus, preserving the spatial location of each cell is critical in relating cellular responses to mechanical stimuli. Our spatial transcriptomics based “mechanomics” platform facilitates spatially-resolved analysis of the molecular profiles of cells with respect to their localin vivomechanical environment by integrating time-lapsedin vivomicro-computed tomography, spatial transcriptomics, and micro-finite element analysis. We investigate the transcriptomic responses of cells as a function of the local strain magnitude by identifying the differential expression of genes in regions of high and low strain within a fracture site. Our platform thus has the potential to address fundamental open questions within the field and to discover mechano-responsive targets to enhance fracture healing.
Massive outsourcing of energetically costly amino acids at the origin of animals
Authors: Kasalo Niko , Domazet-Lošo Mirjana , Domazet-Lošo Tomislav
Published: April 2024

Animals are generally capable of synthesizing eleven amino acids, while the remaining nine, often referred to as essential, must be acquired through diet. This characteristic profoundly impacts animals by defining their ecological lifestyles and evolutionary trajectory. Recent phylogenomic studies reveal that this phenotype results from gene losses that occurred at the root of the animal tree. However, it remains unclear which selective forces, if any, directed this far-reaching metabolic simplification event. Here, we show that essential amino acids are energetically far more expensive to synthesize than non-essential ones, particularly under high respiratory conditions—a hallmark of animal lifestyle. By applying permutation tests, we found that these difference in energy costs, counteracted by pleiotropy, created a selective pressure which led to the outsourcing of essential amino acids. Remarkably, we also found that extant animals use expensive amino acids more frequently compared to their closest unicellular relatives. This shows that animals significantly removed constraints on the usage of essential amino acids under high respiratory conditions by externalizing their production. Together, this implies that stabilizing selection underpinned by energy management drove this metabolic outsourcing in nutrient rich environments, thereby allowing animal genes to evolve more freely through protein sequence space. In this context, we propose that the origin of animals is tightly linked to energy-related adaptations rather than to unpredictable stochastic events, as recently suggested.
The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis inC. elegans
Authors: Breen Peter C. , Kanakanui Kendall G. , Newman Martin A. , Dowen Robert H.
Published: April 2024

The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified theC. elegansF-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations infbxl-5partially suppress the vitellogenesis defects observed in the heterochronic mutantslin-4andlin-29,both of which ectopically expressfbxl-5at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest thatfbxl-5functions in concert withcul-6, a cullin gene, and the Skp1-related geneskr-3to regulate vitellogenesis. Additionally,fbxl-5acts genetically upstream ofrict-1, which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.
Local cryptic diversity in salinity adaptation mechanisms in a wild outcrossingBrassica
Authors: Busoms Silvia , da Silva Ana C. , Escolà Glòria , Abdilzadeh Raziyeh , Curran Emma , Bollmann-Giolai Anita , Bray Sian , Wilson Michael , Poschenrieder Charlotte , Yant Levi
Published: April 2024

It is generally assumed that populations of the same species should evolve shared mechanisms of adaptation to common stressors due to evolutionary constraint. Here, we describe a novel system of within-species local adaptation to coastal habitats,Brassica fruticulosa,and detail surprising mechanistic variability in adaptive responses to extreme salinity. These radically different adaptive responses in neighbouring populations are evidenced by transcriptomes, diverse physiological outputs, and completely distinct genomic selective landscapes. In response to high salinity Northern Catalonian populations restrict root-to-shoot Na+transport, favouring K+uptake. Contrastingly, Central Catalonian populations accumulate Na+in leaves and compensate for the osmotic imbalance with compatible solutes such as proline and elevated Ca2+. Despite contrasting responses, both metapopulations were salinity tolerant relative to all inland accessions. To characterise the genomic basis of these two divergent adaptive strategies in an otherwise non-saline-tolerant endemic, we generate a long-read-based genome and population sequencing of 18 populations (9 inland, 9 coastal) across theB. fruticulosaspecies range. Results of genomic and transcriptomic approaches confirm the physiological observations of completely distinct underlying mechanisms of adaptation to extreme salinity and reveal potential genetic targets of these two recently evolved salinity adaptations. We therefore provide a new model of within-species salinity adaptation and reveal cryptic variation in neighbouring plant populations in the mechanisms of adaptation to an important natural stressor highly relevant to agriculture.

Significance

It’s usually expected that closely related populations of a given species should adapt to the same environmental stressor in the same way due to genetic or physiological constraints. However, this is not commonly tested due to practical constraints. Here we show that, even at the level of neighbouring populations, contrasting adaptive mechanisms control adaptive responses to extreme coastal salinity in a new plant model,Brassica fruticulosa, a close wild relative of many crops of worldwide importance. This indicates multiple options for engineering an agriculturally crucial adaptation: soil salinization. These results will be of great interest to not only those studying fundamental mechanisms of adaptation, but also resilience improvement in Brassica species.
Coupling the role of lipids to the conformational dynamics of the ABC transporter P-gp
Authors: Vecchis Dario De , Schäfer Lars V.
Published: April 2024

The ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) is a multidrug efflux pump that is overexpressed in a variety of cancers and associated with the drug resistance phenomenon. P-gp structures were previously determined in detergent and in nanodiscs, in which different transmembrane helix conformations were found, “straight” and “kinked”, respectively, indicating a possible role of the lipid environment on the P-gp structural ensemble. Here, we investigate the dynamic conformational ensembles and protein-lipid interactions of the two human P-gp inward-open conformers (straight and kinked) employing all-atom molecular dynamics simulations in asymmetric multicomponent lipid bilayers that mimic the highly specialized hepatocyte membrane in which P-gp is expressed. The two conformers are found to differ in terms of the accessibility of the substrate cavity. The MD simulations show how cholesterol and different lipid species wedge, snorkel, and partially enter within the cavity of the straight P-gp conformer solved in detergent. However, the access to the cavity of kinked P-gp conformer solved in nanodiscs is restricted. Furthermore, the volume and dynamic fluctuations of the substrate cavity largely differ between the two P-gp structures, and are modulated by the presence (or absence) of cholesterol in the membrane and/or of ATP. From the mechanistic perspective, our findings indicate that the straight conformer likely precedes the kinked conformer in the functional working cycle of P-pg, with the latter conformation representing a post substrate-bound state. The inaccessibility of the main transmembrane cavity in the kinked conformer might be crucial in preventing substrate disengagement and transport withdrawal. Remarkably, in our unbiased MD simulations, one transmembrane portal helix (TM10) of the straight conformer underwent a spontaneous conformational transition to a kinked conformation, underlining the relevance of both conformations in a native phospholipid environment and revealing structural descriptors defining the transition between two P-gp conformers.
Thymic stromal lymphopoietin contributes to endometriotic lesion proliferation and disease-associated inflammation.
Authors: Aleksieva Stanimira , Lingegowda Harshavardhan , Sisnett Danielle J , McCallion Alison , Zutautas Katherine B , Childs Timothy , Lessey Bruce , Tayade Chandrakant
Published: April 2024

Endometriosis is a chronic disorder in which endometrial-like tissue presents outside the uterus. Patients with endometriosis have been shown to exhibit aberrant immune responses within the lesion microenvironment and in circulation which contribute to the development of endometriosis. Thymic stromal lymphopoietin (TSLP) is an alarmin involved in cell proliferation and the induction of Th2 inflammation in various diseases, such as asthma, atopic dermatitis, pancreatic and breast cancer. Recent studies have detected TSLP within endometriotic lesions and shown that its concentrations are elevated in the peritoneal fluid of patients compared to controls. However, its role in disease pathophysiology remains unclear. Here, we compared TSLP expression in endometriotic lesions to matched patient endometrium and control endometrium samples. We also assessed its effect on the proliferation and apoptosis of human endometriosis-representative cell lines, as well as on lesion development and inflammation in a mouse model of the disease. We demonstrated that TSLP expression was elevated in the stroma of patient endometriotic lesions compared to control endometrial samples. In cell lines, TSLP treatment reduced the apoptosis of endometrial stromal cells and promoted the proliferation of THP-I cells. In mice induced with endometriosis, TSLP treatment induced a Th2 immune response within the lesion microenvironment, and led to TSLP receptor modulation in macrophages, dendritic cells, and CD4+ T cells. Furthermore, treatment increased murine endometriotic lesion proliferation. Overall, these results suggest that TSLP modulates the endometriotic lesion microenvironment and promotes a Th2 immune response that could support lesion development.
ProSAAS is Preferentially Secreted from Neurons During Homeostatic Scaling and Reduces Amyloid Plaque Size in the 5xFAD Mouse Hippocampus
Authors: Mitias Samira , Schaffer Nicholas , Nair Saaya , Hook Chelsea , Lindberg Iris
Published: April 2024

The accumulation of β-amyloid in Alzheimer’s disease greatly impacts neuronal health and synaptic function. To maintain network stability in the face of altered synaptic activity, neurons engage a feedback mechanism termed homeostatic scaling; however, this process is thought to be disrupted during disease progression. Previous proteomics studies have shown that one of the most highly regulated proteins in cell culture models of homeostatic scaling is the small secretory chaperone proSAAS. Our prior work has shown that proSAAS exhibits anti-aggregant behavior against alpha synuclein and β-amyloid fibrillationin vitro, and is upregulated in cell models of proteostatic stress. However, the specific role that this protein might play in homeostatic scaling, and its anti-aggregant role in Alzheimer’s progression, is not clear. To learn more about the role of proSAAS in maintaining hippocampal proteostasis, we compared its expression in a primary neuron model of homeostatic scaling to other synaptic components using Western blotting and qPCR, revealing that proSAAS protein responses to homeostatic up- and down-regulation were significantly higher than those of two other synaptic vesicle components, 7B2 and carboxypeptidase E. However, proSAAS mRNA expression was static, suggesting translational control (and/or reduced degradation). ProSAAS was readily released upon depolarization of differentiated hippocampal cultures, supporting its synaptic localization. Immunohistochemical analysis demonstrated abundant proSAAS within the mossy fiber layer of the hippocampus in both wild-type and 5xFAD mice; in the latter, proSAAS was also concentrated around amyloid plaques. Interestingly, overexpression of proSAAS in the CA1 region via stereotaxic injection of proSAAS-encoding AAV2/1 significantly decreased amyloid plaque burden in 5xFAD mice. We hypothesize that dynamic changes in proSAAS expression play a critical role in hippocampal proteostatic processes, both in the context of normal homeostatic plasticity and in the control of protein aggregation during Alzheimer’s disease progression.
Chronic intermittent fasting impairs β-cell maturation and function in adolescent mice
Authors: Matta Leonardo , Weber Peter , Erener Suheda , Walth-Hummel Alina , Hass Daniela , Bühler Lea K. , Klepac Katarina , Szendroedi Julia , Guerra Joel , Rohm Maria , Sterr Michael , Lickert Heiko , Bartelt Alexander , Herzig Stephan
Published: April 2024

Intermittent fasting (IF) is a nutritional lifestyle intervention with broad metabolic benefits, but whether the impact of IF depends on the individual’s age is unclear. Here, we investigated the effects of IF on systemic metabolism and pancreatic islet function in old, middle-aged, and young mice. Short-term IF improved glucose homeostasis across all age groups, without altering islet function and morphology. In contrast, while chronic IF was beneficial for adult mice, it resulted in impaired β-cell function in the young. Using scRNAseq, we delineated that the β-cell maturation and function score were reduced in young mice. In human islets, a similar pattern was observed in Type 1 (T1D), but not in Type 2 diabetes (T2D), suggesting that the impact of chronic IF in adolescence is linked to the development of β-cell dysfunction. Our study suggests considering the duration of IF in younger people, as it may enhance rather than reduce diabetes outcomes.

Graphical abstract

Long-term IF impairs β-cell function in adolescent mice.

IF-induced impaired β-cell function is associated with impaired proliferative capacity and lower levels of mature cells.

IF-induced impaired β-cell function is associated with a transcriptional change highly conserved in type 1-, but not type 2 diabetes.
Nrf2 regulates the activation-driven expansion of CD4+T-cells by differentially modulating glucose and glutamine metabolism
Authors: Tripathi Aprajita , Dasgupta Debolina , Pant Anil , Bugbee Ashlyn , Yellapu Nanda Kumar , Choi Ben H. Y. , Giri Shailendra , Pyaram Kalyani
Published: April 2024

Upon antigenic stimulation, CD4+T-cells undergo clonal expansion, elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T-cells remains unexplored. Here, we elucidate the role of Nrf2 beyond the traditional antioxidation, in modulating activation-driven expansion of CD4+T-cells by influencing their nutrient metabolism. T-cell-specific activation of Nrf2 enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven proliferation of CD4+T-cells. Mechanistically, high Nrf2 inhibits glucose metabolism through glycolysis but promotes glutamine metabolism via glutaminolysis to support increased T-cell proliferation. Further, Nrf2 expression is temporally regulated in activated CD4+T-cells with elevated expression during the early activation, but decreased expression thereafter. Overall, our findings uncover a novel role of Nrf2 as a metabolic modulator of CD4+T-cells, thus providing a framework for improving Nrf2-targeting therapies and T-cell immunotherapies.
Control over a mixture of policies determines change of mind topology during continuous choice
Authors: Fine Justin M. , Yoo Seng-Bum Michael , Hayden Benjamin Y.
Published: April 2024

Behavior is naturally organized into categorically distinct states with corresponding patterns of neural activity; how does the brain control those states? We propose that states are regulated by specific neural processes that implement meta-control that can blend simpler control processes. To test this hypothesis, we recorded from neurons in the dorsal anterior cingulate cortex (dACC) and dorsal premotor cortex (PMd) while macaques performed a continuous pursuit task with two moving prey that followed evasive strategies. We used a novel control theoretic approach to infer subjects’ moment-to-moment latent control variables, which in turn dictated their blend of distinct identifiable control processes. We identified low-dimensional subspaces in neuronal responses that reflected the current strategy, the value of the pursued target, and the relative value of the two targets. The top two principal components of activity tracked changes of mind in abstract and change-type-specific formats, respectively. These results indicate that control of behavioral state reflects the interaction of brain processes found in dorsal prefrontal regions that implement a mixture over low-level control policies.
Colonial Architecture Modulates the Speed and Efficiency of Multi-Jet Swimming in Salp Colonies
Authors: Damian-Serrano Alejandro , Walton Kai A. , Bishop-Perdue Anneliese , Bagoye Sophie , Du Clos Kevin T. , Gemmell Bradford J. , Colin Sean P. , Costello John H. , Sutherland Kelly R.
Published: April 2024

Salps are marine pelagic tunicates with a complex life cycle including a solitary and colonial stage. Salp colonies are composed of asexually budded individuals that coordinate their swimming by multi-jet propulsion. Colonies develop into species-specific architectures with distinct zooid orientations. We hypothesize that colonial architecture drives differences in swimming performance between salps due to differences in how frontal drag scales with the number of propeller zooids in the colony. Moreover, we hypothesize that faster-swimming taxa are more energetically efficient in their locomotion since less energy would be devoted to overcoming drag forces. We (1) compare swimming speed across salp species and architectures, (2) evaluate how swimming speed scales with the number of zooids in the colony in architectures with constant and scaling frontal cross-sectional area, and (3) compare the metabolic cost of transport across different species and how it scales with swimming speed. To measure their swimming speeds, we recorded swimming salp colonies using in situ videography while SCUBA diving in the open ocean. To estimate the cost of transport, we measured the respiration rates of swimming and anesthetized salps collected in situ using jars equipped with non-invasive oxygen sensors. We found that linear colonies generally swim faster and with a lower cost of transport due to their differential advantage in frontal drag scaling with an increasing number of zooids. These findings underscore the importance of considering propeller arrangement to optimize speed and energy efficiency in bioinspired underwater vehicle design, leveraging lessons learned from the diverse natural laboratory provided by salp diversity.

Summary Statement

Linear arrangements in multi-jet propelled marine colonial invertebrates are faster and more energetically efficient than less streamlined architectures, offering insights for bioinspired underwater vehicle design.
Image-based Strain Analysis Reveals Intracellular Strain Controlled by Nucleo-Cytoskeletal Coupling
Authors: Chen Jerry C.C. , Sloan Iris , Bermudez Alexandra , Choi David , Tsai Ming-Heng , Jin Lihua , Hu Jimmy K. , Lin Neil Y.C.
Published: April 2024

Cells can sense and transduce mechanical forces, such as stretching, and convert these signals into diverse cell biological events. While much effort has been devoted to identifying the downstream biochemical and cellular responses, it is equally crucial to pinpoint the mechanical stimuli within a cell driving these responses. Specifically, much remains unknown about how intracellular strains are distributed and controlled during mechanical deformation. In this study, we developed a microscopy-based intracellular strain measurement technique. Utilizing the intrapopulation mechanical heterogeneity of epithelial monolayers, we observed an inverse relationship between cytoplasmic and nuclear strains. We found that this anti-correlation is abolished by the inhibition of Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, suggesting that nucleo-cytoskeletal coupling controls intracellular strain distribution. We discovered a direct connection between cytoplasmic strain and stretch-induced nucleus size changes, implying that molecular events arising from cytoplasmic deformation may drive nuclear remodeling during stretching. By conducting multivariable analyses, we found that the intracellular strain can be inferred from cell morphology. Overall, our experimental platform and findings provide a foundation for unraveling the relationship between mechanotransduction pathways and upstream intracellular strain.

SIGNIFICANCE

Mechanical stimuli exert influence on epithelial cells, not only orchestrating embryogenesis and regeneration, but also regulating cancer progression and inflammatory conditions. Despite efforts to identify mechanically activated molecular events, understanding how deformation is distributed within cells to induce subcellular responses remains limited. Specifically, the control of subcellular strain distribution during mechanical stretch is unclear. In this study, we developed a microscopy-based method to measure subcellular strain and observed an inverse relationship between cytoplasmic and nuclear strains. Disrupting nucleo-cytoplasmic coupling abolished this relationship, suggesting its role in controlling strain distribution. Additionally, we found that cytoplasmic strain correlates with nucleus size changes during stretching, indicating cytoplasmic events influence nucleus remodeling.
Does global signal regression alter fMRI connectivity patterns related to EEG activity? An EEG-fMRI study in humans
Authors: Xifra-Porxas Alba , Kassinopoulos Michalis , Prokopiou Prokopis , Boudrias Marie-Hélène , Mitsis Georgios. D.
Published: April 2024

Abstract

Functional brain connectivity measures extracted from resting-state functional magnetic resonance imaging (fMRI) scans have generated wide interest as potential noninvasive biomarkers. In this context, performing global signal regression (GSR) as a preprocessing step remains controversial. Specifically, while it has been shown that a considerable fraction of global signal variations is associated with physiological and motion sources, GSR may also result in removing neural activity. Here, we address this question by examining the fundamental sources of resting global signal fluctuations using simultaneous electroencephalography (EEG)-fMRI data combined with cardiac and breathing recordings. Our results suggest that systemic physiological fluctuations account for a significantly larger fraction of global signal variability compared to electrophysiological fluctuations. Furthermore, we show that GSR reduces artifactual connectivity due to heart rate and breathing fluctuations, but preserves connectivity patterns associated with electrophysiological activity within the alpha and beta frequency ranges. Overall, these results provide evidence that the neural component of resting-state fMRI-based connectivity is preserved after the global signal is regressed out.
Nanopore sequencing-based episignature detection
Authors: Geysens Mathilde , Huremagic Benjamin , Souche Erika , Breckpot Jeroen , Devriendt Koenraad , Peeters Hilde , Buggenhout Griet Van , Esch Hilde Van , Bogaert Kris Van Den , Vermeesch Joris Robert
Published: April 2024

Background

A subset of developmental disorders (DD) is characterized by disease-specific genome-wide methylation changes. These episignatures inform about underlying pathogenic mechanisms and can be used to assess the pathogenicity of genomic variants as well as confirm clinical diagnoses. Currently, episignature detection requires the use of indirect methylation profiling microarrays. We hypothesized that long-read whole genome sequencing would not only enable the detection of single nucleotide variants and structural variants but also episignatures.

Methods

Genome-wide nanopore sequencing was performed in forty controls and twenty patients with confirmed or suspected episignature-associated DD, representing thirteen distinct diseases. Following variant and methylome calling, hierarchical clustering and dimensional reduction were used to determine the compatibility with microarray-based episignatures. Subsequently, we developed a support vector machine for each DD.

Results

Nanopore sequencing based methylome patterns were concordant with microarray-based episignatures. Our classifier identified episignatures in 17/20 disease samples and none of the controls. The remaining three patient samples were classified as controls by both our classifier and a commercial microarray assay. In addition, we identified all underlying pathogenic single nucleotide and structural variants and showed haplotype-aware skewed X-inactivation evaluation directs clinical interpretation.

Conclusion

This proof-of-concept study demonstrates nanopore sequencing enables concurrent haplotyped genomic and epigenomic analyses.
The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases
Authors: Konieczny Marek J. , Omarov Murad , Malik Rainer , Richardson Tom G. , Baumeister Sebastian-Edgar , Bernhagen Jürgen , Dichgans Martin , Georgakis Marios K.
Published: April 2024

Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150trans- and 19cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of ACKR1 acting as scavenger for multiple chemokines and the role of TRAFD1 in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug targetcis-MR paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohn’s disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies.